Abstract:
Septic shock is known to lead to, at the end stage, systematic inflammatory reaction syndrome and multiple organ failure (MOF) and cause the patients&#39; death. In both diseases, the patient dies finally of MOF, and the infiltration by inflammatory cells plays a key role for MOF. Thus, development of therapeutic agents for septic shock by suppressing the infiltration by inflammatory cells has been desired. 
     To provide a therapeutic or preventive agent for shock, comprising as an active ingredient a diaminotrifluoromethylpyridine derivative represented by the formula (I) or its salt: 
                                 
wherein X is a cycloalkylcarbonyl group, an alkenylcarbonyl group, a thiophenecarbonyl group or a benzoyl group which may be substituted by a halogen atom; and Y is an alkylsulfonyl group.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application is a 371 of PCT/JP2010/058310, filed on May 17, 2010, and claims priority to Japanese Patent Application No. 2009-129578, filed on May 28, 2009. 
     TECHNICAL FIELD 
     The present invention relates to an anti-shock agent comprising as an active ingredient a diaminotrifluoromethylpyridine derivative or its salt. 
     BACKGROUND ART 
     Patent Document 1 discloses that a diaminotrifluoromethylpyridine derivative or its salt has a phospholipase A 2  inhibitory action and is useful as an active ingredient of an anti-inflammatory agent or an anti-pancreatitis agent. It also discloses that (1) phospholipase A 2  is secreted or activated in platlets or inflammatory cells by stimulations and contributes to the production of a platlet activating factor (PAF) and arachidonic acid metabolites, (2) the arachidonic acid metabolites are closely related to various diseases, for example, inflammatory symptoms such as rheumatic arthritis, arthritis deformans, tendinitis, bursitis, psoriasis and related dermatitis; nasal and bronchial airway troubles such as allergic rhinitis and allergic bronchial asthma; and immediate hypersensitive reactions such as allergic conjunctivitis, (3) on the other hand, phospholipase A 2  secreted from pancreas is activated in the intestine and exhibits a digestive action, but once activated in the pancreas, it is believed to be one of the factors causing pancreatitis, and (4) the above diaminotrifluoromethylpyridine derivative inhibits phospholipase A 2  and thus is effective for treatment of diseases related to phospholipase A 2  such as inflammatory symptoms, nasal and bronchial airway troubles, immediate hypersensitive reactions or pancreatitis, and can be used as an anti-inflammatory agent, an agent for treating bronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, an anti-nephritis agent or an anti-multiple organ failure agent. Patent Document 2 discloses that acute respiratory distress syndrome (ARDS) which occurs when excessive invasion due to various underlying diseases including various shocks is applied to the body, can be treated or prevented by the diaminotrifluoromethylpyridine derivative or its salt. However, these documents failed to disclose that various shocks can be treated by the diaminotrifluoromethylpyridine derivative or its salt. 
     PRIOR ART DOCUMENTS 
     Patent Documents 
     
         
         Patent Document 1: European Patent Publication No. 465913 
         Patent Document 2: European Patent Publication No. 1252889 
       
    
     DISCLOSURE OF INVENTION 
     Technical Problem 
     A shock is considered to be an ischemic disease in a broad sense, and there are various causes such as septic shock, hemorrhagic shock and cardiogenic shock. Septic shock develops in patients with severe Gram-negative infection, and is one of serious diseases which kill the patients in severe cases. There are many patients mainly in the fields of emergency medical care. As an anti-shock agent, steroids and MIRACLID which is one type of protease inhibitors are used. However, the mortality is still high, and more effective agents have been desired. 
     Septic shock leads to, at the end stage, systematic inflammatory reaction syndrome (SIRS) and multiple organ failure (MOF) and causes the patients&#39; death. In both diseases, in precursor clinical conditions which will result in death, the infiltration by inflammatory cells plays a key role. Thus, development of therapeutic agents for septic shock by suppressing the infiltration by inflammatory cells has been desired. 
     Solution to Problem 
     The present inventors have made mouse models with septic shock, the onset of which was peritonitis triggered by the cecal puncture, and conducted studies employing improvement in the survival rate as an index. As a result, they have found that a diaminotrifluoromethylpyridine derivative or its salt is very useful as an anti-shock agent, and accomplished the present invention. 
     That is, the present invention provides a therapeutic or preventive agent for shock, comprising as an active ingredient a diaminotrifluoromethylpyridine derivative represented by the formula (I) or its salt: 
                                
wherein X is a cycloalkylcarbonyl group, an alkenylcarbonyl group, a thiophenecarbonyl group or a benzoyl group which may be substituted by a halogen atom; and Y is an alkylsulfonyl group.
 
     Advantageous Effects of Invention 
     Various shocks such as septic shock can be treated by suppressing the infiltration by inflammatory cells by a diaminotrifluoromethylpyridine derivative or its salt. 
    
    
     DESCRIPTION OF EMBODIMENTS 
     In the formula (I), the alkyl moiety contained in Y may, for example, be C 1-20  alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl moiety contained in X may be C 2-20  alkenyl such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl or nonadecenyl, and they include linear or branched aliphatic structural isomers. The cycloalkyl moiety contained in X may be C 3-8  cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. Further, the halogen atom contained in X may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. 
     Specific examples of the above compounds represented by the formula (I) include N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-thiophenecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide, and their salts. Among them, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide is preferred. 
     The compounds represented by the formula (I) may form a salt. Such a salt may be any pharmaceutically acceptable salt, for example, an alkali metal salt such as a potassium salt or a sodium salt, an alkaline earth metal salt such as a calcium salt, or an organic amine salt such as a triethanolamine salt or a tris(hydroxymethyl)aminomethane salt. Such a salt may have crystal water. 
     The compounds represented by the compound (I) may be produced, for example, by the method disclosed in European Patent Publication No. 465913. Such compounds may have geometrical isomers depending on the type of a substituent, and such isomers (cis-form and trans-form) and mixtures thereof are included in the present invention. 
     The compound represented by the formula (I) or its salt is useful as an active ingredient of an anti-shock agent. Various shocks such as septic shock can be treated by suppressing the infiltration by inflammatory cells by the compound represented by the formula (I) or its salt. That is, the infiltration by inflammatory cells plays a key role in the precursor clinical conditions of various shocks such as septic shock, which will result in death. It is considered that by suppressing the infiltration by inflammatory cells, circulatory disorders by the shock are improved. This anti-shock agent is useful to prevent or treat septic shock and multiple organ failure induced thereby, and ischemic diseases in the heart, kidney, liver, stomach and intestines, the brain, etc. 
     In the case of applying the compound represented by the formula (I) or its salt as an anti-shock agent, it is formulated alone or together with a pharmaceutically acceptable carrier or the like into a drug composition suitable for peroral, parenteral, topical or per rectal administration, such as a tablet, a powder, a capsule, a granule, an injection drug, an ointment, an inhalant or an enema, and it is administered in the form of such a drug formulation. 
     As a drug formulation suitable for peroral administration, a solid composition such as a tablet, a capsule, a powder, a granule or a troche; or a liquid composition such as a syrup suspension, may, for example, be mentioned. The solid composition such as a tablet, a capsule, a powder, a granule or a troche may contain a binder such as fine crystalline cellulose, gum arabic, tragacanth gum, gelatin or polyvinyl chloride; an excipient such as starch, lactose or carboxymethyl cellulose; a disintegrator such as arginic acid, corn starch or carboxymethyl cellulose; a lubricant such as magnesium stearate, light silicic anhydride or colloidal silicon dioxide; a sweetener such as sucrose; or a flavoring agent such as peppermint or methyl salicylate. The liquid composition such as a syrup or a suspension may contain sorbitol, gelatin, methyl cellulose, carboxymethyl cellulose, a vegetable oil such as a peanut oil, an emulsifier such as lecithin as well as a sweetener, a preservative, a colorant or a flavoring agent, as the case requires. Such a composition may be provided in the form of a dried formulation. These formulations preferably contain from 1 to 95 wt % of the active ingredient compound. 
     A drug formulation suitable for parenteral administration may, for example, be an injection drug. The injection drug may be prepared by dissolving the compound in the form of a salt in usual water for injection, or may be formulated into a formulation suitable for injection such as a suspension or an emulsion (in a mixture with a medically acceptable oil or liquid). In such a case, it may contain benzyl alcohol as an antibacterial agent, ascorbic acid as an antioxidant, a medically acceptable buffer solution or a reagent for adjusting the osmotic pressure. Such an injection drug preferably contains from 0.1 to 8 wt % of the active ingredient compound. 
     A drug formulation suitable for topical or per rectal administration may, for example, be an inhalant, an ointment, an enema or a suppository. The inhalant may be formulated by dissolving the compound of the present invention alone or together with a medically acceptable inert carrier in an aerosol or nebulizer solution, or may be administered to the respiratory airway in the form of fine powder for inhalation. In the case of fine powder for inhalation, the particle size is usually not more than 50μ, preferably not more than 10μ. Such an inhalant may be used, if necessary, in combination with other antiasthematic agent or bronchodilator. 
     An ointment may be prepared by a conventional method by an addition of e.g. a commonly employed base. The ointment preferably contains from 0.1 to 30 wt % of the active ingredient compound. 
     A suppository may contain a carrier for formulation which is well known in this field, such as polyethylene glycol, lanolin, cacao butter or fatty acid triglyceride. The suppository preferably contains from 1 to 95 wt % of the active ingredient compound. 
     The above drug compositions suitable for peroral, parenteral, topical or per rectal administration, may be formulated by known methods so that after administration to a patient, the active ingredient will be rapidly discharged, gradually discharged or belatedly discharged. 
     Needless to say, the dose of the compound represented by the formula (I) or its salt varies depending upon the type of the compound, the administration method, the condition of the patient or the animal to be treated, and the optimum dose and the number of administration under a specific condition must be determined by the judgment of a competent doctor. Usually, however, a daily dose to an adult is from about 0.1 mg to about 10 g, preferably from about 1 mg to about 1 g. In the case of the above inhalation method, the dose of the compound of the present invention is preferably from about 0.01 mg to about 1 g per administration. 
     Now, specific Formulation Examples of the therapeutic or preventive agent for shock will be given. However, the formulation of the present invention is not limited thereto. 
     Formulation Example 1 
     Tablet 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 20 
                 mg 
               
               
                   
                 (2) Lactose 
                 150 
                 mg 
               
               
                   
                 (3) Starch 
                 30 
                 mg 
               
               
                   
                 (4) Magnesium stearate 
                 6 
                 mg 
               
               
                   
               
             
          
         
       
     
     The above composition is tabletted so that the components (1) to (4) constitute one tablet. 
     Formulation Example 2 
     Powder, Subtilized Granule or Granule 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 20 
                 mg 
               
               
                   
                 (2) Sugar ester (DK ester F-160, tradename,  
                 180 
                 mg 
               
               
                   
                 manufactured by DAI-ICHI KOGYO  
                   
                   
               
               
                   
                 SEIYAKU CO., LTD.) 
                   
                   
               
               
                   
                 (3) Surfactant (DECA-GREEN 1-L, tradename,  
                 15 
                 mg 
               
               
                   
                 manufactured by Nikko Chemicals Co., Ltd.) 
                   
                   
               
               
                   
                 (4) Light silicic anhydride 
                 25 
                 mg 
               
               
                   
               
             
          
         
       
     
     The above components (1) to (4) are mixed and formed into a powder, or subtilized granule or granule by granulation. Such a powder, subtilized granule or granule may be sealed in a capsule to obtain a capsule drug. 
     Formulation Example 3 
     Hard Gelatin Capsule Drug 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 25 
                 mg 
               
               
                   
                 (2) Starch 
                 200 
                 mg 
               
               
                   
                 (3) Magnesium stearate 
                 10 
                 mg 
               
               
                   
               
             
          
         
       
     
     The above components (1) to (3) are packed in one hard gelatin capsule to obtain a hard gelatin capsule drug. 
     Formulation Example 4 
     Injection Drug 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 1 
                 mg 
               
               
                   
                 (2) Glucose 
                 10 
                 mg 
               
               
                   
                 (3) Tris(hydroxymethyl)aminomethane 
                 2.16 
                 mg 
               
               
                   
               
             
          
         
       
     
     A tris buffer containing the components (1) to (3) is freeze-dried to prepare an injection drug. 
     Formulation Example 5 
     Ointment for External Skin Application 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 0.5 
                 g 
               
               
                   
                 (2) White vaseline 
                 25 
                 g 
               
               
                   
                 (3) Stearyl alcohol 
                 22 
                 g 
               
               
                   
                 (4) Propylene glycol 
                 12 
                 g 
               
               
                   
                 (5) Sodium lauryl sulfate 
                 1.5 
                 g 
               
               
                   
                 (6) Ethyl parahydroxybenzoate 
                 0.025 
                 g 
               
               
                   
                 (7) Propyl parahydroxybenzoate 
                 0.015 
                 g 
               
               
                   
                 (8) Purified water 
                 100 
                 g 
               
               
                   
               
             
          
         
       
     
     The components (1) to (8) are formulated into an ointment for external skin application by a usual method for preparation of an ointment. 
     Formulation Example 6 
     Enema Formulation 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 50 
                 mg 
               
               
                   
                 (2) Macrogol 400 
                 2 
                 g 
               
               
                   
                 (3) Dipotassium phosphate 
                 141 
                 mg 
               
               
                   
                 (4) Potassium dihydrogenphosphate 
                 44 
                 mg 
               
               
                   
                 (5) Methyl parahydroxybenzoate 
                 20 
                 mg 
               
               
                   
                 (6) Purified water 
                 50 
                 g 
               
               
                   
               
             
          
         
       
     
     The active ingredient and methyl parahydroxybenzoate are added to Macrogol 400, followed by stirring to obtain a mixture, to which one obtained by adding dipotassium phosphate and potassium dihydrogenphosphate to the purified water is gradually added to prepare an enema formulation. 
     Formulation Example 7 
     Suppository 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 50 
                 mg 
               
               
                   
                 (2) Higher fatty acid glyceride 
                 1,650 
                 mg 
               
               
                   
               
             
          
         
       
     
     The component (1) is dispersed or dissolved in (2), and packed and sealed in a plastic container having a size appropriate as a suppository, followed by cooling for solidification to prepare a suppository. 
     Formulation Example 8 
     Rectum Remaining Suppository, Controlled Release Suppository 
     
       
         
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 (1) Active ingredient 
                 1 
                 g 
               
               
                   
                 (2) Witepsol W35 
                 19 
                 g 
               
               
                   
               
             
          
         
       
     
     The component (1) is admixed with preliminarily heated and dissolved (2), and the admixture is packed and sealed in a plastic container having a size appropriate as a suppository, followed by cooling for solidification to prepare a suppository. 
     EXAMPLES 
     Test Example 1 
     Therapeutic Effect on Mouse Models with Septic Shock, the Onset of which was Peritonitis Triggered by the Cecal Puncture 
     Therapeutic effects of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cylohexanecarboxamide sodium salt monohydrate (hereinafter referred to as compound 1) on mouse models with septic shock, the onset of which was peritonitis triggered by the cecal puncture, was examined. 
     (1) Formulation of Compound 1 
     The compound 1 was used as a drug formulation. The formulation composition (content per one vial) was as follows. 
                                                                                 (a) Compound 1 (as anhydride)   100   mg           (b) D-mannitol (manufactured by KYOWA    100   mg           HAKKO KOGYO CO., LTD.)                   (c) Tris(hydroxymethyl)aminomethane    21.6   mg                (manufactured by JUNSEI CHEMICAL                CO., LTD.)               (d) Hydrochloric acid (manufactured by    optimum amount           SANKYO KAGAKU CHEMICAL CO., LTD.               (e) Sodium hydroxide    optimum amount           (manufactured by Nippon Rika)                    (f) Distilled water   10   ml           pH 8.7 ± 0.5                    
(2) Animal to be Tested
 
     Animal species: mouse 
     Strain: Crj: BALB/c 
     Purchased from: Charles River Japan Inc., Atsugi Breeding Center 
     Sex: female 
     Age: 7 weeks old when purchased and 8 weeks old when tested 
     The mice were pre-bred for about a week after purchase and then subjected to a test at about 8 weeks old. Breeding in the entire breeding period was carried out in an isolator placed in a large animal room. Ten mice in each group were accommodated in a polycarbonate cage throughout the test period, and they were freely fed on commercially available complete feed pellet (MF, manufactured by O. B. S.) and tap water subjected to activated carbon filtration (with use of a feed water bottle) throughout the breeding period. From the mice, mice which were healthily grown during the pre-breeding period were selected. Mice were randomly selected from the above selected mice and delivered to the respective groups one by one in the order of the animal number. The animal number was put in the order of put into a cage after the grouping. 
     (3) Constitution of Animal Group to be Tested 
     As shown in Table 1, there were groups of treated groups given with 0.1, 1 and 10 mg/kg of the compound 1 and a non-treated group given with a medium (5% glucose), and the number of mice in each group was ten. 
                                                   TABLE 1                       Dose   Number of       Group   Administration   mg/kg × 4 times   animals                                Non-treated group   5% glucose   0   10       Treated group at low   Compound 1   0.1   10       dose of compound 1                   Treated group at   Compound 1   1   10       medium dose of                   compound 1                   Treated group at high   Compound 1   10   10       dose of compound 1                    
(4) Preparation and Administration of Drug
 
     Preparation of the drug was carried out immediately before the induction operation, and administration was carried out by using the prepared liquid for administration. Japanese Pharmacopoeia 5% glucose was injected to a formulated product containing 100 mg of the compound 1 to completely dissolve the compound 1, and a liquid for administration at the maximum dose was prepared by diluting with Japanese Pharmacopoeia 5% glucose, and a liquid for administration at a medium dose and a liquid for administration at a low dose were prepared by stepwise dilution of the liquid for administration at the maximum dose with Japanese Pharmacopoeia 5% glucose. For the non-treated group, Japanese Pharmacopoeia 5% glucose as a medium alone was prepared. Immediately after the induction, 4 hours later, 8 hours later and 12 hours later, the liquid was repeatedly administered subcutaneously to the dorsal neck to maintain the blood concentration. The liquid was administered in a volume of 10 ml/kg for each group. 
     (5) Operation to Induce Septic Shock, the Onset of which was Peritonitis Triggered by the Cecal Puncture of Mice 
     Mice were anesthetized with gas-oxygen-fluothane, and the corpus 8 mm from the cecal apex was ligated through an abdominal incision, one spot in the apex was punctured and transfixed with a 22 G needle, and after leakage of cecal contents was confirmed, the cecum was completely replaced in the abdomen and the abdomen was closed. 
     (6) Test 
     Viability test was carried out for 3 days from immediately after the induction, and the results were summarized every 24 hours. 
     (7) Statistical Analysis 
     Statistical analysis was carried out with respect to the surviving rate. The method is described in detail below. 
     I. Statistics Application 
     Carried out by using EXCEL (data counting), SAS (Shirley-Williams), Notepad for Windows 95 (program). 
     II. Handling of Incomplete Data 
     When it was possible to exclude data due to experimental technical errors or with a certain definite cause, such data were excluded to carry out analysis. The other data were basically not rejected to carry out analysis. No such cases occurred. 
     III. Level of Significance and Two-Sided/One-Sided 
     The level of significance was 5%, and two-sided test was carried out. 
     IV. Test Technique 
     Employing the non-treated group as a control, comparison among groups of a group given with 0.1 mg/kg of the compound 1, a group given with 1 mg/kg of the compound 1 and a group given with 10 mg/kg of the compound 1 was carried out. 
     [Analysis Data] 
     Viability test results: animals which died in 0 to 24 hours were scored 1, animals which died in 24 to 48 hours were scored 2, animals which died in 48 to 72 hours were scored 3, and animals which survived 72 hours or more were scored 4, and the obtained data were used. 
     [Test Technique] 
     Comparison among groups was carried out by Shirley-Williams&#39; multiple comparison test. 
     (8) Test Results 
     The results of the test were shown in Table 2. The prepared septic shock model was a model which suffered from peritonitis induced by the cecal puncture and died of septic shock. From the results of this test, improvement in the surviving rate with statical significance (P&lt;0.001) was confirmed with administration of 10 mg/kg. 
     
       
         
               
             
               
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 (surviving rate) 
               
             
          
           
               
                   
                 Time after induction of septic shock model 
               
             
          
           
               
                 Group 
                 24 hr 
                 48 hr 
                 72 hr 
               
               
                   
               
               
                 Non-treated 
                 20% 
                  0% 
                  0% 
               
             
          
           
               
                 Compound 1; 0.1 
                 mg/kg 
                 20% 
                  0% 
                  0% 
               
               
                 Compound 1; 1 
                 mg/kg 
                 40% 
                 10% 
                 10% 
               
               
                 Compound 1; 10 
                 mg/kg 
                 90% 
                 50% 
                 50%