WO2010137484A1 - ジアミノトリフルオロメチルピリジン誘導体を含有する抗ショック剤 - Google Patents
ジアミノトリフルオロメチルピリジン誘導体を含有する抗ショック剤 Download PDFInfo
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- WO2010137484A1 WO2010137484A1 PCT/JP2010/058310 JP2010058310W WO2010137484A1 WO 2010137484 A1 WO2010137484 A1 WO 2010137484A1 JP 2010058310 W JP2010058310 W JP 2010058310W WO 2010137484 A1 WO2010137484 A1 WO 2010137484A1
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- group
- shock
- salt
- pyridyl
- trifluoromethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to an anti-shock agent containing a diaminotrifluoromethylpyridine derivative or a salt thereof as an active ingredient.
- Patent Document 1 describes that a diaminotrifluoromethylpyridine derivative or a salt thereof has a phospholipase A 2 inhibitory action and is useful as an active ingredient of an anti-inflammatory agent or an anti-pancreatitis agent.
- Hosuhoripa - Ze A 2 is secreted or activated by stimulation, thereby contributing to the production of platelet activating factor (PAF) and metabolites of arachidonic acid
- PAF platelet activating factor
- Arachidonic acid metabolites are present in various pathological conditions such as rheumatoid arthritis, osteoarthritis, tendonitis, bursitis, psoriasis and related skin inflammation; allergic rhinitis, allergic bronchial asthma nasal bronchial airway disorders like symptoms; allergic - that are closely related, such as immediate hypersensitivity reactions such as conjunctivitis, (3) on the other hand, Hosuhoripa secreted from the pancreas - Ze a 2 is
- ARDS acute respiratory distress syndrome
- ARDS which occurs when excessive invasion associated with various underlying diseases including various shocks is applied to a living body
- diaminotrifluoromethylpyridine is diaminotrifluoromethylpyridine. It is described that it can be treated or prevented by a derivative or a salt thereof.
- these documents do not describe that various shocks can be treated with a diaminotrifluoromethylpyridine derivative or a salt thereof.
- shock is considered an ischemic disease in a broad sense, there are various causes such as septic shock, hemorrhagic shock, and cardiogenic shock.
- Septic shock develops in patients with severe Gram-negative bacterial infections and is one of the serious diseases that causes patients to die if the symptoms are severe.
- Miraclide which is a kind of steroid and protease inhibitor
- the mortality rate is still high and the emergence of more effective drugs is desired.
- SIRS systemic inflammatory reaction syndrome
- MOF multiple organ failure
- inflammatory cell infiltration plays a major role in the precursor pathology leading to death. Under such circumstances, development of a therapeutic agent for septic shock by suppressing inflammatory cell infiltration is desired.
- the present inventors have created a septic shock model starting from peritoneitis caused by cecal puncture of mice, and as a result of repeated studies using the improvement of survival rate as an index, diaminotrifluoromethylpyridine derivatives or salts thereof are extremely useful as anti-shock agents.
- the present invention has been found by finding it effective.
- Another object is to provide a therapeutic or prophylactic agent for shock containing a salt thereof as an active ingredient.
- shocks such as septic shock can be treated by suppressing inflammatory cell infiltration with a diaminotrifluoromethylpyridine derivative or a salt thereof.
- examples of the alkyl moiety contained in Y include those having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, nonadecyl, etc. Includes straight chain or branched fatty chain structural isomers.
- examples of the alkenyl moiety contained in X include those having 2 to 20 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl, nonadecenyl, etc., and they are linear or branched fatty chain structures. Also includes those of the opposite sex.
- Examples of the cycloalkyl moiety contained in X include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
- examples of the halogen atom contained in X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- Specific examples of the compound represented by the formula (I) include N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-5-trimethyl).
- the compound represented by the formula (I) may form a salt, and any salt may be used as long as it is pharmaceutically acceptable, for example, an alkali metal salt such as potassium salt or sodium salt, Examples thereof include alkaline earth metal salts such as calcium salts, triethanolamine salts, and organic amine salts such as tris (hydroxymethyl) aminomethane salts. Some of these salts have water of crystallization.
- an alkali metal salt such as potassium salt or sodium salt
- alkaline earth metal salts such as calcium salts, triethanolamine salts, and organic amine salts such as tris (hydroxymethyl) aminomethane salts.
- the compound represented by the formula (I) can be produced, for example, by the method described in European Patent No. 465,913. Further, these compounds have geometric isomers depending on the kind of substituents, but the present invention includes each isomer (cis isomer, trans isomer) and isomer mixtures.
- the compound represented by the formula (I) or a salt thereof is useful as an active ingredient of an anti-shock agent.
- various shocks such as septic shock can be treated by suppressing inflammatory cell infiltration. That is, inflammatory cell infiltration plays a major role in septic shock and other precursor pathologies leading to the death of various types of shock. By suppressing this inflammatory cell infiltration, it is considered that the circulatory disturbance aspect of shock is improved.
- This anti-shock agent is used for the prevention or treatment of septic shock and multi-organ failure induced thereby and ischemic diseases in the heart, kidney, liver, gastrointestinal tract, brain and the like.
- the compound represented by the formula (I) or a salt thereof when administered as an anti-shock agent, it can be used alone, or mixed with a pharmacologically acceptable carrier, orally, parenterally, topically, or rectally.
- a pharmacologically acceptable carrier orally, parenterally, topically, or rectally.
- the pharmaceutical composition suitable for use is administered in the form of tablets, powder packaging, capsules, granules, injections, ointments, inhalants, suppositories and the like.
- preparations suitable for oral use include solid compositions such as tablets, capsules, powders, granules, and troches; and liquid compositions such as syrup suspensions.
- Solid compositions such as tablets, capsules, powders, granules, troches, binders such as microcrystalline cellulose, gum arabic, tragacanth gum, gelatin, polyvinyl chloride; excipients such as starch, lactose, carboxymethylcellulose Contains disintegrants such as alginic acid, corn starch, carboxymethylcellulose; lubricants such as magnesium stearate, light anhydrous silicic acid, colloidal silicon dioxide; sweeteners such as sucrose; flavoring agents such as peppermint and methyl salicylate; it can.
- Liquid compositions such as syrups and suspensions include sorbitol, gelatin, methylcellulose, carboxymethylcellulose, vegetable oils such as peanut oil, emulsifiers such as lecithin, and sweeteners, preservatives, dyes if necessary. And flavoring agents, etc., and these can also be provided as dry formulations. These preparations preferably contain 1 to 95% by weight of the active ingredient compound.
- preparations suitable for parenteral use include injections.
- an injection for example, it may be dissolved in ordinary water for injection in the form of a salt, or it may be in an injectable form of a suspension or emulsion (in a mixture of medically acceptable oil or liquid).
- an antibacterial agent such as benzyl alcohol; an antioxidant such as ascorbic acid, or the like, may contain a medically acceptable buffer or a reagent for regulating osmotic pressure.
- This injection preferably contains 0.1 to 8% by weight of the active ingredient compound.
- preparations suitable for topical or rectal use include inhalants, ointments, enemas, suppositories, and the like.
- inhalants the compound of the present invention itself or the compound of the present invention can be dissolved in an aerosol or nebulizer solution together with a medically acceptable inert carrier, or can be administered to the respiratory tract as a fine powder for inhalation.
- the particles are 50 microns or less, preferably 10 microns or less.
- the ointment is prepared by a conventional method with the addition of a commonly used base.
- the ointment preferably contains 0.1 to 30% by weight of the active ingredient compound.
- Suppositories may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglycerides and the like.
- the suppository preferably contains 1 to 95% by weight of the active ingredient compound.
- the pharmaceutical composition suitable for oral, parenteral, topical or rectal use is released in a known manner in a controlled manner so that the active ingredient is released rapidly after administration to the patient. Or can be formulated to be released later.
- the dose of the compound represented by the formula (I) or a salt thereof varies depending on the kind of the compound, the administration method, the condition of the patient or the animal to be treated, and the appropriate dose and administration under a certain condition.
- the number of times must be determined by the judgment of a specialist, but will usually be administered from about 0.1 mg to about 10 g, preferably from about 1 mg to about 1 g, per adult day.
- the dose of the compound of the present invention per dose in the inhalation method is preferably about 0.01 mg to about 1 g.
- Formulation Example 1 (tablet) (1) Active ingredient 20mg (2) Lactose 150mg (3) Starch 30mg (4) Magnesium stearate 6mg The above components (1) to (4) are formed into a tablet into one tablet.
- Formulation Example 2 (Powder / Fine Granule / Granule) (1) Active ingredient 20mg (2) Sugar ester (Daiichi Kogyo Seiyaku Co., Ltd., trade name: DK ESTER F-160) 180mg (3) Surfactant (made by Nikko Chemicals, trade name: Deca Green 1-L) 15mg (4) Light anhydrous silicic acid 25mg The above (1) to (4) are mixed to form a fine powder or granule by powdering and further granulation. It is also possible to encapsulate these into capsules.
- Formulation Example 3 (Hard gelatin capsule) (1) Active ingredient 25mg (2) Starch 200mg (3) Magnesium stearate 10mg The above components (1) to (3) are packed into a hard gelatin capsule as one tablet to obtain a hard gelatin capsule.
- Formulation Example 4 (Injection) (1) Active ingredient 1mg (2) Glucose 10mg (3) Tris (hydroxymethyl) aminomethane 2.16 mg The Tris buffer containing the above components (1) to (3) is lyophilized to obtain an injection.
- Formulation Example 5 (external ointment for skin) (1) Active ingredient 0.5g (2) 25g white petrolatum (3) Stearyl alcohol 22g (4) Propylene glycol 12g (5) Sodium lauric sulfate 1.5g (6) Ethyl paraoxybenzoate 0.025g (7) 0.015 g of propyl paraoxybenzoate (8) 100 g of purified water
- the above components (1) to (8) are prepared by a general method for preparing ointments to obtain an external ointment for skin.
- Formulation Example 6 (Enema formulation) (1) Active ingredient 50mg (2) Macrogol 400 2g (3) Dipotassium phosphate 141 mg (4) Potassium dihydrogen phosphate 44mg (5) Methyl paraoxybenzoate 20mg (6) 50 g of purified water To the macrogol 400, an active ingredient and methyl parahydroxybenzoate are added, and the mixture is stirred and mixed, and then a solution obtained by adding dipotassium phosphate and potassium dihydrogen phosphate to purified water is gradually added to obtain an enema preparation.
- Formulation Example 7 (suppository) (1) Active ingredient 50mg (2) Higher fatty acid glycerides 1650mg (1) is dispersed or dissolved in (2), filled into a plastic container of an appropriate size as a suppository, sealed, and then cooled and solidified to obtain a suppository.
- Formulation Example 8 (rectal retention suppository / release controlled suppository) (1) Active ingredient 1g (2) 19g of Witepsol W35 (1) is mixed with (2), which has been heated and dissolved in advance, and then filled and sealed in a plastic container of an appropriate size as a suppository, and then cooled and solidified to obtain a suppository.
- Test example therapeutic effect on septic shock model with peritonitis caused by mouse cecal puncture N- (2-ethylsulfonylamino-5-trifluoromethyl-3-type for septic shock model with peritonitis caused by mouse cecal puncture
- Compound 1 The therapeutic effect of pyridyl) cyclohexanecarboxamide monosodium salt monohydrate (hereinafter referred to as Compound 1) was examined.
- the animals were subjected to the test at about 8 weeks of age after pre-breeding for about 1 week after delivery. Breeding during the whole breeding period was performed in an isolator installed in a large animal breeding room. Animals are housed in a polycarbonate cage for 10 animals in each group throughout the entire test period. Commercially available solid feed (OBS, MF) and activated charcoal filtered city water (using water bottles) are allowed to freely ingest throughout the entire breeding period. It was. Animals were selected for which healthy growth was observed during the preliminary breeding period, and the groups were randomly selected from them and divided into groups in order of animal numbers one by one. The animal numbers were assigned in the order they were transferred to cages after grouping. (3) Composition of test animal groups As shown in Table 1, each of the treatment groups administered with Compound 1 concentrations of 0.1, 1 and 10 mg / kg was added with a non-treatment group administered with vehicle (5% glucose). The number of animals in the group was 10.
- Preparation and administration of drug Drug preparation was performed immediately before induction surgery, and subsequent administrations were performed using the administration solution. Inject 100% of compound 1 preparation into pharmacopoeia 5% glucose and completely dissolve, then dilute and prepare the highest-dose administration solution with pharmacopoeia 5% glucose. Prepared by serial dilution with pharmacopoeia 5% glucose. In the non-treatment group, only pharmacopeia 5% glucose as a solvent was prepared. Administration was repeated 4 hours, 8 hours, and 12 hours immediately after the induction, and subcutaneously administered to the dorsal neck to maintain the blood concentration. The dose of each group was 10 ml / kg.
- the survival rate was implemented. Details of the method are shown below. I. The statistical applications were EXCEL (data aggregation), SAS (Shirley-Williams), and Notepad for windows 95 (program). II. Handling of Incomplete Cases If the experimental technique error or the cause is clear and the data can be excluded, the test will be performed without the data. The other data were basically tested without rejection. In addition, the situation applicable to these did not occur. III. Significance level and two-sided / one-sided The two-sided test was performed at a significance level of 5%. IV.
- Test results The results of the tests are shown in Table 2.
- the prepared septic shock model started with peritonitis due to cecal puncture, and resulted in death from septic shock to death.
- P ⁇ 0.001 improvement in survival rate was observed at 10 mg / kg.
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Abstract
Description
敗血症性ショックは病態末期には、全身性炎症反応症候群(SIRS : Systematic Inflammatory Reaction Syndrome)及び多臓器不全(MOF : Multiple Organ failure)に陥り死に至る。両疾患において、死に至る前駆病態では、炎症細胞浸潤が大きな役割を示す。このような中、炎症細胞浸潤を抑制することによる敗血症性ショックの治療剤の開発が所望されている。
(1)有効成分 20mg
(2)乳糖 150mg
(3)デンプン 30mg
(4)ステアリン酸マグネシウム 6mg
以上(1)~(4)の成分を1錠として、錠剤に成型する。
(1)有効成分 20mg
(2)シュガ-エステル(第一工業製薬社製、商品名:
DKエステルF-160) 180mg
(3)界面活性剤(日光ケミカルズ社製、商品名:
デカグリーン1-L) 15mg
(4)軽質無水珪酸 25mg
上記(1)~(4)を混合し、散剤、更に造粒により細粒剤或いは顆粒剤とする。又、これらをカプセルに封入し、カプセル剤とすることも可能である。
(1)有効成分 25mg
(2)デンプン 200mg
(3)ステアリン酸マグネシウム 10mg
以上(1)~(3)の成分を、1錠として硬ゼラチンカプセルにつめ、硬ゼラチンカプセル剤とする。
(1)有効成分 1mg
(2)ブドウ糖 10mg
(3)トリス(ヒドロキシメチル)アミノメタン 2.16mg
以上(1)~(3)の成分を含むトリス緩衝液を凍結乾燥して注射剤とする。
(1)有効成分 0.5g
(2)白色ワセリン 25g
(3)ステアリルアルコ-ル 22g
(4)プロピレングリコ-ル 12g
(5)ラウリン硫酸ナトリウム 1.5g
(6)パラオキシ安息香酸エチル 0.025g
(7)パラオキシ安息香酸プロピル 0.015g
(8)精製水 100g
以上(1)~(8)の成分を軟膏の一般的調製法により調製し、皮膚用外用軟膏を得る。
(1)有効成分 50mg
(2)マクロゴール400 2g
(3)リン酸二カリウム 141mg
(4)リン酸二水素カリウム 44mg
(5)パラオキシ安息香酸メチル 20mg
(6)精製水 50g
マクロゴール400に有効成分及びパラオキシ安息香酸メチルを加え、攪拌して混合したものに、精製水にリン酸二カリウムとリン酸二水素カリウムを加えたものを徐々に加えて注腸製剤を得る。
(1)有効成分 50mg
(2)高級脂肪酸グリセリド 1650mg
(1)を(2)に分散又は溶解させ、坐剤として適切なサイズのプラスチックコンテナーに充填、シールした後、冷却固化させて坐剤を得る。
(1)有効成分 1g
(2)ウイテップゾルW35 19g
予め加熱溶解した(2)に(1)を混和させた後、坐剤として適切なサイズのプラスチックコンテナーに充填、シールした後、冷却固化させて坐剤を得る。
マウス盲腸穿刺による腹膜炎を発端とする敗血症性ショックモデルに対するN-(2-エチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)シクロヘキサンカルボキサミド・一ナトリウム塩・一水和物(以下化合物1と呼ぶ)の治療効果を検討した。
化合物1は製剤品として用いた。製剤処方(1バイアルあたりの含有量)は以下の通りとした。
(a)化合物1(無水物換算) 100mg
(b)マンニト-ル(協和発酵工業製) 100mg
(c)トリス(ヒドロキシメチル)アミノメタン(純正化学製)
21.6mg
(d)塩酸(三共化学製) 適量
(e)水酸化ナトリウム(日本理化製) 適量
(f)蒸留水 10ml
pH 8.7±0.5
動物種:マウス
系統名:Crj : BALB/c
入手先:日本チャールスリバー株式会社 厚木飼育センター
性別 :雌
週齢 :入荷時7週齢及び供試時8週齢
(3)供試動物群構成
第1表の如く、化合物1濃度0.1、1及び10mg/kg投与の治療群に、媒体(5% glucose)投与の非治療群を加えて構成し、各群の匹数は10匹とした。
薬剤調製は誘発手術直前に行い、それ以降の投与は、その投与液を用いて行った。化合物1製剤品100mg入に局方5% glucoseを注入して完全溶解後、最高用量投与液を局方5% glucoseで希釈調製し、その後、中用量及び低用量の投与液を最高用量投与液から局方5% glucoseを用いた段階希釈により調製した。尚、非治療群には溶媒である局方5% glucoseのみを準備した。投与は誘発直後、4時間後、8時間後及び12時間後に背側頸部皮下に反復投与し、血中濃度の維持を図った。各群の投与液は、10ml/kgの投与容量とした。
ハロセン・笑気吸入麻酔下で開腹し、盲腸尖から8mmの体部を結紮した後、先端部を22G注射針で1カ所穿刺貫通させ、盲腸内容物が流出することを確認した後、腹腔内に完納し、閉腹した。
誘発直後から3日間生死判定を行い、その結果を24時間毎に纏めた。
生存率について実施した。以下に方法の詳細を示した。
I.統計アプリケーション
EXCEL(データ集計)、SAS(Shirley-Williams)、メモ帳for windows 95(プログラム)を用いて行った。
II.不完全例の取り扱い
実験手技的なミス、若しくは要因が明確でデータを排除する事が可能な場合、そのデータを除いて検定を行うこととした。その他のデータは、基本的に棄却しないで検定を行うこととした。尚、これらに当てはまる事態は発生しなかった。
III.有意水準及び両側/片側
有意水準は5%で両側検定を行った。
IV.検定手法
非治療群を対照に、化合物1;0.1mg/kg投与群、化合物1;1mg/kg投与群、化合物1;10mg/kg投与群について群間比較を行った。
<解析データ>
生死判定結果:0~24時間で死亡した動物を1、24~48時間で死亡した動物を2、48時間~72時間で死亡した動物を3、72時間以上生存した動物を4とスコアを付けたデータを用いた。
<検定手法>
Shirley-Williamsの多重比較を用いて群間比較を行った。
試験の結果を第2表に示した。作製した敗血症性ショックモデルは、盲腸穿刺による腹膜炎から始まり、敗血症性ショックから死に至るモデルであった。本試験結果において、10mg/kg投与で統計学的に有意(P<0.001)な生存率の改善が認められた。
Claims (7)
- ジアミノトリフルオロメチルピリジン誘導体がN-(2-エチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)シクロヘキサンカルボキサミド、N-(2-メチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)クロトンアミド、N-(2-メチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)-2-チオフェンカルボキサミド、N-(2-メチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)シクロペンタンカルボキサミド又はN-(2-メチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)-4-フルオロベンズアミドである請求項1の治療剤又は予防剤。
- ジアミノトリフルオロメチルピリジン誘導体がN-(2-エチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)シクロヘキサンカルボキサミドである請求項1の治療剤又は予防剤。
- ショックが敗血症性ショック、出血性ショック又は心原性ショックである請求項1の治療剤又は予防剤。
- ショックが敗血症性ショックである請求項1の治療剤又は予防剤。
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ES10780439.5T ES2629428T3 (es) | 2009-05-28 | 2010-05-17 | Agente antichoque que comprende un derivado de diaminotrifluorometilpiridina |
CA2761597A CA2761597C (en) | 2009-05-28 | 2010-05-17 | Anti-shock agent comprising diaminotrifluoromethylpyridine derivative |
EP10780439.5A EP2436672B1 (en) | 2009-05-28 | 2010-05-17 | Anti-shock agent comprising diaminotrifluoromethylpyridine derivative |
US13/320,570 US8604212B2 (en) | 2009-05-28 | 2010-05-17 | Anti-shock agent comprising diaminotrifluoromethylpyridine derivative |
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EP (1) | EP2436672B1 (ja) |
JP (1) | JP5584518B2 (ja) |
CA (1) | CA2761597C (ja) |
ES (1) | ES2629428T3 (ja) |
HU (1) | HUE033310T2 (ja) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019088214A1 (ja) | 2017-11-02 | 2019-05-09 | 石原産業株式会社 | 徐放性医薬組成物 |
WO2019167979A1 (ja) | 2018-03-01 | 2019-09-06 | 石原産業株式会社 | 保存安定性に優れた医薬組成物 |
WO2020230876A1 (ja) | 2019-05-15 | 2020-11-19 | 石原産業株式会社 | N-(2-エチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)シクロヘキサンカルボキサミド・一ナトリウム塩の無水和物結晶体 |
WO2022071233A1 (ja) | 2020-09-29 | 2022-04-07 | 石原産業株式会社 | 優れた保存効力を示す液状医薬組成物 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0465913A2 (en) | 1990-07-10 | 1992-01-15 | Ishihara Sangyo Kaisha, Ltd. | Diaminotrifluoromethylpyrimidine derivatives, process for their production and phospholipase A2 inhibitor containing them |
JPH05170742A (ja) * | 1991-05-24 | 1993-07-09 | Ishihara Sangyo Kaisha Ltd | ジアミノトリフルオロメチルピリジン誘導体、それらの製造方法及びそれらを含有するホスホリパーゼ▲a2▼阻害剤 |
JPH06135934A (ja) * | 1991-12-27 | 1994-05-17 | Ishihara Sangyo Kaisha Ltd | ピリジン誘導体又はその塩を含有するホスホリパーゼ▲a2▼阻害剤、抗炎症剤又は抗膵炎剤 |
JPH11509548A (ja) * | 1995-07-24 | 1999-08-24 | 藤沢薬品工業株式会社 | Pla▲下2▼阻害剤としてのエステル類およびアミド類 |
JP2004503586A (ja) * | 2000-07-14 | 2004-02-05 | イーライ・リリー・アンド・カンパニー | 敗血症の治療方法 |
JP2009129578A (ja) | 2007-11-20 | 2009-06-11 | K-One Create Corp | 棚板用の照明構造 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5260320A (en) | 1990-07-10 | 1993-11-09 | Ishihara Sangyo Kaisha Ltd. | Diaminotrifluoromethylpyridine compounds and phospholipase A2 inhibitor containing them |
US5229403A (en) | 1990-07-10 | 1993-07-20 | Ishihara Sangyo Kaisha Ltd. | Diaminotrifluoromethylpyridine derivatives and phospholipase A2 inhibitor containing them |
ZA981430B (en) | 1997-02-28 | 1998-08-24 | Ishihara Sangyo Kaisha | Anticancer composition |
ES2307626T3 (es) | 2000-01-31 | 2008-12-01 | Ishihara Sangyo Kaisha, Ltd. | Agente terapeutico o preventivo para enfermedades del sistema disgestivo que contiene un derivado de diaminotrifluorometilpiridina. |
WO2001056569A1 (fr) | 2000-02-01 | 2001-08-09 | Ishihara Sangyo Kaisha, Ltd. | Medicaments pour le traitement et la prevention d'affections hepatiques, a base de derives de diaminotrifluoromethylpyridine |
JP4848092B2 (ja) | 2000-02-01 | 2011-12-28 | 石原産業株式会社 | ジアミノトリフルオロメチルピリジン誘導体を含有する肺不全の治療剤又は予防剤 |
US20040110825A1 (en) | 2001-06-29 | 2004-06-10 | Andrew Loh | Method for treating sepsis |
CN101351707B (zh) | 2005-12-28 | 2014-03-26 | 积水医疗株式会社 | 凝集测量用试剂以及凝集测量方法 |
-
2010
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- 2010-05-17 PL PL10780439T patent/PL2436672T3/pl unknown
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0465913A2 (en) | 1990-07-10 | 1992-01-15 | Ishihara Sangyo Kaisha, Ltd. | Diaminotrifluoromethylpyrimidine derivatives, process for their production and phospholipase A2 inhibitor containing them |
JPH05170742A (ja) * | 1991-05-24 | 1993-07-09 | Ishihara Sangyo Kaisha Ltd | ジアミノトリフルオロメチルピリジン誘導体、それらの製造方法及びそれらを含有するホスホリパーゼ▲a2▼阻害剤 |
JPH06135934A (ja) * | 1991-12-27 | 1994-05-17 | Ishihara Sangyo Kaisha Ltd | ピリジン誘導体又はその塩を含有するホスホリパーゼ▲a2▼阻害剤、抗炎症剤又は抗膵炎剤 |
JPH11509548A (ja) * | 1995-07-24 | 1999-08-24 | 藤沢薬品工業株式会社 | Pla▲下2▼阻害剤としてのエステル類およびアミド類 |
JP2004503586A (ja) * | 2000-07-14 | 2004-02-05 | イーライ・リリー・アンド・カンパニー | 敗血症の治療方法 |
JP2009129578A (ja) | 2007-11-20 | 2009-06-11 | K-One Create Corp | 棚板用の照明構造 |
Non-Patent Citations (4)
Title |
---|
HANASAKI, K. ET AL.: "Resistance to Endotoxic Shock in Phospholipase A2 Receptor-deficient Mice", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 52, 1997, pages 32792 - 32797 * |
KIMURA, H. ET AL.: "Synthesis and Antipancreatitis Activities of Novel N-(2- Sulfonylamino-5-trifluoromethyl-3-pyridyl) carboxamide Derivatives as Phospholipase A2 Inhibitors", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 43, no. 10, 1995, pages 1696 - 1700, XP002070541 * |
MARSHALL, L.A. ET AL.: "SB 203347, an inhibitor of 14 kDa phospholipase A2, alters human neutrophil arachidonic acid release and metabolism and prolongs survival in murine endotoxin shock", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 274, 1995, pages 1254 - 1262, XP008157031 * |
See also references of EP2436672A4 * |
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WO2019088214A1 (ja) | 2017-11-02 | 2019-05-09 | 石原産業株式会社 | 徐放性医薬組成物 |
CN111315381A (zh) * | 2017-11-02 | 2020-06-19 | 石原产业株式会社 | 缓释性医药组合物 |
WO2019167979A1 (ja) | 2018-03-01 | 2019-09-06 | 石原産業株式会社 | 保存安定性に優れた医薬組成物 |
CN111787919A (zh) * | 2018-03-01 | 2020-10-16 | 石原产业株式会社 | 保存稳定性优异的医药组合物 |
EP3760200A4 (en) * | 2018-03-01 | 2021-12-15 | Ishihara Sangyo Kaisha, Ltd. | PHARMACEUTICAL COMPOSITION WITH EXCELLENT STABILITY IN STORAGE |
CN111787919B (zh) * | 2018-03-01 | 2024-03-08 | 石原产业株式会社 | 保存稳定性优异的医药组合物 |
WO2020230876A1 (ja) | 2019-05-15 | 2020-11-19 | 石原産業株式会社 | N-(2-エチルスルホニルアミノ-5-トリフルオロメチル-3-ピリジル)シクロヘキサンカルボキサミド・一ナトリウム塩の無水和物結晶体 |
WO2022071233A1 (ja) | 2020-09-29 | 2022-04-07 | 石原産業株式会社 | 優れた保存効力を示す液状医薬組成物 |
KR20230084205A (ko) | 2020-09-29 | 2023-06-12 | 이시하라 산교 가부시끼가이샤 | 우수한 보존 효력을 나타내는 액상 의약 조성물 |
Also Published As
Publication number | Publication date |
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EP2436672A4 (en) | 2012-11-28 |
CA2761597C (en) | 2016-12-20 |
ES2629428T3 (es) | 2017-08-09 |
PT2436672T (pt) | 2017-05-30 |
CA2761597A1 (en) | 2010-12-02 |
PL2436672T3 (pl) | 2017-09-29 |
US20120059039A1 (en) | 2012-03-08 |
EP2436672B1 (en) | 2017-04-12 |
JP5584518B2 (ja) | 2014-09-03 |
US8604212B2 (en) | 2013-12-10 |
JP2011006384A (ja) | 2011-01-13 |
EP2436672A1 (en) | 2012-04-04 |
HUE033310T2 (en) | 2017-11-28 |
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