JPH06507381A - Prostacyclin and carbacyclin derivatives as medicines for the treatment of febrile diseases - Google Patents
Prostacyclin and carbacyclin derivatives as medicines for the treatment of febrile diseasesInfo
- Publication number
- JPH06507381A JPH06507381A JP4504121A JP50412192A JPH06507381A JP H06507381 A JPH06507381 A JP H06507381A JP 4504121 A JP4504121 A JP 4504121A JP 50412192 A JP50412192 A JP 50412192A JP H06507381 A JPH06507381 A JP H06507381A
- Authority
- JP
- Japan
- Prior art keywords
- prostacyclin
- derivatives
- treatment
- carbacyclin
- carrier
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 熱性疾患の処置のための医薬品としてのプロスタサイクリン−およびカルバサイ クリン誘導体本発明は、発熱または播種性の脈管内の凝固障害症を併発し、かつ 脳性の合併症を併発しうる疾患の処置のための医薬品に関する。[Detailed description of the invention] Prostacyclin and carbacyclin as medicines for the treatment of febrile diseases Clin derivatives The present invention is intended for use in patients with fever or disseminated intravascular coagulopathy and This article relates to pharmaceuticals for the treatment of diseases that may have cerebral complications.
前記医薬品は、プロスタサイクリン−およびカルバサイクリン誘導体並びに常用 の助剤および担持剤を含有している。また、本発明は、記載された医薬品の製造 のための前記プロスタサイクリン−およびカルバサイクリン誘導体の使用に関す る。The medicines include prostacyclin and carbacyclin derivatives as well as commonly used Contains auxiliary agents and carriers. The invention also provides for the manufacture of the described pharmaceutical products. Regarding the use of said prostacyclin and carbacycline derivatives for Ru.
欧州特許第１１５９１号明細書、同第５５２０８号明細書、同第９９５３８号明 細書、同第１１９９４９号明細書および同第８４８５６号明細書の記載から、既 に、主として心臓血管および血栓凝固抑制作用に帰因することができるプロスタ サイクリン−およびカルバサイクリン誘導体の薬理学的作用は公知である。European Patent No. 11591, European Patent No. 55208, European Patent No. 99538 From the description in the specifications, Specification No. 119949 and Specification No. 84856, In addition, prosthesis, which can be mainly attributed to cardiovascular and anticoagulant effects, The pharmacological actions of cyclin and carbacycline derivatives are known.
ところで、プロスタサイクリン−およびカルバサイクリン誘導体を含有する医薬 品は、発熱または播種性の脈管内の凝固障害症を併発し、かつ脳性の合併症を併 発しうる疾患の処置に好適であることが見出された。By the way, pharmaceuticals containing prostacyclin and carbacyclin derivatives patients with fever or disseminated intravascular coagulopathy and cerebral complications. It has been found to be suitable for the treatment of diseases that may occur.
また、生理学的に認容性の塩基およびそのβ−シクロデキストリンクラスレート を有する前記プロスタサイクリン−およびカルバサイクリン誘導体の塩も、記載 された疾患の処置に使用することができる。Also, physiologically tolerable bases and their β-cyclodextrin clathrates Salts of said prostacyclin and carbacyclin derivatives having It can be used to treat diseases caused by cancer.
発熱または播種性の脈管内の凝固障害を併発し、かつ多くの場合に、脳性の合併 症を生じる疾患には、例えば敗血症性ショック、ＡＩＤＳ、狂犬病、流行性耳下 腺炎およびアルボウィルスまたはトリパノゾーマによって惹起された疾患並びに 全ての消耗疾患（例えば、腫瘍、結核（Ｔｂｃ）、糖尿病）が数えられる。前記 の疾患は、高まった腫瘍壊死要因（Ｔｕｍｏｒｎｅｋｒｏｓｅｆａｋｔｏｒ）（ ＴＮＦ）−血清含量を伴っている。モノクローナル抗体は、確かにＴＮＦをブロ ックすることはできるが、しかしながら、合成に影響を及ぼすことはできない。Concomitant fever or disseminated intravascular coagulopathy and often cerebral involvement Diseases that cause disease include septic shock, AIDS, rabies, mumps, etc. adenitis and diseases caused by arboviruses or trypanosomes; All wasting diseases (eg tumors, tuberculosis (Tbc), diabetes) are counted. Said The disease is caused by increased tumor necrosis factor (tumornekrosefaktor) ( TNF) - with serum content. Monoclonal antibodies do block TNF. However, they cannot influence the synthesis.
ところで、驚異的なことに、記載されたプロスタサイクリン−およびカルバサイ クリン誘導体は、ＴＮＦの合成を、ＴＮＦ−メツセンジャー−ＲＮＡの段階で、 投与量に応じて抑制することが見出された。By the way, surprisingly, the prostacyclin and carbacyclin Clin derivatives inhibit TNF synthesis at the TNF-messenger-RNA stage. It was found that the inhibition was dose-dependent.
プロスターおよびカルバサイクリンは、ＴＮＦ合成をｍ ＲＮ Ａレベルで抑制 する。従って、これらは、治療薬として、既に存在するＴＮＦに抗して向けられ ているモノクローナル抗体よりも好まれる。モノクローナル抗体は、既に分泌さ れたＴＮＦに対してのみ作用する。形成されたＴＮＦ−αＴＮＦ−免疫複合体は 、再度分解されなければならず、このことは、臨床の合併症を生じることができ る。更に、記載されたプロスターおよびカルバサイクリンは、予防的に、前記の 疾患の際に使用することができ、このことは、モノクローナル抗体には当てはま らない。Prostar and carbacyclin suppress TNF synthesis at the mRNA level do. Therefore, they can be directed against the already existing TNF as therapeutic agents. preferred over monoclonal antibodies. Monoclonal antibodies have already been secreted. It only acts on TNF that has been removed. The formed TNF-αTNF-immune complex is , must be disassembled again, and this can result in clinical complications. Ru. Furthermore, the described prosters and carbacyclines can be used prophylactically to treat the aforementioned This is not the case for monoclonal antibodies. No.
ＰＧＥ、に比べて、新規医薬品の利点は、副作用の明らかな減少にある。ＰＧＥ 、は、例えば発熱さえ生じ、平滑筋系の向上した収縮を生じ、更に領土的に作用 する。これとは異なり、新規医薬品は、脈管保護的かつ抗浮腫的に作用する。Compared to PGE, the advantage of the new drug lies in a distinct reduction in side effects. PGE , for example, even produces fever, produces improved contractions of the smooth muscle system, and acts more territorially. do. In contrast, the new drug acts vasoprotectively and anti-edematically.
アイロブロスト、シカプロスト（Ｃ４ｃａｐｒｏｓｔ） 、ニブターロブロスト （Ｅｐｔａｌｏｐｒｏｓｔ） 、ベラプロスト（Ｂｅｒａｐｒｏｓｔ）およびシ ブロスト（Ｃ１ｐｒｏｓｔ ）は、特に好適なプロスタサイクリン−およびカル バサイクリン誘導体であることが判明した。Airobrost, Cicaprost (C4caprost), Nibutarobrost (Eptaloprost), Beraprost (Beraprost) and C1prost is a particularly suitable prostacyclin and calcium It turned out to be a vacycline derivative.
遊離酸を用いる塩形成には、当業者に、生理学的に認容性の塩を形成するのにつ いて公知であるような無機および有機塩基が好適である。例えば、次のものが記 載される：アルカリ金属ヒドロキシド、例えば水酸化ナトリウムおよび水酸化カ リウｂ、アルカリ土類金属ヒドロキシド、例えば水酸化カルシウム、アンモニア 、アミン、例えばエタノールアミン、ジェタノールアミン、トリエタノールアミ ン、Ｎ−メチルグルカミン、モルホリン、トリス−（ヒドロキシメチル）−メチ ルアミン等。β−シクロデキストリンクラスレート形成は、欧州特許第２５９４ ６８号明細書の記載に相応して行なわれる。Salt formation using the free acid will require those skilled in the art to form physiologically acceptable salts. Inorganic and organic bases, such as those known in the art, are suitable. For example, the following Listed: Alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide. Liu b, alkaline earth metal hydroxides such as calcium hydroxide, ammonia , amines such as ethanolamine, jetanolamine, triethanolamine N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylene Ruamin et al. β-Cyclodextrin clathrate formation is described in European Patent No. 2594 This is done in accordance with the description in the specification of No. 68.
記載されたプロスタサイクリン−およびカルバサイクリン誘導体の製造は、欧州 特許第１１５９１号明細書、同第５５２０８号明細書、同第１１９９４９号明細 書、同第９９５３８号明細書および同第８４８５６号明細書に記載されている。The production of the prostacyclin and carbacyclin derivatives described is carried out in Europe. Patent No. 11591 specification, Patent No. 55208 specification, Patent No. 119949 specification No. 99538 and No. 84856.
前記特許明細書には、プロスタサイクリン−およびカルバサイクリン誘導体につ いて、次の薬理学的性質が記載されている： 末梢動脈および冠状血管の抵抗の低下、血小板凝固の阻止および血小板血栓の溶 解、心筋細胞保護：同時に拍出量および冠状血管の血液潅流を低下させることの ない体系的な血圧の低下；卒中発作の処置、冠状血管の心臓疾患、冠状血管の血 栓、心筋梗塞、末梢動脈疾患、動脈硬化症および血栓の予防および治療、ショッ クの治療、気管支狭窄の阻止、胃酸分泌の阻止および胃および腸の粘膜の細胞保 護；抗アレルギー性の性質、肺の血管抵抗および肺の血圧の低下、腎臓血液潅流 の促進、透析または血液濾過の際のヘパリンの代りにかまたは補薬としての使用 、保存血漿、特に保存血小板の保存、分娩陣痛の阻止、妊娠中毒症の処置、脳血 液潅流および抗増殖の向上。The patent specification mentions prostacyclin and carbacyclin derivatives. The following pharmacological properties have been described: Reduction of resistance in peripheral arteries and coronary vessels, inhibition of platelet coagulation, and lysis of platelet clots protection, myocardial cell protection: simultaneously reducing stroke volume and coronary blood perfusion. No systematic decrease in blood pressure; treatment of stroke, coronary heart disease, coronary blood Prevention and treatment of thrombosis, myocardial infarction, peripheral artery disease, arteriosclerosis and blood clots, treatment of cancer, prevention of bronchial stenosis, prevention of gastric acid secretion, and preservation of cells in the mucous membranes of the stomach and intestines. Protection; anti-allergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, renal blood perfusion promotion, use in place of or as an adjunct to heparin during dialysis or hemofiltration , preservation of preserved plasma, especially preserved platelets, prevention of labor, treatment of preeclampsia, cerebral blood Improved fluid perfusion and anti-proliferation.
記載されたプロスタサイクリン−およびカルバサイクリン誘導体の新規の薬理学 的性質は、記載されていないし、前記欧州特許明細書に記載された作用と直接の 関係もない。Novel pharmacology of prostacyclin and carbacyclin derivatives described properties are not described and are not directly related to the action described in the European patent specification. It doesn't matter.
この化合物の投与量は、患者に投与される場合には、−日当り１ｋｇ当り１〜１ ５００μｇである。製薬学的に認容性の担持剤の単位投与量は、０．０１〜１０ ０ｍｇである。The dosage of this compound, when administered to a patient, is -1 to 1 per kg per day. It is 500 μg. The unit dosage of the pharmaceutically acceptable carrier is 0.01 to 10 It is 0 mg.
常用の水性溶剤中、例えば０．９％のＮａＣ１溶液中での持続注入としての静脈 内投与の投薬は、有利に毎分１ｋｇ当りＯ，ｌｎｇおよび毎分１ｋｇ当り０゜１ μｇの間の投薬量で行なわれる。Intravenous as continuous infusion in conventional aqueous solvents, e.g. 0.9% NaCl solution Advantageously, the dosage for internal administration is 0.1 ng per kg per minute and 0.1 ng per kg per minute. It is carried out in dosages between μg.
従ってまた、本発明は、一般式Ｉの化合物および常用の助剤および担持剤を基礎 とする医薬品に関する。The invention therefore also provides compounds of the general formula I and customary auxiliaries and carriers. related to pharmaceutical products.
本発明による作用物質は、生薬で公知でありかつ常用の助剤との化合物中で、例 えば脳性作用の医薬品の製造に使用されなければならない。The active substances according to the invention can be used in compounds with auxiliaries known and customary in herbal medicine, e.g. For example, it must be used in the production of medicinal products with cerebral effects.
また、本発明は、自体公知の方法で、自体公知の助剤および担持剤との、脳性合 併症の際に作用する化合物を、生薬の処方物にすることによって特徴づけられる 本発明による医薬品を製造するための方法に関する。Furthermore, the present invention also provides for brain-based synthesis using a method known per se, with auxiliary agents and carriers known per se. It is characterized by the preparation of herbal medicines, which are compounds that act in the treatment of complications. The present invention relates to a method for producing a medicament.
例 ｌ 試験管内試験により、アイロブロストは、ＬＰＳ ５０μｇ ／ ｍ ｌによっ て誘発された、ＮＭＲＩマウス−腹腔マクロファージのＴＮＦ生産を、投与量に 応じて抑制することが明らかである（図１、図２）。Example l In an in vitro test, Airobrost was treated with 50μg/ml of LPS. TNF production in NMRI mice-peritoneal macrophages induced by It is clear that the effect is suppressed accordingly (Fig. 1, Fig. 2).
澱粉溶液２％の腹腔内注射によって、ＮＭＲＩマウス中で、局所的な不妊炎症を 感染させる。３〜５日後に、この動物を殺し、かつマクロファージを取得する。Local infertility inflammation was induced in NMRI mice by intraperitoneal injection of 2% starch solution. Infect. After 3-5 days, the animals are sacrificed and macrophages are obtained.
癒着していない細胞を分離する。Separate non-adherent cells.
マクロファージの活性化のために、リポポリサツカリド（ＬＰＳ）を、１．５μ ｇ／ｍｌおよび５０μｇ／ｍｌの濃厚液を使用する。For activation of macrophages, lipopolysaccharide (LPS) was added at 1.5μ g/ml and 50 μg/ml concentrates are used.
ＴＮＦ効力検定として、ＴＮＦ感応細胸系列Ｗ Ｅ ＨＩ １６４（市販されて いる）を使用する。ＷＥＨ１１６４の細胞溶解の規模は、ＴＮＦの存在量と比例 している。杯状平底微量滴定板（Ｎａｐｆｆｌａｃｈｂｏｄｅｎｍｉｋｒｏｔｉ ｔｅｒ−Ｐｌａｔｔｅｎ） ９６個中に、培養上清および血清を、希釈の順序で 滴定する。ＴＭＵ−ＴＮＦを用いる滴定順序を、標準として使用する。As a TNF efficacy assay, the TNF-sensitive small breast series WE HI 164 (commercially available ). The scale of WEH1164 cell lysis is proportional to the amount of TNF present. are doing. Cup-shaped flat bottom microtitration plate ter-Platten) culture supernatant and serum in the order of dilution. Titrate. A titration sequence with TMU-TNF is used as a standard.
生き残っている細胞の数を、比色定量的ＭＴＴ試験に基づいて定める。The number of surviving cells is determined based on the colorimetric MTT test.
計算を、ＴＭＵ−ＴＮＦの標準滴定順序との比較によってプロビット分析を用い て実施する。Calculations were performed using probit analysis by comparison with standard titration sequences of TMU-TNF. Implemented.
試験は、ＴＮＦｏ、５Ｕ／ｍｌまで測定することができる。抗ＴＮＦ抗血清の添 加によって、ＴＮＦαおよびＴＮＦβの間で区別することができる。The test can measure up to 5 U/ml of TNFo. Addition of anti-TNF antiserum Depending on the addition, a distinction can be made between TNFα and TNFβ.
例 ２ 未処理のマウスおよびアイロブロスト処理されたマウスの血清ＴＮＦ含量を、試 験する。Example 2 Serum TNF content of untreated and Airoblast-treated mice was tested. experiment.
アイロブロストは、最後の注射の更に４日後にも、血清中のＴＮＦ含量を著しく 抑制している。Airobrost significantly lowers serum TNF content even 4 days after the last injection. It's suppressed.
国際調査報告 ＯＥ ９２００１００international search report OE 9200100
Claims (7)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4104607.2 | 1991-02-12 | ||
| DE4104607A DE4104607A1 (en) | 1991-02-12 | 1991-02-12 | PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A MEDIUM FOR TREATING FEVERED DISEASES |
| PCT/DE1992/000100 WO1992014438A2 (en) | 1991-02-12 | 1992-02-11 | Prostacycline and carbacycline derivatives as agents for treating feverish complaints |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06507381A true JPH06507381A (en) | 1994-08-25 |
Family
ID=6425075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4504121A Pending JPH06507381A (en) | 1991-02-12 | 1992-02-11 | Prostacyclin and carbacyclin derivatives as medicines for the treatment of febrile diseases |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0571462A1 (en) |
| JP (1) | JPH06507381A (en) |
| KR (1) | KR930702990A (en) |
| AU (1) | AU660449B2 (en) |
| CA (1) | CA2104024A1 (en) |
| DE (1) | DE4104607A1 (en) |
| WO (1) | WO1992014438A2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3230246B2 (en) * | 1991-04-11 | 2001-11-19 | 東レ株式会社 | Malignant tumor metastasis inhibitor |
| US5496850A (en) * | 1991-04-11 | 1996-03-05 | Toray Industries, Inc. | Antimetastasis agent of malignant tumors |
| DE4124695C2 (en) * | 1991-07-22 | 1994-12-22 | Blitstein Willinger Eveline Dr | Use of carbacyclin derivatives for the treatment of psoriasis vulgaris |
| DE4124693A1 (en) * | 1991-07-22 | 1993-01-28 | Schering Ag | Use of carbocycline derivs. - esp. iloprost, cicaprost, eptaloprost, beraprost or ciprostene, for treatment of vitiligo |
| DE4226615C1 (en) * | 1992-08-07 | 1994-05-19 | Schering Ag | Use of prostane derivatives for the treatment of chronic polyarthritis |
| DE19530884C2 (en) * | 1995-08-11 | 1997-07-31 | Schering Ag | Use of prostane derivatives and their combination with antibiotics for the treatment of bacterial meningitis |
| WO1998037895A1 (en) * | 1997-02-27 | 1998-09-03 | Toray Industries, Inc. | Drugs for ameliorating pulmonary circulation |
| US6340693B1 (en) * | 1997-03-14 | 2002-01-22 | Toray Industries, Inc. | Protective agent for nervous system structural cells |
| JPH11228417A (en) * | 1998-02-06 | 1999-08-24 | Teijin Ltd | Neuropathy remedy |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2845770A1 (en) * | 1978-10-19 | 1980-04-30 | Schering Ag | NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| US4256883A (en) * | 1979-03-14 | 1981-03-17 | Research Corporation | Pyridoza prostacyclin analogues and N-oxides thereof |
| JPS58124778A (en) * | 1982-01-20 | 1983-07-25 | Toray Ind Inc | 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivative |
| DE3226550A1 (en) * | 1982-07-13 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3740838A1 (en) * | 1987-11-27 | 1989-06-08 | Schering Ag | CYCLODEXTRINCLATHRATE OF 5-CYANO-PROSTACYCLINE DERIVATIVES AND THEIR USE AS MEDICINAL PRODUCTS |
| DE68918726T2 (en) * | 1988-02-23 | 1995-03-02 | Teijin Ltd | Antidiabetic agents containing isocarbacyclin derivatives. |
-
1991
- 1991-02-12 DE DE4104607A patent/DE4104607A1/en not_active Withdrawn
-
1992
- 1992-02-11 JP JP4504121A patent/JPH06507381A/en active Pending
- 1992-02-11 EP EP92904665A patent/EP0571462A1/en not_active Withdrawn
- 1992-02-11 WO PCT/DE1992/000100 patent/WO1992014438A2/en not_active Application Discontinuation
- 1992-02-11 CA CA002104024A patent/CA2104024A1/en not_active Abandoned
- 1992-02-11 AU AU12433/92A patent/AU660449B2/en not_active Ceased
-
1993
- 1993-08-11 KR KR1019930702386A patent/KR930702990A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR930702990A (en) | 1993-11-29 |
| AU1243392A (en) | 1992-09-15 |
| EP0571462A1 (en) | 1993-12-01 |
| DE4104607A1 (en) | 1992-08-13 |
| WO1992014438A2 (en) | 1992-09-03 |
| CA2104024A1 (en) | 1992-08-13 |
| AU660449B2 (en) | 1995-06-29 |
| WO1992014438A3 (en) | 1993-01-07 |
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