EP0571462A1 - Prostacycline and carbacycline derivatives as agents for treating feverish complaints - Google Patents

Prostacycline and carbacycline derivatives as agents for treating feverish complaints

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Publication number
EP0571462A1
EP0571462A1 EP92904665A EP92904665A EP0571462A1 EP 0571462 A1 EP0571462 A1 EP 0571462A1 EP 92904665 A EP92904665 A EP 92904665A EP 92904665 A EP92904665 A EP 92904665A EP 0571462 A1 EP0571462 A1 EP 0571462A1
Authority
EP
European Patent Office
Prior art keywords
diseases
treatment
prostacyclin
agent
carbacyclin derivatives
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.)
Withdrawn
Application number
EP92904665A
Other languages
German (de)
French (fr)
Inventor
Eveline Blitstein-Willinger
Karl-Heinz Thierauch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0571462A1 publication Critical patent/EP0571462A1/en
Withdrawn legal-status Critical Current

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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

Definitions

  • the present invention relates to agents for the treatment of diseases which are associated with fever or disseminated intravascular coagulopathy and can be accompanied by cerebal complications.
  • agents contain prostacyclin and carbacyclin derivatives and conventional auxiliaries and carriers.
  • the invention also relates to the use of these prostacyclin and carbacyclin derivatives for the preparation of the agents mentioned.
  • agents containing prostacyclin and carbacyclin derivatives are suitable for the treatment of diseases which are associated with fever or disseminated intravascular coagulopathy and can be accompanied by cerebral complications.
  • the salts of these prostacyclin and carbacyclin derivatives with physiologically compatible bases and their ⁇ -cyclodextrin clathrates can also be used to treat the diseases mentioned.
  • the diseases which are accompanied by fever or disseminated intravascular coagulopathy and which in many cases lead to cerebral complications include, for example, septic shock, AIDS, rabies, humps and diseases caused by arboviruses or trypanosomes as well as all consuming diseases (eg tumors , TB, diabetes). These diseases are accompanied by increased tumor necrosis factor (TNF) serum levels. Honoclonal antibodies can block TNF, but cannot influence the synthesis.
  • TNF tumor necrosis factor
  • the prostacyclin and carbacyclin derivatives mentioned inhibit the synthesis of TNF in a dose-dependent manner at the level of the TNF messenger RNA.
  • Prosta- and Ca.rbacyclins inhibit TNF synthesis at the mRNA level. They are therefore preferred as therapeutic agents to monoclonal antibodies that are only directed against already existing TNF.
  • the monoclonal antibodies only act on the already secreted TNF.
  • the TNF-s_TNF immune complexes formed must in turn be broken down, which can lead to clinical complications.
  • the prostatic and carbacyclins mentioned can be used prophylactically in these diseases, which is out of the question for the monoclonal antibodies.
  • Opposite P6E the advantage of the new agents lies in the significant reduction in side effects. PGE generates e.g. even fever, leads to increased constriction of the smooth husk and also has an abortive effect.
  • the new agents are protective and anti-edematous.
  • Iloprost, cicaprost, eptaloprost, beraprost and ciprosten have proven to be particularly suitable prostacyclin and carbacyclin derivatives.
  • Inorganic and organic bases are suitable for salt formation with the free acids, as are known to the person skilled in the art for the formation of physiologically compatible salts.
  • examples include: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanola in. Triethanolamine, N-ethylglucamine, horpholine, tris (hydroxymethyl) methylamine, etc.
  • the / 3-cyclodextrin clathrate is formed in accordance with EP 259468.
  • prostacyclin and carbacyclin derivatives lowering of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection; Reduction in systemic blood pressure without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral arterial disorders, arteriosclerosis and thrombosis, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection of the stomach and Intestinal mucosa; antiallergic properties, reduction of pulmonary vascular resistance and blood pressure, promotion of renal blood flow, use instead of heparin or as an adjuvant in dialysis or hemofiltration, preservation of preserved blood plasma, especially preserved blood platelets, inhibition of labor pains, treatment of pregnancy toxicosis, increased cerebral circulation and antiproliferation.
  • the dose of the compounds is 1-1500 ⁇ g / kg / day when administered to the human patient.
  • the unit dose for the pharmaceutically acceptable carrier is 0.01-100 mg.
  • the dosing of IV administration as a continuous infusion in conventional aqueous solvents e.g. 0.9% NaCl solution, preferably in doses between 0.1 ng / kg / min and 0.1 ⁇ g / kg / min.
  • the invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and carriers.
  • the active compounds according to the invention are to be used in conjunction with the auxiliaries known and customary in the field of galenics, e.g. serve for the production of cerebral agents.
  • the invention also relates to a process for the preparation of the agents according to the invention, which is characterized in that the compounds which act in the case of cerebral complications and the auxiliaries and excipients known per se are galenically formulated in a manner known per se.
  • example 1 the compounds which act in the case of cerebral complications and the auxiliaries and excipients known per se are galenically formulated in a manner known per se.
  • NMRI houses by intraperitoneal injection of 2 Z starch solution. After 3-5 days, the animals are sacrificed and the macrophages obtained.
  • the non-adherent cells are separated.
  • Lipopolysaccharide is used in concentrations of 1, 5 ⁇ g and 50 ⁇ g / ml to activate the macrophages.
  • the TNF-sensitive cell line WEHI 164 (to be obtained commercially) is used as the TNF assay.
  • the extent of cell lysis of WEHI 164 is proportional to the amount of TNF present.
  • the culture supernatants and sera are diluted in 96 well flat microtiter plates A titration series with TMÜ-TNF is used as standard.
  • the calculation is carried out by comparison with the standard titration series of TMU-TNF using probit analysis.
  • the test allows a determination of up to 0.5 U / ml TNF.
  • an anti-TNF antiserum it is possible to differentiate between TNF ⁇ and TNFß.
  • the serum TNF levels of the untreated and the iloprost-treated mice are examined.
  • Iloprost significantly inhibits TNF levels in the serum even 4 days after the last injection.

Abstract

On utilise des dérivés de prostacycline et de carbacycline pour produire un agent thérapeutique de maladies qui s'accompagnent de fièvre ou d'une coagulopathie intravasculaire disséminée et qui peuvent être suivies de complications cérébrales.Prostacycline and carbacycline derivatives are used to produce a therapeutic agent for diseases which are accompanied by fever or disseminated intravascular coagulopathy and which may be followed by brain complications.

Description

PROSTACYCLIN- UND CARBACYCLINDERIVATE ALS HITTEL ZUR BEHANDLUNG VON PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A TREATMENT FOR
FIEBRIGEN ERKRANKUNGENFeverish diseases
Die vorliegende Erfindung betrifft Hittel zur Behandlung von Krankheiten, die mit Fieber oder disseminierter intravaskulärer Koagulopathie einher¬ gehen und von cerebalen Komplikationen begleitet sein können.The present invention relates to agents for the treatment of diseases which are associated with fever or disseminated intravascular coagulopathy and can be accompanied by cerebal complications.
Diese Hittel enthalten Prostacyclin- und Carbacyclinderivate und übliche Hilfs- und Trägerstoffe. Die Erfindung betrifft auch die Verwendung dieser Prostacyclin- und Carbacyclinderivate zur Herstellung der genannten Hittel.These agents contain prostacyclin and carbacyclin derivatives and conventional auxiliaries and carriers. The invention also relates to the use of these prostacyclin and carbacyclin derivatives for the preparation of the agents mentioned.
Aus EP 11591, EP 55208, EP 99536, EP 119949 und EP 64856 sind bereits phar- makologische Wirkungen der Prostacyclin- und Carbacyclinderivate bekannt, die sich hauptsächlich auf die cardio-vaskul re und thromboaggregationshem- mende Wirkung zurückführen lassen.From EP 11591, EP 55208, EP 99536, EP 119949 and EP 64856, pharmacological effects of the prostacyclin and carbacyclin derivatives are already known, which can be attributed mainly to the cardiovascular and antiplatelet effects.
Es wurde nun gefunden, daß Prostacyclin- uznd Carbacyclinderivate enthal¬ tende Hittel zur Behandlung von Krankheiten, die mit Fieber oder dissemi¬ nierter intravaskulärer Koagulopathie einhergehen und von cerebralen Kom¬ plikationen begleitet sein können, geeignet sind. Es können auch die Salze dieser Prostacyclin- und Carbacyclinderivate mit physiologisch verträgli¬ chen Basen und deren ß-Cyclodextrinclathrate zur Behandlung der genannten Krankheiten eingesetzt werden.It has now been found that agents containing prostacyclin and carbacyclin derivatives are suitable for the treatment of diseases which are associated with fever or disseminated intravascular coagulopathy and can be accompanied by cerebral complications. The salts of these prostacyclin and carbacyclin derivatives with physiologically compatible bases and their β-cyclodextrin clathrates can also be used to treat the diseases mentioned.
Zu den Krankheiten, die von Fieber oder disseminierter intravaskulärer Koagulopathie begleitet sind und in vielen Fällen zu cerebralen Komplika¬ tionen führen, zählen zum Beispiel der septische Schock, AIDS, Tollwut, Humps und durch Arboviren oder Trypanosomen verursachte Krankheiten sowie alle konsumierenden Erkrankungen (z.B. Tumoren, Tbc, Diabetes). Diese Krankheiten sind von einem erhöhten Tumornekrosefaktor (TNF)-Serumspiegel begleitet. Honoclonale Antikörper können zwar TNF blockieren, jedoch nicht auf die Synthese Einfluß nehmen.The diseases which are accompanied by fever or disseminated intravascular coagulopathy and which in many cases lead to cerebral complications include, for example, septic shock, AIDS, rabies, humps and diseases caused by arboviruses or trypanosomes as well as all consuming diseases (eg tumors , TB, diabetes). These diseases are accompanied by increased tumor necrosis factor (TNF) serum levels. Honoclonal antibodies can block TNF, but cannot influence the synthesis.
Es wurde nun überraschenderweise gefunden, daθ die genannten Prostacyclin- und Carbacyclinderivate die Synthese von TNF auf der Stufe der TNF-messen- ger-RNA dosisabhängig hemmen. Prosta- und Ca.rbacycline hemmen die TNF-Synthese auf mRNA-Ebene. Sie sind damit als Therapeutika den monoklonalen Antikörpern vorzuziehen, die nur gegen bereits vorhandenem TNF gerichtet sind. Die monoklonalen Antikörper wirken nur auf das bereits sezernierte TNF. Die gebildeten TNF-s_TNF-Imun- kommplexe müssen wiederum abgebaut werden, was zu klinischen Komplikationen führen kann. Außerdem können die genannten Prosta- und Carbacycline prophy¬ laktisch bei diesen Erkrankungen eingesetzt werden, was für die monoklona¬ len Antikörper nicht in Frage kommt.It has now surprisingly been found that the prostacyclin and carbacyclin derivatives mentioned inhibit the synthesis of TNF in a dose-dependent manner at the level of the TNF messenger RNA. Prosta- and Ca.rbacyclins inhibit TNF synthesis at the mRNA level. They are therefore preferred as therapeutic agents to monoclonal antibodies that are only directed against already existing TNF. The monoclonal antibodies only act on the already secreted TNF. The TNF-s_TNF immune complexes formed must in turn be broken down, which can lead to clinical complications. In addition, the prostatic and carbacyclins mentioned can be used prophylactically in these diseases, which is out of the question for the monoclonal antibodies.
Gegenüber P6E. liegt der Vorteil der neuen Hittel in der deutlichen Reduk¬ tion von Nebenwirkungen. PGE erzeugt z.B. selbst Fieber, führt zu erhöhter Konstriktion der glatten Huskulatur und wirkt obendrein abortiv. Die neuen Mittel wirken dagegen βefäß-protektiv und antiödematös.Opposite P6E. the advantage of the new agents lies in the significant reduction in side effects. PGE generates e.g. even fever, leads to increased constriction of the smooth husk and also has an abortive effect. The new agents, on the other hand, are protective and anti-edematous.
Als besonders geeignete Prostacyclin- und Carbacyclinderivate erweisen sich Iloprost, Cicaprost, Eptaloprost, Beraprost und Ciprosten.Iloprost, cicaprost, eptaloprost, beraprost and ciprosten have proven to be particularly suitable prostacyclin and carbacyclin derivatives.
Zur Salzbildung mit den freien Säuren sind anorganische und organische Ba¬ sen geeignet, wie sie dem Fachmann zur Bildung physiologisch verträglicher Salze bekannt sind. Beispielsweise seien genannt: Alkalihydroxide, wie Na¬ trium- und Kaliumhydroxid, Erdalkalihydroxide, wie Calciumhydroxid, Ammoni¬ ak, Amiπe, wie Äthanolamin, Diäthanola in. Triäthanolamin, N-Hethylgluca- in, Horpholin, Tris-(hydroxymethyl)-methylamin u.s.w. Die /3-Cyclodextrin- clathrat-Bildung erfolgt entsprechend EP 259468.Inorganic and organic bases are suitable for salt formation with the free acids, as are known to the person skilled in the art for the formation of physiologically compatible salts. Examples include: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanola in. Triethanolamine, N-ethylglucamine, horpholine, tris (hydroxymethyl) methylamine, etc. The / 3-cyclodextrin clathrate is formed in accordance with EP 259468.
Die Herstellung der genannten Prostacyclin- und Carbacyclinderivate wird detailliert in EP 11591. 55208, 119949. 99538 und 84856 beschrieben.The preparation of the prostacyclin and carbacyclin derivatives mentioned is described in detail in EP 11591, 55208, 119949, 99538 and 84856.
In diesen Patentschriften werden für die Prostacyclin- und Carbacyclinderi¬ vate folgende pharmakologische Eigenschaften beschrieben: Senkung des peripheren arteriellen und koronaren vaskulären Widerstandes, Inhibierung der Thrombozytenaggregation und Auflösung von Plättchenthrom¬ ben, myocardiale Zytoprotektion; Senkung des systemischen Blutdruckes ohne zugleich Schlagvolumen und koronare Durchblutung zu senken; Behandlung von Schlaganfall, Prophylaxe und Therapie koronarer Herzerkrankungen, koronarer Thrombose, des Herzinfarkts, peripherer Arterienerkraπkungen, Arterioskle- rose und Thrombose, Therapie des Schocks, Inhibierung der Bronchokonstrik- tion, Inhibierung der Magensäuresekretion und Zytoprotektion der Magen- und Darmschleimhaut; antiallergische Eigenschaften, Senkung des pulmonalen vas- kulären Widerstandes und des pulmonalen Blutdruckes, Förderung der Nieren¬ durchblutung, Anwendung an Stelle von Heparin oder als Adjuvans bei der Dialyse oder Hämofiltration, Konservierung von Blutplasmakonserven, beson¬ ders von Blutplättchenkonserven, Inhibierung von Geburtswehen, Behandlung von Schwangerschaftstoxikose, Erhöhung der zerebralen Dur chblutung und Antiproliferation.In these patents, the following pharmacological properties are described for prostacyclin and carbacyclin derivatives: lowering of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection; Reduction in systemic blood pressure without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral arterial disorders, arteriosclerosis and thrombosis, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection of the stomach and Intestinal mucosa; antiallergic properties, reduction of pulmonary vascular resistance and blood pressure, promotion of renal blood flow, use instead of heparin or as an adjuvant in dialysis or hemofiltration, preservation of preserved blood plasma, especially preserved blood platelets, inhibition of labor pains, treatment of pregnancy toxicosis, increased cerebral circulation and antiproliferation.
Die für die genannten Prostacyclin- und Carbacyclinderivate neuen pharmako- logischen Eigenschaften werden nicht beschrieben und stehen auch in keinem direkten Zusammenhang mit den in den EP-Patentschriften beschriebenen Wir¬ kungen.The new pharmacological properties for the prostacyclin and carbacyclin derivatives mentioned are not described and are also not directly related to the effects described in the EP patents.
Die Dosis der Verbindungen ist 1-1500 μg/kg/Tag, wenn sie am menschlichen Patienten verabreicht werden. Die Einheitsdosis für den pharmazeutischen akzeptablen Träger beträgt 0,01-100 mg.The dose of the compounds is 1-1500 μg / kg / day when administered to the human patient. The unit dose for the pharmaceutically acceptable carrier is 0.01-100 mg.
Die Dosierung einer i.v.-Verabreichung als Dauerinfusion in üblichen wäßri¬ gen Lösungsmitteln, z.B. 0.9Ziger NaCl-Lösung, erfolgt vorzugsweise in Do¬ sierungen zwischen 0,1 ng/kg/min und 0,1 μg/kg/min.The dosing of IV administration as a continuous infusion in conventional aqueous solvents, e.g. 0.9% NaCl solution, preferably in doses between 0.1 ng / kg / min and 0.1 μg / kg / min.
Die Erfindung betrifft damit auch Arzneimittel auf Basis der Verbindungen der allgemeinen Formel I und üblicher Hilfs- und Trägerstoffe.The invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and carriers.
Die erfindungsgemäßen Wirkstoffe sollen in Verbindung mit den in der Gale- nik bekannten und üblichen Hilfsstoffen z.B. zur Herstellung von cerebral wirkenden Hitteln dienen.The active compounds according to the invention are to be used in conjunction with the auxiliaries known and customary in the field of galenics, e.g. serve for the production of cerebral agents.
Die Erfindung betrifft auch ein Verfahren zur Herstellung der erfindungsge- mäβen Hittel, das dadurch gekennzeichnet ist, daß man in an sich bekannter Weise die bei cerebralen Komplikationen wirkenden Verbindungen mit den an sich bekannten Hilfs- und Trägerstoffen in eine galenische Formulierung bringt. Beispiel 1The invention also relates to a process for the preparation of the agents according to the invention, which is characterized in that the compounds which act in the case of cerebral complications and the auxiliaries and excipients known per se are galenically formulated in a manner known per se. example 1
In vitro Versuche zeigen . , daß Iloprost die durch 50μg/ml LPS induzierte TNF-Produktion der NMRI-Mäuse-Peritonealmakrophagen dosisabhängig hemmt (Abb. 1,2).Show in vitro experiments. that iloprost inhibits the TNF production of the NMRI mouse peritoneal macrophages induced by 50μg / ml LPS in a dose-dependent manner (Fig. 1,2).
Durch intraperitoneale Injektion von 2 Z Stärkelösung wird in NMRI-Häusen eine lokale sterile Entzündung gesetzt. Nach 3-5 Tagen werden die Tiere getötet und die Makrophagen gewonnen.Local sterile inflammation is set in NMRI houses by intraperitoneal injection of 2 Z starch solution. After 3-5 days, the animals are sacrificed and the macrophages obtained.
Die nicht adhärenten Zellen werden abgetrennt.The non-adherent cells are separated.
Zur Aktivierung der Makrophagen wird Lipopolysaccharid (LPS) in den Konzen¬ trationen von 1, 5 μg und 50 μg/ml benutzt.Lipopolysaccharide (LPS) is used in concentrations of 1, 5 μg and 50 μg / ml to activate the macrophages.
Als TNF-Assay wird die TNF-sensitive Zellinie WEHI 164 (im Handel zu er¬ halten] verwendet. Das Ausmaß der Zellyse von WEHI 164 ist proportional zur vorhandenen Menge an TNF. In 96 Napfflachbodenmikrotiter-Platten werden die Kulturύberstände und Seren in einer Verdύnnungsreihe austitriert. Eine Ti¬ trationsreihe mit TMÜ-TNF wird als Standard benutzt.The TNF-sensitive cell line WEHI 164 (to be obtained commercially) is used as the TNF assay. The extent of cell lysis of WEHI 164 is proportional to the amount of TNF present. The culture supernatants and sera are diluted in 96 well flat microtiter plates A titration series with TMÜ-TNF is used as standard.
Die Zahl der überlebenden Zellen wird anhand des kolorimetrischen HTT- Testes bestimmt.The number of surviving cells is determined using the colorimetric HTT test.
Die Berechnung wird durch den Vergleich mit der Standardtitrationsreihe von TMU-TNF mittels der Probitanalyse durchgeführt.The calculation is carried out by comparison with the standard titration series of TMU-TNF using probit analysis.
Der Test erlaubt eine Bestimmung von bis zu 0,5 U/ml TNF. Durch Zugabe eines anti-TNF-Antiserums kann zwischen TNFα und TNFß differenziert werden.The test allows a determination of up to 0.5 U / ml TNF. By adding an anti-TNF antiserum it is possible to differentiate between TNFα and TNFß.
BEISPIEL 2EXAMPLE 2
Die Serum TNF-Spiegel der unbehandelten und der Iloprost behandelten Mäuse werden untersucht.The serum TNF levels of the untreated and the iloprost-treated mice are examined.
Iloprost hemmt signifikant die TNF-Spiegel im Serum auch noch 4 Tage nach der letzten Injektion. Iloprost significantly inhibits TNF levels in the serum even 4 days after the last injection.

Claims

P A T E N T A N S P R Ü C H E PATENT CLAIMS
1. Verwendung von Prostacyclin- und Carbacyclinderivaten zur Herstellung eines Mittels zur Behandlung von Krankheiten, die mit Fieber oder disse¬ minierter intravaskulärer Koagulopathie einhergehen und von cerebralen Komplikationen begleitet sein können.1. Use of prostacyclin and carbacyclin derivatives for the preparation of an agent for the treatment of diseases which are associated with fever or dissected intravascular coagulopathy and can be accompanied by cerebral complications.
2. Verwendung von Prostacyclin- und Carbacyclinderivaten zur Herstellung eines Hittels zur Behandlung von septischem Schock, AIDS, Tollwut, Humps durch Arbo-Viren und durch Trypanosomen verursachte Krankheiten und von konsumierenden Erkrankungen.2. Use of prostacyclin and carbacyclin derivatives for the manufacture of an agent for the treatment of septic shock, AIDS, rabies, humps caused by Arbo viruses and diseases caused by trypanosomes and of consuming diseases.
3. Hittel zur Behandlung von Krankheiten gemäß Anspruch 1, enthaltend Pro¬ stacyclin- oder Carbacyclinderivate und übliche Hilfs- und Trägerstoffe.3. agent for the treatment of diseases according to claim 1, containing prostatic cyclin or carbacyclin derivatives and customary auxiliaries and carriers.
4. Hittel zur Behandlung von Krankheiten gemäß Anspruch 2, enthaltend Pro¬ stacyclin- oder Carbacyclinderivate und übliche Hilfs- und Trägerstoffe.4. agent for the treatment of diseases according to claim 2, containing Pro¬ stacycline or carbacyclin derivatives and customary auxiliaries and carriers.
5. Verwendung der Prostacyclin- und Carbacyclinderivate Iloprost, Cica¬ prost, Eptaloprost, Beraprost und Ciprosten zur Herstellung eines Hit¬ tels gemäß Anspruch 1.5. Use of the prostacyclin and carbacyclin derivatives Iloprost, Cica¬ prost, Eptaloprost, Beraprost and Ciprosten for the production of a Hit¬ title according to claim 1.
6. Verwendung von Iloprost, Cicaprost, Eptaloprost, Beraprost und Ciprosten zur Herstellung eines Hittels gemäß Anspruch 2.6. Use of iloprost, cicaprost, eptaloprost, beraprost and ciprosten for the preparation of a means according to claim 2.
7. Hittel zur Behandlung von Krankheiten gemäß Anspruch 2, enthaltend Ilo¬ prost, Cicaprost, Eptaloprost, Beraprost oder Ciprosten und übliche Hilfs- und Trägerstoffe. 7. agent for the treatment of diseases according to claim 2, containing Ilo¬ prost, Cicaprost, Eptaloprost, Beraprost or Ciprosten and conventional auxiliaries and carriers.
EP92904665A 1991-02-12 1992-02-11 Prostacycline and carbacycline derivatives as agents for treating feverish complaints Withdrawn EP0571462A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4104607A DE4104607A1 (en) 1991-02-12 1991-02-12 PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A MEDIUM FOR TREATING FEVERED DISEASES
DE4104607 1991-02-12

Publications (1)

Publication Number Publication Date
EP0571462A1 true EP0571462A1 (en) 1993-12-01

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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)

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See references of WO9214438A2 *

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JPH06507381A (en) 1994-08-25
WO1992014438A3 (en) 1993-01-07
CA2104024A1 (en) 1992-08-13
AU1243392A (en) 1992-09-15
DE4104607A1 (en) 1992-08-13
WO1992014438A2 (en) 1992-09-03
KR930702990A (en) 1993-11-29
AU660449B2 (en) 1995-06-29

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