EP0571462A1 - Derives de prostacycline et de carbacycline utiles comme agents therapeutiques de maladies febriles - Google Patents

Derives de prostacycline et de carbacycline utiles comme agents therapeutiques de maladies febriles

Info

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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current

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

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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.
EP92904665A 1991-02-12 1992-02-11 Derives de prostacycline et de carbacycline utiles comme agents therapeutiques de maladies febriles Withdrawn EP0571462A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4104607A DE4104607A1 (de) 1991-02-12 1991-02-12 Prostacyclin- und carbacyclinderivate als mittel zur behandlung von fiebrigen erkrankungen
DE4104607 1991-02-12

Publications (1)

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

Family

ID=6425075

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92904665A Withdrawn EP0571462A1 (fr) 1991-02-12 1992-02-11 Derives de prostacycline et de carbacycline utiles comme agents therapeutiques de maladies febriles

Country Status (7)

Country Link
EP (1) EP0571462A1 (fr)
JP (1) JPH06507381A (fr)
KR (1) KR930702990A (fr)
AU (1) AU660449B2 (fr)
CA (1) CA2104024A1 (fr)
DE (1) DE4104607A1 (fr)
WO (1) WO1992014438A2 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3230246B2 (ja) * 1991-04-11 2001-11-19 東レ株式会社 悪性腫瘍転移抑制剤
US5496850A (en) * 1991-04-11 1996-03-05 Toray Industries, Inc. Antimetastasis agent of malignant tumors
DE4124695C2 (de) * 1991-07-22 1994-12-22 Blitstein Willinger Eveline Dr Verwendung von Carbacyclinderivaten zur Behandlung von Psoriasis vulgaris
DE4124693A1 (de) * 1991-07-22 1993-01-28 Schering Ag Carbacyclinderivate als mittel zur behandlung von vitiligo
DE4226615C1 (de) * 1992-08-07 1994-05-19 Schering Ag Verwendung von Prostan-Derivaten zur Behandlung von chronischer Polyarthritis
DE19530884C2 (de) * 1995-08-11 1997-07-31 Schering Ag Verwendung von Prostan-Derivaten sowie deren Kombination mit Antibiotika zur Behandlung von bakteriellen Meningitis
EP0925787A4 (fr) * 1997-02-27 1999-12-01 Toray Industries Medicaments permettant d'ameliorer la circulation pulmonaire
US6340693B1 (en) * 1997-03-14 2002-01-22 Toray Industries, Inc. Protective agent for nervous system structural cells
JPH11228417A (ja) * 1998-02-06 1999-08-24 Teijin Ltd 神経障害治療剤

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2845770A1 (de) * 1978-10-19 1980-04-30 Schering Ag Neue prostacyclin-derivate und verfahren zu ihrer herstellung
US4256883A (en) * 1979-03-14 1981-03-17 Research Corporation Pyridoza prostacyclin analogues and N-oxides thereof
JPS58124778A (ja) * 1982-01-20 1983-07-25 Toray Ind Inc ５，６，７−トリノル−４，８−インタ−ｍ−フエニレンＰＧＩ↓２誘導体
DE3226550A1 (de) * 1982-07-13 1984-01-19 Schering AG, 1000 Berlin und 4709 Bergkamen Neue carbacycline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE3740838A1 (de) * 1987-11-27 1989-06-08 Schering Ag Cyclodextrinclathrate von 5-cyano-prostacyclinderivaten und ihre verwendung als arzneimittel
DE68918726T2 (de) * 1988-02-23 1995-03-02 Fujisawa Pharmaceutical Co Isocarbacyclinderivate enthaltende Antidiabetika.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9214438A2 *

Also Published As

Publication number Publication date
DE4104607A1 (de) 1992-08-13
CA2104024A1 (fr) 1992-08-13
JPH06507381A (ja) 1994-08-25
AU1243392A (en) 1992-09-15
KR930702990A (ko) 1993-11-29
WO1992014438A3 (fr) 1993-01-07
AU660449B2 (en) 1995-06-29
WO1992014438A2 (fr) 1992-09-03

Similar Documents

Publication Publication Date Title
EP0259468B1 (fr) Cyclodextrineclathrates de derives de carbacycline et leur utilisation comme medicaments
DE68910138T2 (de) Fumagillin als angiostatisches Mittel.
WO1993014761A1 (fr) Derives de prostacycline et de carbacycline utilises comme agents pour le traitement de la sclerose multiple
EP0571462A1 (fr) Derives de prostacycline et de carbacycline utiles comme agents therapeutiques de maladies febriles
DE3343934A1 (de) M-chlor-(alpha)-tert.-butylaminopropiophenon und seine verwendung zur senkung des cholesterolspiegels
EP0191792B1 (fr) Derives de prostacycline a action cytoprotectrice sur les reins
DE69819012T2 (de) Pharmazeutische zusammensetzung zur reduzierung der mcp-1 proteinsynthese
FR2568774A2 (fr) Medicaments favorisant les proprietes d'ecoulement du sang et leur utilisation en therapeutique
EP0571457B1 (fr) Iloprost a activite antipaludique contre la malaria cerebrale
EP1019055B1 (fr) Antagoniste d'endotheline et beta-bloquants sous forme d'association
DE3311922A1 (de) Antifibrotische mittel
CH677790A5 (fr)
EP0324745B1 (fr) Agents topiques contenant des derives de prostacycline
DE4124695C2 (de) Verwendung von Carbacyclinderivaten zur Behandlung von Psoriasis vulgaris
DE2357074A1 (de) Gefaesserweiterndes und sympatholytisches arzneimittel
DE2952590A1 (de) Verwendung von pyridinderivaten zur behandlung von blutandrang verursachendem herzversagen
DE69621939T2 (de) Verwendung von prostanderivaten und deren kombination mit antibiotika in der behandlung bakterieller infektionen
DE69019431T2 (de) Verwendung von 15-Keto-Prostansäure-Derivaten zur Herstellung eines Medikaments für die Verbesserung der Ausscheidung des Kaliumions.
DE2823834C2 (de) Farnesylcarbonsäure-α-bisabololester, Verfahren zu dessen Herstellung und diesen enthaltendes Mittel
DE1950403A1 (de) Neue pharmazeutische Zusammensetzungen auf der Basis von Formocaseinen
DE3340873A1 (de) Verwendung von magnesium-salicylat oder magnesium-acetylsalicylat
DE69414196T2 (de) Sulfat eines n-acetyleneuraminicsaurehomopolymers, verfahren zur herstellung, anti-hiv-droge enthaltend dieses sulfat, verfahren zur behandlung von aids mit diesem sulfat, verwendung dieses sulfats in der behandlung von aids und in der herstellung von medikamenten
DE3448256C2 (en) Cytoprotective action of prostacyclin derivatives on the pancreas
DE3875647T2 (de) Verwendung von 2-(2-phenyl-2-(2-pyridyl))ethyl-2-imidazolin oder eines salzes davon zur herstellung eines antiasthmatikums.
DE4139733A1 (de) Carbacyclinderivate als mittel zur behandlung von krankheitsbildern, die zum atopie-kreis gehoeren

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930811

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19951109

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 19971218