EP0349621A1 - Cyclodextrinclathrate von 5-cyano-prostacyclinderivaten und ihre verwendung als arzneimittel - Google Patents

Cyclodextrinclathrate von 5-cyano-prostacyclinderivaten und ihre verwendung als arzneimittel

Info

Publication number
EP0349621A1
EP0349621A1 EP89900181A EP89900181A EP0349621A1 EP 0349621 A1 EP0349621 A1 EP 0349621A1 EP 89900181 A EP89900181 A EP 89900181A EP 89900181 A EP89900181 A EP 89900181A EP 0349621 A1 EP0349621 A1 EP 0349621A1
Authority
EP
European Patent Office
Prior art keywords
group
free
acid
chain
functionally modified
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Withdrawn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
EP89900181A
Other languages
German (de)
English (en)
French (fr)
Inventor
Werner Skuballa
Helmut Dahl
Helmut VORBRÜGGEN
Olaf Loge
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 EP0349621A1 publication Critical patent/EP0349621A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • the present invention relates to cyclodextrin clathrates of 5-cyano-prostacyclin analogs and agents containing them.
  • 5-cyano-prostacyclin analogs are pharmacologically and medically valuable active substances, the production and use of which are described, for example, in DE-OS 2753244. These substances have a significantly improved specificity and, above all, a much longer effect compared to natural prostacyclin with a similar spectrum of activity.
  • inclusion compounds of these 5-cyano-prostacyclin analogs with cyclodextrins do not have the disadvantages mentioned, i.e. their water solubility is improved, the rate of dissolution is increased, and the inclusion compounds are in crystalline form. In addition, their stability to heat, light and oxygen is increased and their galenical preparation (preparation of solutions or tablets) is facilitated.
  • the invention relates to cyclodextrin clathrates of 5-cyano-prostacyclin analogs of the general formula I.
  • R 5 wo ⁇ the radical OR_, where R. can be hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical, or the radical NHR, with R, in the
  • B is a straight-chain or branched-chain alkyl group with 2-10 C atoms
  • W is a free or functionally modified hydroxymethylene group
  • OH group can be ⁇ or ⁇
  • D is a straight-chain or branched alkylene group with 1-5 C atoms
  • E is an oxygen or sulfur atom or a direct bond.
  • R is an alkyl, cycloalkyl, or an optionally substituted aryl or a heterocyclic group
  • R- a free or functionally modified hydroxy group and, if R represents hydrogen, the salts thereof with physiologically compatible bases.
  • alkyl group R straight or branched alkyl groups with 1-10 C atoms are to be considered, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl. Heptyl, hexyl, decyl.
  • the alkyl groups R can optionally be substituted 1 to more times by halogen atoms, alkoxy groups, optionally substituted aryl groups, dialkylamines and trialkyla monium.
  • Preferred alkyl groups are those which are monosubstituted. Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.
  • alkyl groups R are those with 1-4 carbon atoms, such as. For example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.
  • Suitable aryl groups R are both substituted and unsubstituted aryl groups, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, one phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with 1-4 C atoms.
  • the substituents in the 3- and 4-position on the phenyl ring are preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in 4-position by hydroxy.
  • the cycloalkyl group R can contain 4-10, preferably 5 and 6 carbon atoms in the ring.
  • the rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.
  • Suitable heterocyclic groups are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and others.
  • acids are organic carboxylic acids and sulforic acid with 1-15 carbon atoms, which belong to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way.
  • substituents are alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms.
  • Examples include the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, Caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecyl acid, Saurincherre, tridecylic acid, myristic acid, pentadecylic acid, trimethyl- acetic acid, cyclopentylacetic acid, cyclohexylacetic acid, Cyclopropancarbonkla- acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ⁇ thoxyessigkla, mono-, di- - and trichloroacetic acid, aminoacetic acid, diethyla inoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, be
  • sulfonic acids include methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, ⁇ -chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, NN-dimethylaminosulfonic acid, N, N-diethylaminosulfonic acid - (ß-Chloroethyl) aminosulfonic acid, pyrrolidino, piperidino, piperazino, N-methylpiperazino and morpholinosulfonic acid in question.
  • hydroxyl groups R_ and in W can be functionally modified, for example
  • ether and acyl radicals are suitable as ether and acyl radicals. Easily removable ether residues such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, ⁇ -ethoxyethyl, trimethylsilyl, dimethyl-tert-butyl-silyl and tri-p-benzyl-silyl radical are preferred.
  • acyl radicals as those mentioned for R come into question; Examples include acetyl, propionyl, butyryl, and Bezzoyl.
  • Suitable alkyl groups R are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1-6, carbon atoms, which may be substituted by optionally substituted aryl. Examples include methyl, ethyl, pro-, pyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, Pentenyl, benzyl and p-chlorobenzyl.
  • the cycloalkyl group can contain 4-10, preferably 5 and 6 carbon atoms in the ring.
  • the rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.
  • Suitable substituted or unsubstituted aryl groups R are: phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, one phenyl group, 1-3 alkyl groups each having 1-4 C atoms, one Chloromethyl, fluoromethyl, trifluoromethyl, carboxy, alkoxy or hydroxy group.
  • the substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.
  • Suitable heterocyclic groups R are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl-, 4-pyridyl and others.
  • Suitable alkylene groups B are straight-chain or branched-chain, saturated and unsaturated alkylene radicals, preferably saturated with 2-10, in particular 2-5, carbon atoms. Examples include ethylene, 1,2-propylene, ethyl ethylene, trimethylene, tetramethylene, pentamethylene and others.
  • Suitable alkylene groups D are straight-chain saturated 1-5 or branched-chain saturated alkylene radicals having 2-5 carbon atoms.
  • the radicals mentioned for B come into consideration as examples.
  • the compounds of general formula I are dissolved in a pharmaceutically acceptable solvent, for example an alcohol, preferably ethanol, a ketone, for example acetone or an ether, for example diethyl ether, and with aqueous solutions of ⁇ -, ⁇ - or f-Cyclodextrin, preferably ⁇ -cyclodextrin, mixed at 20-80 ° C, or the acids in the form of the aqueous solutions of their salts, for example the sodium or potassium salts, are mixed with the cyclodextrin and after solution with the equivalent amount of a Acid, for example hydrochloric acid or sulfuric acid.
  • a pharmaceutically acceptable solvent for example an alcohol, preferably ethanol, a ketone, for example acetone or an ether, for example diethyl ether
  • the clathrates can be obtained in a stoichiometric composition with a reproducible active ingredient content.
  • the clathrates made in accordance with this invention are valuable pharmaceuticals.
  • the clathrates can be used in their anhydrous, hygroscopic form or in an aqueous, less hygroscopic form.
  • the new clathrates of 5-cyano-prostacyclins according to Formula I are in the stoichiometric ratio of carbacyclin: cyclodextrin or have a higher cyclodextrin content.
  • 5-cyano-16-methyl-prostacyclin forms a complex of the composition 1: 2.5 (12.12 l of prostacyclin) or any lower values with ⁇ -cyclodextrin.
  • the clathrates made in accordance with this invention are valuable pharmaceuticals.
  • the clathrates of this invention are hypotensive and bronchodilatory. They are also suitable for inhibiting platelet aggregation. They have a cytoprotective effect on the stomach, intestine, heart, liver, kidney and pancreas. Consequently, the new cyclodextrin clathrates of the formula I are valuable pharmaceutical active substances. In addition, with a similar spectrum of activity, they have a higher specificity and, above all, a substantially longer activity compared to corresponding prostaglandins. Compared to PGI, they are characterized by greater stability.
  • the high tissue specificity of the new prostaglandia is shown in the examination on smooth-muscular organs, such as on the guinea pig ileum or on the isolated rabbit trachea, where a considerably lower stimulation can be observed than when applying natural prostaglandi from E, A or F -Type.
  • the new 5-cyano-prostacyclin clathrates have the properties typical of prostacyclins, such as, for example, lowering the peripheral arterial and coronary vascular resistance, inhibiting platelet aggregation and dissolving platelet thrombi, myocardial cytoprotection and thus lowering the systemic blood pressure and without simultaneously reducing stroke volume reduce coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, myocardial infarction, peripheral artery disease, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system, therapy of shock, inhibition of bronchoconstriction, inhibition of the bronchoconstriction Gastric acid secretion, cytoprotection of the gastric and intestinal mucosa, cytoprotection in the liver, kidney, heart and pancreas, also in organ transplants, anti-allergic properties, reduction in pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow,
  • carbacyclins of this invention can also be used in combination, for example with ⁇ -blockers or diuretics.
  • the 5-cyano-prostacyclin clathrates of this invention can also be used in combination, for example with ⁇ -blockers, diuretics, phosphonic diester inhibitors, calcium antagonists, non-steroidal anti-inflammatories, leukotriene synthesis inhibitors, leukotriene antagonists, thromboxane synthesis inhibitors or thromboxane antagonists.
  • the clathrates according to the invention can be used in liquid or solid pharmaceutical formulations, the formulations being able to be administered enterally, parenterally, vaginally or rectally, or they can also be incorporated into surgical sutures and plastics.
  • the prostaglandin-cyclodextrin clathrate with carrier substances and auxiliary substances such as lactoxes is used to manufacture tablets.
  • aqueous cyclodextrin clathrate solutions are lyophilized together with lactose.
  • the lyophilisates can then be brought to the desired concentration with physiological saline.
  • the invention therefore includes pharmaceutical preparations and formulations which contain a cyclodextrin clathrate of a carbacyclin analog as the active ingredient.
  • the content of prostacyclinanol in the clathrate was determined by post-pressure liquid chromatography and was 4%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Nanotechnology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Medical Informatics (AREA)
  • Materials Engineering (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
EP89900181A 1987-11-27 1988-11-25 Cyclodextrinclathrate von 5-cyano-prostacyclinderivaten und ihre verwendung als arzneimittel Withdrawn EP0349621A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3740838 1987-11-27
DE19873740838 DE3740838A1 (de) 1987-11-27 1987-11-27 Cyclodextrinclathrate von 5-cyano-prostacyclinderivaten und ihre verwendung als arzneimittel

Publications (1)

Publication Number Publication Date
EP0349621A1 true EP0349621A1 (de) 1990-01-10

Family

ID=6341738

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89900181A Withdrawn EP0349621A1 (de) 1987-11-27 1988-11-25 Cyclodextrinclathrate von 5-cyano-prostacyclinderivaten und ihre verwendung als arzneimittel

Country Status (11)

Country Link
US (1) US5010065A (en, 2012)
EP (1) EP0349621A1 (en, 2012)
JP (1) JPH02502379A (en, 2012)
AT (1) AT396687B (en, 2012)
BE (1) BE1001327A3 (en, 2012)
CH (1) CH677790A5 (en, 2012)
DE (1) DE3740838A1 (en, 2012)
FR (1) FR2623807B1 (en, 2012)
GB (1) GB2231045B (en, 2012)
IT (1) IT1227576B (en, 2012)
WO (1) WO1989004828A1 (en, 2012)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5227372A (en) * 1990-03-07 1993-07-13 Children's Medical Center Corporation Method for retaining ophthalmological agents in ocular tissues
DE4104607A1 (de) * 1991-02-12 1992-08-13 Schering Ag Prostacyclin- und carbacyclinderivate als mittel zur behandlung von fiebrigen erkrankungen
DE4135193C1 (en, 2012) * 1991-10-22 1993-03-11 Schering Ag Berlin Und Bergkamen, 1000 Berlin, De
US5694021A (en) * 1994-02-28 1997-12-02 Kabushiki Kaisha Toshiba System for executing charge control of a secondary battery and detecting the capacitance thereof
US5896596A (en) * 1997-10-22 1999-04-27 Nitto Kogyo Co., Ltd. Apparatus for generating massaging water stream
EP2043629A1 (en) * 2006-07-18 2009-04-08 Bayer Schering Pharma Aktiengesellschaft 5-cyano-prostacyclin derivatives as agents for the treatment of autoimmune diseases
JP5271272B2 (ja) 2006-11-16 2013-08-21 ジェンムス ファーマ インコーポレイティド Ａ型インフルエンザウィルス感染の治療のための薬剤としてのｅｐ２およびｅｐ４作動薬
JP2013508282A (ja) 2009-10-14 2013-03-07 ジェンムス ファーマ インコーポレイティド ウイルス感染のための併用療法処置
US20160184387A1 (en) 2013-08-09 2016-06-30 Dominique Charmot Compounds and methods for inhibiting phosphate transport
WO2020237096A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Combination for lowering serum phosphate in a patient

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS503362B1 (en, 2012) * 1970-06-10 1975-02-04
DE2405146A1 (de) * 1974-01-31 1975-08-07 Siemens Ag Mengenmessgeraet mit einem in einer kammer angeordneten rotor
HU179141B (en, 2012) * 1977-09-23 1982-08-28
DE2753244A1 (de) * 1977-11-25 1979-06-07 Schering Ag Neue prostacyclinderivate und verfahren zu ihrer herstellung
DE2912409A1 (de) * 1978-03-31 1979-10-11 Ono Pharmaceutical Co 6,9-methano-pgi tief 2 -analoge
JPS5540923A (en) * 1978-09-14 1980-03-22 Ono Sokki Co Ltd Flow meter
JPS56150039A (en) * 1980-04-22 1981-11-20 Sankyo Co Ltd Clathrate compound of prostacycline derivative
DE3448257C2 (en) * 1984-07-25 1988-08-18 Schering Ag, 1000 Berlin Und 4709 Bergkamen, De Cytoprotective action of prostacyclin derivatives on the kidney
DE3608088C2 (de) * 1986-03-07 1995-11-16 Schering Ag Pharmazeutische Präparate, enthaltend Cyclodextrinclathrate von Carbacyclinderivaten

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8904828A1 *

Also Published As

Publication number Publication date
FR2623807B1 (fr) 1990-08-31
JPH02502379A (ja) 1990-08-02
FR2623807A1 (fr) 1989-06-02
US5010065A (en) 1991-04-23
IT1227576B (it) 1991-04-16
GB2231045B (en) 1992-04-29
AT396687B (de) 1993-11-25
GB2231045A (en) 1990-11-07
IT8822760A0 (it) 1988-11-28
DE3740838A1 (de) 1989-06-08
CH677790A5 (en, 2012) 1991-06-28
ATA901688A (de) 1993-03-15
BE1001327A3 (fr) 1989-09-26
GB8916355D0 (en) 1990-07-04
WO1989004828A1 (en) 1989-06-01

Similar Documents

Publication Publication Date Title
AT397084B (de) Verfahren zur herstellung von neuen cyclodextrin-clathraten von carbacyclinanaloga
DE3850676T2 (de) Hypotensive okulare Mittel.
DE69511181T2 (de) Mittel für Behandlung der Leber-Gallenerkrankungen
DE3048906A1 (de) Neue carbacycline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
EP0059158A2 (de) Azaprostacycline, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
EP0716648B1 (de) Neue 9-chlor-prostaglandin-derivate
DE3873007T2 (de) Kathartica.
EP0215860A1 (de) 9-halogenprostaglandine, verfahren zu ihrer herstellung.
AT396687B (de) Cyclodextrinclathrate von 5-cyanoprostacyclinderivaten und ihre verwendung als arzneimittel
JPS6152146B2 (en, 2012)
DE69024744T2 (de) Behandlung der hepatobilären Erkrankung mit 15-Ketoprostaglandin-Derivaten
EP0243369B1 (de) 9-halogenprostaglandin-clathrate und ihre verwendung als arzneimittel
EP0656889B1 (de) 9-chlor-prostaglandin-ester und -amide und ihre verwendung für die herstellung von arzneimitteln
DE68918726T2 (de) Isocarbacyclinderivate enthaltende Antidiabetika.
DE4008925A1 (de) 9-halogenprostaglandin-clathrate und ihre verwendung als arzneimittel
EP0224275B1 (de) Neue Carbacycline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
WO1986000895A1 (en) New carbacyclines, preparation thereof and drug containing them
DE3116386A1 (de) Trans-(delta)(pfeil hoch)2(pfeil hoch)-pge-alkylsulfonylamide
DE3221193A1 (de) Neue carbacyclinester, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
WO1989000990A1 (fr) Nouveaux derives de carbacycline substitues en 9, leur procede de fabrication et leur emploi a titre de medicaments
DE69006964T2 (de) Behandlung von Hyperlipidemia mit 15-keto-Prostaglandin-Verbindungen.
EP0051557A1 (de) 5-Cyan-prostacyclinderivate, Verfahren zu ihrer Herstellung und ihrer Verwendung als Arzneimittel
EP0163672A1 (de) 20-alkyl-7-oxoprostacyclinderivate und verfahren zu ihrer herstellung.
DE3306125A1 (de) Neue carbacycline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE3320014A1 (de) Neue 5-azaprostacyclinderivate, ihre herstellung und anwendung

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: 19890726

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE DE FR IT LU NL SE

17Q First examination report despatched

Effective date: 19910227

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19930518