WO1992004332A1 - Imidazole derivatives, their preparation and pharmaceutical compositions - Google Patents
Imidazole derivatives, their preparation and pharmaceutical compositions Download PDFInfo
- Publication number
- WO1992004332A1 WO1992004332A1 PCT/GB1991/001544 GB9101544W WO9204332A1 WO 1992004332 A1 WO1992004332 A1 WO 1992004332A1 GB 9101544 W GB9101544 W GB 9101544W WO 9204332 A1 WO9204332 A1 WO 9204332A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- pharmaceutically acceptable
- compounds
- compound
- acceptable salt
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/70—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- C07D409/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- the present invention relates to novel substituted imidazole compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
- the present invention therefore provides in a irst aspect compounds of structure (I) :
- each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl;
- R 1 is hydrogen, C- ⁇ alkyl, optionally substituted phenyl or optionally substituted heteroaryl;
- Y is oxygen or sulphur;
- n is 4 to 12; and
- X is 5-tetrazolyl, S0 3 H, P(0) (0R) 2 , P(0) (0H) 2 , or
- R is hydrogen or C 1 _ 4 alkyl, or a pharmaceutically acceptable salt thereof.
- each group Ar is the same and is optionally substituted phenyl or optionally substituted heteroaryl. More suitably, each group Ar is the same and is optionally substituted phenyl. Preferably each group Ar is the same and is unsubstituted phenyl.
- R 1 is hydrogen, C 1- alkyl, optionally substituted phenyl or optionally substituted heteroaryl.
- R 1 is optionally substituted phenyl; most preferably unsubstituted phenyl.
- Y is oxygen or sulphur; preferably Y is oxygen.
- n is 4 to 12; preferably n is 4 to 8, most preferably n is 6 or 7.
- X is 5-tetrazolyl, S0 3 H, P(0) (0R) 2 , P(0) (OH) 2 or P(0) (R) (OR) in which R is hydrogen or c 1- _ 4 alkyl.
- R is hydrogen or c 1- _ 4 alkyl.
- X is S0 3 H.
- Suitable substituents for phenyl groups Ar and R 1 include, for example, 1-3 groups which may be the same or different and are selected from 1 _ 4 alkyl, haloC 1 _ 4 alkyl such as CF 3 , halogen, hydroxy and C 1 _ 4 alkoxy.
- Suitable heteroaryl groups include, for example, saturated or unsaturated 5- or 6-membered rings comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur.
- Preferred such rings include, for example, thienyl and furyl rings.
- Particularly preferred compounds of structure (I) include: sodium 6-(1,4,5-triphenylimidazol-2-yloxy)hexane- sulphonate; sodium 7-(l,4,5-triphenylimidazol-2-yloxy)heptane- sulphonate; 7-(1,4,5-triphenylimidazol-2-yloxy)heptanemethyl- phosphinate; and 7-(1,4 ,5-triphenylimidazol-2-yloxy)heptanephosphonate.
- the compounds of structure (I) can be prepared using procedures analogous to those known in the art.
- the present invention therefore provides in a further aspect a process for the preparation of compounds of structure (I) in which X is other than 5-tetrazolyl which comprises reaction of a compound of structure (II) :
- R 1 , Y and n are as described for structure (I) and L is a leaving group, with a suitable source of the group X; and optionally thereafter forming a pharmaceutically acceptable salt thereof.
- Compounds of structure (I) in which X is 5-tetrazolyl can be prepared from compounds of structure (II) by standard techniques, for example, when L is bromine, by reaction with sodium cyanide in a suitable solvent such as dimethylsulphoxide , to form the intermediate compound in which L is cyano; followed by reaction with tri-n-butyl tin azide in, for example, tetrahydrofuran to form the desired compound of structure (I) .
- Suitable leaving groups L will be apparent to those skilled in the art and include, for example, halogen, such as bromine.
- Suitable sources of the group X will again be apparent to those skilled in the art and include, for example, where X is S0 3 Na, sodium sulphite.
- the reaction between the compounds of structure (II) and the source of X is carried out in a solvent at elevated temperature.
- X is S0 3 Na
- the reaction is carried out in aqueous ethanol at reflux temperature for a suitable period to allow the reaction to go to completion; and where X is a phosphorus containing group the reaction is carried out in an organic solvent such as toluene or xylene.
- the compounds of structure (II) can be prepared from compounds of structure (III) :
- Ar, Y and R 1 are as described for structure (I) by reaction with, for example, a compound of formula L 1 (CH 2 ) n L, in which L and L 1 are suitable leaving groups, in the presence of a base such as potassium carbonate and a suitable solvent such as butanone.
- Suitable groups L are as described for structure (II) .
- Suitable groups L 1 will be apparent to those skilled in the art, and include halogen, in particular bromine.
- the compounds of structure (I) and their pharmaceutically acceptable salts have been found to be PGI 2 agonists and as such are useful in therapy for the treatment of disease conditions in which such an effect is beneficial. More specifically, the compounds are expected to have utility as antithrombotic, vasodilatory, anti- atherosclerotic, antiinflammatory and cytoprotective agents. In particular, as antithrombotic and vasodilatory agents, the compounds are expected to be useful in the treatment of cardiovascular occlusive disorders including spasmodic and thrombotic disorders; coronary heart disease (primary and secondary prevention) ; stroke; post-operative thrombosis utilisation including post-angioplasty; deep vein thrombosis; peripheral vascular disease and Reynaud's disease.
- the compounds would be expected to reduce atherosclerotic plaque formation; and as cytoprotective agents the compounds would be expected to protect liver and gastric mucosa, protect against mucosal and ulcerative damage and reduce infarct size in myocardial infarct.
- the compounds have antihyperlipidaemic properties and as such are expected to be of use as lipid lowering agents, and in the treatment of atherosclerosis and its sequelae.
- the compounds of the present invention are usually administered in a standard pharmaceutical composition.
- the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
- a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
- a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
- suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
- a composition in the form of a capsule can be prepared using routine encapsulation procedures.
- pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s) , for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a typical suppository formulation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
- composition is in unit dose form such as a tablet or capsule.
- Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- the present invention also provides a method of mimicking the effects of PGI 2 which comprises administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof; and a method of treatment of cardiovascular disorders which comprises administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof.
- the pharmaceutically acceptable compounds of the invention will normally be administered to a subject in a daily dosage regimen.
- a daily dosage regimen for an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous , or intramuscular dose of between 0.1 mg and 100 g, preferably between 0.1 mg and 25 mg, of the compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
- the compounds will be administered for a period of continuous therapy, for example for a week or more.
- Platelets were prepared from freshly drawn human blood. Blood was collected into acid citrate anticoagulant, centrifuged (5 min at 500g) , and the upper layer of platelet-rich plasma was removed. This platelet-rich plasma was incubated with aspirin (lOOuM) for 10 min at 37°C and then centrifuged (15 min at 200g) . The platelet pellet was resuspended (at approx.
- test compound or 0.1% DMSO vehicle was added 2 min before the aggregatory stimulus (l ⁇ M U46619) .
- the extent of aggregation was assessed 4 min after addition of the stimulus, and was calculated as % of the control response in the absence of test compound. Dose-response curves were constructed for measurement of IC 50 values for each compound.
- Membranes were prepared from outdated platelet-rich plasma concentrates obtained from the Blood Transfusion Service. The platelets were homogenised in buffer containing Tris-Cl (5mM, pH 7.4 at 20°C) and EDTA (0.25mM), and then centrifuged (10 min at 26,000g). The membrane pellet was washed twice by homogenisation in buffer containing Tris-Cl (50mM, pH 7.4 at 20°C) and EDTA (0.25 mM) , followed by centrifugation.
- Tris-Cl Tris-Cl
- EDTA 0.25mM
- membranes For measurement of [ 3 H]iloprost binding, membranes (0.4-0.8mg) were incubated in the presence of Tris-Cl (50mM, pH 7.4 at 20°C) , MgCl 2 (4mM) , EDTA (40 ⁇ M) , [ 3 H]iloprost (10nM) , DMSO (1.85%), and varying concentrations of the test compounds. For determination of non-specific binding, 20 ⁇ M iloprost was included. The tubes (triplicates for each condition) were set up on ice, and then incubated for 30 min at 37°C. The incubations were terminated by rapid filtration on Whatman GF/B filters using a Brandel Harvester. The filters were washed and then counted for radioactivity. The K ⁇ of the test compounds for inhibition of binding of [ 3 H]iloprost to human platelet membranes was calculated from the IC 50 for displacement of [ 3 H]iloprost binding.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9019838.3 | 1990-09-11 | ||
GB909019838A GB9019838D0 (en) | 1990-09-11 | 1990-09-11 | Compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992004332A1 true WO1992004332A1 (en) | 1992-03-19 |
Family
ID=10682013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1991/001544 WO1992004332A1 (en) | 1990-09-11 | 1991-09-10 | Imidazole derivatives, their preparation and pharmaceutical compositions |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0548168A1 (en) |
JP (1) | JPH06500789A (en) |
AU (1) | AU8528091A (en) |
GB (1) | GB9019838D0 (en) |
WO (1) | WO1992004332A1 (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3714179A (en) * | 1970-09-08 | 1973-01-30 | Searle & Co | 1-alkyl-2-furfurylthioimidazoles and congeners |
EP0019688A1 (en) * | 1977-07-07 | 1980-12-10 | Ciba-Geigy Ag | Diaza compounds and process for their preparation |
EP0104342A1 (en) * | 1982-07-29 | 1984-04-04 | A. Nattermann & Cie. GmbH | Triphenylimidazolyloxyalcanoic acids and their derivatives, process for their preparation and pharmaceutical compositions containing them |
EP0130526A1 (en) * | 1983-07-02 | 1985-01-09 | A. Nattermann & Cie. GmbH | Imidazol-2-yl mercapto alkanoic acids, process for producing the same and pharmaceutical preparations containing the same |
EP0359197A1 (en) * | 1988-09-14 | 1990-03-21 | The Du Pont Merck Pharmaceutical Company | Antihypercholesterolemic 4,5-diaryl-2-substituted thioimidazoles |
WO1991009021A1 (en) * | 1989-12-11 | 1991-06-27 | Rhone-Poulenc Sante | Imidazoles |
WO1991010662A1 (en) * | 1990-01-12 | 1991-07-25 | Rhone-Poulenc Rorer S.A. | 2-substituted 4,5-diphenyl-imidazoles |
-
1990
- 1990-09-11 GB GB909019838A patent/GB9019838D0/en active Pending
-
1991
- 1991-09-10 EP EP91916250A patent/EP0548168A1/en not_active Withdrawn
- 1991-09-10 JP JP3515536A patent/JPH06500789A/en active Pending
- 1991-09-10 WO PCT/GB1991/001544 patent/WO1992004332A1/en not_active Application Discontinuation
- 1991-09-10 AU AU85280/91A patent/AU8528091A/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3714179A (en) * | 1970-09-08 | 1973-01-30 | Searle & Co | 1-alkyl-2-furfurylthioimidazoles and congeners |
EP0019688A1 (en) * | 1977-07-07 | 1980-12-10 | Ciba-Geigy Ag | Diaza compounds and process for their preparation |
EP0104342A1 (en) * | 1982-07-29 | 1984-04-04 | A. Nattermann & Cie. GmbH | Triphenylimidazolyloxyalcanoic acids and their derivatives, process for their preparation and pharmaceutical compositions containing them |
EP0130526A1 (en) * | 1983-07-02 | 1985-01-09 | A. Nattermann & Cie. GmbH | Imidazol-2-yl mercapto alkanoic acids, process for producing the same and pharmaceutical preparations containing the same |
EP0359197A1 (en) * | 1988-09-14 | 1990-03-21 | The Du Pont Merck Pharmaceutical Company | Antihypercholesterolemic 4,5-diaryl-2-substituted thioimidazoles |
WO1991009021A1 (en) * | 1989-12-11 | 1991-06-27 | Rhone-Poulenc Sante | Imidazoles |
WO1991010662A1 (en) * | 1990-01-12 | 1991-07-25 | Rhone-Poulenc Rorer S.A. | 2-substituted 4,5-diphenyl-imidazoles |
Also Published As
Publication number | Publication date |
---|---|
JPH06500789A (en) | 1994-01-27 |
EP0548168A1 (en) | 1993-06-30 |
AU8528091A (en) | 1992-03-30 |
GB9019838D0 (en) | 1990-10-24 |
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