EP0505434A1 - Naphtyridinones substituees heterocycliques, procedes et compositions les employant - Google Patents

Naphtyridinones substituees heterocycliques, procedes et compositions les employant

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Publication number
EP0505434A1
EP0505434A1 EP91901027A EP91901027A EP0505434A1 EP 0505434 A1 EP0505434 A1 EP 0505434A1 EP 91901027 A EP91901027 A EP 91901027A EP 91901027 A EP91901027 A EP 91901027A EP 0505434 A1 EP0505434 A1 EP 0505434A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
mammal
alkyl
compound according
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Withdrawn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
EP91901027A
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German (de)
English (en)
Inventor
David J. Blythin
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.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
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Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0505434A1 publication Critical patent/EP0505434A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to certain heterocyclic substituted naphthyridinones and to methods and compositions using such compounds.
  • Z is, for example, an amine functional group and X and Y are, for example, H, a halogen atom, a lower alkyl group, a trifluoromethyl, an alkoxy, a methylthio, a nitro or a cyano.
  • X and Y are, for example, H, a halogen atom, a lower alkyl group, a trifluoromethyl, an alkoxy, a methylthio, a nitro or a cyano.
  • n is 0 to 5 and it is possible for R-j and R2 to form a piperazine ring substituted by an alkyl or an aromatic nucleus which may or may not be substituted, or alternatively to form an imidazole ring.
  • R-j and R2 are disclosed as ulcer-inhibiting drugs.
  • Z-i and Z 2 are the same or different and each independently represents -O- or -S-;
  • R 1 , R2, R3_ R4 a nd R5 are the same or different and each may be independently selected from the group consisting of, for example, H, alkyl having from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, etc.; in addition, two of R 1 , R 2 and R 3 can be joined together to represent a ring which can contain from 2 to 8 carbon atoms, such as a pyrrole, piperidine or morpholine ring; m is an integer of from 0 to 3; n is an integer of from 0 to 2;
  • Q represents an aryl or an aromatic heterocyclic group which can optionally be substituted with 1 to 3 substituents Y; and each Y substituent is independently selected from the group consisting of, for example, hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO2, alkoxy having from 1 to 6 carbon atoms, trifluoromethyl, cyano, etc.
  • R is H or alkyl
  • A is O or S
  • R 1 represents alkanediyl
  • R 2 represents a covalent bond or -alkanediyl-O-;
  • R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or hydroxyalkyl having 2 to 6 carbon atoms between the N atom and the OH group;
  • Q represents phenyl, 1 - or 2-naphthyl, 1 -, 2-, 3-, 4-, 5-, 6- or
  • A is preferably O and Q is preferably phenyl or substituted phenyl.
  • W is preferably
  • Particularly preferred compounds include:
  • compositions comprising a compound of formula I above in combination with a pharmaceutically acceptable carrier and methods of treating allergic reactions, inflammation, inflammatory bowel disease, peptic ulcers and hyperproliferative skin disease in a mammal comprising administering to said mammal an effective amount or a compound of formula I for such purpose.
  • Certain compounds of this invention may exist in isomeric forms.
  • the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
  • Certain compounds of the invention of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate.
  • solvated forms including hydrated forms, e.g., hemihydrate.
  • pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of the invention.
  • Certain compounds of the invention e.g., those with a strongly basic amine group, also form pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral, sulfonic and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of this invention.
  • alkyl (including the alkyl portions of hydroxyalkyl, alkoxy, alkylthio, alkylsuifinyl and alkylsulfonyl) - represents a straight or branched, saturated hydrocarbon chain having from 1 to 10, preferably from 1 to 6, carbon atoms; alkanediyl - represents a divalent, saturated straight or branched hydrocarbon chain, having from 1 to 10, preferably from 1 to 6, carbon atoms; cycloalkyl - represents a saturated carbocyclic ring having from 3 to 10, preferably from 3 to 6 carbon atoms; halo - represents fluoro, chloro, bromo or iodo; substituted phenyl (including the substituted phenyl portion of substituted benzyl) - represents a phenyl group in which 1 to 3 hydrogen atoms thereof are replaced by the same or different substituents independently chosen from
  • L represents a conventional leaving group such as chloro, bromo, iodo, tosyl, mesyl, etc. and R 4 can be H or alkyl.
  • Step A the compound of Formula II wherein R 4 is H can be reacted with an amine of Formula QNH2 in aqueous solution with an acid catalyst such as para-toluene sulfonic acid.
  • Step A when R 4 is alkyl (preferably not methyl), the compound QNH2 can be reacted in excess (preferably more than 2 equivalents) with the compound of Formula II and heated, preferably to about 125°C, for a time sufficient to provide the desired reaction, e.g., by following the reaction with thin layer chromatography.
  • This reaction can be run neat or in a suitable solvent such as toluene, xylene, etc.
  • R 4 in Formula HI is H, it is preferably converted to an ester (i.e., R 4 is alkyl) by reaction under standard esterification conditions with, for example, potassium carbonate and diethyl sulfate in dimethylformamide.
  • Step B the ester of Formula HI is reduced with a suitable reducing agent such as lithium aluminum hydride, lithium borohydride or lithium triethylborohydride ("Super Hydride ® ").
  • a suitable reducing agent such as lithium aluminum hydride, lithium borohydride or lithium triethylborohydride
  • the reaction is preferably cooled, e.g., to a temperature of from about -20°C to about room temperature.
  • the reaction is normally performed in an ether such as diethylether under reflux.
  • With lithium borohydride the reaction is run initially at room temperature, then heated at reflux (e.g., in tetrahydrofuran) until the reaction is complete, e.g., as shown by thin layer chromatography.
  • the compound of Formula IV is oxidized in Step C with a suitable oxidizing agent such as activated manganese dioxide in a suitable solvent, such as benzene, toluene, xylene, chloroform, etc., at elevated temperature (e.g., about 50°C to about 120°C), preferably with removal of water formed in the reaction.
  • a suitable oxidizing agent such as activated manganese dioxide in a suitable solvent, such as benzene, toluene, xylene, chloroform, etc.
  • Step D the compound of Formula V is reacted with a compound of the Formula W-CH2-C0 2 alkyl in the presence of a catalytic amount of a suitable base.
  • exemplary bases include potassium t- butoxide, sodium ethoxide, etc.
  • the reaction can be performed in a suitable solvent such as tetrahydrofuran (preferably containing a small quantity of a protic solvent such as t-butanol) or an alcohol solvent, preferably corresponding to the alcohol portion of the ester W-CH 2 -C0 2 alkyl.
  • suitable solvent such as tetrahydrofuran (preferably containing a small quantity of a protic solvent such as t-butanol) or an alcohol solvent, preferably corresponding to the alcohol portion of the ester W-CH 2 -C0 2 alkyl.
  • Other possible solvents include ether type solvents such as dioxane, dimethoxyethane, etc.
  • the reaction can be run at any suitable temperature,
  • Step E the compound of Formula V is reacted with a suitable alkyl organometallic agent MAIkyl, wherein M is, for example, a magnesium halide or lithium.
  • a suitable solvent such as an ether , e.g., diethylether or tetrahydrofuran.
  • the reaction is preferably run at or below room temperature, e.g. from about 25°C to about -20°C.
  • the reaction is neutralized with a mineral acid to provide the compound of Formula VI.
  • the conditions and reactants for Steps F and G are essentially the same as those set forth above for Steps C and D, respectively.
  • the compounds of this invention wherein A is sulfur may be obtained by treating the purified 2-carbonyl compound of formula I with thiating reagents well known in the art. Lawesson's Reagent ⁇ 2,4- bis(4-methoxyphenyl-1 ,3-dithia-2,4-diphosphetane-2,4-disulfide ⁇ or one of its analogues, in toluene, or phosphorus pentasulfide in pyridine are suitable for this purpose.
  • the reaction is carried out in an inert solvent such as toluene or xylene at elevated temperatures, e.g. from about 50°C to about 140°C.
  • the compounds of this invention may be employed as anti- allergy agents in the treatment of, for example, asthma, allergic or seasonal rhinitis, and/or chronic bronchitis.
  • the anti-allergy method of this invention is identified by tests which measure a compound's ability to inhibit leukotriene release.
  • the anti-allergy method of this invention is identified by tests which measure a compound's inhibition of leukotriene release in sensitized guinea pigs.
  • Male Hartley guinea pigs 250-300 g are sensitized with 5 mg ovalbumin injected i.p. and 5 mg injected s.c. in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4.
  • the sensitized animals are used 3-4 weeks later at which time they weigh 450-500 g.
  • Sensitized guinea pigs are killed by a blow to the head and the lungs removed and cleaned of visible connective tissue, trachea and large blood vessels.
  • the lungs from individual animals are sliced into fragments approximately 1 mm in thickness using a Mcllwain tissue chopper and then washed with oxygenated Tyrode's buffer. Weighed aliquots (approximately 400 mg wet weight) of lung are transferred into vials containing 2 ml of fresh Tyrode's solution
  • mice Male Hartley guinea pigs (250-300 g) are sensitized with 5 mg ovalbumin injected i.p. and 5 mg injected s.c. in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4. The sensitized animals are used 3-4 weeks later at which time they weigh 450-500 g. The sensitized guinea pigs are fasted overnight and the following morning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml diallybarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane).
  • dialurethane 0.1 g/ml diallybarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane.
  • the trachea are cannulated and the animals are ventilated by a Harvard ® rodent respirator at 50 strokes/minute with a stroke volume of 5 ml.
  • a side arm to the tracheal cannula is connected to a pressure transducer (Harvard) to obtain a continuous measure of intratracheal pressure which is recorded on a polygraph (Harvard).
  • the jugular vein is cannulated for the i.v. administration of substances.
  • the sensitized guinea pigs are injected i.v. with 1 mg/kg propranolol, 5 mg/kg indomethacin and 2 mg/kg mepyramine given together in a volume of 1 ml/kg.
  • the animals are challenged with antigen (0.5% ovalbumin) as an aerosol generated from a DeVilbiss ® Model 65 ultrasonic nebulizer and delivered through the tracheal cannula for 30 seconds.
  • Bronchoconstriction is measured as the peak increase in intratracheal pressure occurring within 15 minutes after antigen challenge.
  • Test compounds are administered orally 2 hours before challenge with ovalbumin. Suppression of anaphylactic bronchospasm is expressed as a percent inhibition of the peak increase in intratracheal pressure by comparison to a vehicle-treated control group.
  • the compounds of this invention are also useful for the treatment of inflammation. Thus, they are useful in the treatment of arthritis, bursitis, tendonitis, gout and other physical conditions characterized by inflammation.
  • the anti-inflammatory use of the compounds of this invention may be demonstrated by the Reversed Passive Arthus Response Technique, as described below.
  • Lyophilized anti-bovine serum albumin (IgG fraction), obtained from Cappel Laboratories, is suspended in sterile distilled water and diluted with cold, pyrogen-free saline (PFS) just prior to use. The final concentration of anti-bovine serum albumin is 0.5 mg/ml of PFS. Both BSA and anti-BSA solutions are iced during use. Drugs are suspended or solubilized in an aqueous solution of methyl cellulose (MC) with an homogenizer just prior to administration.
  • MC methyl cellulose
  • Groups of animals (6/group) are dosed with drug in MC by gavage once daily for 3 days. The last dose is administered one hour prior to sensitization with BSA. Controls are given MC alone and a drug-standard is usually included in each assay for verification purposes. Drugs are prepared and diluted so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for each experiment. Thus each rat receives an oral dose in a volume of approximately 2.0 cc. One hour after the last dose the animals are , lightly anesthetized with ether and "sensitized" by injection of 0.2 ml of PFS containing 1.0 mg of BSA into the penile vein.
  • Results are expressed by the change in paw volume ( ⁇ paw volume) from the control reading for each animal to that recorded 2 and 4 hours post-challenge. All drug treated groups are compared to the MC control for significant differences with an analysis of variance.
  • the compounds of this invention are also useful in the treatment of peptic ulcers and stress ulceration, and to promote healing of gastric and/or duodenal ulcers.
  • the antiulcer activity of the compounds of this invention is identified by standard tests which measure the cytoprotective effect in rats, e.g., by inducing gastrointestinal damage with ethanol prior to administering a compound of the invention.
  • the compounds may be used as conjunctive therapeutic agents for coadministration with such anti- inflammatory/analgesic agents as aspirin, indomethacin, phenylbutazone, ibuprofen, naproxen, tolmetin and other agents.
  • anti- inflammatory/analgesic agents as aspirin, indomethacin, phenylbutazone, ibuprofen, naproxen, tolmetin and other agents.
  • the compounds of this invention prevent the untoward side effects of irritation and damage to the gastrointestinal tract caused by such agents.
  • the compounds of formula I are useful in the treatment of hyperproliferative skin disease, e.g., psoriasis, which utility may be demonstrated by the Arachidonic Acid Mouse Ear Test as described below.
  • mice Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/groups and allowed to acclimate 1-3 weeks prior to use.
  • Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.01 ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions are induced by applying 10 ⁇ l of AA to both surfaces of one ear (4 mg total).
  • Test drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas eial-, Fed. Proc. 43. Abstract 2983, p. 1927 (1984) and Young filal., J. Invest. Dermatol. 82. pp. 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any difference in topical abso ⁇ tion which could occur with any drug applied in an aqueous ethanol vehicle. The test drug is applied 30 minutes prior to challenge with AA.
  • the severity of the inflammation is measured as a function of increased ear weight.
  • a 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg. Mean ⁇ standard error and all possible comparisons are made via Duncan's Multiple Range Statistic.
  • Administration of the dose can be intravenous, intranasal, parenteral, oral, subcutaneous, intramuscular, topical, transdermal or any other acceptable method.
  • the compounds of the present invention can be administered in any number of conventional dosage forms.
  • Solid dosage forms include capsules, tablets, pills, powders, suspensions, solutions, cachets or suppositories.
  • Parenteral preparations include sterile solutions or suspensions.
  • Inhalation administration can be in the form of a nasal or oral spray, or by insufflation.
  • Topical dosage forms can be creams, ointments, lotions, transdermal devices (e.g., of the conventional reservoir or matrix patch type) and the like.
  • compositions contemplated by the above dosage forms can be prepared with conventional pharmaceutically acceptable excipients and additives, using conventional techniques.
  • pharmaceutically acceptable excipients and additives include carriers, binders, flavorings, buffers, thickeners, color agents, dispersing agents, suspending agents, perfumes, preservatives, lubricants, etc.
  • the compounds of the invention can be administered in an amount ranging from about 0.1 mg/kg body weight to about 25 mg/kg body weight, preferably from about 0.1 mg/kg body weight to about 5 mg/kg body weight per day.
  • a typical recommended dosage regimen is oral administration of from 10 mg/day to 1500 mg/day, preferably from 10 mg/day to 250 mg/day, in two to four divided doses to achieve relief of the symptoms of inflammation.
  • Determination of the proper dosage of a compound of the invention for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound, Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the amount and frequency of administration of the compounds of formula I and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptom being treated.
  • a 1 L 3-neck flask was equipped with an addition funnel with a glass stopper, a reflux condenser closed with a drying tube, and a dry N 2 inlet.
  • An excess of LiBH 4 (3g) was added to dry tetrahydrofuran (THF; 35mL) contained in the flask.
  • THF dry tetrahydrofuran
  • the mixture was stirred magnetically.
  • Ethyl 2-(3-cyanophenyl)aminonicotinate (30g) was dissolved in dry THF (250mL) in the dropping funnel, and then this solution was added dropwise to the solution in the flask. After all had been added, the mixture was heated gradually to the reflux point (ca. 70°C).
  • Super HydrideTM lithium triethylborohydride; 250mL of a 1 M solution in THF
  • This solution was added to the flask dropwise, keeping the temperature around 0°C. After all had been added the reaction mixture was allowed to warm to room temperature and was stirred overnight. Thin layer chromatography was used to follow the course of the reaction. Reaction was completed by the addition of a further 100mL of the Super-HydrideTM solution at room temperature. The total product was poured over ice (400g), with stirring, and the pH was adjusted to 5 with cone. HCI. Solid NaCI was added to salt out the organic layer which was separated.
  • active compound refers to 3-(4-morpholinyl)-1 -phenyl-1 ,8-naphthyridin-2(1 H)- one. However, this compound may be replaced by equally effective amounts of other compounds of formula I.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sont décrites des naphtyridinones substituées hétérocycliques contenant de l'azote de la formule (I), efficaces dans le traitement de réactions allergiques, d'inflammations, d'affections intestinales inflammatoires, d'ulcères gastro-duodénaux et de maladies hyperprolifératives de la peau, ainsi que des compositions pharmaceutiques les employant, ou un sel pharmaceutiquement acceptable de ladite formule, dans laquelle: A représente O ou S; W représente (a) ou (b); R représente H ou alkyle; R1 représente alcanediyle; R2 représente une liaison covalente ou -alcanediyle-O-; R3 représente alkyle, cycloalkyle, benzyle, benzyle ou hydroxyalkyle substitué, benzyle ou hydroxyalkyle substitué, Q représente phényle, 1- ou 2- naphthyle, 1-, 2-, 3-, 4-, 5-, 6-, ou 7-indényle ou 1-, 2-, 3-, 4-, 5-, 6- ou 7- indanyle, dont chacun peut être facultativement remplacé par 1 à 3 groupes Y ci-dessous définis; et chaque Y est indépendamment choisi parmi alkyle, halo, nitro, alkoxy, alkylthio, -CF3, -CN, cycloalkyle, alkylsulfinyle ou alkylesulfonyle.
EP91901027A 1989-12-04 1990-11-30 Naphtyridinones substituees heterocycliques, procedes et compositions les employant Withdrawn EP0505434A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44558789A 1989-12-04 1989-12-04
US445587 1989-12-04

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EP0505434A1 true EP0505434A1 (fr) 1992-09-30

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Country Status (5)

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EP (1) EP0505434A1 (fr)
JP (1) JPH0749430B2 (fr)
AU (1) AU6960391A (fr)
CA (1) CA2070400A1 (fr)
WO (1) WO1991008208A1 (fr)

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FR2654104B1 (fr) * 1989-11-07 1992-01-03 Adir Nouveaux derives du 1,2-benzisoxazole, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent.

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SE418550B (sv) * 1979-10-12 1981-06-09 Lars Eriksson Batteripolklemma med snabbkopplingsanordning for dess anslutning till en batteripol
US4695118A (en) * 1985-07-02 1987-09-22 Garnik Magdesyan Battery terminal post clamp
NZ218774A (en) * 1986-01-06 1990-06-26 Carpibem 3-substituted phenylnaphthyridines and pharmaceutical compositions
JPH07116187B2 (ja) * 1987-07-22 1995-12-13 シェリング・コーポレーション 二環式化合物、それらを薬剤として使用すること、それらの製法、およびそれらの製造に有用な中間体

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JPH04506357A (ja) 1992-11-05
CA2070400A1 (fr) 1991-06-05
WO1991008208A1 (fr) 1991-06-13
AU6960391A (en) 1991-06-26
JPH0749430B2 (ja) 1995-05-31

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