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WO1991009023A1 - 1-aryloxy-2-propanolamine a substitution n-heteroaralkyle et derives de propylamine possedant une activite antiarrhythmique de classe iii - Google Patents

1-aryloxy-2-propanolamine a substitution n-heteroaralkyle et derives de propylamine possedant une activite antiarrhythmique de classe iii Download PDF

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Publication number
WO1991009023A1
WO1991009023A1 PCT/US1990/007061 US9007061W WO9109023A1 WO 1991009023 A1 WO1991009023 A1 WO 1991009023A1 US 9007061 W US9007061 W US 9007061W WO 9109023 A1 WO9109023 A1 WO 9109023A1
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Prior art keywords
carbon atoms
pharmaceutically acceptable
acceptable salts
methyl
arh
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PCT/US1990/007061
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English (en)
Inventor
John Anthony Butera
Jehan Framoz Bagli
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Wyeth LLC
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American Home Products Corp
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • Class HI antiarrhythmic agents may be categorized as having the ability to markedly prolong dog Purkinje fiber action potential duration without producing signifi ⁇ cant changes in maximal upstroke velocity. Unlike Class I anti-arrhythmic agents, a pure Class III agent displays no effect on cardiac sodium channels. The electrophysiologic properties of a compound defining a Class HI activity profile are observed in vivo as negligible effects on atrial, ventricular and H-V conduction lines while producing a marked increase (greater than 20 percent) in both the atrial and ventricular refractory period. In contrast, Class I agents will demonstrate a marked slowing of ventricular con ⁇ duction velocity, generally without significant changes in the refractory period. Recent reviews of these agents are by: Bexton et al., Pharmac. Ther., 12, 315-55 (1982); Vaughan-Williams, J. Clin. Pharmacol., 24, 129-47 (1984); and Steinberg et al, Ann.
  • R 1 is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 car ⁇ bon atoms, perfluoroalkylsulfonamido of 1 to 6 carbon atoms, perfluoroalkylamido of 1 to 6 carbon atoms, alkylsulfone or alkylsulfoxide of 1 to 6 carbon atoms, NO 2 , CN, or 1- imidazoyl; R 2 is straight or branched alkyl chain of 1 to 6 carbon atoms ;
  • X is O, S, or NR 3 wherein R 3 is H or a straight or branched alkyl chain of 1 to 6 carbon atoms;
  • Y is
  • R 4 is H, -NHSO2 (Ci to alkyl), -NHCO(C ⁇ to CO alkyl) or NO2- and Z is O,
  • R 5 is H, Ci to C( ⁇ alkyl or the alkylsulfonamido of 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof.
  • alkyl as a group or part of a group e.g. alkylsulfonamido
  • alkylsulfonamido examples are methyl, ethyl, propyl, isopropyl and butyl.
  • perfluoroalkyl examples are CF3 , C 2 F5 and C3F7.
  • aryl examples of phenyl, naphth-1-yl and naphth-2-yl.
  • Preferred values for R 1 are nitro and alkylsulfonamido such as methylsulfonamido.
  • X is O.
  • Preferred values of Het are examples of Het are examples of Het.
  • R 4 is hydrogen or alkylsulfonamido, e.g. methylsulfonamido.
  • a preferred aspect of the present invention are the compounds of formula (II)
  • R 1 is NO 2 or methylsulfonamido
  • Y is CH 2 or CHOH
  • Het is selected from the group consisting of
  • R 4 is H or methylsulfonamido and the pharmaceutically acceptable salts thereof.
  • a further preferred aspect of the present invention are the compounds N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methane- sulfonamide;
  • Optical isomers may be obtained in pure form by standard separation techniques.
  • a racemic mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a resolving agent for example by salt formation or formation of a covalent bond.
  • the resulting mixture of optically active diastereoisomers may be separated by standard techniques (e.g. crystallization or chromatography) and individual optically active diastereoisomers then treated to remove the resolving agent thereby releasing the single enantiomer of the compound of the invention.
  • Chiral chromatography using a chiral support, eluent or ion pairing agent may also be used to separate enantiomeric mixtures directly.
  • Stereospecific synthesis using optically active starting materials and/or chiral reagent catalyst and/or solvents may also be employed to prepare a particular enantiomer.
  • the compound of formula (I) is prepared by an addition process creating an optical center then carrying out the reaction using a chiral catalyst or reagent or in a chiral environment can give the product as a single enantiomer.
  • the pharmaceutically acceptable salts of the antiarrhythmic agents of this inven ⁇ tion are prepared directly by neutralization of the free base.
  • physiologically ac ⁇ ceptable salts may be formed with organic or inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, sulfamic, nitric, methylsulfonic, acetic, maleic, suc- cinic, fumaric, tartaric, citric, salicylic, lactic, napthalenesulfonic acid and the like.
  • This invention also provides processes for preparing the compounds of formula (I). More particularly, the compounds of formula (I) may be prepared by one of the following processes:
  • R 1 and X are as defined above and L is a leaving group, e.g. an aryl- or alkyl- sulphonyloxy group such as p-tolyl- or methane -sulphonyloxy, with a compound of formula (III) as defined above, to give a compound of formula (I) wherein Y is CH2; or reacting a compound of formula (IV) as defined above with a compound of formula
  • R 1 , X, Y and Het are as defined above, with an aldehyde of formula R 3 CHO wherein R 3 represents hydrogen or alkyl of 1 to 5 carbon atoms; or h) acylating a compound of formula (I) wherein R 1 is amino to give a corresponding compound of formula (I) wherein R 1 is an alkyl-, aryl- or perfluoroalkyl-sulfonamido group or a perfluoroalkylamido group; or i) acidifying a compound of formula (I) to give an acid addition salt or neutralizing an acid addition salt of a compound of formula (I) to give the free base.
  • reaction may be conveniently carried out at room temperature or with heating in a polar inert solvent such as an alcohol, acetone or acetonitrile.
  • a polar inert solvent such as an alcohol, acetone or acetonitrile.
  • reaction may be carried out in the presence of a suitable base such as diisopropylamine, triethylamine or an alkali metal carbonate or bicarbonate in an inert polar solvent.
  • a suitable base such as diisopropylamine, triethylamine or an alkali metal carbonate or bicarbonate in an inert polar solvent.
  • the reductive amination may be effected using hydrogen in the presence of a suitable catalyst such as palladium on carbon or sodium cyanoborohydride according to standard procedures, e.g. using an alcohol solvent.
  • a suitable catalyst such as palladium on carbon or sodium cyanoborohydride according to standard procedures, e.g. using an alcohol solvent.
  • Process f) may be conveniently carried out using a reducing agent such as diborane or lithium aluminiumhydride in an inert solvent.
  • Process h may be carried out under standard acylation procedures optionally in the presence of a base.
  • the compounds of this invention wherein Y is CHOH may be prepared by reac ⁇ tion of an appropriately substituted aryl epoxide with the required secondary amine in solvents such as acetone or acetonitrile:
  • R 1 , R 2 , Het and X are as defined above.
  • the compounds can be prepared by the reaction of an appropri ⁇ ately substituted alkyl halide with the required secondary amine in the presence of a suit ⁇ able base in solvents such as acetone or acetonitrile:
  • R 1 , R 2 , Het and X are as defined above and W is chlorine or bromine.
  • the compounds of this invention demonstrate antiarrhythmic activity when tested in the standard experimental animal in accordance with the following procedure.
  • Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized with sodium pentobarbital (35 mg kg i.v. supplemented with 5 mg kg/h) and artificially ventilated with room air (minute volume: 200 mL kg).
  • a right thoracotomy was performed at the fifth intercostal space and the heart suspended in a pericardial cradle.
  • Bipolar electrodes for stimulation were sutured to the free wall of the right atrium and to the right ventricle.
  • Arterial blood pressure and lead II ECG were displayed on a chart recorder and monitored on an oscilloscope.
  • the dog heart was paced by a stimulus for driving a constant current isolation unit.
  • VFT Ventricular fibrillation threshold
  • Dogs were randomized to receive either test drug or vehicle by i.v. route. Animals treated with vehicle do not show any significant increase of VFT. The ability of test agents to elevate the threshold generally is accepted as an indication of potential antifibrillary activity, as vehicle-treated animals on repeated trials do not show any appreciable increase of VFT. This conclusion is supported by the observation that a substantial fraction of the animals treated with the test drug spontaneously defibrillate and return to sinus rhythm. Spontaneously defibrillation of vehicle treated animals is an exceedingly rare phenomenon.
  • the compounds of this invention display a Class Dl antiarrhythmic profile.
  • the Class HI antiarrhythmic activity was established in vitro and in vivo in accordance with the following standard test procedures:
  • Bundles of free-running Purkinje fibers with attached myocardium obtained from either ventricle of adult dog heart were pinned without stretching to the bottom of a 10 mL tissue chamber and continuously superfused with oxygenated Tyrode's solution at a flow rate of 5 mL/minute.
  • the composition of the Tyrode's solution was (mM): NaCl, 138; KC14; CaCh, 2; MgCh, 0.5; NaHCO 3 , 24; dextrose, 5.5.
  • the solution was aerated with 95% 02-5% CO2 at 37°C. Bath temperature was maintained at 37 ⁇ 0.5°C. by circulating the pre-warmed superfusate through a thermostatically controlled water bath immediately prior to entering the tissue chamber.
  • the preparations were stimulated through bipolar Teflon-coated silver wires, bared at the tips, placed on the endocardial surface of the attached myocardium, using a digital stimulator set to deliver constant current pulses 1.5-msec in duration at cycle lengths of 300 or 1000 msec. Stimulus strength was set at approximately 2 x diastolic threshold, and adjusted as required throughout the experiment. All preparations were allowed to equilibrate in the tissue chamber for at least 1 hour before measurements were begun. Subsequently, a minimum of 60 minutes were allowed for equilibration with each drug-containing superfusate before post-drug measurements were made. Impalements were made at 6 to 10 sites throughout the preparation before and after drug exposure. Offset potentials were rechecked after each impalement.
  • Glass microelectrodes filled with 3M KC1 were coupled to high impedance negative capacitance electrometers and Ag/AgCl half-cells used as reference electrodes.
  • the first derivative of the action potential upstroke (V max ) was obtained using an analog differentiator circuit, coupled to a peak-hold circuit that retained the recorded value of Vmax f° r 30 to 70-msec.
  • Action potential and V max tracings were displayed on a storage oscilloscope, and photographed for later analysis.
  • chart paper recordings of V m ax were obtained using the peak-hold device output.
  • Fresh stock solutions of drug were prepared for each experiment. Compounds were dissolved in distilled water at total concentrations of 1 to 10 mg/mL, and subsequently diluted to a final concentration of 3 to 10 ⁇ M in appropriate volumes of normal Tyrode's solution for evaluation.
  • V max maximal upstroke velocity
  • Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized with sodium pentobarbital (35 mg kg i.v. supplemented with 5 mg kg/h) and artificially ventilated with room air (minute volume: 200 mL/kg).
  • the heart was exposed by a right thoractomy performed at the fifth intercostal space and suspended in a pericardial cradle.
  • Epicardial electrodes for stimulation and recording were sutured to the free wall of the lower right atrium and near the base of the right ventricle.
  • Each electrode set contained a linear array of electrodes consisting of 1 bipolar stimulating electrode and 2 bipolar recording electrodes embedded in a rigid acrylic matrix.
  • the stimulating bipole was 7 mm from the proximal recording electrode, which in turn was 10 mm from the distal recording bipole.
  • Each electrode array was oriented to be parallel to the epicardial fiber axis.
  • Arterial blood pressure and lead II ECG were displayed on a chart recorder and monitored on an oscilloscope. Conduction times and refractory periods were measured during pacing at a cycle length of 300 msec. The dog heart was paced by a stimulator driving a constant current isolation unit. Electrical signals from the atrial and ventricular electrodes were displayed on a digital oscilloscope and recorded by a ink-jet recorder. Diastolic threshold was determined before and after each trial. Refractory periods of the right atrium and right ventricle (AERP and VERP) were determined by introducing an extrastimulus (S2) every 8 paced beats (Si). The extrastimulus was followed by a 4-second rest interval during which no pacing occurred.
  • AERP and VERP extrastimulus
  • Both Si and S2 were of identical intensity (twice threshold) and duration (2 msec).
  • the S1-S2 interval was gradually decreased in 2-msec steps until the extra-stimulus failed to induce a propagated response. This S 1 -S2 interval was considered to define effective refractory period.
  • Atrial and ventricular (ACT and VCT) conduction times were measured as the time interval between the 2 electrograms recorded at the proximal and distal sites of the recording electrode array.
  • the time of activation for electrograms with predominantly biphasic complexes was taken as the moment when the trace crossed the zero reference line, and for triphasic complexes, as the peak of the major deflection.
  • the compounds are estab ⁇ lished as antiarrhythmic agents useful in the treatment of cardiac arrhythmia and condi ⁇ tions characterized by coronary arteries vasospasm.
  • the compounds may be administered orally or parenterally in suitable dosage forms compatible with the route of administration, whether oral, intraperitoneal, intramuscular, intravenous, inter- nasal, buccal, etc.
  • the effective dose range determined in the animal test models has been established at from about 1 to about 5 milligrams per kilogram host body weight (preferably from 2 to 10 mg kg) i.v., and from about 2 to about 10 mg/kg (preferably 5 to 20 mg/kg) p.o., to be administered in single or plural doses as needed to relieve the
  • SUBSTITUTE SHEET arrhythmatic dysfunction The specific dosage regimen for a given patient will depend upon age, pathological state, severity of dysfunction, size of the patient, etc.
  • Oral admin ⁇ istration is performed with either a liquid or solid dosage unit in any conventional form such as tablets, capsules, solutions, etc., which comprise a unit dose (e.g. from about 50 milligrams to about 400 milligrams) of the active ingredient alone or in combination with adjuvants needed for conventional coating, tableting, solubilizing, flavoring or col ⁇ oring.
  • Parenteral administration with liquid unit dosage forms may be via sterile solutions or suspensions in aqueous or oleaginous medium. Isotonic aqueous vehicle for injection is preferred with or without stabilizers, preservatives and emulsifiers.
  • this invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Step 4) Preparation of l-[(lH-Ben_rimidazol-2-ylmethyl)methylamino]-3-(4-nitro- phenoxy)-2-propanol Dihydrochloride 2-(Met-hyla_a_ nomethyl)ben._imidazole (0.459 g, 3.07 mmol) was added to a solu ⁇ tion of l,2-epoxy-3-(p-nitrophenoxy)propane (0.600 g, 3.07 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated in vacuo.
  • Methanesulfonyl chloride (5.06 mL, 65.32 mmol) was added to a stirred solution of 3-[(4-amino)phenoxy]-l-propene (8.11 g, 54.43 mmol) in pyridine (80 mL) at 0°C. The mixture was stirred for 72 hours and was then poured slowly into ice-water and extracted with ether. The organic phase was washed with cold IN HCl and was then extracted with IN NaOH solution. The aqueous phase was acidified and the product (9.05 g, 73%) precipitated out as a white solid.
  • Step 1) Preparation of 2-j ⁇ -[3-(4-Nitrophenoxy)propyl]memylaminomethyl]- quinoline
  • 2-(methylaminomethyl)quinoline prepared by the pro ⁇ cedure of Example 3, Step 1, (3.67 g, 21.35 mmol), sodium iodide (2.78 g, 18.56 mmol), and potassium carbonate (3.08 g, 138.21 mmol) in acetonitrile (80 mL) was added 3- chloropropyl-4-nitrophenyl ether (4.00 g, 18.56 mmol).
  • the mixture was stirred at 80°C overnight, concentrated and partitioned between 10% K2CO3 and ethyl acetate.
  • the organic phase was washed with brine, dried (MgSO4), and concentrated to afford an oil.
  • the product was purified by HPLC (10% MeOH/OfeCh) to afford 2.34 g (36%) of pure product as a yellow oil.
  • Methanesulfonylchloride (0.52 mL, 6.73 mmol) was added dropwise to a stirred solution of N-[(4-aminophenoxy)propoxy[methyl]]aminomethylquinoline (1.80 g, 5.61 mmol) in pyridine (20 mL) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with ice chips and extracted with ethyl acetate.
  • Step 2 Preparation of 2-(Methylaminomethyl)quinoxaline
  • 2-(bromomethyl)quinoxaline (3.0 g, 13.4 mmol) was added portionwise to a stirring solution of methylamine (30%) in ethanol (100 mL) at 0°C.
  • the reaction was stirred at 0°C for 2 hours, concentrated, and partitioned between 10% aqueous potassium carbonate/ethyl acetate.
  • the organic phase was dried (MgS ⁇ 4), decolorized (charcoal) and concentrated. Purification was accomplished by eluting the sample through a short silica plug to yield 1.80 g (78%) of a brown oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

1-aryloxy-2-propanolamine à substitution N-hétéroalkyle et dérivés de propalamine possédant une activité antiarrhythmique, compositions pharmaceutiques et leurs procédés de production.
PCT/US1990/007061 1989-12-11 1990-12-03 1-aryloxy-2-propanolamine a substitution n-heteroaralkyle et derives de propylamine possedant une activite antiarrhythmique de classe iii Ceased WO1991009023A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45139189A 1989-12-11 1989-12-11
US451,391 1989-12-11
US52178790A 1990-05-10 1990-05-10
US521,787 1990-05-10

Publications (1)

Publication Number Publication Date
WO1991009023A1 true WO1991009023A1 (fr) 1991-06-27

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PCT/US1990/007061 Ceased WO1991009023A1 (fr) 1989-12-11 1990-12-03 1-aryloxy-2-propanolamine a substitution n-heteroaralkyle et derives de propylamine possedant une activite antiarrhythmique de classe iii

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AU (1) AU6977391A (fr)
IE (1) IE904447A1 (fr)
PT (1) PT96141A (fr)
WO (1) WO1991009023A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0778274A1 (fr) * 1995-12-07 1997-06-11 Helopharm G. Petrik GmbH Amidinohydrazones dérivées des cétones du benzo(b)furanne, procédé pour leur préparation et médicaments contenant ces composés
US5856578A (en) * 1994-05-27 1999-01-05 Norvartis Corporation Process for the preparation of unsaturated amino compounds
WO2002076963A1 (fr) 2001-03-21 2002-10-03 Merck Patent Gmbh Derives bicycliques de guanidine et leurs utilisations therapeutiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034116A2 (fr) * 1980-02-11 1981-08-19 Berlex Laboratories, Inc. N-(3-phénoxy-2-hydroxypropyle)benzimidazole-1-alcanoylamines
EP0281254A1 (fr) * 1987-02-07 1988-09-07 Pfizer Limited Agents antiarythmiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034116A2 (fr) * 1980-02-11 1981-08-19 Berlex Laboratories, Inc. N-(3-phénoxy-2-hydroxypropyle)benzimidazole-1-alcanoylamines
EP0281254A1 (fr) * 1987-02-07 1988-09-07 Pfizer Limited Agents antiarythmiques

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5856578A (en) * 1994-05-27 1999-01-05 Norvartis Corporation Process for the preparation of unsaturated amino compounds
EP0778274A1 (fr) * 1995-12-07 1997-06-11 Helopharm G. Petrik GmbH Amidinohydrazones dérivées des cétones du benzo(b)furanne, procédé pour leur préparation et médicaments contenant ces composés
US5747508A (en) * 1995-12-07 1998-05-05 Helopharm G. Petrik Gmbh Amidinohydrazones of ketones derived from benzo B!furan, methods for their production, and pharmaceuticals containing these compounds
WO2002076963A1 (fr) 2001-03-21 2002-10-03 Merck Patent Gmbh Derives bicycliques de guanidine et leurs utilisations therapeutiques

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PT96141A (pt) 1991-09-30
AU6977391A (en) 1991-07-18
IE904447A1 (en) 1991-06-19

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