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WO1994011369A1 - DERIVES DU 5-[(IMIDAZO[4,5-b]PYRIDIN-3-YL)METHYL]BENZOFURANNE UTILISES COMME ANTIHYPERTENSEURS - Google Patents

DERIVES DU 5-[(IMIDAZO[4,5-b]PYRIDIN-3-YL)METHYL]BENZOFURANNE UTILISES COMME ANTIHYPERTENSEURS Download PDF

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Publication number
WO1994011369A1
WO1994011369A1 PCT/EP1993/003157 EP9303157W WO9411369A1 WO 1994011369 A1 WO1994011369 A1 WO 1994011369A1 EP 9303157 W EP9303157 W EP 9303157W WO 9411369 A1 WO9411369 A1 WO 9411369A1
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WO
WIPO (PCT)
Prior art keywords
methyl
compound
imidazo
chloro
benzofuranyl
Prior art date
Application number
PCT/EP1993/003157
Other languages
English (en)
Inventor
Duncan Bruce Judd
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU54649/94A priority Critical patent/AU5464994A/en
Publication of WO1994011369A1 publication Critical patent/WO1994011369A1/fr

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    • 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

Definitions

  • This invention relates to benzofuran derivatives, processes for their preparation and pharmaceutical compositions containing them.
  • physiologically acceptable acid addition salts of the compounds of the present invention may be derived from inorganic or organic acids.
  • examples of such salts include hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, methanesulphonates or trifluoroacetates.
  • the compounds may also form salts with suitable bases.
  • suitable bases include alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. dimethylammonium, triethylammonium, 2-hydroxyethyldimethylammonium, piperazinium, N,N- dimethyipiperazinium, tetraethylammonium, piperidinium, ethylenediammonium and choline).
  • the salts referred to above will be physiologically acceptable, but other salts may find use, for example in the preparation of the compounds of the present invention and the physiologically acceptable salts thereof.
  • the compounds of the present invention may be used in the treatment or prophylaxis of hypertension (for example, essential, malignant or resistant, caused by oral contraceptives, coarctation of the aorta or renal vascular disease) and pulmonary hypertension.
  • hypertension for example, essential, malignant or resistant, caused by oral contraceptives, coarctation of the aorta or renal vascular disease
  • pulmonary hypertension for example, pulmonary hypertension
  • the compounds of the present invention may also be used in the treatment or prophylaxis of congestive heart failure, acute or chronic heart failure, aortic or cardiac insufficiency, post-myocardial infarction, renal insufficiency and renal failure (for example, as a result of diabetic nephropathy, glomerular nephritis, scleroderma or renal crisis), proteinuria, Bartter's syndrome, secondary hyperaldosteronism, Reynaud's syndrome, cerebrovascular insufficiency, peripheral vascular disease, diabetic retinopathy, glaucoma, atherogenesis and for the improvement of vascular compliance.
  • Cognitive disorders such as dementia (e.g. Alzheimer's disease) and other CNS disorders, such as anxiety disorders, schizophrenia, depression and alcohol or drug (e.g. cocaine) dependency.
  • cognitive disorders such as dementia (e.g. Alzheimer's disease) and other CNS disorders, such as anxiety disorders, schizophrenia, depression and alcohol or drug (e.g. cocaine) dependency.
  • a compound of the present invention or a physiologically acceptable salt or solvate thereof for the manufacture of a therapeutic agent for the treatment of the aforementioned diseases, especially hypertension.
  • a method of treating the aforementioned diseases, especially hypertension comprises administering an effective amount to a patient in need of such treatment of a compound of the present invention or a physiologically acceptable salt or solvate thereof.
  • the compounds of the present invention or a physiologically acceptable salt or solvate thereof may advantageously be used in conjunction with one or more other therapeutic agents, such as for example diuretics and/or different antihypertensive agents such as ⁇ -blockers, calcium channel blockers or ACE inhibitors. It is to be understood that such combination therapy constitutes a further aspect of the present invention.
  • a compound of the present invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • compositions comprising at least one compound of the present invention or a physiologically acceptable salt or solvate thereof adapted for use in human or veterinary medicine.
  • Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compounds according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • binding agents for example mucilage of starch or polyvinylpyrrolidone
  • fillers for example, lactose, microcrystalline cellulose or maize-starch
  • lubricants for example, magnesium stearate or stearic acid
  • disintegrants for example, potato starch, croscarmellose sodium or sodium starch glycollate
  • wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid.
  • suspending agents for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose
  • emulsifying agents for example, sorbitan mono-oleate
  • non-aqueous vehicles which may include edible oils
  • the compounds or their salts or esters may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • suppositories e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • both tablets and capsules may be manufactured in the form of sustained release formulations, such that they provide a controlled continuous release of the compounds according to the invention over a period of hours.
  • the compounds of the present invention and their physiologically acceptable salts and solvates may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
  • the pharmaceutical formulations according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.
  • each unit will preferably contain 5mg to 500mg, advantageously where the compounds are to be administered orally 25mg to 400mg of the active compound.
  • the daily dosage as employed for adult human treatment will preferably range from 5mg to 3g, most preferably from 25mg to Ig which may be administered in I to 4 daily doses, preferably in 1 or 2 daily doses.
  • the compounds of the present invention may be prepared by a number of processes as described below.
  • R 1 is ethyl and R2 is methyl
  • a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane or chloroform in the presence of a base, e.g. triethylamine.
  • R 1 is ethyl or propyl and R3 is a Chalky! group
  • a reducing agent such as sodium borohydride or lithium aluminium hydride in a suitable solvent such as an alcohol (e.g. methanol or tert-butanol) or an ether (e.g. tetrahydrofuran) at any suitable temperature up to reflux; or by methylation (to convert the -CO2R ⁇ group into -C(CH3)2OH) using a Grignard reagent such as methyl magnesium bromide in an inert solvent such as an ether (e.g. tetrahydrofuran).
  • the methylation reaction is completed by a hydrolysis step, using, for example a solution of ammonium chloride. The reaction is conveniently effected at a temperature between -78°C and the reflux temperature of the solvent.
  • the intermediate compounds of formula (II) may be prepared from their corresponding amines by a triflamide formation according to the method of process (A).
  • the corresponding amines may be prepared by methods analogous to those described herein below.
  • the intermediate compounds of formula (I) may be prepared by the alkylation of a compound of formula (III)
  • L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or an alkyl- or arylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy, and A is a protected amine group, for example, in the form of a carbamate using a tert-butoxycarbonyl (t-BOC) protecting group) with a suitable imidazopyridine compound of formula (IV)
  • the alkylation reaction is preferably effected under basic conditions, for example, in the presence of sodium hydride, potassium carbonate or sodium methoxide.
  • the reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, or a substituted amide e.g. dimethylformamide, at a temperature between 0°C and the reflux temperature of the solvent.
  • Deprotection of the amine group may be effected using techniques well known in the art, for example, by acid hydrolysis using trifluoroacetic acid in a suitable solvent such as a dichloromethane, conveniently at room temperature.
  • intermediate compounds of formula (I) may be prepared by reduction of the corresponding nitro compound using standard reducing conditions, for example, hydrogenolysis in the presence of a metal catalyst such as palladium or an oxide thereof on a support such as charcoal in a solvent such as an ether (e.g. tetrahydrofuran) and conveniently at room temperature and pressure.
  • a metal catalyst such as palladium or an oxide thereof on a support such as charcoal
  • a solvent such as an ether (e.g. tetrahydrofuran) and conveniently at room temperature and pressure.
  • a compound of formula (V) can be converted into a compound of formula (III) using N-chloro amides, tert- butyl hypochlorite or N-bromosuccinimide.
  • Halogenation of the side chain may be catalysed by light, thus the reaction can be illuminated with a suitable artificial light source, and preferably in the presence of a free radical initiator such as azobisisobutyronitrile (AIBN) or benzoyl peroxide.
  • AIBN azobisisobutyronitrile
  • diphenylphosphorylazide in the presence of a base such as triethylamine and in a solvent such as an alcohol (e.g. tert-butanol).
  • a base such as triethylamine
  • a solvent such as an alcohol (e.g. tert-butanol).
  • the compound of formula (VI) may be prepared from the corresponding des-chloro compound by a two step reaction. Firstly, 2-(5-methyl-2-benzofuranyl)benzoic acid is treated with a chlorinating agent such as N-chlorosuccinimide to give the intermediate of formula (VII)
  • the chlorolactone of formula (VII) is then rearranged in the presence of a catalyst such as diazabicyclo[4.5.0]undec-7-ene (DBU) to give the compound of formula (VI).
  • a catalyst such as diazabicyclo[4.5.0]undec-7-ene (DBU) to give the compound of formula (VI).
  • Example 2 3-[[3-Chloro-2-[2-[[(trifluoromethyl)suphonyl]amino]phenylj-5- benzofuranyl]methyl]-2-ethyl-7-methyl-3H-imidazo[4.5-b]pyridine-5-methanol
  • Sodium borohydride 0.49g was added to a stirred suspension of intermediate 15 (1.911 g) in lert-butanol (50ml). The mixture was heated to reflux for 15 mins and the methanol (3.5ml) was carefully added dropwise. The mixture was stirred at reflux for 2 hours. The cooled mixture was poured into dilute brine (100ml) and extracted with ethyl acetate (2x80ml).
  • Methyl magnesium bromide (15M solution in THF/toluene; 13.3ml) was added dropwise to a stirred solution of Intermediate 16 (2.90g) in dry THF (50ml) at 0° and the mixture stirred for 2 hours. Water (150ml) was added cautiously and the resultant mixture acidified to pH5-6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3x175ml). The combined extracts were washed with saturated brine (100ml), dried and concentrated in vacuo to give a brown oil.
  • the compounds of the invention are tested in vitro for angiotensin II receptor antagonism.
  • Aortic strips are obtained from male New Zealand white rabbits and prepared for recording isometric contractions in response to cumulative addition of angiotensin II.
  • the potencies of test antagonists are assessed by measuring their abilities to displace the angiotensin II cumulative concentration response curve.
  • the method used is that of Ackerly et al., Proc. Natl. Acad. Sci., 74(12), pp5725- 28 (1977) with the exception that the final composition of the physiological salt solution is as given below in the Table:
  • the tissues are initially challenged with K + (80mM) and then washed at 0, 5, 10 and 15 minutes after the response to K + has plateaued. After a further 45 minutes an angiotensin II cumulative response curve is constructed (0.1 nM to 0.1 ⁇ M in 10- fold increments) and the tissues are washed as before. A second, third and fourth angiotensin II cumulative response curve (0.1nM to 0.1 ⁇ M in 3-fold increments) is then constructed at hourly intervals (15 minutes washing after each curve followed by 45 minutes equilibration). The compounds of the invention (30 ⁇ M) are tested for angiotensin II receptor antagonism by application 45 minutes before construction of the fourth angiotensin II curve.
  • the third and fourth angiotensin II curves are expressed graphically and a concentration ratio (CR) is calculated by dividing the angiotensin II EC50 value obtained in the presence of the test antagonist (i.e. fourth curve) by the angiotensin II EC50 value obtained in the absence of the test antagonist (i.e. third curve).
  • the potency of the test antagonist is expressed as a pKb which is calculated from the equation:
  • a pKb is estimated using the double reciprocal plot technique for insurmountable antagonists, described by T.P. Kenakin, Pharmacol. Rev., 36(3), pp165-222 (esp. 203-204) (1984).
  • the compounds of the present invention have been found to induce a sustained reduction in blood pressure following oral administration to renal artery ligated hypertensive rats (Hilditch et al, Br. J. Pharmacol., 104, 423P (1991)).
  • the compounds of the invention inhibit the action of the hormone angiotensin II and are therefore useful in the treatment of conditions in which it is desirable to inhibit angiotensin II activity.
  • a compound of the present invention or a physiologically acceptable salt or solvate thereof for use in the treatment of conditions associated with excessive or unregulated angiotensin II activity.
  • a compound of the present invention or a physiologically acceptable salt or solvate thereof for the manufacture of a therapeutic agent for the treatment of conditions associated with excessive or unregulated angiotensin II activity.
  • a method for the treatment of conditions associated with excessive or unregulated angiotensin II activity in a mammal including man comprising administration of an effective amount to a mammal in need of such treatment a compound of the present invention or a physiologically acceptable salt or solvate thereof.
  • compounds of the present invention will be of value in the treatment of conditions associated with activation of the Renin-Angiotensin System.
  • a compound of the present invention or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition associated with activation of the Renin-Angiotensin system.
  • a compound of the present invention or a physiologically acceptable salt or solvate thereof for the manufacture of a therapeutic agent for the treatment of a condition associated with activation of the Renin-Angiotensin System.
  • a method for the treatment of a condition associated with the activation of the Renin- Angiotensin System in a mammal including man comprising administration of an effective amount to a mammal in need of such treatment of a compound of the present invention or a physiologically acceptable salt or solvate thereof.
  • the contents of the cartridges may be administered using a powder inhaler.
  • Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts.
  • Antioxidants and metal chelating salts may also be included.
  • the solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass.
  • the injection is sterilised by heating in an autoclave using one of the acceptable cycles.
  • the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.
  • the solution may be packed under an inert atmosphere of nitrogen.

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

Abstract

L'invention concerne les composés: N-[2-[3-chloro-5-[(5,7-diméthyl-2-éthyl-3H-imidazo[4,5-b]pyridin-3-yl)méthyl]-2-benzofuranyl]phényl]trifluorométhanesulfonamide; 3-[[3-chloro-2-[2-[[(trifluorométhyl)sulfonyl]amino]phényl]-5-benzofuranyl]méthyl]-2-éthyl-7-méthyl-3H-imidazo[4,5-b]pyridine-5-méthanol; N-[2-[3-chloro-5-[[2-éthyl-5-[2-(hydroxypropyl)]-7-méthyl-3H-imidazo[4,5-b]pyridin-3-yl]méthyl]-2-benzofuranyl]phényl]trifluorométhanesulfonamide; 3-[[3-chloro-2-[2-[[(trifluorométhyl)sulfonyl]amino]phényl]-5-benzofuranyl]méthyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine-5-méthanol; N-[2-[3-chloro-5-[[5-[2-(hydroxypropyl)]-7-méthyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl]méthyl]-2-benzofuranyl]phényl]trifluorométhanesulfonamide. L'invention concerne également les sels et les solvates de ces dérivés acceptables sur le plan pharmaceutique, ainsi que leur préparation, les compositions pharmaceutiques les contenant et leur utilisation en médecine, en particulier dans le traitement de l'hypertension.
PCT/EP1993/003157 1992-11-13 1993-11-11 DERIVES DU 5-[(IMIDAZO[4,5-b]PYRIDIN-3-YL)METHYL]BENZOFURANNE UTILISES COMME ANTIHYPERTENSEURS WO1994011369A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54649/94A AU5464994A (en) 1992-11-13 1993-11-11 Antihypertensive 5-{(imidazo{4,5-b}pyridin-3-yl)methyl}benzofuran derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929223860A GB9223860D0 (en) 1992-11-13 1992-11-13 Chemical compounds
GB9223860.9 1992-11-13

Publications (1)

Publication Number Publication Date
WO1994011369A1 true WO1994011369A1 (fr) 1994-05-26

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PCT/EP1993/003157 WO1994011369A1 (fr) 1992-11-13 1993-11-11 DERIVES DU 5-[(IMIDAZO[4,5-b]PYRIDIN-3-YL)METHYL]BENZOFURANNE UTILISES COMME ANTIHYPERTENSEURS

Country Status (7)

Country Link
CN (1) CN1105665A (fr)
AU (1) AU5464994A (fr)
GB (1) GB9223860D0 (fr)
IL (1) IL107588A0 (fr)
MX (1) MX9307009A (fr)
WO (1) WO1994011369A1 (fr)
ZA (1) ZA938422B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066161A1 (fr) * 1999-04-28 2000-11-09 Takeda Chemical Industries, Ltd. Preventifs / remedes / inhibiteurs de progression pour retinopathie simplex ou retinopathie preproliferante
WO2001015674A3 (fr) * 1999-08-30 2002-03-28 Aventis Pharma Gmbh Utilisation d'inhibiteurs du systeme renine-angiotensine dans la prevention de manifestations cardio-vasculaires
US6852743B1 (en) * 1999-07-21 2005-02-08 Takeda Pharmaceutical Company Limited Preventives for the recurrence of cerebrovascular failure and agents for ameliorating troubles following cerebrovascular failure and inhibiting progress thereof
JP2022552185A (ja) * 2019-10-09 2022-12-15 バイオクリスト ファーマスーティカルズ，インコーポレイテッド 経口補体因子ｄ阻害剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434249A2 (fr) * 1989-12-01 1991-06-26 Glaxo Group Limited Dérivés de benzofurane
EP0514197A1 (fr) * 1991-05-16 1992-11-19 Glaxo Group Limited Dérivés de benzofuranne antihypertensifs, substitué par des groupes N-imidazolyle-méthyle qui sont condensées au cycles à six chaînons, éventuellement contenant de l'azote

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434249A2 (fr) * 1989-12-01 1991-06-26 Glaxo Group Limited Dérivés de benzofurane
EP0514197A1 (fr) * 1991-05-16 1992-11-19 Glaxo Group Limited Dérivés de benzofuranne antihypertensifs, substitué par des groupes N-imidazolyle-méthyle qui sont condensées au cycles à six chaînons, éventuellement contenant de l'azote

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066161A1 (fr) * 1999-04-28 2000-11-09 Takeda Chemical Industries, Ltd. Preventifs / remedes / inhibiteurs de progression pour retinopathie simplex ou retinopathie preproliferante
US7064141B1 (en) 1999-04-28 2006-06-20 Takeda Pharmaceutical Company Limited Method for preventing, treating or inhibiting development of simple retinopathy and preproliferative retinopathy
CZ301913B6 (cs) * 1999-04-28 2010-07-28 Takeda Pharmaceutical Company Limited Farmaceutický prípravek pro predcházení, lécení nebo inhibování vývoje jednoduché retinopatie nebo predproliferacní retinopatie
US6852743B1 (en) * 1999-07-21 2005-02-08 Takeda Pharmaceutical Company Limited Preventives for the recurrence of cerebrovascular failure and agents for ameliorating troubles following cerebrovascular failure and inhibiting progress thereof
WO2001015674A3 (fr) * 1999-08-30 2002-03-28 Aventis Pharma Gmbh Utilisation d'inhibiteurs du systeme renine-angiotensine dans la prevention de manifestations cardio-vasculaires
US7368469B2 (en) 1999-08-30 2008-05-06 Sanofi-Aventis Deutschland Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
CZ300687B6 (cs) * 1999-08-30 2009-07-15 Sanofi - Aventis Deutschland GmbH Léciva s obsahem ramiprilu k ošetrování kardiovaskulárních príhod
AU2009200746B2 (en) * 1999-08-30 2011-07-28 Sanofi-Aventis Deutschland Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
AU2009200746B8 (en) * 1999-08-30 2011-08-18 Sanofi-Aventis Deutschland Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
JP2022552185A (ja) * 2019-10-09 2022-12-15 バイオクリスト ファーマスーティカルズ，インコーポレイテッド 経口補体因子ｄ阻害剤

Also Published As

Publication number Publication date
MX9307009A (es) 1995-01-31
GB9223860D0 (en) 1993-01-06
IL107588A0 (en) 1994-02-27
AU5464994A (en) 1994-06-08
ZA938422B (en) 1994-08-09
CN1105665A (zh) 1995-07-26

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