WO1994009778A1 - Combinaisons d'antagonistes et de diuretiques recepteurs de l'angiotensine ii - Google Patents

Combinaisons d'antagonistes et de diuretiques recepteurs de l'angiotensine ii Download PDF

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Publication number
WO1994009778A1
WO1994009778A1 PCT/US1993/010163 US9310163W WO9409778A1 WO 1994009778 A1 WO1994009778 A1 WO 1994009778A1 US 9310163 W US9310163 W US 9310163W WO 9409778 A1 WO9409778 A1 WO 9409778A1
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WO
WIPO (PCT)
Prior art keywords
diuretic
antagonist
hydrochlorothiazide
formulation
dose
Prior art date
Application number
PCT/US1993/010163
Other languages
English (en)
Inventor
Edward B. Nelson
Charles S. Sweet
Original Assignee
Merck & Co., Inc.
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 Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU54491/94A priority Critical patent/AU5449194A/en
Publication of WO1994009778A1 publication Critical patent/WO1994009778A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin

Definitions

  • A-II antagonists Both diuretics and A-II antagonists have an effect on the renin-angiotensin-aldosterone system.
  • A-II antagonists lower blood pressure by blocking the angiotensin II receptors important in regulating blood pressure.
  • Diuretics regulate the sodium-balance, and
  • This invention is concerned with pharmaceutical formulations for the treatment of essential hypertension and disorders associated therewith such as heart failure, cardiac or vascular hypertrophy, renal failure, proteinuria, ischemia or restenosis, which have as active ingredients an A-II antagonist and a diuretic wherein the diuretic is at a dose level below the recognized clinically effective dose.
  • the A-II antagonist is found to have greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose as monotherapy.
  • the diuretic is being administered at dose levels that would be ineffective as an antihypertensive if used alone and similarly ineffective in causing adverse reactions.
  • novel pharmaceutical formulations of this invention comprise: a pharmaceutical carrier; an A-II antagonist at the dose level normally employed in monotherapy, which is usually about 0.1 to about 1000 mg preferably about 1-100 mg, depending on the A-II antagonist; and a diuretic at a dose level which is the highest non-pharmacological dose.
  • the formulation is designed for oral administration and is presented as tablets, capsules, gel caps, caplets, sublingual dosage form or as a sustained release formulation. It may also be designed as an elixir for oral administration, a suppository for rectal administration, or a patch for transdermal administration, or a biodegradable stint for local intraarterial administration.
  • excipients which can be incorporated in tablets, capsules and the like are: a binder such as gum tragacanth, acacia, com starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as com starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry.
  • a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • novel formulations of this invention are useful in the treatment of essential hypertension, and heart failure, cardiac or vascular hypertrophy, renal failure, proteinuria, ischemia or restenosis.
  • Typical of the A-II antagonists useful in the novel formulation and method of treatment of this invention are the following compounds I through XI:
  • the preferred A-II antagonist for use in the novel formulation and method of treatment of this invention is compound IV.
  • the diuretics useful in the novel formulation and method of treatment of this invention are: hydrochlorothiazide (HCTZ), furosemide, altizide, trichlormethazide, triflumethazide, bemetizide, cyclothiazide, methylchlothiazide, azosemide, chlorothiazide, butizide, bendroflumethazide, cyclopenthiazide, benzclortriazide, polythiazide, hydroflumethazide, benzthiazide, ethiazide, penflutazide, chlorthalidone, butazolimide, spironolactone, amiloride or triamterene.
  • Preferred diuretics for incorporation in the novel formulation of this invention are hydrochlorothiazide, trichlormethazide, furosemide, chlorthalidone, and altizide, especially hydrochlorothiazide.
  • the novel method of treatment of this invention comprises the administration of a unit dose of the novel pharmaceutical formulation, one to three times a day depending on the patient and the severity of the indication being treated. Usually once or twice a day is adequate.
  • Compound I 100 50 25 hydrochlorothiazide 6.25 6.25 6.25
  • Compound II 100 50 25 hydrochlorothiazide 6.25 6.25 6.25

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention se rapporte à des formulations pharmaceutiques comprenant, comme ingrédients actifs, un antagoniste récepteur de l'angiotensine II (A-II) à un dosage s'avérant normalement efficace comme antihypertensif, et un diurétique à un dosage inférieur à son dosage minimum effectif et qui ont une plus grande efficacité qu'on ne l'aurait supposé pour ramener la pression sanguine de patients hypertensifs à des valeurs normotendues.
PCT/US1993/010163 1992-10-26 1993-10-22 Combinaisons d'antagonistes et de diuretiques recepteurs de l'angiotensine ii WO1994009778A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54491/94A AU5449194A (en) 1992-10-26 1993-10-22 Combinations of angiotensin-ii receptor antagonists and diuretics

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US96624192A 1992-10-26 1992-10-26
US966,241 1992-10-26

Publications (1)

Publication Number Publication Date
WO1994009778A1 true WO1994009778A1 (fr) 1994-05-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/010163 WO1994009778A1 (fr) 1992-10-26 1993-10-22 Combinaisons d'antagonistes et de diuretiques recepteurs de l'angiotensine ii

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AU (1) AU5449194A (fr)
WO (1) WO1994009778A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5459148A (en) * 1992-12-17 1995-10-17 Sankyo Company, Limited Biphenyl derivatives and their use for the treatment of hypertension and cardiac disease
WO1996040258A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Therapie mixte a base de spironolactone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
WO1996040256A1 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Procede de traitement de la cardiofibrose avec une combinaison de spironolactone et d'un antagoniste de l'angiotensive ii
WO1996040255A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Procede de traitement de la fibrose cardiaque par une combinaison therapeutique d'un antagoniste de l'angiotensine ii et d'un antagoniste de l'aldosterone epoxy-steroide
WO1996040257A1 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Therapie mixte a base d'un antagoniste epoxy-steroidien de l'aldosterone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
FR2735365A1 (fr) * 1995-06-14 1996-12-20 Sanofi Sa Utilisation d'un antagoniste de l'angiotensine ii et d'un derive du benzofurane pour la preparation d'un medicament utile dans le traitement des affections cardiovasculaires
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
US5721263A (en) * 1993-06-07 1998-02-24 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
US6294197B1 (en) 1996-06-27 2001-09-25 Novartis Ag Solid oral dosage forms of valsartan
EP1275391A1 (fr) 1995-06-07 2003-01-15 Sanofi-Synthelabo Composition pharmaceutique contenant de l'irbesartan et un diurétique
EP1306088B1 (fr) * 1993-06-07 2007-09-05 Takeda Pharmaceutical Company Limited Combinaison d'un benzimidazole ayant une activité antagoniste de l'angiotensine-II avec un diurétique
US8226977B2 (en) 2004-06-04 2012-07-24 Teva Pharmaceutical Industries Ltd. Pharmaceutical composition containing irbesartan
WO2013050339A1 (fr) 2011-10-03 2013-04-11 Ems S/A Compositions pharmaceutiques d'hypotenseurs
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164407A (en) * 1989-07-03 1992-11-17 Merck & Co., Inc. Substituted imidazo-fused 5-membered ring heterocycles and their use as angiotensin ii antagonsists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164407A (en) * 1989-07-03 1992-11-17 Merck & Co., Inc. Substituted imidazo-fused 5-membered ring heterocycles and their use as angiotensin ii antagonsists

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AMERICAN JOURNAL OF PHYSIOLOGY, Vol. 263 (3, part 2), issued 1992, QING et al., "Chronic Captopril and Losortan (DuP 753) Administration in Rats with High-Output Heart Failure", pages H833-H840. *
CHEMICAL ABSTRACTS, Vol. 117, No. 18, issued 1992, SMITHKLINE BECKMAN CORP., "Antihypertensive", Abstract No. 178319h. *
GOODMAN AND BILMAN'S, "The Pharmacological Basis of Therapeutics", (6th -Edition), Published 1980, by MACMILLAN (N.Y.), see pages 808-811, and 911. *
JOURNAL OF HYPERTENSION, Vol. 1, Supplement 2, issued 1993, ANDREN et al., "Enaslapril with Either a 'Very Low' or 'Low' Dose of Hydrochlorothiazide is Equally Effective in Essential Hypertension...", pages 384-386. *
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol. 252, No. 2, issued 1990, CHIU et al., "Nonpeptide Angiotensin II Receptor Antagonists. VII. Cellular and Biochemical Pharmacology of DuP 753 an Orally Active Antihypertensive Agent", pages 711-718. *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
US5646171A (en) * 1991-02-21 1997-07-08 Sankyo Company, Limited Angiotensin II antagonist 1-biphenylmethylimidazole compounds and their therapeutic use
US5459148A (en) * 1992-12-17 1995-10-17 Sankyo Company, Limited Biphenyl derivatives and their use for the treatment of hypertension and cardiac disease
US6420405B2 (en) 1993-06-07 2002-07-16 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
EP1306088B1 (fr) * 1993-06-07 2007-09-05 Takeda Pharmaceutical Company Limited Combinaison d'un benzimidazole ayant une activité antagoniste de l'angiotensine-II avec un diurétique
EP1844774A3 (fr) * 1993-06-07 2008-08-20 Takeda Pharmaceutical Company Limited Composition pharmaceutique pour le traitement de maladies liées à l'angiotensine II
US5721263A (en) * 1993-06-07 1998-02-24 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
EP2277520A3 (fr) * 1993-06-07 2011-08-24 Takeda Pharmaceutical Company Limited Composition pharmaceutique pour le traitement de maladies liées à l'angiotensine II
WO1996040257A1 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Therapie mixte a base d'un antagoniste epoxy-steroidien de l'aldosterone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
WO1996040258A3 (fr) * 1995-06-07 1997-01-23 Searle & Co Therapie mixte a base de spironolactone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
WO1996040255A3 (fr) * 1995-06-07 1997-01-23 Searle & Co Procede de traitement de la fibrose cardiaque par une combinaison therapeutique d'un antagoniste de l'angiotensine ii et d'un antagoniste de l'aldosterone epoxy-steroide
EP1275391B1 (fr) * 1995-06-07 2011-03-30 Sanofi-Aventis Composition pharmaceutique contenant de l'irbesartan et un diurétique
EP1275391A1 (fr) 1995-06-07 2003-01-15 Sanofi-Synthelabo Composition pharmaceutique contenant de l'irbesartan et un diurétique
WO1996040255A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Procede de traitement de la fibrose cardiaque par une combinaison therapeutique d'un antagoniste de l'angiotensine ii et d'un antagoniste de l'aldosterone epoxy-steroide
WO1996040256A1 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Procede de traitement de la cardiofibrose avec une combinaison de spironolactone et d'un antagoniste de l'angiotensive ii
WO1996040258A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Therapie mixte a base de spironolactone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
US6984633B2 (en) 1995-06-07 2006-01-10 G.D Searle & Co. Method to treat cardiofibrosis with a combination therapy of an angiotensin II antagonist and epoxymexrenone
EP0752249A3 (fr) * 1995-06-14 1997-01-15 Sanofi Utilisation d'un antagoniste de l'angiotensine II et d'un dérivé du benzofurane à activité antiarythmique pour la préparation d'un médicament utile dans le traitement des affections cardiovasculaires
US6218414B1 (en) 1995-06-14 2001-04-17 Sanofi Use of an angiotensin II antagonist and a benzofuran derivative in the treatment of cardiovascular complaints
EP0752249A2 (fr) * 1995-06-14 1997-01-08 Sanofi Utilisation d'un antagoniste de l'angiotensine II et d'un dérivé du benzofurane à activité antiarythmique pour la préparation d'un médicament utile dans le traitement des affections cardiovasculaires
FR2735365A1 (fr) * 1995-06-14 1996-12-20 Sanofi Sa Utilisation d'un antagoniste de l'angiotensine ii et d'un derive du benzofurane pour la preparation d'un medicament utile dans le traitement des affections cardiovasculaires
US6858228B2 (en) 1996-06-27 2005-02-22 Novartis Ag Solid oral dosage forms of valsartan
US6485745B1 (en) 1996-06-27 2002-11-26 Novartis Ag Solid oral dosage forms of valsartan
US6294197B1 (en) 1996-06-27 2001-09-25 Novartis Ag Solid oral dosage forms of valsartan
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US9132089B2 (en) 2000-08-30 2015-09-15 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US8226977B2 (en) 2004-06-04 2012-07-24 Teva Pharmaceutical Industries Ltd. Pharmaceutical composition containing irbesartan
US8414920B2 (en) 2004-06-04 2013-04-09 Teva Pharmaceutical Industries Ltd. Pharmaceutical composition containing irbesartan
WO2013050339A1 (fr) 2011-10-03 2013-04-11 Ems S/A Compositions pharmaceutiques d'hypotenseurs
US20140314848A1 (en) * 2011-10-03 2014-10-23 Ems S.A. Pharmaceutical compositions of antihypertensives

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