EP0556204A1 - Composition pharmaceutique contenant un inhibiteur d'eca et un inhibiteur d'activite de thromboxane a2 pour traiter des nephropathies - Google Patents

Composition pharmaceutique contenant un inhibiteur d'eca et un inhibiteur d'activite de thromboxane a2 pour traiter des nephropathies

Info

Publication number
EP0556204A1
EP0556204A1 EP91918149A EP91918149A EP0556204A1 EP 0556204 A1 EP0556204 A1 EP 0556204A1 EP 91918149 A EP91918149 A EP 91918149A EP 91918149 A EP91918149 A EP 91918149A EP 0556204 A1 EP0556204 A1 EP 0556204A1
Authority
EP
European Patent Office
Prior art keywords
imidazol
inhibitor
acid
thromboxane
activity
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Withdrawn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
EP91918149A
Other languages
German (de)
English (en)
Inventor
Patricia Salvati
Teresa Micheletti
Paolo Cozzi
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.)
Pfizer Italia SRL
Original Assignee
Farmitalia Carlo Erba SRL
Carlo Erba SpA
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 Farmitalia Carlo Erba SRL, Carlo Erba SpA filed Critical Farmitalia Carlo Erba SRL
Publication of EP0556204A1 publication Critical patent/EP0556204A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • composition containing an ACE inhibitor and an inhibitor of thromboxane A2 activity for treating nephropathies.
  • the present invention relates to a product containing an angiotensin converting enzyme inhibitor (ACEI) and an inhibitor of thromboxane activity, useful in the treatment of nephropathies.
  • ACEI angiotensin converting enzyme inhibitor
  • nephropathies in mammals can be treated by the combined use of an agent capable of inhibiting thromboxane A 2 activity and an ACEI, at lower doses of ACEI, otherwise not therapeutically effective. It has also been found that with the combined use of an agent capable of inhibiting thromboxane activity and an ACEI, it is possible to obtain a therapeutic effect greater than that otherwise obtainable with the single agents when administered alone.
  • a first object of the present invention is therefore a pharmaceutical composition containing an ACEI and an inhibitor of thromboxane A 2 activity, and a pharmaceutically acceptable carrier and /or diluent, useful in the treatment of nephropathies.
  • An object of the instant invention is also the use of an ACEI and of an inhibitor of thromboxane A 2 activity in the preparation of a pharmaceutical composition useful in the treatment of nephropathies .
  • a further object of the present invention is a product containing an angiotensin converting enzyme inhibitor and an inhibitor of thromboxane A 2 activity as a combined preparation for simultaneous , separate or sequential use in the treatment of nephropathies .
  • Object of the present invention is also a combined method of treatment of nephropathies and hyperlipidaemia secondary to nephrotic syndrome in mammals , including humans , in need of such treatment, said method comprising administering
  • an angiotensin converting enzyme inhibitor or a pharmaceutical composition containing it
  • combined method of treatment is meant to include both separate and substantially simultaneous administration of an ACEI or a pharmaceutical composition containing it and an inhibitor of thomboxane activity or a pharmaceutical composition containing it.
  • nephropathies that can be treated according to the present invention are diabetic nephropathy, nephropathy secondary to lupus erithematosus , gloraerulosclerosis, Cyclosporin-A induced nephrosis, renal damages secondary to CHF (congestive heart failure) and the several forms of glomerular and tubular damages associated with proteinuria.
  • the products, according to the present invention can be useful in the treatment of hyperlipidaemia secondary to nephrotic syndrome.
  • inhibitor of thromboxane A 2 activity is meant to comprise both thromboxane synthase inhibitors, thromboxane receptor antagonists and compounds endowed with both said mechanisms of action.
  • inhibitors of thromboxane synthetase in accordance with the present invention are for instance the imidazole derivatives described in the English patent GB-B-2122997 , International patent application WO 90 0 3970 and English patent application GB 9004347.2. Accordingly, preferred compounds among those described in CB-B-2122997 and WO 9003970 are those of following formula (I)
  • R is COR 1 , in which R 1 is OH, NH 2 or OR 2 wherein R 2 is C 1 -C 4 alkyl;
  • A is a group C wherein R 2 is hydrogen or C 1 -C 4 alkyl, or a group and the pharmaceutically acceptable salts thereof.
  • Ph means phenyl optionally substituted by a halogen atom
  • R 3 is C 3 -C 7 alkyl; a phenyl, pyridyl or thienyl ring unsubstituted or substituted by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or trifluoromethyl; or a cyclohexyl or cycloheptyl ring;
  • T is a C 2 -C 4 alkylene or phenylene group
  • x is a bond or a -O-CH 2 group
  • R 4 is hydrogen or C 1 -C 4 alkyl and the pharmaceutically salts thereof.
  • compounds of formula (II) are: 5-[1-phenyl-2-(imidazol-1-yl)ethylidene]aminoxypentanoic acid; ethyl 5-[1-(3-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylidene] aminoxypentanoate;
  • inhibitors of thromboxane synthetase are imidazo [1,5-a] pyridine-5-hexanoic acid [Ku et al. Biophys. Res. Comm. 112 (3)-889, 1983], RS-5186 (Thrombosis research, 51, 507, 1988): DP-1904 (J. Med. Chem. 32, 1326, 1989): and (E)-3,4-(1-imidazolylmethyl)phenyl-2-propenoic acid and their pharmaceutically acceptable salts.
  • Examples of antagonists of thromboxane receptors, in accordance with the present invention are:
  • EP045 and EP092 (Armstrong et al., Br. J. Pharmacol. 84,595, 1985), 4-[2-(4-chloro-benzensulfonamido)-ethyl] phenylacetic acid (U. S.
  • ACEI examples of ACEI, in accordance with the present invention are those described in EP-A-161801 and in EP-A-240366; in particular (+)-[(2S,6R)-6[(S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2-(2- thienyl) perhydro-1-thiazepin-4-yl] acetic acid (CS-622) and their pharmaceutically acceptable salts.
  • Other examples of ACEI are the following: captopril ( Ondetti et al. , Science, 196 , 441 , 1977) , benazepril ( Schaller et al. , Eur. J . Clin . Pharra.
  • compositions of the inhibitors of thromboxane activity and of ACEI are the salts with physiologically acceptable bases and /or acids as well known to experts in the art of pharmaceutical technique.
  • control animals also showed hyperlidemia with high cholesterol (264 ⁇ 11 mg/dl) and triglyceride (285 ⁇ 36 mg/dl) values.
  • the combination has a beneficial effect on secondary hyperlipidemia which is not achieved with an ACEI alone.
  • the doses of ACEI and inhibitor of the thromboxane activity which can be administered in accordance with the present invention obviously depends on several factors, e.g. the administration route and the disease to be treated. In particular the exact dosage must be chosen on the basis of specific conditions of the patient under treatment in order to ensure the most suitable blood levels.
  • the dosage of the ACEI is suitably in the range from about 0.1 mg to about 300 mg p.o. per day, for example from about 0.5 mg to about 200 mg p.o. per day.
  • the dosage of the thromboxane A 2 inhibitor is suitably in the range from about 10 mg to about 3000 mg p.o. per day, for example from about 50 mg to about 2000 mg p.o. per day.
  • the drug in the case of the ACEI captopril, the drug can be administered to an adult at doses ranging between about 20 and about 100 mg p.o. per day. In the case of enalapril between about 2.5 and about 20 mg p.o., 1 to 3 tiroes per day.
  • the oral dose in an adult can vary from about 100 mg to about 800 mg per dose 1 to 3 times per day.
  • the pharmaceutical formulations of the present invention suitable for the oral administration can be prepared in the form of capsules, sugar- coated tablets, each containing a preestablished amount of active principle; or in the form of powder or granulates; or as solutions or suspensions in an aqueous or non aqueous liquid; or in the form of oil- in-water or water-in-oil emulsions.
  • solutions or suspensions for subcutaneous administration can contain along with the active principle a pharmaceutically acceptable excipient and/or vehicle e.g. sterile water, olive oil, ethyl oleate, glycols, such as propylenic glycol.
  • a pharmaceutically acceptable excipient and/or vehicle e.g. sterile water, olive oil, ethyl oleate, glycols, such as propylenic glycol.
  • the suppositories can contain along with the active principle a pharmaceutically acceptable vehicle such as cocoa butter, polyethylenic glycol or lecithin.
  • a pharmaceutically acceptable vehicle such as cocoa butter, polyethylenic glycol or lecithin.
  • Example 1 capsules (100 mg)
  • the follwing pharmaceutical preparation can be obtained

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition pharmaceutique contenant un inhibiteur de l'enzyme de conversion de l'angiotensine (ECA) et un inhibiteur de l'activité de la thromboxane A2, ou un sel pharmaceutiquement acceptable de ces agents, utile pour le traitement de néphropathies et d'hyperlipidémies complémentaires au syndrome néphrotique.
EP91918149A 1990-10-16 1991-10-16 Composition pharmaceutique contenant un inhibiteur d'eca et un inhibiteur d'activite de thromboxane a2 pour traiter des nephropathies Withdrawn EP0556204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2175790 1990-10-16
IT021757A IT9021757A1 (it) 1990-10-16 1990-10-16 Prodotto per il trattamento delle nefropatie

Publications (1)

Publication Number Publication Date
EP0556204A1 true EP0556204A1 (fr) 1993-08-25

Family

ID=11186438

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91918149A Withdrawn EP0556204A1 (fr) 1990-10-16 1991-10-16 Composition pharmaceutique contenant un inhibiteur d'eca et un inhibiteur d'activite de thromboxane a2 pour traiter des nephropathies

Country Status (9)

Country Link
EP (1) EP0556204A1 (fr)
JP (1) JPH06501943A (fr)
AU (1) AU8725191A (fr)
IE (1) IE913585A1 (fr)
IL (1) IL99667A0 (fr)
IT (1) IT9021757A1 (fr)
PT (1) PT99238A (fr)
WO (1) WO1992006713A1 (fr)
ZA (1) ZA918038B (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9206713A1 *

Also Published As

Publication number Publication date
ZA918038B (en) 1992-06-24
JPH06501943A (ja) 1994-03-03
IL99667A0 (en) 1992-08-18
IT9021757A1 (it) 1992-04-17
WO1992006713A1 (fr) 1992-04-30
IE913585A1 (en) 1992-04-22
AU8725191A (en) 1992-05-20
IT9021757A0 (it) 1990-10-16
PT99238A (pt) 1992-09-30

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