EP0389535A1 - Inhibiteurs de la renine, procedes de preparation et d'utilisation de ces inhibiteurs et compositions les contenant - Google Patents

Inhibiteurs de la renine, procedes de preparation et d'utilisation de ces inhibiteurs et compositions les contenant

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Publication number
EP0389535A1
EP0389535A1 EP88910298A EP88910298A EP0389535A1 EP 0389535 A1 EP0389535 A1 EP 0389535A1 EP 88910298 A EP88910298 A EP 88910298A EP 88910298 A EP88910298 A EP 88910298A EP 0389535 A1 EP0389535 A1 EP 0389535A1
Authority
EP
European Patent Office
Prior art keywords
nhch
phe
nso
sta
pharmaceutically acceptable
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.)
Pending
Application number
EP88910298A
Other languages
German (de)
English (en)
Inventor
Harriet Wall Hamilton
John Cooke Hodges
Joseph Thomas Repine
Ila Sircar
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.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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 Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP0389535A1 publication Critical patent/EP0389535A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Renin is a natural enzyme which is-released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renins have been sought as an agent for control of hypertension, congestive heart failure, and hyperaldosteronism.
  • the present invention concerns novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, and hyperaldosteronism, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
  • United States 4,479,941 covers certain renin-inhibitory peptides of the formula
  • European Application No. 85/308759 covers certain renininhibitory dipeptides of the formula wherein m is 0 or 1 and R 1 -R 5 are a variety of organic groups.
  • A is an N-protecting group
  • R 1 , R 3 , R 5 and R 7 are lower alkyl or lipophilic or aromatic amino acid side chains and may be the same or different
  • R 2 , R 4 and R 6 are hydrogen or lower alkyl and may be the same or different
  • X is hydrogen, lower alkyl or -CH 2 -OR 8 , wherein R 8 is hydrogen, lower alkyl or alkaryl
  • R 9 is lower alkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, alkaryloxy or thioalkyl and pharmaceutically acceptable salts thereof.
  • R 1 is COR or SO 2 R 1 ;
  • R 2 is optionally substituted lower alkyl, phenyl, naphthyl, cyclohexyl or pyridyl;
  • R 3 is hydrogen, lower alkenyl, phenyl, naphthyl, 3-6C cycloalkyl, monocyclic heterocyclic or substituted lower alkyl;
  • Z 1 is i-Pr, phenyl, cyclohexyl;
  • X-Y is a dipeptide.
  • European Application No. 220-665 covers peptidyl; amino cycloalkyl; hydroxy alkanoic acid derivatives of the formula
  • Z 1-4 peptide-linked aminoacid gps. selected from Abu, Ada, Ala, Arg, Asn, Bia, Cal, Dab, Gin, Gly, His, N(im)-alkyl-His, Ile, Leu, tert-Leu, Lys, Met, ⁇ -Nal, ⁇ -Nal, Nbg, Nle, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr and Val; and
  • E OH, OA, NH 2 , NHA or N(A) 2 .
  • the compounds are useful as renin and acid protease inhibitors.
  • the present invention relates to novel peptides of the formula
  • the invention also includes pharmaceutical compositions comprising an effective amount of the above peptide- of formula I in admixture with a pharmaceutically acceptable carrier or excipient and a method for treating renin-associated hypertension in a patient suffering therefrom comprising administering to said patient the above pharmaceutical composition in unit dosage form.
  • the invention includes a pharmaceutical composition comprising an effective amount of a peptide of formula I above in admixture with a pharmaceutically acceptable carrier or excipient, and a method for treating hyperaldosteronism in a patient suffering therefrom comprising administering to said patient the above pharmaceutical composition in unit dosage form.
  • the invention includes a pharmaceutical composition comprising an effective amount of a peptide of formula I in admixture with a pharmaceutically acceptable carrier or excipient, and a method for treating congestive heart failure in a patient suffering therefrom comprising administering to said patient the above pharmaceutical composition in unit dosage form.
  • the present invention also includes the use of peptides of formula I above as diagnostic tools for the identification of cases of hypertension due to renin excess.
  • the invention further includes methods for preparing peptides of formula I above and novel intermediates used in their preparation.
  • the peptides of the present invention are represented by the formula
  • R and R' are each independently hydrogen or lower alkyl
  • A is a saturated ring of from 1 to 5 carbon atoms wherein Z' is CH 2 , O, S, or NR, n is an integer of from 0 to 3; and D is N, S, O, or CH.
  • Z' is CH 2 , O, S, or NR
  • n is an integer of from 0 to 3
  • D is N, S, O, or CH.
  • R and R' are each independently hydrogen or lower alkyl
  • Z' is CH 2 , O, S, NH, NR with R defined as above; n is 0-3;
  • D is N, S, O, CH;
  • Py is 2-pyridyl, 3-pyridyl, or 4-pyridyl.
  • X is PHE, HOMOPHE, TYR, TYR(OMe), NAPHTHYLALA, CYCLOHEXYLALA, LEU, TRP, HIS, or (NMe)PHE;
  • Y is GLN, HIS, LEU, PGY, MET, TZA, ALG, PPG, CPM, EMG, BYG, NIA,
  • R and R' are each independently H, benzyl, or lower alkyl;
  • B is a chain of from three to six carbon atoms which is saturated, olefinic, or acetylenic;
  • W is STA, CYSTA, or PHSTA, CHSTA, DFKSTA, DFKCYS, DFKCHS, ASTA, ACYS;
  • Preferred compounds of the present invention are those
  • X is PHE TYR(OMe) or NAPHTHYLALA
  • W is STA, CHSTA, DFKCYS
  • DFKSTA or CYSTA U is and Y is HIS, - TZA, ALG, PGY,
  • the compounds of the present invention have the advantage of increased hydrophilicity relative to renin inhibitors known in the art. This property makes the compound more readily absorbed.
  • the compounds include solvates and hydrates and pharmaceutically acceptable acid addition salts of the basic compounds of formula I above.
  • the term pharmaceutically acceptable acid addition salt is intended to mean a relatively nontoxic acid addition salt either from inorganic or organic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, benzoic, gluconic, fumaric, succinic, ascorbic, maleic, tartaric, methanesulfonic, and the like.
  • 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 form with a base. Unless otherwise specified the L form is the preferred embodiment.
  • the modified peptides of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration.
  • the present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.
  • novel peptides may be prepared in accordance with well-known procedures for preparing peptides from their constituent amino acids.
  • Other of the novel peptides of the present invention are prepared by a step-wise procedure or by a fragment coupling procedure depend, g upon the particular final product desired.
  • BOC-protected statine (1) is reacted with DCC, HOBT, and a primary amine, for example, 2-methylbutylamine, to form the corresponding BOC-protected compound (2).
  • the reaction takes place in an inert solvent such as methylene chloride, tetrahydrofuran, chloroform, dioxane, or ethyl acetate.
  • the preferred solvent is methylene chloride.
  • the reaction time varies from 1 to 24 hours. Preferably it takes about 2 to 6 hours.
  • the reaction temperature may also vary from about 15°C to 30°C. Preferably it is approximately 25°C.
  • the above compound (2) is reacted with a strong acid such as trifluoroacetic, HBr, or HCl to remove the BOC-protecting group thus forming corresponding compound (3) with a free amino terminus.
  • a strong acid such as trifluoroacetic, HBr, or HCl
  • HC1 is used.
  • Compound 3 is then reacted with BOC-protected LYS(Z) to form the corresponding compound (4).
  • This reaction takes place in an inert solvent, for example DMF, with DCC, HOBT, and triethylamine as activating agents at temperatures of from 0°C to 25oC. The reaction may take as long as 72 hours.
  • This compound (4) is reacted with a strong acid, such as trifluoroacetic acid, to form the corresponding compound with a free amino terminus (5).
  • the reaction takes place in an inert solvent, preferably dichloromethane, at about 25°C, taking from 0.5 to 2 hours.
  • This compound (5) is reacted with L-N,N-dimethylsulfamylphenylalanine, DCC, and HOBT in an inert solvent such as DMF at approximately room temperature for from 4 to 24 hours to form the Z-protected tripeptide (6).
  • the Z group is then removed by catalytic hydrogenation in a polar, inert solvent such as methanol forming peptide (7).
  • the catalyst is preferably palladium on carbon.
  • This peptide (7) is reacted with an acylating agent such as methyl isocyanate, methyl isothiocyanate, acetyl chloride, methyl chloroformate, N,N-dimethylsulfam ⁇ l chloride, or
  • Sulfamyl amino acid derivatives are prepared by reaction of a sulfamyl chloride with the desired amino acid in a mixture of aqueous base and organic solvents at 0 to 40oC.
  • Bases include NaOH, NaHCO 3 , Na 2 CO 3 , KOH, KHCO 3 , K 2 CO 3 .
  • Organic solvents include THF, dioxane, and acetonitrile.
  • sulfamyl amino acids are prepared by reaction of a sulfamyl chloride with the tetra-alkylammonium salt of the desired aminoacid in anhydrous organic solvents at 0 to 40°C.
  • Salts include tetra-n-butylammonium, tetra-n-propylammonium, tetra-ethylammonium, tetra-methylammonium and benzyl-trimethylammonium.
  • Organic solvents include THF, dioxane, 1,2-dimethoxyethane, acetonitrile, 2-propanol, t-butanol, chloroform, dichloromethane and 1,2-dichloroethane.
  • Carbamyl amino acid derivatives are, prepared by reaction of a carbamyl chloride, organic base, and an amino acid ester in an aprotic solvent, followed by saponification or hydrogenolysis of the ester.
  • Bases include triethyl amine, diisopropyl ethyl amine, pyridine, and 4-dimethylaminopyrido.
  • Solvents include dichloromethane, THF, chloroform, acetonitrile, and dioxane.
  • This compound (10) is treated with strong acid such as methanolic hydrogen chloride in an inert solvent, preferably dichloromethane, at about 25°C, taking 10 to 60 minutes to remove the BOC-protecting group.
  • strong acid such as methanolic hydrogen chloride in an inert solvent, preferably dichloromethane, at about 25°C, taking 10 to 60 minutes to remove the BOC-protecting group.
  • the resulting compound (11) is reacted with an amino acid derivative such as L-N,N-dimeth ⁇ lsuI.fam ⁇ lphen ⁇ lalanine, DCC, and HOBT in a polar solvent such as DMF, at about 25°C, for 24 to 48 hours to form a compound of the present invention (8).
  • an amino acid derivative such as L-N,N-dimeth ⁇ lsuI.fam ⁇ lphen ⁇ lalanine, DCC, and HOBT in a polar solvent such as DMF, at about 25°C, for 24 to 48 hours to form a compound of the present invention (8).
  • Peptide coupling depends on activating the carboxy terminus and condensing it with another peptide containing a free amino terminus.
  • other methods of activating the carboxyl group of a protected amino acid include:
  • the invention includes a process for the preparation of compounds of formula I wherein A is
  • the invention also includes a second process for the preparation of compounds of formula I where A is
  • the invention also includes a process for the preparation of compounds of formula I wherein A is
  • the invention also includes novel sulfamyl-amino acid intermediates including specifically: Me 2 NSO 2 -PHE,
  • the compounds of the present invention are useful for treating renin-associated hypertension, congestive heart failure, and hyperaldosteronism. They are also useful as diagnostic tools for determining the presence of renin-associated hypertension or hyperaldosteronism.
  • lower alkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pent ⁇ l, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimeth ⁇ lpropyl, n-hex ⁇ l,. and the like.
  • compositions which comprise an effective amount of the compound in combination with a pharmaceutically acceptable carrier are part of the present invention.
  • An important aspect of the present invention is a method of treating renin-associated hypertension in a mammal which comprises administering a pharmaceutical composition containing an effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier to the mammal.
  • Another equally important aspect of the present invention is a method of treating hyperaldosteronism in a mammal which comprises administering a pharmaceutical composition containing an effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier to the mammal.
  • An additional aspect of the present invention is a method for treating congestive heart failure in a mammal which comprises administering a pharmaceutical composition containing an effective amount of a compound in combination with a pharmaceutically acceptable carrier to the mammal.
  • the effectiveness of the aforementioned compounds is determined by a test for in vitro renin inhibitory activity. This activity is determined by a standard radioimmunoassay for angiotensin I. In this assay the enzyme, renin, incubated for two hours at 37° in the presence of a substrate, angiotensinogen, generates the product, angiotensin I. Test compounds are added to the incubation mixture. Relative activity is reported as the IC 50 , which is the molar concentration of test compound causing a 50% inhibition of the renin activity.
  • the compounds of the present invention have a significant effect on the activity of renin and thus are useful for the treatment of hypertension, hyperaldosteronism, and congestive heart failure.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powder and tablets preferably contain from 5 to 10 to about 70 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, tragacanth, methylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • the compound of the present invention may be administered orally, buccally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water/propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethyleneglycol solution. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • solid form preparations are most conveniently provided in unit dosage form and as such are used to provide a single liquid dosage unit.
  • sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon, or other volumetric container.
  • the solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the liquid utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol, and the like, as well as mixtures thereof. Naturally, the liquid utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active compound in a unit dose, of preparation may be varied or adjusted from 1 mg to 500 mg, preferably 5 to 100 mg according to the particular application and the potency of the active ingredient.
  • the compositions can, if desired, also contain other compatible therapeutic agents.
  • the mammalian dosage range for a 70 kg subject is from 1 to 1500 mg/kg of body weight per day or preferably 25 to 750 mg/kg of body weight per day optionally in divided portions.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with small dosages which 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.
  • BOC-STA (27.53 g, 0.1 mole, US Patent 4,397,786) and HOBT.H 2 O (14.2 g, 0.105 mole) were dissolved in 40 ml DMF. 300 ml CH 2 Cl 2 was added, and the mixture was cooled to 0°. A solution of DCC (21.66 g, 0.105 mole) in 50 ml CH 2 Cl 2 was added, followed by S-2-methylbutylamine (12 ml, 0.1 mole). After stirring at 0° for two hours, the mixture was allowed to warm to 25° over 1.5 hours. The mixture was filtered, and the solvent was removed in vacuo.
  • L-1-Naphthylalanine (860 mg) was converted to its tetra-n-but ⁇ lammonium salt and dissolved in anhydrous THF (25 mL). This solution was treated with morpholinosulfamyl chloride (370 mg) and stirred for 21 hours at room temperature in a stoppered flask. The resulting mixture was partitioned between ethyl acetate and IN HCl. The organic layer was washed with 0.5 N NaOH and the basic aqueous layer was acidified to pH 2 with concentrated hydrochloric acid.
  • Methyl, benzyl isonitroso malonate was prepared from methyl, benzyl malonate (obtained from Aldrich Chemical Corp.) by the procedure described in Organic Synthesis, Col. Vol. V, p. 373. The crude product thus obtained was reduced to the title compound by the procedure described in the Journal of the American Chemical Society, Vol. 75, p. 1970, April 20, 1953. Crude product was used without further purification or analyses in the following step.
  • ALG was prepared according to the procedure described in the Journal of the American Chemical Society, Vol. 109, pp. 4649-4659, 1987.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à de nouveaux peptides inhibiteurs de la rénine, qui sont utiles dans le traitement de l'hypertension associée à la rénine, des défaillances cardiaques congestives et de l'hyperaldostéronisme. Les procédés de préparation de ces peptides, de nouveaux composés intermédiaires servant à leur préparation, des compositions contenant ces peptides et des procédés servant à leur utilisation sont décrits. Un procédé de diagnostic, qui utilise ces composés pour déterminer la présence d'hypertension associée à la rénine, de défaillances cardiaques congestives ou d'hyperaldostéronisme, est également décrit.
EP88910298A 1987-10-26 1988-10-25 Inhibiteurs de la renine, procedes de preparation et d'utilisation de ces inhibiteurs et compositions les contenant Pending EP0389535A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11377287A 1987-10-26 1987-10-26
US113772 1987-10-26
US20602388A 1988-06-17 1988-06-17
US206023 1988-06-17

Publications (1)

Publication Number Publication Date
EP0389535A1 true EP0389535A1 (fr) 1990-10-03

Family

ID=26811447

Family Applications (2)

Application Number Title Priority Date Filing Date
EP19880117744 Withdrawn EP0314060A3 (fr) 1987-10-26 1988-10-25 Inhibiteurs de la rénine, procédé pour les préparer, méthodes pour son emploi, et compositions les contenant
EP88910298A Pending EP0389535A1 (fr) 1987-10-26 1988-10-25 Inhibiteurs de la renine, procedes de preparation et d'utilisation de ces inhibiteurs et compositions les contenant

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP19880117744 Withdrawn EP0314060A3 (fr) 1987-10-26 1988-10-25 Inhibiteurs de la rénine, procédé pour les préparer, méthodes pour son emploi, et compositions les contenant

Country Status (5)

Country Link
EP (2) EP0314060A3 (fr)
JP (1) JPH03500880A (fr)
KR (1) KR890701619A (fr)
AU (1) AU2783189A (fr)
WO (1) WO1989003841A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5071837A (en) * 1990-11-28 1991-12-10 Warner-Lambert Company Novel renin inhibiting peptides
DE69842121D1 (de) 1997-12-10 2011-03-17 Cyclosporine Therapeutics Ltd Omega-3 fettsäure enthaltende pharmazeutische zusammensetzungen
EP1159273A1 (fr) 1999-03-02 2001-12-05 Boehringer Ingelheim Pharmaceuticals Inc. Composes utiles en tant qu'inhibiteurs reversibles de la cathepsine s
US6420364B1 (en) 1999-09-13 2002-07-16 Boehringer Ingelheim Pharmaceuticals, Inc. Compound useful as reversible inhibitors of cysteine proteases
WO2004085505A2 (fr) * 2003-03-24 2004-10-07 Sequoia Pharmaceuticals, Inc. Conjugues actifs sur le plan biologique a action prolongee

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1676454A3 (ru) * 1984-11-30 1991-09-07 Санкио Компани Лимитед (Фирма) Способ получени пептидов или их фармацевтически приемлемых солей
CA1286846C (fr) * 1985-02-12 1991-07-23 Catherine Cazaubon Derives peptidiques inhibant la renine et les proteases acides
DE3538749A1 (de) * 1985-10-31 1987-05-07 Merck Patent Gmbh Peptide
DE3540495A1 (de) * 1985-11-15 1987-05-21 Merck Patent Gmbh Aminosaeurederivate
EP0249096B1 (fr) * 1986-06-10 1995-01-11 Merck Patent Gmbh Dérivés d'acides aminés inhibant la rénine.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8903841A1 *

Also Published As

Publication number Publication date
EP0314060A3 (fr) 1991-06-19
WO1989003841A1 (fr) 1989-05-05
JPH03500880A (ja) 1991-02-28
EP0314060A2 (fr) 1989-05-03
AU2783189A (en) 1989-05-23
KR890701619A (ko) 1989-12-22

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