WO1999019346A1 - Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline - Google Patents

Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline Download PDF

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Publication number
WO1999019346A1
WO1999019346A1 PCT/EP1998/005943 EP9805943W WO9919346A1 WO 1999019346 A1 WO1999019346 A1 WO 1999019346A1 EP 9805943 W EP9805943 W EP 9805943W WO 9919346 A1 WO9919346 A1 WO 9919346A1
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WO
WIPO (PCT)
Prior art keywords
compounds
general formula
combination
endothelin
treatment
Prior art date
Application number
PCT/EP1998/005943
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German (de)
English (en)
Inventor
Michael Puhl
Wilhelm Amberg
Heinz Hillen
Andreas Kling
Stefan Hergenröder
Claus Otto Markert
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to EP98950050A priority Critical patent/EP1023318A1/fr
Priority to AU96264/98A priority patent/AU9626498A/en
Priority to JP2000515917A priority patent/JP2001519440A/ja
Publication of WO1999019346A1 publication Critical patent/WO1999019346A1/fr

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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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new compounds and the use of these compounds for the production of pharmaceutical preparations for the treatment of diseases which are associated with the biological action of endothelin.
  • the invention further relates to pharmaceutical compounds suitable for ECE inhibition.
  • Endothelin is a 21 amino acid peptide that is synthesized and released by vascular endothelium. 5 Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, "endothelin” or “ET” denotes one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. This vasoconstriction is known to be caused by the binding of endothelin 0 to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Co mun., 154, 868-875, 1988).
  • endothelin causes persistent vascular contraction in peripheral, renal and cerebral blood vessels, which can lead to disease.
  • endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med Association 26_4, 2868 (1990), Nature, 114 (1990), N. Engl. J. Med. 212, 205 (1989), N. Engl. J. Med.
  • ET A and ET B receptor At least two endothelin receptor subtypes, ET A and ET B receptor, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances that inhibit the binding of endothelin to one or both receptors should antagonize the physiological effects of endothelin and should therefore be valuable pharmaceuticals.
  • a disadvantage of these receptor antagonists is that En5 dothelin has already formed and the action of the endothelin has to be antagonized after its formation. Substances that form an education of the endothelin from its precursor, the so-called “big endothelin", attack at an earlier stage of the endothelin effect and thus represent a sought-after alternative to the endothelin receptor antagonists.
  • Inhibitors based on dipeptide derivatives, the N-terminal of a mercaptocarboxylic acid are described in EP-A-0 524 553, WO 94/17036 and WO 96/22998 as inhibitors for NEP and / or ACE.
  • WO 96/11209 describes such compounds and their preparation as inhibitors for matrix metalloproteases and TNF.
  • ECE inhibitors should also have a good effect against other proteases such as ACE.
  • R 1 H substituted or unsubstituted, branched or unbranched Ci-Cs-alkyl, Ci-C ⁇ -alkylaryl or Ci-C ⁇ -alkylhetaryl, substituted or unsubstituted aryl or hetaryl,
  • R 2 substituted or unsubstituted 2-thienylmethyl-, ß-naphthylmethyl-, N-Boc-indol-3-ylmethyl '
  • R 3 H substituted or unsubstituted acyl, dissolved.
  • the invention also relates to a process for the preparation of the abovementioned compounds of the general formula I, characterized in that compounds of the general formula II
  • ECE endothelin conversion enzyme
  • the compounds according to the invention are advantageously suitable for the production of pharmaceutical preparations for the treatment of diseases which are associated with the biological action of endothelin.
  • the substituents R 1 - R 2 and R 3 in the above formula I have the following meanings:
  • R 1 is hydrogen, substituted or unsubstituted, branched or unbranched Ci-C ⁇ -alkyl, Ci-C ⁇ -alkylaryl or Cj . -C 8 alkylhetaryl, substituted or unsubstituted aryl or hetaryl, wherein
  • Ci-Cs-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl -, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4 - Methylpentyl, 1, 1-dimethylbutyl,
  • 1,2-dimethylb tyl 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2 -trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl -1-methylpropyl, 1-ethyl -2-methylpropyl, n-heptyl or n-octyl;
  • Ci-Cs-alkylaryl branched or unbranched Ci-Cs-alkylaryl, such as Ci-Cs-alkyl-phenyl- or Ci-C ⁇ -alkyl-naphthyl residues such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl , 2-methylpropylphenyl, 1, 1-dimethylethylphenyl, pentylphenyl, 1-methylbutylphenyl, 2-methylbutylphenyl, 3-methylbutylphenyl, 2,2-dimethylpropylphenyl, 1-ethylpropylphenyl, hexylphenyl, heptylphenyl, octylphenyl, methylnaphthyl , Ethylnaphthyl, propynaphthyl, 1-
  • Ci-C ⁇ -alkylhetaryl residues the simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings, which may optionally contain one or more heteroatoms such as S, N or 0;
  • Aryl such as phenyl, naphthyl, anthranyl or phenanthryl; Hetaryl simple or condensed aromatic ring systems with one or more heteroaromatic 5- to 8-membered rings, which may optionally contain one or more heteroatoms such as S, N or 0, such as thienyl, pyridyl or indoyl. 5
  • R 3 H substituted or unsubstituted acyl, in particular in the form of an acetyl or benzoyl radical
  • the compounds according to the invention can be present as free compounds, or in the form of their physiologically active salts, their renomeric and / or isomeric forms or in the form of the combination of the free compounds and the various salts.
  • the compounds according to the invention are also to be understood as meaning the enantiopure or diastereomerically pure compounds, their salts or mixtures thereof.
  • the enantiomeric or diastereomeric forms of the compounds according to the invention can be purified or prepared in a known manner, for example by forming diastereomer salts, by chiral chromatography processes or by stereoselective synthesis.
  • the compounds of the formula I were prepared by standard methods of peptide chemistry and protective group chemistry, which the person skilled in the art from, for example, Müller et al. (Houben Weyl Methods of Organic Chemistry, Vol. XV Thieme Verlag Stuttgart),
  • the protective group SGi includes all protective groups known to those skilled in protein synthesis, such as t-butyl, benzyl, benzyloxycarbonyl, trityl, methyl or polymer-bound protective groups in the form of the commercially available polystyrene resins, such as e.g. 2-chlorotrityl chloride resin or Wang resin (Bachern, Nobvabiochem) are suitable.
  • Preferred protective groups are t-butyl and 2-chlorotrityl resins.
  • Fluorenylmethoxycarbonyl, t-butyloxycarbonyl or benzyloxycarbonyl are suitable as the protective group SG.
  • Activation methods of choice are uronium salts or carbodiimides such as DCC, WSC.
  • Polymeric protective group 2C1-trityl is preferred for SGi, fluorenylmethoxycarbonyl for SG and DIC in the presence of HOBt as the activation method.
  • Compounds of the general formula I which are distinguished by the central amino acid D-2-Nal, Trp-Boc or D-Thi thus have a very balanced pharmacology and therefore have advantages in the treatment of diseases in the indication area cardiovascular.
  • the compounds of formula I, their stereomeric, diastereomeric forms and / or physiologically active salts, and their tautomeric or isomeric forms are suitable for the production of pharmaceutical preparations suitable for ECE inhibition for the treatment of diseases, preferably for the production of medicaments that are used to treat diseases associated with the biological effects of endothelin.
  • the enantiomerically pure or diastereomerically pure compounds are preferred as the active ingredient.
  • the compounds of formula I are preferably administered in the form of those pharmaceutical preparations in which the release takes place under conditions such as those in certain body compartments, e.g. in the stomach, intestines, bloodstream, liver, predominate.
  • the invention furthermore relates to combination preparations from pharmaceutical preparations which contain inhibitors of the formula I and inhibitors of the renin-angiotensin system.
  • Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and, above all, angiotensin converting enzyme (ACE) inhibitors.
  • ACE angiotensin converting enzyme
  • the combinations can be applied in a common galenical form or separately in time and space.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotonically). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • compositions which contain compounds of the formula I for inhibiting the endothelin conversion enzyme are to be understood in principle as all galenical administration forms, whether solid or liquid, such as tablets, film-coated tablets, capsules, powders, granules, dragees, supposito- Rien, solutions, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1991).
  • the administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.
  • a calcium antagonist with the inhibitors of the formula I can be used as an agent for the treatment of diseases which are based on vasoconstriction or are associated with pathological vasoconstriction. Examples are: All forms of high blood pressure (including pulmonary hypertension), coronary heart disease, heart failure, renal and myocardial ischemia, acute and chronic renal failure.
  • the combinations according to the invention are generally administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. Administration can also be rectal, for example in the form of suppositories, or parenteral, for example in the form of injection solutions, done.
  • the active ingredient can be administered in the form of preparations which contain both active ingredients together, such as tablets or capsules, or separately as an ad-hoc combination of individual substances which can be administered simultaneously or in 5 steps.
  • a combination according to the invention with pharmaceutically inert, inorganic or organic excipients 10 can be processed to produce tablets, coated tablets, coated tablets and hard gelatin capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as such excipients for tablets, dragees and hard gelatin capsules.
  • Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
  • Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like.
  • Suitable excipients for injection solutions are water, alcohols, polyols, glycerin, vegetable oils.
  • natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients.
  • the pharmaceutical preparations can also contain e Konservier insurance agents, solubilizers, stabilizing agents. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
  • Example 2 ECE inhibitor tests, IC 50 determinations
  • ECE endothelin conversion enzyme
  • the enzyme preparations used were further purified by mono-Q chromatography and WGA lectin chromatography.
  • the preparations thus obtained contained no interfering foreign protease activities and had specific activities in the range of 1-20 mU / mg.
  • 5 ⁇ l of this enzyme solution were mixed with 495 ⁇ l test buffer (100 mM Pi, 500 mM NaCl, 0.1 mg / ml BSA pH 7.2) and each with 5 ⁇ l correspondingly concentrated solutions (10 " 3 M, 10" 4 M, 10 " 5 M etc.) of the inhibitors were pre-incubated in the test buffer for 10 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux composés ainsi que leur utilisation pour produire des préparations pharmaceutiques servant à traiter des maladies liées à l'effet biologique de l'endothéline. L'invention concerne en outre des composés pharmaceutiques appropriés pour inhiber l'enzyme de conversion de l'endothéline (ECE).
PCT/EP1998/005943 1997-10-14 1998-09-18 Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline WO1999019346A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98950050A EP1023318A1 (fr) 1997-10-14 1998-09-18 Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline
AU96264/98A AU9626498A (en) 1997-10-14 1998-09-18 Dipeptides for the treatment of diseases related to the biological effect of endothelin
JP2000515917A JP2001519440A (ja) 1997-10-14 1998-09-18 エンドセリンの生物学的作用と関連している疾病を治療するためのジペプチド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19745151A DE19745151A1 (de) 1997-10-14 1997-10-14 Neue Verbindungen zur Behandlung von Krankheiten, die mit der biologischen Wirkung von Endothelin assoziiert sind
DE19745151.9 1997-10-14

Publications (1)

Publication Number Publication Date
WO1999019346A1 true WO1999019346A1 (fr) 1999-04-22

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PCT/EP1998/005943 WO1999019346A1 (fr) 1997-10-14 1998-09-18 Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline

Country Status (6)

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EP (1) EP1023318A1 (fr)
JP (1) JP2001519440A (fr)
AU (1) AU9626498A (fr)
DE (1) DE19745151A1 (fr)
WO (1) WO1999019346A1 (fr)
ZA (1) ZA989313B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092622A2 (fr) * 2001-05-15 2002-11-21 Novartis Ag Derives dipeptidiques
WO2003006041A1 (fr) * 2001-07-12 2003-01-23 Takeda Chemical Industries, Ltd. Agents prophylactiques/therapeutiques contre les tumeurs malignes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013545A1 (fr) * 1991-01-31 1992-08-20 Abbott Laboratories Inhibiteurs d'enzymes de conversion d'endotheline
EP0524553A1 (fr) * 1991-07-23 1993-01-27 Institut National De La Sante Et De La Recherche Medicale (Inserm) Acylmercaptoalcanoyldipeptides, procédés de leur préparation et leur utilisation thérapeutique
WO1994017036A1 (fr) * 1993-01-22 1994-08-04 Institut National De La Sante Et De La Recherche Medicale (Inserm) Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs
WO1997032849A1 (fr) * 1996-03-04 1997-09-12 Hoechst Marion Roussel Derives soufres comportant une liaison retroamide comme inhibiteurs d'enzymes de conversion d'endotheline

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013545A1 (fr) * 1991-01-31 1992-08-20 Abbott Laboratories Inhibiteurs d'enzymes de conversion d'endotheline
EP0524553A1 (fr) * 1991-07-23 1993-01-27 Institut National De La Sante Et De La Recherche Medicale (Inserm) Acylmercaptoalcanoyldipeptides, procédés de leur préparation et leur utilisation thérapeutique
WO1994017036A1 (fr) * 1993-01-22 1994-08-04 Institut National De La Sante Et De La Recherche Medicale (Inserm) Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs
WO1997032849A1 (fr) * 1996-03-04 1997-09-12 Hoechst Marion Roussel Derives soufres comportant une liaison retroamide comme inhibiteurs d'enzymes de conversion d'endotheline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CORIC, PASCALE ET AL: "Optimal recognition of neutral endopeptidase and angiotensin-converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors", J. MED. CHEM. (1996), 39(6), 1210-19 CODEN: JMCMAR;ISSN: 0022-2623, 1996, XP002092013 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092622A2 (fr) * 2001-05-15 2002-11-21 Novartis Ag Derives dipeptidiques
WO2002092622A3 (fr) * 2001-05-15 2003-04-10 Novartis Ag Derives dipeptidiques
US6777443B2 (en) 2001-05-15 2004-08-17 Novartis Ag Dipeptide derivatives
US6992105B2 (en) 2001-05-15 2006-01-31 Novartis Ag Dipeptide derivatives
EP2239268A1 (fr) * 2001-05-15 2010-10-13 Novartis AG Dérivés de dipeptide
WO2003006041A1 (fr) * 2001-07-12 2003-01-23 Takeda Chemical Industries, Ltd. Agents prophylactiques/therapeutiques contre les tumeurs malignes

Also Published As

Publication number Publication date
AU9626498A (en) 1999-05-03
ZA989313B (en) 2000-04-13
DE19745151A1 (de) 1999-04-15
EP1023318A1 (fr) 2000-08-02
JP2001519440A (ja) 2001-10-23

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