EP0000741B1 - Dérivés des acides indolylacétoxyacétiques avec des aminoacides, leur préparation et leur utilisation dans des médicaments - Google Patents

Dérivés des acides indolylacétoxyacétiques avec des aminoacides, leur préparation et leur utilisation dans des médicaments Download PDF

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Publication number
EP0000741B1
EP0000741B1 EP78100523A EP78100523A EP0000741B1 EP 0000741 B1 EP0000741 B1 EP 0000741B1 EP 78100523 A EP78100523 A EP 78100523A EP 78100523 A EP78100523 A EP 78100523A EP 0000741 B1 EP0000741 B1 EP 0000741B1
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Prior art keywords
ace
carbon atoms
general formula
group
compounds
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EP78100523A
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English (en)
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EP0000741A3 (en
EP0000741A2 (fr
Inventor
Karl-Heinz Dr. Boltze
Hans-Dieter Dr. Dell
Haireddin Dr. Jacobi
Wolfgang Dr. Opitz
Günter Schöllnhammer
Dieter Dr. Vollbrecht
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Troponwerke GmbH
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Troponwerke GmbH
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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
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
    • 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
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • the present invention relates to new indolacetoxyacetylamino acid derivatives, processes for their preparation and their use in medicaments, in particular in anti-inflammatories and anti-inflammatory drugs.
  • physiologically compatible addition salts can be formed with organic and inorganic bases.
  • salts are preferably sodium salts, potassium, magnesium, ammonium, methylammonium, dimethylammonium salts or the 2-hydroxy, ethyl ammonium salt.
  • addition salts which are physiologically compatible can also be formed with acids.
  • salts are halides, preferably chlorides, sulfates, citrates, tartrates, maleinates and sulfonates.
  • the compounds of general formula (I) according to the invention have a more advantageous activity than the indomethacinserine derivatives of DOS 2 413 125 known from the prior art, as can be seen from the following table.
  • the active substances were administered orally to rats half an hour before the kaolin application (dose: see columns 2 and 4).
  • dose see columns 2 and 4
  • the inhibition was determined 4 hours after the edema challenge to control groups (see columns 3 and 5).
  • the serine derivative according to the invention was compared with the known serine derivative of indomethacin by determining DE 50 in each case. This shows that the serine derivative according to the invention has a DE 50 of 2.14 mg / kg body weight in rats after oral administration and a DE 50 of 2.17 mg / kg body weight in subcutaneous administration. The corresponding DE so values of the serine derivative of indomethacin were in any case over 100 mg / kg body weight.
  • reaction sequence of variant a) can be represented by the following formula:
  • chloroformic acid esters of the general formula (11) which can be used as starting compounds are known and the ACE-OH used as starting compound is also known (DOS 2 234 651).
  • the mixed anhydrides of the general formula (111) formed as an intermediate are new, but cannot be identified, since - like the majority of the mixed anhydrides known in the literature - they decompose during processing (cf.Houben-Weyl, Methods of Organic Chemistry, 4th edition, volume 15/2, page 17, 3rd paragraph).
  • diluents inert organic solvents are suitable as diluents, in particular those which are polar aprotic. Examples include: tetrahydrofuran, dioxane, dimethylformamide, hexamethylphosphoric triamide.
  • the reaction is conveniently carried out in the presence of acid binders.
  • acid binders All customary agents which are able to bind the hydrogen chloride released can be used as the acid binder. These preferably include alkali metal hydroxides and carbonates or organic bases such as pyridine and triethylamine.
  • reaction temperatures are expediently below 0 ° C., since otherwise racemizations occur; they can be varied within a certain range.
  • temperatures between 0 to -25 ° C, preferably between -10 and -20 ° C.
  • the reaction is usually carried out at normal pressure.
  • the reaction time is between 6 and 24 hours, preferably 14 to 20 hours.
  • Working up is preferably carried out by evaporation in vacuo, taking up in one of the customary organic solvents, neutral washing, optionally cleaning on silica gel and recrystallization.
  • reaction scheme If an activated ester of the general formula (V) is used for the reaction instead of a mixed anhydride of ACE-OH, the reaction of variant b) can be represented by the following reaction scheme:
  • the compounds of the general formula (V) used as reactants are not yet known, but can be prepared in a manner known per se by reacting 1 mol of ACE-OH and 1 mol of the correspondingly substituted phenol in a polar aprotic organic solvent, e.g. Tetrahydrofuran, in the presence of 1 mole of a carbodiimide, e.g. Dicyclohexylcarbodiimide or carbonyldiimidazole can be obtained in about 1 1/2 hour reaction time at room temperature.
  • a polar aprotic organic solvent e.g. Tetrahydrofuran
  • Process (V) (I) according to the invention is advantageously carried out in the presence of diluents.
  • diluents are the organic solvents known for this reaction, preferably dimethylformamide, dioxane, pyridine or their mixtures with water.
  • addition salts of (IV) are used for reactions, the process is advantageously carried out in the presence of acid binders.
  • acid binders include: alkali metal hydroxides, carbonates or strong organic amines, preferably triethylamine.
  • the reaction temperatures can be varied within a certain range. Normally one works at 15 to 25 ° C, since the reaction times are disproportionately longer at lower temperatures, but the formation of racemates is promoted at higher temperatures. A certain racemate formation cannot be ruled out even in the reaction at room temperature.
  • the process is usually carried out at normal pressure.
  • 1 mol of the amino acid derivative (IV) is preferably used per mole of the activated ester (V).
  • Working up is expediently carried out by diluting the mixture with water, taking it up in a suitable organic solvent, neutralizing, evaporating and recrystallizing from suitable solvents.
  • the serine derivatives of the general formula (VI) used as starting compounds are known.
  • the reaction is preferably carried out in the presence of diluents.
  • Polar aprotic organic solvents can be used as diluents. Examples include tetrahydrofuran, dioxane, dimethylformamide, hexamethylphosphoric triamide.
  • the reaction according to the invention is preferably carried out in the presence of a dehydrating agent.
  • a dehydrating agent examples include dicyclohexylcarbodiimide or carbonyldiimidazole in the presence of catalytic amounts of a basic catalyst, preferably sodium hydride.
  • reaction temperatures can be varied over a wide range; Usually one works between 10 and 40 ° C, preferably between 15 and 25 ° C.
  • ACE-OH 1 mol of the ACE-OH is first reacted with 1 mol of carbonyldiimidazole and 1 mol of the amino acid derivative is only added after CO 2 evolution has ended.
  • Working up is carried out in a conventional manner, preferably by evaporation in vacuo, taking up in a suitable solvent and cleaning on silica gel.
  • the amino protective group R 6 is cleaved off according to the methods known from the literature in peptide chemistry.
  • the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, capsules, dragées, pills, granules, aerosols, syrups, emulsions, suspensions, solutions, ointments, gels, creams, jellies, using inert, non-toxic, pharmaceutically suitable Carriers or solvents.
  • the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application takes place in the usual way, preferably orally or parenterally, locally, intramuscularly or intravenously.
  • tablets in addition to the carrier substances mentioned, can also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives such as starch, preferably potato starch, gelatin and the like.
  • Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
  • the active ingredients can be mixed with various flavor enhancers or colorants in addition to the auxiliaries mentioned.
  • solutions of the active ingredients can be used using suitable liquid carrier materials.
  • the dosage is about 10 up to 200, especially 30 to 80 mg per dose.
  • the compound is formed in a known manner by adding trifluoroacetic acid to the compound from Example 15.
  • Example 15 analogous to Example 15 from 10.15 g ACE-OH and 5.7 g Boc-Serinethylester.
  • a suspension of 0.005 mol of phenylalanyl tyrosine methyl ester trifluoroacetate in 15 ml of absolute dimethylformamide is initially mixed with stirring at 0 ° C. with 0.005 mol of triethylamine and after 10 minutes with 0.005 mol of ACE-2,4,5-trichlorophenyl ester. After stirring for 2 hours, lastly at room temperature, 150 ml of water are added to the reaction mixture, the mixture is extracted three times with ethyl acetate and the organic phase is extracted three times with nHCl solution. The solution is then washed neutral with water, dried over Na 2 S0 4 and evaporated. After recrystallization from acetone / petroleum ether, 84% of theory of N-ACE-phenylalanyl tyrosine methyl ester of mp 131 to 132 ° C. is obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Claims (3)

1. Dérivés d'indolylacétoxyacétylaminoacides de formule générale (I)
Figure imgb0071
dans laquelle
m et n représentent les chiffres 0 or 1,
X représente un groupe -NH- ou __OCH2__,
R1, R2 et R3 sont identiques ou différents et représentent chacun l'hydrogène, un alkyle en C1__C5 éventuellement substitué par hydroxy, alcoxy en C1__ C4, alkylthio en C1__C4 ou par un phénylalcoxycarbonylamino contenant 1 à 4 atomes de carbone dans la partie alkyle, ou un groupe phényle ou phénylalkyle contenant 1 à 4 atomes de carbone dans la partie alkyle, les noyaux phényle étant éventuellement substitués par trifluorométhyle, alcoxy en C1__C4, hydroxy ou halogène, ou un groupe hétérocycle-méthyle à 5 ou 6 chaînons, dans lequel 1 ou 2 chaînons peuvent être remplacés par l'azote et sur lequel est éventuellement condensé un noyau benzénique, ou bien, dans le cas où m et n sont égaux chacun à 0, Ri représente en outre un groupe amino, un groupe alcoxycarbonylamino ou un groupe phénylalcoxycarbonylamino contenant chaque fois 1 à 5 atomes de carbone dans la partie alcoxy,
R4 représente un groupe hydroxy, alcoxy en C1__C4, phénylalcoxy contenant 1 à 4 atomes de carbone dans la partie alkyle, benzylamino ou phénylamino,

ainsi que leurs sels physiologiquement compatibles formés avec des acides et des bases.
2. Procédé pour la préparation de dérivés d'indoleacétoxyacétylaminoacides de formule générale (I) selon la revendication 1, caractérisé en ce que:
a) on fait réagir l'acide [1-(4-chlorobenzyl)-5-méthoxy-2-méthyl-3-indolyl]-acétoxyacétique (ci-après dénommé ACE-OH) avec des esters chloroformiques de formule générale
Figure imgb0072
Rs représente un groupe alkyle en C1__C5,
en anhydrides mixtes de formule générale (III)
Figure imgb0073
dans laquelle
R5 a la signification indiquée ci-dessus,

et on fait réagir ceux-ci avec des composés de formule générale (IV)
Figure imgb0074
dans laquelle
m, n et R, à R4 ont la signification indiquée dans la revendication 1, ou bien
b) on condense le composé ACE-OH avec un phénol substitué correspondant en un ester activé de formule générale (V)
Figure imgb0075
dans laquelle
Y représente 2 à 5 atomes d'halogène ou 1 ou 2 groupes nitro et on fait réagir avec des composés de formule générale (IV), ou bien
c) dans le cas où les dérivés d'aminoacides contenant des groupes hydroxy doivent être liés sous forme ester, on fait réagir le composé ACE-OH avec des composés de formule générale (VI)
Figure imgb0076
dans laquelle
R4 a la signification indiquée ci-dessus et
R6 représente un groupement protecteur du reste amino habituel dans la chimie des peptides, et on élimine ensuite le reste R6 de manière connue et, éventuellement, on transforme les composés de formule générale (I) ainsi obtenus avec des acides et des bases en les sels physiologiquement compatibles.
3. Médicaments contenant au moins un dérivé d'indolylacétoxyacétylaminoacide selon la revendication 1.
EP78100523A 1977-08-06 1978-07-27 Dérivés des acides indolylacétoxyacétiques avec des aminoacides, leur préparation et leur utilisation dans des médicaments Expired EP0000741B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19772735537 DE2735537A1 (de) 1977-08-06 1977-08-06 Indolacetoxyacetylaminosaeurederivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE2735537 1977-08-06

Publications (3)

Publication Number Publication Date
EP0000741A2 EP0000741A2 (fr) 1979-02-21
EP0000741A3 EP0000741A3 (en) 1979-03-07
EP0000741B1 true EP0000741B1 (fr) 1981-07-22

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EP78100523A Expired EP0000741B1 (fr) 1977-08-06 1978-07-27 Dérivés des acides indolylacétoxyacétiques avec des aminoacides, leur préparation et leur utilisation dans des médicaments

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EP (1) EP0000741B1 (fr)
JP (1) JPS5430160A (fr)
DE (2) DE2735537A1 (fr)
IT (1) IT7826537A0 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3034005C2 (de) * 1980-09-10 1982-12-09 A. Nattermann & Cie GmbH, 5000 Köln Indolessigsäure-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zubereitungen
DE3206887A1 (de) * 1982-02-26 1983-09-15 Troponwerke GmbH & Co KG, 5000 Köln Verfahren zur herstellung von 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-3-indolacetoxyessigsaeure
DE3206885A1 (de) * 1982-02-26 1983-09-15 Troponwerke GmbH & Co KG, 5000 Köln Indolderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
JPS59204172A (ja) * 1983-04-28 1984-11-19 Kowa Co アセメタシンの製造法
JPH0417306Y2 (fr) * 1984-12-26 1992-04-17
KR900701752A (ko) * 1988-07-05 1990-12-06 이베 사치아끼 인돌 아세트산 유도체, 그의 제조법 및 이를 유효성분으로 하는 의약
US6207700B1 (en) 1999-01-07 2001-03-27 Vanderbilt University Amide derivatives for antiangiogenic and/or antitumorigenic use
US6762182B1 (en) 1999-01-07 2004-07-13 Vanderbilt University Converting cox inhibition compounds that are not COX-2 selective inhibitors to derivatives that are COX-2 selective inhibitors
US6306890B1 (en) 1999-08-30 2001-10-23 Vanderbilt University Esters derived from indolealkanols and novel amides derived from indolealkylamides that are selective COX-2 inhibitors
US7491744B2 (en) 2004-04-26 2009-02-17 Vanderbilt University Indoleacetic acid and indenacetic acid derivatives as therapeutic agents with reduced gastrointestinal toxicity
EP1604656A1 (fr) 2004-06-09 2005-12-14 Schwarz Pharma Ag Utilisation nouvelle de peptides pour le traitement de la sclérose amytrophique latérale (ALS)
WO2007149456A2 (fr) 2006-06-19 2007-12-27 Vanderbilt University Méthodes et compositions de diagnostic et de ciblage thérapeutique de cox-2
WO2013059245A1 (fr) 2011-10-17 2013-04-25 Vanderbilt University Analogues de l'indométacine destinés au traitement du cancer de la prostate résistant à la castration

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2234651C3 (de) * 1972-07-14 1978-11-09 Troponwerke Gmbh & Co Kg, 5000 Koeln Eckige Klammer auf l-(p-Chlorbenzoyl)-5-methoxy-2-methyl-3-indol] -acetoxj essigsaure, ihre Salze mit Basen, Verfahren zu ihrer Herstellung sowie pharmakologische Zubereitungen
DE2413125C2 (de) * 1974-03-15 1983-06-30 Schering Ag, 1000 Berlin Und 4619 Bergkamen Indolylacetylaminosäurederivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneipräparate

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Publication number Publication date
DE2735537A1 (de) 1979-02-22
JPS5430160A (en) 1979-03-06
EP0000741A3 (en) 1979-03-07
EP0000741A2 (fr) 1979-02-21
DE2860858D1 (en) 1981-10-29
IT7826537A0 (it) 1978-08-04

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