EP0000741B1 - Indolacetoxyacetylaminoacid derivatives, process for their preparation and their use in drugs - Google Patents

Indolacetoxyacetylaminoacid derivatives, process for their preparation and their use in drugs Download PDF

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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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ace
carbon atoms
general formula
group
compounds
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EP0000741A2 (en
EP0000741A3 (en
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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    • 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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  • 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)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description

Die vorliegende Erfindung betrifft neue Indolacetoxyacetylaminosäurederivate, Verfahren zu ihrer Herstellung sowie ihre Verwendung in Arzneimitteln, insbesondere in Entzündungshemmern und Antirheumatika.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.

Die Erfindung betrifft neue Indolacetoxyacetylaminoessigsäurederivate der allgemeinen Formel (I)

Figure imgb0001
in welcher

  • m und n für die Ziffern 0 oder 1 stehen,
  • X für eine -HN- oder ―OCH2-Gruppe steht,
  • R1, R2 und R3 gleich oder verschieden sind und jeweils für Wasserstoff, eine gegebenenfalls durch Hydroxy, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkylthio mit 1 bis 4 Kohlenstoffatomen oder durch Phenalkyloxycarbonylamino mit 1 bis 4 Kohlenstoffatomen im Alkylteil, substituiertes Alkyl mit 1 bis 5 Kohlenstoffatomen, oder für eine Phenyl- oder Phenalkylgruppe mit 1 bis 4 Kohlenstoffatomen im Alkylteil, wobei die Phenylringe gegebenenfalls durch Trifluormethyl, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Hydroxy oder Halogen substituiert sind oder für eine Heterocyclusmethylgruppe mit 5 bis 6 Ringgliedern, in welcher 1 oder 2 Glieder durch Stickstoff ersetzt sein können und an welche gegebenenfalls ein Benzolring annelliert ist, stehen oder für den Fall, daß m und n jeweils 0 bedeuten R1 zusätzlich für eine Aminogruppe, eine Alkoxycarbonylaminogruppe oder eine Phenalkoxycarbonylaminogruppe mit jeweils 1 bis 5 Kohlenstoffatomen im Alkoxyteil steht,
  • R4 für Hydroxy, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Phenalkoxy mit 1 bis 4 Kohlenstoffatomen im Alkoxyteil, Amino, Alkylamino mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Benzylamino oder Phenylamino steht,

sowie ihre gegebenenfalls mit Säuren und Basen gebildeten physiologisch verträglichen Salze.The invention relates to new indolacetoxyacetylaminoacetic acid derivatives of the general formula (I)
Figure imgb0001
 in which
  • m and n stand for the digits 0 or 1,
  • X represents an -HN or ―OCH 2 group,
  • R 1 , R 2 and R 3 are the same or different and each represents hydrogen, one optionally substituted by hydroxy, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms or by phenalkyloxycarbonylamino having 1 to 4 carbon atoms in the alkyl part, alkyl substituted with 1 to 5 carbon atoms, or for a phenyl or phenalkyl group with 1 to 4 carbon atoms in the alkyl part, where the phenyl rings are optionally substituted by trifluoromethyl, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen or for a heterocycle methyl group with 5 to 6 ring members, in which 1 or 2 members can be replaced by nitrogen and to which a benzene ring is optionally fused, or in the event that m and n each represent 0, R 1 additionally represents an amino group, an alkoxycarbonylamino group or a phenalkoxycarbonylamino group each having 1 to 5 carbon atoms in the Is alkoxy part,
  • R 4 stands for hydroxy, alkoxy with 1 to 4 carbon atoms, phenalkoxy with 1 to 4 carbon atoms in the alkoxy part, amino, alkylamino with 1 to 4 carbon atoms in the alkyl part, benzylamino or phenylamino,

as well as their physiologically tolerable salts which may be formed with acids and bases.

Es wurde gefunden, daß man die erfindungsgemäßen Verbindungen der allgemeinen Formel (1), in welcher X, m, n und R, bis R4 die oben angeführte Bedeutung haben, erhält, wenn man

  • a) [1-(4-Chlorbenzoyl)-5-methoxy-2-methyl-3-indolyl)acetoxyessigsäure (nachfolgend als ACE-OH bezeichnet) mit Chlorameisensäureestern der allgemeinen Formel
    Figure imgb0002
    in welcher
    • R5 für eine Alkylgruppe mit 1 bis 5 Kohlenstoffatomen steht,

    zu gemischten Anhydriden der allgemeinen Formel (III)
    Figure imgb0003
    in welcher
    • R5 die oben angegebene Bedeutung hat,

    umsetzt und diese mit Verbindungen der allgemeinen Formel (IV)
    Figure imgb0004
    in welcher
    • m, n und R, bis R4 die in Anspruch 1 angeführte Bedeutung haben, zur Reaktion bringt, oder
  • b) die Verbindung ACE-OH mit einem entsprechend substituierten Phenol zu einem aktivierten Ester der allgemeinen Formel
    Figure imgb0005
    in welcher
    • Y für 2 bis 5 Halogenatome oder 1 bis 2 Nitrogruppen steht,

    kondensiert und mit Verbindungen der allgemeinen Formel (IV) umsetzt oder
  • c) für den Fall, daß Hydroxylgruppen enthaltende Aminosäurederivate esterartig verknüpft werden sollen, die Verbindung ACE-OH mit Verbindungen der allgemeinen Formel (VI)
    Figure imgb0006
    in welcher
    • R4 die oben angeführte Bedeutung hat und
    • R6 für eine in der Peptidchemie übliche Aminoschutzgruppe steht,

umsetzt und anschließend den · Rest R6 in bekannter Weise abspaltet und gegebenenfalls die so erhaltenen Verbindungen der allgemeinen Formel (I) mit Säuren und Basen in die physiologisch verträglichen Salze verwandelt.It has been found that the compounds of the general formula (1) according to the invention in which X, m, n and R to R 4 have the meaning given above are obtained if
  • a) [1- (4-Chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl) acetoxyacetic acid (hereinafter referred to as ACE-OH) with chloroformic acid esters of the general formula
    Figure imgb0002
     in which
    • R 5 represents an alkyl group with 1 to 5 carbon atoms,

    to mixed anhydrides of the general formula (III)
    Figure imgb0003
     in which
    • R 5 has the meaning given above,

    implemented and this with compounds of general formula (IV)
    Figure imgb0004
     in which
    • m, n and R until R 4 have the meaning given in claim 1, or
  • b) the compound ACE-OH with an appropriately substituted phenol to an activated ester of the general formula
    Figure imgb0005
     in which
    • Y represents 2 to 5 halogen atoms or 1 to 2 nitro groups,

    condensed and reacted with compounds of the general formula (IV) or
  • c) in the event that amino acid derivatives containing hydroxyl groups are to be linked in ester form, the compound ACE-OH with compounds of the general formula (VI)
    Figure imgb0006
     in which
    • R 4 has the meaning given above and
    • R 6 represents an amino protective group which is customary in peptide chemistry,

reacted and then the radical R 6 is split off in a known manner and, if appropriate, the compounds of the general formula (I) thus obtained are converted into the physiologically tolerable salts with acids and bases.

Für den Fall, daß die Verbindungen der allgemeinen Formel (I) eine freie Säuregruppe enthalten (R4 = OH), können mit organischen und anorganischen Basen physiologisch verträgliche Additionssalze gebildet werden.In the event that the compounds of the general formula (I) contain a free acid group (R 4 = OH), physiologically compatible addition salts can be formed with organic and inorganic bases.

Als Beispiele solcher Salze seien vorzugsweise genannt Natriumsalze-, Kalium-, Magnesium-, Ammonium-, Methylammonium-, Dimethylammoniumsalze oder auch das 2-Hydroxye,thyl- ammoniumsalz.Examples of such salts are preferably sodium salts, potassium, magnesium, ammonium, methylammonium, dimethylammonium salts or the 2-hydroxy, ethyl ammonium salt.

Für den Fall, daß die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) eine freie Aminogruppe aufweisen, können ebenfalls mit Säuren physiologisch verträgliche Additionssalze gebildet werden.In the event that the compounds of the general formula (I) according to the invention have a free amino group, addition salts which are physiologically compatible can also be formed with acids.

Als Beispiele solcher Salze seien genannt Halogenide, vorzugsweise Chloride, Sulfate, Citrate, Tartrate, Maleinate und Sulfonate.Examples of such salts are halides, preferably chlorides, sulfates, citrates, tartrates, maleinates and sulfonates.

Überraschenderweise zeigen die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) eine vorteilhaftere Wirksamkeit als die aus dem Stand der Technik bekannten Indometacinserinderivate der DOS 2 413 125, wie aus der folgenden Tabelle hervorgeht.Surprisingly, 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.

In dieser Tabelle werden die erfindungsgemäßen Aminosäurederivate den entsprechenden Aminosäurederivaten des Indometacins gegenübergestellt. Als pharmakologisches Testmodell zur Bestimmung der entzündungshemmenden Wirkung wurde das Kaolinödem an der Rattenpfote (vgl. KEMPER et al, Z. ges. exp. Med. 131 (1959), 407) verwendet. Hierbei zeigte es sich, daß die erfindungsgemäßen Aminosäurederivate überraschenderweise eine deutlich stärkere Wirkung zeigen als die aus dem Stand der Technik bekannten Aminosäurederivate des Indometacins (vgl. DT-OS 2 413 125).In this table the amino acid derivatives according to the invention are compared with the corresponding amino acid derivatives of indomethacin. Kaolin edema on the rat paw was used as a pharmacological test model for determining the anti-inflammatory effect (cf. KEMPER et al, Z. ges. Exp. Med. 131 (1959), 407). It was found that the amino acid derivatives according to the invention surprisingly have a significantly stronger effect than the amino acid derivatives of indomethacin known from the prior art (cf. DT-OS 2 413 125).

Die Applikation der Wirkstoffe erfolgte an Ratten oral eine halbe Stunde vor der Kaolinapplikation (Dosis: s. Spalten 2 und 4). Die Hemmung wurde 4 Stunden nach der Ödemprovokation gegenüber Kontrollgruppen bestimmt (s. Spalten 3 und 5).

Figure imgb0007
The active substances were administered orally to rats half an hour before the kaolin application (dose: see columns 2 and 4). The inhibition was determined 4 hours after the edema challenge to control groups (see columns 3 and 5).
Figure imgb0007

Weiterhin wurde das erfindungsgemäße Serinderivat mit dem bekannten Serinderivat des Indometacins verglichen, indem jeweils die DE50 ermittelt wurde. Hierbei zeigt sich, daß das erfindungsgemäße Serinderivat bei Ratten nach oraler Applikation eine DE50 von 2,14 mg/kg Körpergewicht und bei subkutaner Applikation eine DE50 von 2,17 mg/kg Körpergewicht besitzen. Die entsprechenden DEso - Werte des Serinderivates von Indometacin lagen in jedem Fall über 100 mg/kg Körpergewicht.Furthermore, 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.

Es wurden eine weitere Anzahl von Aminosäurederivaten des Indometacins, die bisher noch nicht bekannt waren, hergestellt und in dem obengenannten Testmodell zur Bestimmung der Entzündungshemmung geprüft. Hierbei zeigte sich, daß diese Derivate nach oraler Verabreichung von 50 bzw. 100 mg-Dosen nur eine sehr geringe oder keine entzünungshemmende Wirkung besitzen, wie aus der folgenden Aufstellung ersichtlich ist.

  • Glutaminsäurederivat (178-180°C; 100 mg-kg; 3,5%);
  • Glutaminsäuredibenzylesterderivat (143-144°C; 50 mg/kg; 6,6%);
  • Tyrosinbenzylesterderivat (124-126°C; 100 mg/kg; 0,0%);
  • Phenylglycinbenzylesterderivat (148-151 °C; 100 mg/kg; 0,0%);
  • Tryptophenbenzylesterderivat (164-165°C; 100 mg/kg; 0,0%);
  • Histidinderivat (230°C/Zers.; 50 mg/kg; 10,6%);
  • N-Methylglycinderivat (165-166°C; 100 mg/kg; 21%);
  • Histindinbenzylesterderivat (218-219°C; 100 mg/kg; 0,0%);
  • (in Klammern die Angaben für Schmelzpunkt, Menge der oral verabreichten Substanz und Ödemhemmung in %).
A further number of amino acid derivatives of indomethacin, which were not yet known, were produced and tested in the above-mentioned test model for determining the anti-inflammatory effect. It was found that these derivatives have little or no anti-inflammatory activity after oral administration of 50 or 100 mg doses, as can be seen from the following table.
  • Glutamic acid derivative (178-180 ° C; 100 mg-kg; 3.5%);
  • Glutamic acid dibenzyl ester derivative (143-144 ° C; 50 mg / kg; 6.6%);
  • Tyrosine benzyl ester derivative (124-126 ° C; 100 mg / kg; 0.0%);
  • Phenylglycine benzyl ester derivative (148-151 ° C; 100 mg / kg; 0.0%);
  • Tryptophenbenzyl ester derivative (164-165 ° C; 100 mg / kg; 0.0%);
  • Histidine derivative (230 ° C / dec .; 50 mg / kg; 10.6%);
  • N-methylglycine derivative (165-166 ° C; 100 mg / kg; 21%);
  • Histine benzene ester derivative (218-219 ° C; 100 mg / kg; 0.0%);
  • (in brackets the information for melting point, amount of the orally administered substance and edema inhibition in%).

Demgegenüber zeigen die erfindungsgemäßen Aminosäurederivate überraschenderweise eine deutlich bessere entzündungshemmende Wirkung, wie aus der folgenden Aufstellung ersichtlich ist.

  • N-ACE-Phenylalanyltyrosinmethylester (Beispiel 19; 12,5 mg/kg; 52,8%);
  • N-ACE-Glycylalanylphenylalanylmethylester (Beispiel 20; 50 mg/kg; 42%);
  • N-ACE-Phenylalanin DE50 (Beispiel 7; 5,1 mg/kg);
  • N-ACE-Methionin (Beipiel 3; 25 mg/kg; 49,7%);
  • N-ACE-O-Methylserin DE50 (Beispiel 10; 27,9 mg/kg);
  • N-ACE-Serinmethylester DE50 (Beispiel 1; 19,7 mg/kg);
  • O-ACE-Serinethylester (Beispiel 18; 12,5 mg/kg; 49,7%);
  • O-ACE-Serinmethylester (Beispiel 16; 25 mg/kg; 51,1%).
In contrast, the amino acid derivatives according to the invention surprisingly show a significantly better anti-inflammatory effect, as can be seen from the following table.
  • N-ACE phenylalanyl tyrosine methyl ester (Example 19; 12.5 mg / kg; 52.8%);
  • N-ACE-glycylalanylphenylalanylmethyl ester (Example 20; 50 mg / kg; 42%);
  • N-ACE-phenylalanine DE 50 (Example 7; 5.1 mg / kg);
  • N-ACE methionine (Example 3; 25 mg / kg; 49.7%);
  • N-ACE-O-methylserine DE 50 (Example 10; 27.9 mg / kg);
  • N-ACE serine methyl ester DE 50 (Example 1; 19.7 mg / kg);
  • O-ACE serine ethyl ester (Example 18; 12.5 mg / kg; 49.7%);
  • O-ACE serine methyl ester (Example 16; 25 mg / kg; 51.1%).

Diese Testergebnisse zeigen eindeutig die überraschend vorteilhafte Wirkung der erfindungsgemäßen Aminosäurederivate. Bei Kenntnis des Standes der Technik konnte nicht erwartet werden, daß die Einführung eines Aminosäureesters in die ACE-Verbindung einen so sprunghaften Wirkungsanstieg verursacht. Man hätte vielmehr erwarten müssen, daß die Wirkung der erfindungsgemäßen Verbindungen mit der Wirkung der entsprechenden Indometacin-Aminosäurederivate vergleichbar wäre.These test results clearly show the surprisingly advantageous effect of the amino acid derivatives according to the invention. Knowing the state of the art, it could not be expected that the introduction of an amino acid ester into the ACE compound would cause such a sudden increase in activity. One would rather have expected that the action of the compounds according to the invention would be comparable to the action of the corresponding indomethacin amino acid derivatives.

Verwendet man ACE-OH und Chlorameisensäureester als Ausgangsverbindungen, so kann der Reaktionsablauf der Variante a) durch das folgende Formelschema wiedergegeben werden:

Figure imgb0008
If ACE-OH and chloroformate are used as starting compounds, the reaction sequence of variant a) can be represented by the following formula:
Figure imgb0008

Die als Ausgangsverbindungen verwendbaren Chlorameisensäureester der allgemeinen Formel (11) sind bekannt und die als Ausgangsverbindung verwendete ACE-OH ist ebenfalls bekannt (DOS 2 234 651).The 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).

Die als Zwischenprodukt gebildeten gemischten Anhydride der allgemeinen Formel (111) sind neu, können aber nicht indentifiziert werden, da sie sich - wie auch der überwiegende Teil der literatur- bekannten gemischten Anhydride - bei der Aufarbeitung zersetzen (vgl. Houben-Weyl, Methoden der Organischen Chemie, 4. Auflage, Band 15/2, Seite 17, 3. Absatz).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).

Die als Ausgangsverbindungen verwendbaren Verbindungen der allgemeinen Formel (IV) sind weitgehend literaturbekannt oder können nach bekannten Methoden hergestellt werden (vgl. u.a. Houben-Weyl, Methoden der organischen Chemie, 4. Auflage, Band 15/1 und 2).The compounds of the general formula (IV) which can be used as starting compounds are largely known from the literature or can be prepared by known methods (see, inter alia, Houben-Weyl, Methods of Organic Chemistry, 4th Edition, Vol. 15/1 and 2).

Die Reaktion erfolgt zweckmäßig in Gegenwart von Verdünnungsmitteln. Als Verdünnungsmittel kommen inerte organische Lösungsmittel in Frage, insbesondere solche, die polar aprotisch sind. Beispielhaft seien genannt: Tetrahydrofuran, Dioxan, Dimethylformamid, Hexamethylphosphorsäuretriamid.The reaction is conveniently carried out in the presence of diluents. Inert organic solvents are suitable as diluents, in particular those which are polar aprotic. Examples include: tetrahydrofuran, dioxane, dimethylformamide, hexamethylphosphoric triamide.

Die Reaktion erfolgt zweckmäßig in Gegenwart von Säurebindern. Als Säurebinder können alle üblichen Mittel verwendet werden, welche den freiwerdenden Chlorwasserstoff zu binden vermögen. Hierzu gehören vorzugsweise Alkalihydroxide und -carbonate oder organische Basen wie Pyridin und Triethylamin.The reaction is conveniently carried out in the presence of 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.

Die Reaktionstemperaturen liegen zweckmäßigerweise unterhalb von 0°C, da andernfalls Racemisierungen auftreten; sie können in einem gewissen Bereich variiert werden.The reaction temperatures are expediently below 0 ° C., since otherwise racemizations occur; they can be varied within a certain range.

Im allgemeinen arbeitet man bei Temperaturen zwischen 0 bis -25°C, vorzugsweise zwischen -10 und -20°C.In general, temperatures between 0 to -25 ° C, preferably between -10 and -20 ° C.

Die Umsetzung erfolgt üblicherweise bei Normaldruck.The reaction is usually carried out at normal pressure.

Bei der Durchführung des erfindungsgemäßen Verfahrens setzt man vorzugsweise auf 1 Mol ACE-OH, 1 Mol Chlorameisensäureester, 1 Mol des Aminosäurederivates sowie 1 Mol des Säurebinders ein.When carrying out the process according to the invention, preference is given to using 1 mol of ACE-OH, 1 mol of chloroformate, 1 mol of the amino acid derivative and 1 mol of the acid binder.

Die Reaktionszeit liegt zwischen 6 und 24 Stunden, vorzugsweise bei 14 bis 20 Stunden.The reaction time is between 6 and 24 hours, preferably 14 to 20 hours.

Die Aufarbeitung erfolgt vorzugsweise durch Eindampfen im Vakuum, Aufnehmen in eins der üblichen organischen Lösungsmittel, Neutralwaschen, gegebenenfalls Reinigen an Kieselgel und Rekristallisation.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.

Verwendet man für die Reaktion anstelle eines gemischten Anhydrids von ACE-OH einen aktivierten Ester der allgemeinen Formel (V), so kann die Reaktion der Variante b) durch das folgende Reaktionsschema wiedergegeben werden:

Figure imgb0009
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:
Figure imgb0009

Die als Reaktionspartner verwendeten Verbindungen der allgemeinen Formel (V) sind bisher nicht bekannt, können aber in an sich bekannter Weise durch Umsetzung von 1 Mol ACE-OH und 1 Mol des entsprechend substituierten Phenols in einem polar aprotischen organischen Lösungsmittel, wie z.B. Tetrahydrofuran, in Gegenwart von 1 Mol eines Carbodiimids, wie z.B. Dicyclohexylcarbodiimid oder Carbonyldiimidazol in etwa 1 1/2-stündiger Reaktionszeit bei Raumtemperatur erhalten werden.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.

Das erfindungsgemäße Verfahren (V) ­ (I) erfolgt zweckmäßig in Gegenwart von Verdünnungsmitteln. Als Verdünnungsmittel kommen die für diese Reaktion literatur-bekannten organischen Lösungsmittel, vorzugsweise Dimethylformamid, Dioxan, Pyridin oder deren Gemische mit Wasser in Frage.Process (V) (I) according to the invention is advantageously carried out in the presence of diluents. Suitable diluents are the organic solvents known for this reaction, preferably dimethylformamide, dioxane, pyridine or their mixtures with water.

Soweit Additionssalze von (IV) zu Reaktionen verwendet werden, erfolgt das Verfahren zweckmäßig in Gegenwart von Säurebindern. Beispielhaft seien genannt: Alkalihydroxide, -carbonate oder starke organische Amine, vorzugsweise Triethylamin.If addition salts of (IV) are used for reactions, the process is advantageously carried out in the presence of acid binders. Examples include: alkali metal hydroxides, carbonates or strong organic amines, preferably triethylamine.

Die Reaktionstemperaturen können in einem gewissen Bereich variiert werden. Normalerweise arbeitet man bei 15 bis 25°C, da bei niedrigeren Temperaturen die Reaktionszeiten unverhältnismäßig verlängert werden, bei höheren Temperaturen jedoch die Racematbildung gefördert wird. Eine gewisse Racematbildung ist auch bei der Reaktion bei Raumtemperatur nicht auszuschließen./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.

Das Verfahren wird üblicherweise bei Normaldruck durchgeführt.The process is usually carried out at normal pressure.

Bei der Durchführung des erfindungsgemäßen Verfahrens wird vorzugsweise pro Mol des aktivierten Esters (V) 1 Mol des Aminosäurederivates (IV) eingesetzt. Die Aufarbeitung erfolgt zweckmäßigerweise durch Verdünnen des Ansatzes mit Wasser, Aufnehmen in einem geeigneten organischen Lösungsmittel, Neutralisieren, Eindampfen und Rekristallisieren aus geeigneten Lösungsmitteln.When carrying out the process according to the invention, 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.

Für den Fall, daß die Aminosäurederivate der allgemeinen Formel (VI) esterartig mit ACE-OH verknüpft werden sollen, kann die Reaktion der Variante c) durch das nachfolgende reaktionsschema wiedergegeben werden:

Figure imgb0010
In the event that the amino acid derivatives of the general formula (VI) are to be linked ester-like with ACE-OH, the reaction of variant c) can be represented by the following reaction scheme:
Figure imgb0010

Die als Ausgangsverbindungen verwendeten Serinderivate der allgemeinen Formel (VI) sind bekannt. Die Reaktion erfolgt vorzugsweise in Gegenwart von Verdünnungsmitteln. Als Verdünnungsmittel können polar aprotische organische Lösungsmittel verwendet werden. Beispielhaft seien genannt Tetrahydrofuran, Dioxan, Dimethylformamid, Hexamethylphosphorsäuretriamid.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.

Die erfindungsgemäße Reaktion erfolgt vorzugsweise in Gegenwart eines wasserentziehenden Mittels. Beispielhaft seien genannt Dicyclohexylcarbodiimid oder Carbonyldiimidazol in Gegenwart katalytischer Mengen eines basischen Katalysators, vorzugsweise Natriumhydrid.The reaction according to the invention is preferably carried out in the presence of a dehydrating agent. Examples include dicyclohexylcarbodiimide or carbonyldiimidazole in the presence of catalytic amounts of a basic catalyst, preferably sodium hydride.

Die Reaktionstemperaturen können in größerer Breite variiert werden; üblicherweise arbeitet man zwischen 10 und 40°C, vorzugsweise zwischen 15 und 25°C.The reaction temperatures can be varied over a wide range; Usually one works between 10 and 40 ° C, preferably between 15 and 25 ° C.

Zweckmäßigerweise bringt man zunächst 1 Mol der ACE-OH mit 1 Mol Carbonyldiimidazol zur Reaktion und fügt 1 Mol des Aminosäurederivates erst nach beendeter CO2-Entwicklung hinzu. Die Aufarbeitung erfolgt in üblicher Weise, vorzugsweise durch Eindampfen im Vakuum, Aufnehmen in ein geeignetes Lösungsmittel und Reinigen an Kieselgel. Die Abspaltung der Aminoschutzgruppe R6 erfolgt nach den in der Peptidchemie üblichen literaturbekannten Methoden.Expediently, 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.

Als neue Wirkstoffe seien beispielhaft genannt:

  • N―ACE-Serinmethylester;
  • N-ACE-Serin;
  • N-ACE-Methionin;
  • N-ACE-Tyrosin;
  • N-ACE-Tryptophan;
  • N-ACE-DL-Threonin;
  • N-ACE-Phenylalanin;
  • N-ACE-Serin-N'-methylamid;
  • N-ACE-Histidinmethylester;
  • N-ACE-Serinbenzylester;
  • O-ACE-Serinmethylester;
  • O-ACE-Serinethylester;
  • N-ACE-Phenylalanyltyrosinmethylester;
  • N-ACE-Glycylalanylphenylalaninmethylester;
  • N-a-ACE-N-y-benzyloxycarbonyldiaminobutyrylphenylalanylphenylalaninmethylester.
Examples of new active ingredients are:
  • N ― ACE serine methyl ester;
  • N-ACE serine;
  • N-ACE methionine;
  • N-ACE tyrosine;
  • N-ACE tryptophan;
  • N-ACE-DL-threonine;
  • N-ACE phenylalanine;
  • N-ACE-serine-N'-methylamide;
  • N-ACE histidine methyl ester;
  • N-ACE serine benzyl ester;
  • O-ACE serine methyl ester;
  • O-ACE serine ethyl ester;
  • N-ACE phenylalanyl tyrosine methyl ester;
  • N-ACE-glycylalanylphenylalanine methyl ester;
  • Na-ACE-Ny-benzyloxycarbonyldiaminobutyrylphenylalanylphenylalanin methyl ester.

Als ACE sei hier und im weiteren Verlauf der Rest

Figure imgb0011
verstanden.As ACE, the rest is here and later
Figure imgb0011
 Roger that.

Die neuen Wirkstoffe können in bekannter Weise in die üblichen Formulierungen überführt werden wie Tabletten, Kapseln, Dragees, Pillen, Granulate, Aerosole, Sirupe, Emulsionen, Suspensionen, Lösungen, Salben, Gele, Cremes, Gallerten, unter Verwendung inerter, nichttoxischer, pharmazeutisch geeigneter Trägerstoffe oder Lösungsmittel. Hierbei soll die therapeutisch wirksame Verbindung jeweils in einer Konzentration von etwa 0,5 bis 90 Gew.-% der Gesamtmischung vorhanden sein, d.h. in Mengen, die ausreichend sind, um den angegebenen Dosierungsspielraum zu erreichen.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. Here, 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.

Die Formulierungen werden beispielsweise hergestellt durch Verstrecken der Wirkstoffe mit Lösungsmitteln und/oder Trägerstoffen, gegebenenfalls unter Verwendung von Emulgiermitteln und/ oder Dispergiermitteln, wobei z.B. im Falle der Benutzung von Wasser als Verdünnungsmittel gegebenenfalls organische Lösungsmittel als Hilfslösungsmittel verwendet werden können.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.

Als Hilfsstoffe seien beispielhaft aufgeführt:

  • Wasser, nichttoxische organische Lösungsmittel wie Paraffine (z.B. Erdölfraktionen), pflanzliche Ole (z.B. Erdnuß-/Sesamöl), Alkohole (z.B. Ethylalkohol, Glycerin), Glykole (z.B. Propylenglykol, Polyethylenglykol); feste Trägerstoffe wie z.B. natürliche Gesteinsmehle (z.B. Kaoline, Tonerden, Talkum, Kreide), synthetische Gesteinsmehle (z.B. hochdisperse Kieselsäure, Silikate), Zucker (z.B. Roh-, Milch- und Traubenzucker); Emulgiermittel wie nichtionogene und anionische Emulgatoren (z.B. Polyoxyethylen-Fettsäureester, Polyoxyethylen-Fettalkohol-Ether, Alkylsulfonate und Arylsulfonate), Dispergiermittel (z.B. Lignin, Sulfitablaugen, Methylcellulose, Stärke und Polyvinylpyrrolidon) und Gleitmittel (z.B. Magnesiumstearat, Talkum, Stearinsäure und Natrimlaurylsulfat).
Examples of auxiliary substances are:
  • Water, non-toxic organic solvents such as paraffins (eg petroleum fractions), vegetable oils (eg peanut / sesame oil), alcohols (eg ethyl alcohol, glycerin), glycols (eg propylene glycol, polyethylene glycol); solid carriers such as natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic rock flour (e.g. highly disperse silica, silicates), sugar (e.g. raw, milk and dextrose); Emulsifiers such as non-ionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, sulfite lye, methyl cellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g. magnesium stearate and talc sulfate), stearic acid.

Die Applikation erfolt in üblicher Weise, vorzugsweise oral oder parenteral, lokal, intramuskulär oder intravenös.The application takes place in the usual way, preferably orally or parenterally, locally, intramuscularly or intravenously.

Im Falle der oralen Anwendung können Tabletten, selbstverständlich außer den genannten Trägerstoffen auch Zusätze wie Natriumcitrat, Calciumcarbonat und Dicalciumphosphat, zusammen mit verschiedenen Zuschlagstoffen wie Stärke, vorzugsweise Kartoffelstärke, Gelatine und dergleichen enthalten.In the case of oral use, tablets, of course 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.

Weiterhin können Gleitmittel wie Magnesiumstearat, Natriumlaurylsulfat und Talkum zum Tablettieren mitverwendet werden. Im Falle wäßriger Suspensionen und/oder Elixiere, die für orale Anwendungen gedacht sind, können die Wirkstoffe außer mit den genannten Hilfsstoffen mit verschiedenen Geschmacksaufbesserern oder Farbstoffen versetzt werden.Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and / or elixirs which are intended for oral applications, the active ingredients can be mixed with various flavor enhancers or colorants in addition to the auxiliaries mentioned.

Für den Fall der parenteralen Anwendung können Lösungen der Wirkstoffe unter Verwendung geeigneter flüssiger Trägermaterialien eingesetzt werden.In the case of parenteral use, solutions of the active ingredients can be used using suitable liquid carrier materials.

Für den Fall der lokalen Anwendung kommen vorzugsweise Lösungen, Emulsionen, Salben, Gele, Cremes, Aerosole oder Gallerten mit geeigneten vorgenannten Hilfsstoffen in Betracht.In the case of local application, preference is given to solutions, emulsions, ointments, gels, creams, aerosols or jellies with suitable auxiliaries mentioned above.

Im allgemeinen hat es sich als vorteilhaft erwiesen, bei oraler Applikation Mengen von etwa 1 bis 100 mg, insbesondere 10 bis 40 mg pro Dosis bei 2- bis 3-maliger täglicher Verabreichung zur Erzielung wirksamer Ergebnisse einzusetzen, bei rektaler Applikation beträgt die Dosierung etwa 10 bis 200, insbesondere 30 bis 80 mg pro Dosis.In general, it has proven to be advantageous to use amounts of about 1 to 100 mg, in particular 10 to 40 mg per dose, for oral administration in order to achieve effective results in the case of oral administration 2 to 3 times a day; in the case of rectal administration, the dosage is about 10 up to 200, especially 30 to 80 mg per dose.

Beispiel 1example 1 N-ACE-SerinmethylesterN-ACE serine methyl ester

Figure imgb0012
5 g (0,012 Mol) ACE-OH werden in 50 ml absolutem Tetrahydrofuran gelöst, mit 1,8 ml (0,0131 Mol) Triethylamin versetzt, auf -10°C gekühlt und während einer halben Stunde tropfenweise mit 1,7 ml (0,0131 Mol) Chlorameisensäuren-n-butylester versetzt. Das so gebildete gemischte Anhydrid ACE―O―COO-n-C4H9 kann nicht isoliert werden, da es sich bereits bei Raumtemperatur zersetzt. Es wird - wie auch in den weiteren Beispielen - in Lösung weiterverarbeitet, indem man 2,05 g (0,0131 Mol) L-Serinmethylester, gelöst in 20 ml Dimethylformamid und weiter 1,8 ml Triethylamin bei -10°C und weiteren 12-stündigem Stehen bei -18°C wird der Ansatz bei 3 Torr und 30°C eingedampft, der Rückstand in Chloroform gelöst, mit 2 n HCI und dann mit Wasser neutralgewaschen, über Na2S04 getrocknet, filtriert und eingedampft. Nach Reinigen an Kieselgel mit einem Gemisch aus Chloroform/Methanol, Eindampfen, Aufnehmen des Rückstandes in 50 ml Ethanol und Zufügen von Wasser bis zur beginnenden Kristallisation werden 5,05 g ACE-Serinmethylester (=82,1% der Theorie) vom Fp. 88°C erhalten.
Figure imgb0012
 5 g (0.012 mol) of ACE-OH are dissolved in 50 ml of absolute tetrahydrofuran, 1.8 ml (0.0131 mol) of triethylamine are added, the mixture is cooled to -10 ° C., and 1.7 ml (0 , 0131 mol) of chloroformate n-butyl ester. The mixed anhydride ACE ― O ― COO-nC 4 H 9 thus formed cannot be isolated because it decomposes at room temperature. As in the other examples, it is processed further in solution by 2.05 g (0.0131 mol) of L-serine methyl ester, dissolved in 20 ml of dimethylformamide and further 1.8 ml of triethylamine at -10 ° C. and a further 12 - Standing at -18 ° C, the mixture is evaporated at 3 torr and 30 ° C, the residue dissolved in chloroform, washed neutral with 2N HCl and then with water, dried over Na 2 S0 4 , filtered and evaporated. After cleaning on silica gel with a mixture of chloroform / methanol, evaporation, taking up the residue in 50 ml of ethanol and adding water until crystallization begins, 5.05 g of ACE-serine methyl ester (= 82.1% of theory) of mp. 88 ° C obtained.

Figure imgb0013
(c = 0,5; Dimethylformamid).
Figure imgb0013
 (c = 0.5; dimethylformamide).

Für C25H25ClN2O8

Figure imgb0014
For C 25 H 25 ClN 2 O 8
Figure imgb0014

In gleicher Weise können hergestellt werden:The following can be produced in the same way:

Beispiel 2Example 2 N-ACE-SerinN-ACE serine

Figure imgb0015
mit L-Serin; Fp. 133°C, Ausbeute 70,8% der Theorie.
Figure imgb0015
 with L-serine; Mp 133 ° C, yield 70.8% of theory.

Figure imgb0016
(c=0,5; Dimethylformamid).
Figure imgb0016
 (c = 0.5; dimethylformamide).

Für C24H23ClN2O8

Figure imgb0017
For C 24 H 23 ClN 2 O 8
Figure imgb0017

Beispiel 3Example 3 N-ACE-MethioninN-ACE methionine

Figure imgb0018
Fp. 165°C, Ausbeute 70,1% der Theorie.
Figure imgb0018
 Mp 165 ° C, yield 70.1% of theory.

Figure imgb0019
(c = 0,5; Dimethylformamid).
Figure imgb0019
 (c = 0.5; dimethylformamide).

Für C26H27ClN2O7S

Figure imgb0020
For C 26 H 27 ClN 2 O 7 S
Figure imgb0020

Beispiel 4Example 4 N-ACE-TyrosinN-ACE tyrosine

Figure imgb0021
Fp. 111 °C, Ausbeute 34,7% der Theorie.
Figure imgb0021
 Mp 111 ° C, yield 34.7% of theory.

[α]20 D = +7,3 (c = 0,5; Dimethylformamid).[α] 20 D = +7.3 (c = 0.5; dimethylformamide).

Für C30H27ClN2O8

Figure imgb0022
For C 30 H 27 ClN 2 O 8
Figure imgb0022

Beispiel 5Example 5 N-ACE-TryptophanN-ACE tryptophan

Figure imgb0023
sintert bei 120 bis 150°C, Ausbeute 65,3% der Theorie.
Figure imgb0023
 sinters at 120 to 150 ° C, yield 65.3% of theory.

Figure imgb0024
(c = 0,5; Dimethylformamid).
Figure imgb0024
 (c = 0.5; dimethylformamide).

Für C32H28ClN3O7

Figure imgb0025
For C 32 H 28 ClN 3 O 7
Figure imgb0025

Beispiel 6Example 6 N―ACE-DL-ThreoninN ― ACE-DL-threonine

Figure imgb0026
Fp. 119°C, Ausbeute 47% der Theorie.
Figure imgb0026
 Mp 119 ° C, yield 47% of theory.

Figure imgb0027
(c=0,5; Dimethylformamid).
Figure imgb0027
 (c = 0.5; dimethylformamide).

Für C25H25ClN2O8

Figure imgb0028
For C 25 H 25 ClN 2 O 8
Figure imgb0028

Beispiel 7Example 7 N-ACE-PhenylalaninN-ACE phenylalanine

Figure imgb0029
Fp. 174°C, Ausbeute 57,8% der Theorie.
Figure imgb0029
 Mp 174 ° C, yield 57.8% of theory.

[α]20 D = +4,9 (c = 0,5; Dimethylformamid).[α] 20 D = +4.9 (c = 0.5; dimethylformamide).

Für C30H27ClN2O7

Figure imgb0030
For C 30 H 27 ClN 2 O 7
Figure imgb0030

Beispiel 8Example 8 N-ACE-AlaninN-ACE alanine

Figure imgb0031
Fp. 140°C, Ausbeute 48% der Theorie.
Figure imgb0031
 Mp 140 ° C, yield 48% of theory.

[a]ö =-4,6 (c=0,5; Dimethylformamid).[a] ö = -4.6 (c = 0.5; dimethylformamide).

Für C24H23ClN2O7

Figure imgb0032
For C 24 H 23 ClN 2 O 7
Figure imgb0032

Beispiel 9Example 9 N-ACE-PhenylglycinN-ACE phenylglycine

Figure imgb0033
Fp. 179 bis 182°C, Ausbeute 57,6% der Theorie.
Figure imgb0033
 Mp 179 to 182 ° C, yield 57.6% of theory.

[α]20 D = +61,8 (c = 0,5; Dimethylformamid).[α] 20 D = +61.8 (c = 0.5; dimethylformamide).

Für C29H25ClN2O7

Figure imgb0034
For C 29 H 25 ClN 2 O 7
Figure imgb0034

Beispiel 10Example 10 N―ACE-DL-O-MethylserinN ― ACE-DL-O-methylserine

Figure imgb0035
Fp. 96°C, Ausbeute 39% der Theorie.
Figure imgb0035
 Mp 96 ° C, yield 39% of theory.

[α]20 D= 0 (c=0,5%: Dimethylformamid).[α] 20 D = 0 (c = 0.5%: dimethylformamide).

Für C25H25CIN2O8

Figure imgb0036
For C 25 H 25 CIN 2 O 8
Figure imgb0036

Beispiel 1 1Example 1 1 N__ ACE__DL-SerinmethylamidN__ ACE__DL-serine methyl amide

Figure imgb0037
Fp. 141°C, Ausbeute 42,3% der Theorie.
Figure imgb0037
 Mp 141 ° C, yield 42.3% of theory.

[α]20 D = +3,2 (c = 0,5; Dimethylformamid).[α] 20 D = +3.2 (c = 0.5; dimethylformamide).

Für C25H26CIN307

Figure imgb0038
For C 25 H 26 CIN 3 07
Figure imgb0038

Beispiel 12Example 12 ACE-2,4,5-TrichlorphenylesterACE-2,4,5-trichlorophenyl ester

Figure imgb0039
2 g (0,0048 Mol) ACE-OH und 1 g (0,0051 Mol) 2,4,5-Trichlorphenol werden in 25 ml Tetrahydrofuran gelöst, mit 1 g (0,0048 Mol) Dicyclohexylcarbodiimid versetzt und 1,5 Stunden bei Raumtemperatur gerührt. Anschließend wird der ausgefallene Dicyclohexylharnstoff abgesaugt, die Lösung eingedampft und mit 20 ml Ethanol verrieben. Nach beendeter Kristallisation wird abgesaugt und der Kristallbrei mit Ethanol und Petrolether gewaschen.
Figure imgb0039
 2 g (0.0048 mol) of ACE-OH and 1 g (0.0051 mol) of 2,4,5-trichlorophenol are dissolved in 25 ml of tetrahydrofuran, 1 g (0.0048 mol) of dicyclohexylcarbodiimide and 1.5 hours stirred at room temperature. The precipitated dicyclohexylurea is then suctioned off, the solution is evaporated and triturated with 20 ml of ethanol. After crystallization is suctioned off and the crystal slurry is washed with ethanol and petroleum ether.

Fp. 132 bis 134°C, Ausbeute 2,3 g = 80,4% der Theorie.Mp 132 to 134 ° C, yield 2.3 g = 80.4% of theory.

Es handelt sich um ein Zwischenprodukt für die Herstellung der folgenden Verbindungen.It is an intermediate for the preparation of the following compounds.

Beispiel 13Example 13 N__ ACE- HistidinmethylesterN__ ACE histidine methyl ester

Figure imgb0040
4,86 g (0,02 Mol) L-Histidinmethylesterdihydrochlorid und 8,3 ml (0,06 Mol) Triethylamin werden in 100 ml Dimethylformamid gelöst und bei -10°C mit 5,67 g (0,02 Mol) der im Beispiel 12 beschriebenen Verbindung versetzt.
Figure imgb0040
 4.86 g (0.02 mol) of L-histidine methyl ester dihydrochloride and 8.3 ml (0.06 mol) of triethylamine are dissolved in 100 ml of dimethylformamide and at -10 ° C with 5.67 g (0.02 mol) of the Example 12 compound added.

Nach mehrstündigem Rühren und Stehen bei Raumtemperatur wird der Ansatz mit Wasser verdünnt und mehrfach mit Ethylenchlorid extrahiert. Die Ethylenchloridlösung wird mit nHCI ausgeschüttelt und mit Wasser neutralgewaschen. Die organische Phase wird anschließend über Na2S04 getrocknet, filtriert und eingedampft. Der Rückstand wird in Chloroform/Methanol (9:1) an Kieselgel gereinigt.After stirring for several hours and standing at room temperature, the mixture is diluted with water and extracted several times with ethylene chloride. The ethylene chloride solution is shaken out with nHCI and washed neutral with water. The organic phase is then dried over Na 2 S0 4 , filtered and evaporated. The residue is purified in chloroform / methanol (9: 1) on silica gel.

Fp. 119°C, Ausbeute 3,7 g = 34% der Theorie.Mp 119 ° C, yield 3.7 g = 34% of theory.

[α]20 D = +3,5 (c = 3,5; Dimethylformamid).[α] 20 D = +3.5 (c = 3.5; dimethylformamide).

Für C28H27CIN4O7

Figure imgb0041
For C 28 H 27 CIN 4 O 7
Figure imgb0041

Beispiel 14Example 14 N-ACE-SerinbenzylesterN-ACE serine benzyl ester

Figure imgb0042
analog Beispiel 13 unter Verwendung von L-Serinbenzylester.
Figure imgb0042
 analogously to Example 13 using L-serine benzyl ester.

Fp. 158 bis 159°C, Ausbeute 67% der Theorie.Mp 158-159 ° C, yield 67% of theory.

[α]20 D = 10,9 (c=0,5; Dimethylformamid).[α] 20 D = 10.9 (c = 0.5; dimethylformamide).

Für C31H29CIN2O8

Figure imgb0043
For C 31 H 29 CIN 2 O 8
Figure imgb0043

Beispiel 15Example 15 O__ ACE__N-Boc-SerinmethylesterO__ ACE__N-Boc serine methyl ester

Figure imgb0044
4,15 g (0,01 Mol) ACE-OH werden in 15 ml Tetrahydrofuran gelöst, mit 1,78 g (0,011 Mol) 1,1'-Carbodiimidazol) versetzt und bis zur Beendigung der C02 Entwicklung gerührt.
Figure imgb0044
 4.15 g (0.01 mol) of ACE-OH are dissolved in 15 ml of tetrahydrofuran, mixed with 1.78 g (0.011 mol) of 1,1'-carbodiimidazole) and stirred until the CO 2 evolution has ended.

In dieser Lösung wird eine Lösung von 2,25 g (0,01 Mol) N-Bac-Serinmethylester in 10 ml Tetrahydrofuran in Gegenwart katalytischer Mengen von Natriumhydrid hinzugefügt und 7 Stunden bei 35°C gerührt. Anschließend wird die Lösung bei 3 Torr eingedampft, der Rückstand wird in Ethylacetat aufgenommen und an Kieselgel gereinigt. Die Verbindung ist ein Öl. Ausbeute 5,1 g (=82% der Theorie).In this solution, a solution of 2.25 g (0.01 mol) of N-Bac serine methyl ester in 10 ml of tetrahydrofuran is added in the presence of catalytic amounts of sodium hydride and the mixture is stirred at 35 ° C. for 7 hours. The solution is then evaporated at 3 torr, the residue is taken up in ethyl acetate and purified on silica gel. The compound is an oil. Yield 5.1 g (= 82% of theory).

Beispiel 16Example 16 0__ ACE- Serinmethylestertrifluoracetat0__ ACE serine methyl ester trifluoroacetate

Figure imgb0045
Die Verbindung entsteht in bekannter Weise durch Versetzen der Verbindung aus Beispiel 15 mit Trifluoressigsäure.
Figure imgb0045
 The compound is formed in a known manner by adding trifluoroacetic acid to the compound from Example 15.

Fp. 69 bis 70°C, Ausbeute 65% der Theorie.Mp 69 to 70 ° C, yield 65% of theory.

[α]20 D = +0,8 (c = 0,5; Dimethylformamid).[α] 20 D = +0.8 (c = 0.5; dimethylformamide).

Für C25H25CIN2O8. C2HF302

Figure imgb0046
For C 25 H 25 CIN 2 O 8 . C 2 HF 3 0 2
Figure imgb0046

Beispiel 17Example 17 O__ ACE__N-Boc-SerinethylesterO__ ACE__N-Boc-Serine ethyl ester

Figure imgb0047
analog Beispiel 15 aus 10,15 g ACE-OH und 5,7 g Boc-Serinethylester.
Figure imgb0047
 analogous to Example 15 from 10.15 g ACE-OH and 5.7 g Boc-Serinethylester.

Fp. 99 bis 100°C, Ausbeute 6,2 g (Rohprodukt).Mp 99 to 100 ° C, yield 6.2 g (crude product).

Beispiel 18Example 18 O__ ACE-SerinethylestertrifluoracetatO__ ACE serine ethyl ester trifluoroacetate

Figure imgb0048
Analog Beispiel 16 aus der in Beispiel 17 beschriebenen Verbindung.
Figure imgb0048
 Analogously to Example 16 from the compound described in Example 17.

Fp. 56 bis 58°C, Ausbeute 77% der Theorie.Mp 56 to 58 ° C, yield 77% of theory.

[α]20 D =-2,4 (c = 0,5; Dimethylformamid).[α] 20 D = -2.4 (c = 0.5; dimethylformamide).

Für C26H27CIN2O8 . C2HF302

Figure imgb0049
For C 26 H 27 CIN 2 O8. C 2 HF 3 0 2
Figure imgb0049

Beispiel 19Example 19 N__ ACE- PhenylalanyltyrosinmethylesterN__ ACE-phenylalanyl tyrosine methyl ester

Figure imgb0050
Eine Suspension von 0,005 Mol Phenylalanyltyrosinmethylestertrifluoracetat in 15 ml absolutem Dimethylformamid wird unter Rühren bei 0°C zunächst mit 0,005 Mol Triethylamin und nach 10 Minuten mit 0,005 Mol ACE-2,4,5-trichlorphenylester versetzt. Nach 2-stündigem Rühren, zuletzt bei Raumtemperatur, wird das Reaktionsgemisch mit 150 ml Wasser versetzt, dreimal mit Ethylacetat extrahiert und die organische Phase dreimal mit nHCI-Lösung ausgeschüttelt. Anschließend wird die Lösung mit Wasser neutralgewaschen, über Na2S04 getrocknet und eingedampft. Nach Rekristallisation aus Aceton/Petrolether werden 84% der Theorie an N-ACE-Phenylalanyltyrosinmethylester vom Fp. 131 bis 132°C erhalten.
Figure imgb0050
 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.

[α]20 D = -5,2 (c = 0,5; Dimethylformamid).[α] 20 D = -5.2 (c = 0.5; dimethylformamide).

Für C40H38CIN3O9

Figure imgb0051
For C 40 H 38 CIN 3 O 9
Figure imgb0051

Beispiel 20Example 20 ACE-GlycylalanylphenylalaninmethylesterACE-Glycylalanylphenylalaninmethylester

Figure imgb0052
analog Beispiel 19 mit Glycylalanylphenylalaninmethylesterhydrochlorid; Fp. 145 bis 147°C (aus Isopropanol); Ausbeute 83% der Theorie.
Figure imgb0052
 analogously to Example 19 with glycylalanylphenylalanine methyl ester hydrochloride; Mp 145-147 ° C (from isopropanol); Yield 83% of theory.

[α]20 D = -7,2 (c = 0,5; Dimethylformamid).[α] 20 D = -7.2 (c = 0.5; dimethylformamide).

Für C36H37CIN4O9

Figure imgb0053
For C 36 H 37 CIN 4 O 9
Figure imgb0053

Beispiel 21Example 21 a) N-α-Formyl-N-γ-benzyloxycarbonyldiaminobutyrylphenylalaninhydrazida) N-α-Formyl-N-γ-benzyloxycarbonyldiaminobutyrylphenylalanine hydrazide

53 g (0,12 Mol) N-α-Formyl-N-γ-benzyloxycarbonyldiaminobutyrylphenylalaninmethylester werden bei 40°C in 400 ml Methanol gelöst und mit 10 g (ca. 0,16 Mol) 80 %igem Hydrazinhydrat versetzt. Nach 24-stündigem Stehen bei Raumtemperatur wird der ausgefallene Niederschlag abgesaugt, die Mutterlauge auf 50 ml eingeengt und erneut zur Kristallisation gebracht.

  • Fp. 205 bis 207°C (aus wäßrigem Dimethylformamid);
  • Ausbeute 50 g = 94% der Theorie;
  • [α]20 D = 11,5 (c = 2; Dimethylformamid).
  • Für C22H27N5O5
    Figure imgb0054
53 g (0.12 mol) of N-α-formyl-N-γ-benzyloxycarbonyldiaminobutyrylphenylalanin methyl ester are dissolved in 400 ml of methanol at 40 ° C. and 10 g (approx. 0.16 mol) of 80% hydrazine hydrate are added. After standing at room temperature for 24 hours, the precipitate which has separated out is filtered off with suction, the mother liquor is concentrated to 50 ml and brought to crystallization again.
  • Mp. 205 to 207 ° C (from aqueous dimethylformamide);
  • Yield 50 g = 94% of theory;
  • [α] 20 D = 11.5 (c = 2; dimethylformamide).
  • For C 22 H 27 N 5 O 5
    Figure imgb0054

b) N-α-Formyl-N-γ-benzyloxycarbonyldiaminobutyrylphenylalanylphenylalaninmethylesterb) N-α-formyl-N-γ-benzyloxycarbonyldiaminobutyrylphenylalanylphenylalaninmethylester

88,3 g (0,2 Mol) der vorstehend unter a) beschriebenen Verbindungen werden unter Erwärmen in 1000 ml Dimethylformamid gelöst und mit 20 ml Eisessig und 400 ml nHCI vermischt. Nach Abkühlen auf -10°C werden zunächst langsam 14,4 g (0,208 Mol) Natriumnitrit in 60 ml Wasser und anschließend eine vorgekühlte Lösung von 35,8 g (0,02 Mol) L-Phenylalaninmethylesterhydrochlorid, gelöst in 200 ml Dimethylformamid, hinzugefügt. Die Reaktionslösung wird mit etwa 54 g Triethylamin neutralgestellt und 24 Stunden im Kühlschrank aufbewahrt. Nach Aufschlämmen mit doppelter Menge Wasser wird der ausgefallene Niederschlag abfiltriert, mit n Salzsäure und Wasser gewaschen, getrocknet und aus Methanol rekristallisiert.

  • Fp. 179 bis 181°C, Ausbeute 106 g = 92% der Theorie;
  • [α]20 D =-22,5 (c = 2; Dimethylformamid).
  • Für C32H36N407
    Figure imgb0055
88.3 g (0.2 mol) of the compounds described above under a) are dissolved with heating in 1000 ml of dimethylformamide and mixed with 20 ml of glacial acetic acid and 400 ml of nHCl. After cooling to -10 ° C., 14.4 g (0.208 mol) of sodium nitrite in 60 ml of water are first slowly added, followed by a precooled solution of 35.8 g (0.02 mol) of L-phenylalanine methyl ester hydrochloride, dissolved in 200 ml of dimethylformamide . The reaction solution is neutralized with about 54 g of triethylamine and stored in the refrigerator for 24 hours. After slurrying with double the amount of water, the precipitate is filtered off, washed with n hydrochloric acid and water, dried and recrystallized from methanol.
  • Mp 179 to 181 ° C, yield 106 g = 92% of theory;
  • [α] 20 D = -22.5 (c = 2; dimethylformamide).
  • For C 32 H 36 N 4 0 7
    Figure imgb0055

c) N-y-Benzyloxycarbonyldiaminobutyrylphenylalanylphenylalaninmethylesterhydrochloridc) N-y-benzyloxycarbonyldiaminobutyrylphenylalanylphenylalanin methyl ester hydrochloride

52 g (0.0885 Mol) der vorstehend unter b) beschriebenen Verbindung werden in 150 ml Methanol und 35 ml n methanolischer HCI suspendiert und 20 Stunden bei Raumtemperatur gerührt. Die nunmehr klare Lösung wird eingedampft und der Rückstand aus Methanol/Ether rekristallisiert.

  • Fp. 220 bis 222°C, Ausbeute 29 g (= 54% der Theorie).
  • [α]20 D = +1,65 (c = 2; Dimethylformamid).
  • Für C31H37CIN4O6. 1/2 H20
    Figure imgb0056
52 g (0.0885 mol) of the compound described above under b) are suspended in 150 ml of methanol and 35 ml of methanolic HCl and stirred for 20 hours at room temperature. The now clear solution is evaporated and the residue is recrystallized from methanol / ether.
  • Mp 220-222 ° C, yield 29 g (= 54% of theory).
  • [α] 20 D = +1.65 (c = 2; dimethylformamide).
  • For C 31 H 37 CIN 4 O 6 . 1/2 H 2 0
    Figure imgb0056

d) N-a-ACE-N-y-Benzyloxycarbonyldiaminobutyrylphenylalanylphenylalaninmethylesterd) N-a-ACE-N-y-benzyloxycarbonyldiaminobutyrylphenylalanylphenylalanin methyl ester

Figure imgb0057
analog Beispiel 19 aus vorstehend unter c) beschriebener Verhindung und ACE-2,4,5-Trichlorphenylester.

  • Fp. 224 bis 227°C (aus Dioxan/Ether 2:1); Ausbeute 69% der Theorie.
  • [α]20 D =-20,6 (c=0,5; Dimethylformamid).
  • Für C52H52CIN5O11
    Figure imgb0058
Figure imgb0057
 analogous to Example 19 from the prevention described above under c) and ACE-2,4,5-trichlorophenyl ester.
  • Mp 224-227 ° C (from dioxane / ether 2: 1); Yield 69% of theory.
  • [α] 20 D = -20.6 (c = 0.5; dimethylformamide).
  • For C 52 H 52 CIN 5 O 11
    Figure imgb0058

Claims (3)

1. Indolylacetoxyacetylaminoacetic acid derivatives of the general formula (I)
Figure imgb0065
in which
m and n represent the numbers 0 or 1,
X represents a -NH- or __OCH2__ group,
R1, R2 and R3 are identical or different and each represent hydrogen, an alkyl with 1 to 5 carbon atoms optionally substituted by hydroxy, alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms or by phenalkyloxycarbonylamino with 1 to 4 carbon atoms in the alkyl part, or represents a phenyl or phenalkyl group with 1 to 4 carbon atoms in the alkyl part, the phenyl rings optionally being substituted by trifluoromethyl, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen or represents a heterocyclic methyl group with 5 to 6 ring members, in which 1 or 2 members can be replaced by nitrogen and to which a benzene ring is optionally fused, or in the case where m and n each represent 0, R, additionally represents an amino group, an alkoxycarbonylamino group or a phenalkoxycarbonylamino group with in each case 1 to 5 carbon atoms in the alkoxy part,
R4 represents hydroxy, alkoxy with 1 to 4 carbon atoms, phenalkoxy with 1 to 4 carbon atoms in the alkoxy part, amino, alkylamino with 1 to 4 carbon atoms in the alkyl part, benzylamino or phenylamino,

and their physiologically acceptable salts appropriately formed with acids and bases.
2. Process for the preparation of indolylacetoxyacetylaminoacetic acid derivatives of the general formula (I) according to Claim 1, characterised in that
a) [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyllacetoxyacetic acid (designated ACE-OH in the following) is reacted with chloroformic acid esters of the general formula
Figure imgb0066
in which
Rs represents an alkyl group with 1 to 5 carbon atoms,

to give mixed anhydrides of the general formula (III)
Figure imgb0067
in which
R5 has the meaning indicated above,

and these are reacted with compounds of the general formula (IV)
Figure imgb0068
in which
m, n and R1 to R4 have the meaning indicated in Claim 1, or
b) the compound ACE-OH is subjected to a condensation reaction with an appropriately substituted phenol to give an activated ester of the general formula (V)
Figure imgb0069
in which
Y represents 2 to 5 halogen atoms or 1 to 2 nitro groups,

and the activated ester is reacted with compounds of the general formula (IV) or
c) in the case where aminoacid derivatives containing hydroxyl groups are to be linked in an ester- like manner, the compound ACE-OH is reacted with compounds of the general formula (VI)
Figure imgb0070
in which
R4 has the meaning indicated above and
R6 represents an amino-protective group which is customary in peptide chemistry,

and the radical R4 is then split off in a known manner, and the compounds of the general formula (I) thus obtained are optionally converted into the physiologically acceptable salts using acids and bases.
3. Medicaments containing at least one indolylacetoxyacetylaminoacetic acid derivative according to Claim 1.
EP78100523A 1977-08-06 1978-07-27 Indolacetoxyacetylaminoacid derivatives, process for their preparation and their use in drugs Expired EP0000741B1 (en)

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DE3034005C2 (en) * 1980-09-10 1982-12-09 A. Nattermann & Cie GmbH, 5000 Köln Indole acetic acid derivatives, process for their preparation and pharmaceutical preparations containing them
DE3206887A1 (en) * 1982-02-26 1983-09-15 Troponwerke GmbH & Co KG, 5000 Köln METHOD FOR THE PRODUCTION OF 1- (4-CHLOROBENZOYL) -5-METHOXY-2-METHYL-3-INDOLACETOXYACETIC ACID
DE3206885A1 (en) * 1982-02-26 1983-09-15 Troponwerke GmbH & Co KG, 5000 Köln INDOLDER DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS
JPS59204172A (en) * 1983-04-28 1984-11-19 Kowa Co Preparation of acemetacin
JPH0417306Y2 (en) * 1984-12-26 1992-04-17
EP0382854B1 (en) * 1988-07-05 1994-12-14 Zeria Pharmaceutical Co., Ltd. Indoleacetic acid derivatives, process for their preparation, and medicines containing same as active ingredients
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
CA2562783A1 (en) 2004-04-26 2005-12-01 Vanderbilt University Indoleacetic acid and indenacetic acid derivatives as therapeutic agents with reduced gastrointestinal toxicity
EP1604656A1 (en) 2004-06-09 2005-12-14 Schwarz Pharma Ag Novel use of peptide compounds for treating amyotrophic lateral sclerosis (ALS)
WO2007149456A2 (en) 2006-06-19 2007-12-27 Vanderbilt University Methods and compositions for diagnostic and therapeutic targeting of cox-2
EP2768499A4 (en) 2011-10-17 2015-08-26 Univ Vanderbilt Indomethacin analogs for the treatment of castrate-resistant prostate cancer

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