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 as medicaments, in particular as anti-inflammatories and anti-inflammatory drugs.
• an optionally substituted alkyl group for R 1 to R 3 preferably denotes a straight-chain or branched-chain alkyl group having up to 5 carbon atoms.
• Examples include the methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups, especially the methyl, ethyl and isobutyl group.
• halogen atoms in particular by chlorine, bromine, fluorine, hydroxyl, mercapto, alkoxy or alkylthio groups, amino groups, acylamino groups, carboxyl groups and nitro groups, the alkyl, alkoxy and acyl groups mentioned up to 4 C - Contain atoms, in particular hydroxyl, amino, marcapto, methoxy and methyl mercapto groups.
• An optionally substituted aralkyl group for R 1 to R 3 preferably denotes the benzyl group, phenylethyl group or phenylisopropyl group, in particular the benzyl group; it can be substituted by 1 to 2 hydroxyl groups, lower alkoxy groups having 1 to 4 carbon atoms, nitro groups, halogen atoms, preferably by a hydroxyl group.
• An optionally substituted Heterocyclusmethyl administrat for R 1 to R 3 is preferably a thenyl, Pyrrolmethyl-, -pyrrolidinylmethyl-, P iperidinmethyl-, Indolmethyl-, imidazolemethyl-, Chinolinmethyl distr, in particular the Indolylnethyl distr and Imidazolmethyl distr; it can be substituted, preferably by halogen atoms, lower alkyl or alkoxy groups having 1 to 4 carbon atoms or nitro groups.
• An optionally substituted amino group for R 1 is preferably an acylamino group, in particular a lower alkoxycarbonyl group with up to 5 carbon atoms or a benzyloxycarbonyl group.
• An optionally substituted aryl group for R 1 to R 3 preferably denotes a phenyl or naphthyl group which is optionally monosubstituted to trisubstituted by halogen atoms, hydroxyl groups, alkoxy groups having up to 4 carbon atoms, nitro groups, trifluoromethyl groups and / or lower alkyl groups having up to 4 carbon atoms is.
• An optionally substituted alkoxy group for R 4 preferably represents an alkoxy group having 1 to 4 carbon atoms, in particular a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyloxy group, which in turn can be mono- to trisubstituted by halogen atoms, hydroxyl groups and / or alkoxy groups having up to 4 carbon atoms.
• An optionally substituted aralkoxy group for R 4 means in particular the benzyl, phenylethyl, phenylpropyl, phenylisopropyloxy group, preferably the benzyloxy group; it can be substituted by 1 to 2 halogen atoms or alkoxy groups having 1 to 2 carbon atoms.
• An optionally substituted arylamino group for R 4 preferably denotes the phenylamino group, which can be substituted by halogen atoms, alkyl or alkoxy groups having 1 to 4 carbon atoms or by a trifluoromethyl group.
• An optionally substituted aralkylamino group for R 4 is in particular a benzyl, phenylethyl, phenylpropyl or phenylisopropylamino group, which can also be substituted as described above for the arylamino group.
• 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-hydroxyethylammonium 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 show a more advantageous active ingredient than the indomethacinserine derivatives of DOS 2 413 125 known from the prior art.
• the compounds according to the invention thus represent an enrichment of pharmacy.
• reaction sequence of variant a) can be represented by the following formula:
• chloroformic acid esters of the general formula (II) 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 (III) formed as an intermediate are new, but cannot be identified because, 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 tetrahydrofuan, 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 hydroxides and carbonates or organic bases such as pyridine and triethylarin.
• reaction temperatures are expediently below 0 ° C., since otherwise racemizations occur; they can be varied within a certain range. In general, mar works at temperatures between O o to -25 o 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 known in a manner known per se by reacting 1 mol of ACE-OH and 1 M cl of the correspondingly substituted phenol in a polar aprotic organic solvent, such as, for example, tetrahydrofuran. in the presence of 1 mole of a carbodiimide, such as D icyclohexycarbodiimid or carbonyldiimidazole are obtained in approximately 1 1/2 hours of reaction at room temperature.
• a polar aprotic organic solvent such as, for example, tetrahydrofuran.
• 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 mixtures thereof 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 anines, preferably triethylamine.
• the reaction temperatures can be varied within a certain range. Normally one works at 15-25 ° C, since the reaction times are extended disproportionately 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 xol of the amino acid derivative (IV) is preferably used per mole of the activated ester (V).
• the 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. Examples include dicyclohexylcarbodiinide 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.
• 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 the CO 2 evolution has ended.
• Working up is carried out in the usual way, 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 compounds can be converted in a known manner into the customary formulations, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, solutions, ointments, gels, creams, jellies, using inert, non-toxic; pharmaceutically acceptable 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 pre-stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as a diluent, organic solvents can optionally be used as auxiliary solvents.
• the application takes place in the usual way, preferably orally or parenterally, lckally, intramuscularly or intravenously.
• tablets in addition to the carrier substances mentioned, can also contain additives such as sodium citrate, calcium carbomate and dicalcium phosphate, together with various additives such as starch, preferably potato starch, gelatin and the like. Glidants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
• aqueous suspensions and / or. ' Elixirs which are intended for oral applications, can be mixed with various flavor enhancers or colorants in addition to the additives 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.
• a suspension of 0.005 mol of phenylalanyl tyrosine methyl ester trifluoroacetate in 15 ml 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 two hours, finally at room temperature, the reaction mixture is mixed with 150 ml of water, extracted three times with xthylacetate and the organic phase is extracted three times with nHCl solution. The solution is then washed neutral with water, dried over Na 2 SO 4 and evaporated.
• N ⁇ -Forryl-N ⁇ -benzyloxycarbonyldiaminobutyrylphenylahanyl phenylalanimethyl
• N ⁇ -ACE-N ⁇ -Benznloxvcarbonyldiaminobutyrylphenylalany1 phenylalanine methyl ester

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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)

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• 1977
  • 1977-08-06 DE DE19772735537 patent/DE2735537A1/de not_active Withdrawn
• 1978
  • 1978-07-27 EP EP78100523A patent/EP0000741B1/fr not_active Expired
  • 1978-07-27 DE DE7878100523T patent/DE2860858D1/de not_active Expired
  • 1978-08-04 JP JP9469878A patent/JPS5430160A/ja active Pending
  • 1978-08-04 IT IT7826537A patent/IT7826537A0/it unknown

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