EP0000741A2 - 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 PDFInfo
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- EP0000741A2 EP0000741A2 EP7878100523A EP78100523A EP0000741A2 EP 0000741 A2 EP0000741 A2 EP 0000741A2 EP 7878100523 A EP7878100523 A EP 7878100523A EP 78100523 A EP78100523 A EP 78100523A EP 0000741 A2 EP0000741 A2 EP 0000741A2
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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 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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Abstract
Description
Die vorliegende Erfindung betrifft neue Indolacetoxyacetylaminosäurederivate, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel, insbesondere als Entzündungshemmer und Antirheumatika.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.
Die Erfindung betrifft neue Indolylacetoxyacetylaminoessigsäurederivate der allgemeinen Formel .
- m und n für die Ziffern O oder 1 stehen,
- X für eine -NH- oder -OCH2-Gruppe steht,
- R1,R2 und R3 gleich oder verschieden sein können und für ein Wasserstoffatom, eine gegebenenfalls substituierte Alkylgruppe, eine gegebenenfalls substituierte Arylgruppe, eine gegebenenfalls substituierte Aralkylgruppe, eine gegebenenfalls substituierte Heterocyclusmethylgruppe mit 1 oder 2 Ringen und mit je 5, 6 oder 7 Ringgliedern, in denen 1 oder 2 Glieder durch Heteroatome ersetzt sein können, und für den Fall, daß m und n für die Ziffer O stehen,
- R1 für eine Aminogruppe, eine Alkoxycarbonylgruppe oder eine Aralkoxycarbonylgruppe steht,
- R4 für eine Hydroxygruppe oder für eine gegebenenfalls substituierte Alkoxygruppe, eine gegebenenfalls substituierte Aralkoxygruppe, eine Aminogruppe oder eine gegebenenfalls substituierte Alkylaminogruppe, eine gegebenenfalls substituierte Aralkylaminogruppe, eine gegebenenfalls substituierte Arylaminogruppe steht,
sowie deren gegebenenfalls mit Säuren und Basen gebildeten physiologisch verträglichen Salze.
- m and n stand for the digits O or 1,
- X represents an -NH or -OCH 2 group,
- R 1 , R 2 and R 3 may be the same or different and represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted heterocycle methyl group with 1 or 2 rings and each with 5, 6 or 7 Ring members in which 1 or 2 members can be replaced by heteroatoms, and in the event that m and n stand for the number O,
- R 1 represents an amino group, an alkoxycarbonyl group or an aralkoxycarbonyl group,
- R 4 represents a hydroxyl group or an optionally substituted alkoxy group, an optionally substituted aralkoxy group, an amino group or an optionally substituted alkylamino group, an optionally substituted aralkylamino group, an optionally substituted arylamino group,
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 (I), in welcher X, m, n und R1 bis R4 die oben angeführte Bedeutung haben, erhält, wenn man
- a) [1-(4-Chlorbenzoyl)-5-methoxy-2-methyl-3-indoly1]acetoxy- essigsäure (nachfolgend als ACE-OH bezeichnet) mit Chlorameisensäureestern der allgemeinen Formel
- R5 für eine Alkylgruppe steht, zu gemischten Anhydriden der allgemeinen Formel
- R5 die oben angegebene Bedeutung hat, umsetzt und diese mit Verbindungen der allgemeinen Formel
- m, n, R1 bis R4 die oben angeführte Bedeutung haben, zur Reaktion bringt
oder - R5 für eine Alkylgruppe steht, zu gemischten Anhydriden der allgemeinen Formel
- b) die Verbindung ACE-OH mit einem entsprechend substituierten Phenol zu einem aktivierten Ester der allgemeinen Formel
- Y für 2 bis 5 Halogenatome, 1 bis 2 Nitrogruppen oder für mehrere andere Elektronen-anziehende Gruppen steht,
kondensiert und mit Verbindungen der allgemeinen Formel (IV), in welcher m, n, R1 bis R4 die oben angeführte Bedeutung haben, umsetzt
oder - c) für den Fall, daß Hydroxylgruppen enthaltende Aminosäurederivate esterartig verknüpft werden sollen, die Verbindung ACE-OH mit Verbindungen der allgemeinen Formel
- R4 die oben angeführte Bedeutung hat und
- R6 für eine in der Peptidchemie übliche Aminoschutzgruppe, beispielsweise für eine Alkoxycarbonyl-oder eine Aralkoxycarbonylgruppe steht, umsetzt und anschließend den Rest R4 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 (I) according to the invention in which X, m, n and R 1 to R 4 have the meaning given above are obtained if
- a) [1- (4-Chlorobenzoyl) -5-methoxy-2-methyl-3-indoly1] acetoxyacetic acid (hereinafter referred to as ACE-OH) with chloroformic acid esters of the general formula
- R 5 represents an alkyl group, to mixed anhydrides of the general formula
- R 5 has the meaning given above, and this with compounds of the general formula
- m, n, R 1 to R 4 have the meaning given above, brings about the reaction
or - R 5 represents an alkyl group, to mixed anhydrides of the general formula
- b) the compound ACE-OH with a correspondingly substituted phenol to an activated ester of the general formula
- Y represents 2 to 5 halogen atoms, 1 to 2 nitro groups or for several other electron-attracting groups,
condensed and reacted with compounds of the general formula (IV) in which m, n, R 1 to R 4 have the meaning given above
or - c) in the event that amino acid derivatives containing hydroxyl groups are to be linked in an ester-like manner, the compound ACE-OH with compounds of the general formula
- R 4 has the meaning given above and
- R 6 is an amino protective group which is customary in peptide chemistry, for example an alkoxycarbonyl or an aralkoxycarbonyl group, and then the radical R 4 is split off in a known manner
and optionally the compounds of the general formula (I) thus obtained are converted into the physiologically tolerable salts with acids and bases.
In der allgemeinen Formel (I) bedeutet eine gegebenenfalls substituierte Alkylgruppe für R, bis R3 vorzugsweise eine gerade- oder verzweigtkettige Alkylgruppe mit bis zu 5 C-Atomen. Beispielhaft seien genannt die Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl- und Isobutylgruppen, insbesondere die Methyl-, Äthyl- und Isobutylgruppe. Sie ist vorzugsweise substituiert durch Halogenatome, insbesondere durch Chlor, Brom, Fluor, Hydroxy-, Mercapto-, Alkoxy- bzw. Alkylthiogruppen, Aminogruppen, Acylaminogruppen, Carboxylgruppen und Nitrogruppen, wobei die genannten Alkyl-, Alkoxy- und Acylgruppen bis zu 4 C-Atome enthalten, insbesondere Hydroxy-, Amino-, Marcapto-, Methoxy-und Methylmercaptogruppen.In the general formula (I), 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. It is preferably substituted by 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.
Eine gegebenenfalls substituierte Aralkylgruppe für R1 bis R3 bedeutet vorzugsweise die Benzylgruppe, Phenyläthylgruppe oder Phenylisopropylgruppe, insbesondere die Benzylgruppe; sie kann substituiert sein durch 1 bis 2 Hydroxygruppen, niedere Alkoxygruppen mit 1 bis 4 C-Atomen, Nitrogruppen, Halogenatome, vorzugsweise durch eine Hydroxygruppe.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.
Eine gegebenenfalls substituierte Heterocyclusmethylgruppe für R1 bis R3 bedeutet vorzugsweise eine Thenyl-, Pyrrolmethyl-, Pyrrolidinylmethyl-, Piperidinmethyl-, Indolmethyl-, Imidazolmethyl-, Chinolinmethylgruppe, insbesondere die Indolylnethylgruppe und Imidazolmethylgruppe; sie kann substituiert sein vorzugsweise durch Halogenatome, niedere Alkyl- bzw. Alkoxygruppen mit 1 bis 4 Kohlenstoffatomen oder Nitrogruppen.An optionally substituted Heterocyclusmethylgruppe for R 1 to R 3 is preferably a thenyl, Pyrrolmethyl-, -pyrrolidinylmethyl-, P iperidinmethyl-, Indolmethyl-, imidazolemethyl-, Chinolinmethylgruppe, in particular the Indolylnethylgruppe and Imidazolmethylgruppe; it can be substituted, preferably by halogen atoms, lower alkyl or alkoxy groups having 1 to 4 carbon atoms or nitro groups.
Eine gegebenenfalls substituierte Aminogruppe für R1 bedeutet vorzugsweise eine Acylaminogruppe, insbesondere eine niedere Alkoxycarbonylgruppe mit bis zu 5 C-Atomen oder eine Benzyloxycarbonylgruppe.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.
Eine gegebenenfalls substituierte Arylgruppe für R1 bis R3 bedeutet vorzugsweise eine Phenyl- oder Naphthylgruppe, die gegebenenfalls durch Halogenatome, Hydroxylgruppen, Alkoxygruppen mit bis zu 4 Kohlenstoffatomen, Nitrogruppen, Trifluormethylgruppen und/oder niedere Alkylgruppen mit bis zu 4 Kohlenstoffatomen ein- bis dreifach substituiert ist.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.
Eine gegebenenfalls substituierte Alkoxygruppe für R4 steht vorzugsweise für eine Alkoxygruppe mit 1 bis 4 C-Atomen, insbesondere für eine Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, sekundäre Butyl- oder tertiäre Butyloxygruppe, welche ihrerseits durch Halogenatome, Hydroxygruppen und/oder Alkoxygruppen mit bis zu 4 Kohlenstoffatomen ein-.bis dreifach substituiert sein können.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.
Eine gegebenenfalls substituierte Aralkoxygruppe für R4 bedeutet insbesondere die Benzyl-, Phenyläthyl-, Phenylpropyl-, Phenylisopropyloxygruppe, vorzugsweise die Benzyloxygruppe; sie kann substituiert sein durch 1 bis 2 Halogenatome oder Alkoxygruppen mit 1 bis 2 Kohlenstoffatomen.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.
Eine gegebenenfalls substituierte Arylaminogruppe für R4 bedeutet vorzugsweise die Phenylaminogruppe, welche durch Halogenatome, Alkyl- bzw. Alkoxygruppen mit 1 bis 4 Kohlenstoffatomen oder durch eine Trifluormethylgruppe substituiert sein kann.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.
Eine gegebenenfalls substituierte Aralkylaminogruppe für R4 steht insbesondere für eine Benzyl-, Phenyläthyl-, Phenylpropyl- oder Phenylisopropylaminogruppe,welche ebenfalls wie vorstehend für die Arylaminogruppe beschrieben substituiert sein kann.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.
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-Hydroxyäthylammoniumsalz.Examples of such salts are preferably sodium salts, potassium, magnesium, ammonium, methylammonium, dimethylammonium salts or the 2-hydroxyethylammonium 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 Verbindurgen der allgemeinen Formel (I) eine vorteilhaftere Wirk- sankiet als die aus dem Stand der Technik bekannten Indometacinserinderivate der DOS 2 413 125.
Die erfindungsgemäßen Verbindungen stellen somit eine Bereicherung der Pharmazie dar.Surprisingly, 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.
Verwendet man ACE-OH und Chlorameisensäureester als Ausgangsverbindungen, so kann der Reaktionsablauf der Variante a) durch das folgende Formelschema wiedergegeben werden:
Die als Ausgangsverbindungen verwendbaren Chlorameisensäureester der allgemeinen Formel (II) sind bekannt und die als Ausgangsverbindung verwendeteACE-OH ist ebenfalls bekannt (DOS 2 234 651).The 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).
Die als Zwischenprodukt gebildeten gemischten Anhydride der allgemeinen Formel (III) sind neu, können aber nicht indentifiziert werden, da sie sich - wie auch der überwiegende Teil der literaturbekannten 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 (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).
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, Bd 15/1 u 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 (cf., 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 Tetrahydrofuan, 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 tetrahydrofuan, 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 Alkalihydroxyde und -carbonate oder organische Basen wie Pyridin und Triäthylarin.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 hydroxides and carbonates or organic bases such as pyridine and triethylarin.
Die Reaktionstemperaturen liegen zweckmäßigerweise unterhalb von 0° C, da andernfalls Racemisierungen auftreten; sie können in einen gewissen Bereich variiert werden. Im allgemeinen arbeitet mar bei Temperaturen zwischen Oo bis -25o C, vorzugsweise zwischen -10° und -20° C.The 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.
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 Xol 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 xol of the amino acid derivative and 1 mol of the acid binder.
Die Feaktionszeit 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:
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 Mcl des entsprechend substituierten Phenols in einem polar aprotischen organischen Lösungsmittel, wie z.B. Tetrahydrofuran, in Gegenwart von 1 Mol eines Carbodiimids, wie z.B. Dicyclohexycarbodiimid 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 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.
Das erfindungsgem'äße Verfahren (V) → (I) erfolgt zweckmäßig in Gegenwart von Verdünnungsmitteln. Als Verdünnungsmittel kommen die für diese Reaktion literaturbekannten 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 mixtures thereof with water.
Soweit Additionssalze von (IV) zu Peaktionen verwendet werden, erfolgt das Verfahren zweckmäßig in Gegenwart von Säurebindern. Beispielhaft seien genannt Alkalihydroxyde, -carbonate oder starke organische Anine, vorzugsweise Triäthylamin.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 anines, preferably triethylamine.
Die Reaktionstemperaturen können in einem gewissen Bereich variiert werden. Normalerweise arbeitet man bei 15-25° C, da bei niedrigeren Terperaturen die Reaktionszeiten unverhältnisräßig verlängert werden, bei höheren Temperaturen jedoch die Racematbildung gefördert wird. Eine gewisse Racematbildung ist auch bei der Reaktion bei Raumtemperatur nicht auszuschließen.*
Das Verfahren wird üblicherweise bei Normaldruck durchgeführt.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.
Bei der Durchführung des erfindungsgemäßen Verfahrens wird vorzugsweise pro Mol des aktivierten Esters(V).1 Xol des Aminosäurederivates (IV) eingesetzt. Die Aufarbeitung erfolgt zweckräßigerweise durch Verdünnen des Ansatzes mit Wasser, Aufnegmen in einem geeigneten organischen Lösungsmittel, Neutralisieren, Eindampfen und Rekristallisieren aus geeigneten Lösungsmitteln.When carrying out the process according to the invention, 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.
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:
Die als Ausgangsverbindungen verwendeten Serinderivate der allgemeinen Formel (VI) sind bekannt. Die Peaktion erfolgt vorzugsweise in Gegenwart von Verdünnungsmitteln. Als Verdännungsmittel können polar aprotische organische Lösungsmittel verwendet werden. Beispielhaft seien genannt Tetrahydrofuran, Dioxan, Dimethylformamid, Hexamethylphosphorsäuretriamid. Die erfindungsgeräße Reaktion erfolgt vorzugsweise in Gegenwart eines wasserentziehenden Mittels. Beispielhaft seien genannt Dicyclohexylcarbodiinid oder Carbonyldiimidazol in Gegenwart katalytischer Mengen eines basischen Katalysators, vorzugsweise Natriunhydrid.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.
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 C02-Entwicklung hinzu. Die Aufarbeitung erfolgt in üblicher Weise, vorzugsweise durch Eindampfen im Vakuum, Aufnehmen in einen geeigneten Lösungsmittel und Reinigen an Kieselgel. Die Abspaltung der Aminoschutzgruppe R6 erfolgt nach den in der Peptidchemie üblichen literaturbekannten Methoden.Appropriately, 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.
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'-methylanid,
- N-ACE-Histidinriethylester, N-ACE-Serinbenzylester,
- 0-ACE-Serinnethylester, O-ACE-Serinäthylester,
- N-ACE-Phenylalanyltyrosinmethylester,
- N-ACE-Glycylalanylphenylalaninmethylester,
- Nα-ACE-Nγ-benzyloxycarbonyldiaminobutyrylphenylalanylphenyl= alaninmethylester.
- 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'-methylanide,
- N-ACE histidine diethyl ester, N-ACE serine benzyl ester,
- 0-ACE serine methyl ester, O-ACE serine ethyl ester,
- N-ACE-phenylalanyl tyrosine methyl ester,
- N-ACE-glycylalanylphenylalanine methyl ester,
- N α -ACE-N γ -benzyloxycarbonyldiaminobutyrylphenylalanylphenyl = alanine methyl ester.
Als ACE sei hier und im weiteren Verlauf der Rest
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 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. 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 Vorstrecken 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 Hilfslösungsnittel verwendet werden können.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.
Als Hilfsstoffe seien beispielhaft aufgeführt:
- Wasser, nichttoxische organische Lösungsmittel wie Paraffine (z.B. Erdölfraktionen), pflanzliche Öle (z.B. Erdnuß-/Sesamöl), Alkohole (z.B. Äthylalkohol, Glycerin), Glykole (z.B. Propylenglykol, Polyäthylenglykol); feste Trägerstoffe wie z.B. natürliche Gesteinsmehle. (z.B. Kaoline, Tonerden, Talkun, Kreide), synthetische Gesteinsrehle (z.B. hochdisperse Kieselsäure, Silikate), Zucker (z.B. Reh-, Milch- und Traaubenzuoker); Emulgiermittel wie nichtionogene und. anionische Enulgatoren (z.B. Polyoxyäthylen-Fettsäureester, Polyoxyäthylen-Fettalkohol-Xther, Alkylsulfonate und Arylsulfonate), Dispergiermittel (z.B. Lignin, Sulfitablaugen, Methylcellulose, Stärke und Polyvinylpyrrolidon) und Gleitmittel (z.B. Magnesiumstearat, Talkum, Stearinsäure und Natriumlaurylsulfat).
- Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol); solid carriers such as natural rock powder. (eg kaolins, clays, talc, chalk), synthetic rock (eg highly disperse silica, silicates), sugar (eg roe deer, milk and grape juices); Emulsifiers such as nonionic and. anionic enulsifiers (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and arylsulfonates), dispersants (e.g. lignin, sulfite lye, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl).
Die Applikation erfolgt in üb1icher Weise, vorzugsweise oral oder parenteral, lckal,intramuskulär oder intravenös.The application takes place in the usual way, preferably orally or parenterally, lckally, intramuscularly or intravenously.
Im Falle der oralen Anwendung können Tabletten, selbstverständlich außer den genannten Trägerstoffen auch Zusätze wie Natriuncitrat, Calciumcarbomat und Dicalciumphosphat, zusammen mit verschiedenen Zuschlagstoffen wie Stärke, vorzugsweise Kartoffelstärke, Gelatine und dergleichen enthalten. Weiterhin können Gleitnittel 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.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 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. In the case of 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.
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 in the case of oral administration in order to achieve effective results when administered 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.
Für C 25 H 25 CIN 2 O8
Es handelt sich um ein Zwischenprodukt für die Herstellung der folgenden Verbindungen.It is an intermediate for the preparation of the following compounds.
In dieser Lösung wird eine Lösung von 2,25 g (0,01 Mol) N-Boc-Serinmethylester in 10 ml Tetrahydrofuran in Gegenwart katalytischer Mengen von Natriumhydrid hinzugegügt und 7 Stunden bei 35°C gerührt. Anschließend wird die Lösung bei 3 Torr eingedampft, der Rückstand wird in Äthylacetat 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-Boc-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).
53 g (C,12 Mol) Nα-Formyl-Nγ-benzyloxycarbonyldiaminobutyryl= phenylalaninmethylester werden bei 40°C in 400 ml Methanol gelöst und mit 10 g (ca. 0,16 Mol) 80 %igen Hydrazinhydrat versetzt. Nach 24-stilndigem Stehen bei Raunterperatur wird der ausgefallene Niederschlag abgesaugt, die Mutterlauge auf 50 ml eingeengt und erneut zur Kristallisation gebracht. Fp. 205-207°C (aus wäßrigem Dimethylfornamid); Ausbeute 50 g = 94 % der Theorie;
88,3 g (0,2 Mol) der vorstehend unter a) beschriebenen Verbindung we-den unter Erwärmen in 1000 ml Dimethylformamid gelöst und rit 20 nl Eisessig und 400 ml nHCl 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-Phenylalanmethylester= hydrochlorid, gelöst in 200 ml Dinethylformamid, hinzugefügt. Die Peaktionslösung wird mit etwa 54 g Triäthylamin neutralgestellt und 24 8td. im Kühlschrank aufbewahrt. Nach Aufschlämmen rit doppelter Menge Wasser wird der ausgefallene Niderschlag abfiltriert, mit n Salzsäure und Wasser gewaschen, getrocknet und aus Methanol rekristallisiert. Fp. 179-181°C,
52 g (0,0885 Mol) der vorstehend unter b) beschriebenen Verbindung werden in 150 ml Methanol und 35 ml n methanolischer HCl suspendiert und 20 Stunden bei Raumtemperatur gerührt. Die nunmehr klare Lösung wird eingedampft und der Rückstand aus Methanol/Äther rekristallisiert. Fp. 220-222°C, Ausbeute 29 g (= 54 % der Theorie).
Claims (5)
sowie deren gegebenenfalls mit Säuren und Basen gebildeten physiologisch verträglichen Salze.
as well as their physiologically tolerable salts which may be formed with acids and bases.
oder
kondensiert und mit Verbindungen der allgemeinen Formel (IV), in welcher m, n, R1 bis R4 die oben angeführte Bedeutung haben, umsetzt
oder
und gegebenenfalls die so erhaltenen Verbindungen der allgemeinen Formel (I) mit Säuren und Basen in die physiologisch verträglichen Salze verwandelt.2) Process for the preparation of indolylacetoxyacetylaminoacetic acid derivatives according to claim 1, characterized in that
or
condensed and reacted with compounds of the general formula (IV) in which m, n, R 1 to R 4 have the meaning given above
or
and optionally the compounds of the general formula (I) thus obtained are converted into the physiologically tolerable salts with acids and bases.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE2735537 | 1977-08-06 | ||
DE19772735537 DE2735537A1 (en) | 1977-08-06 | 1977-08-06 | INDOLACETOXYACETYLAMINO ACID DERIVATIVES, METHOD FOR THEIR MANUFACTURING AND USE AS A MEDICINAL PRODUCT |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0000741A2 true EP0000741A2 (en) | 1979-02-21 |
EP0000741A3 EP0000741A3 (en) | 1979-03-07 |
EP0000741B1 EP0000741B1 (en) | 1981-07-22 |
Family
ID=6015810
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---|---|---|---|
EP78100523A Expired EP0000741B1 (en) | 1977-08-06 | 1978-07-27 | Indolacetoxyacetylaminoacid derivatives, process for their preparation and their use in drugs |
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EP (1) | EP0000741B1 (en) |
JP (1) | JPS5430160A (en) |
DE (2) | DE2735537A1 (en) |
IT (1) | IT7826537A0 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0047358A1 (en) * | 1980-09-10 | 1982-03-17 | A. Nattermann & Cie. GmbH | Indol acetic derivatives, process for producing the same and pharmaceutical compositions comprising the same |
EP0382854A1 (en) * | 1988-07-05 | 1990-08-22 | Zeria Pharmaceutical Co., Ltd. | Indoleacetic acid derivatives, process for their preparation, and medicines containing same as active ingredients |
US7718161B2 (en) | 2004-06-09 | 2010-05-18 | Ucb Pharma Gmbh | Method for treating a motoneuron disorder |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
JPS59204172A (en) * | 1983-04-28 | 1984-11-19 | Kowa Co | Preparation of acemetacin |
JPH0417306Y2 (en) * | 1984-12-26 | 1992-04-17 | ||
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 |
US6207700B1 (en) | 1999-01-07 | 2001-03-27 | Vanderbilt University | Amide derivatives for antiangiogenic and/or antitumorigenic use |
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 |
JP2007534702A (en) | 2004-04-26 | 2007-11-29 | バンダービルト・ユニバーシティ | Indoleacetic acid and indeneacetic acid derivatives as therapeutic agents with low gastrointestinal toxicity |
CN101528222A (en) | 2006-06-19 | 2009-09-09 | 范德比尔特大学 | Methods and compositions for diagnostic and therapeutic targeting of COX-2 |
US9346803B2 (en) | 2011-10-17 | 2016-05-24 | Vanderbilt University | Indomethacin analogs for the treatment of castrate-resistant prostate cancer |
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FR2192828A1 (en) * | 1972-07-14 | 1974-02-15 | Troponwerke Dinklage & Co | |
DE2413125A1 (en) * | 1974-03-15 | 1975-10-09 | Schering Ag | INDOLYLACETYLAMINO ACID DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS |
-
1977
- 1977-08-06 DE DE19772735537 patent/DE2735537A1/en not_active Withdrawn
-
1978
- 1978-07-27 EP EP78100523A patent/EP0000741B1/en not_active Expired
- 1978-07-27 DE DE7878100523T patent/DE2860858D1/en not_active Expired
- 1978-08-04 IT IT7826537A patent/IT7826537A0/en unknown
- 1978-08-04 JP JP9469878A patent/JPS5430160A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2192828A1 (en) * | 1972-07-14 | 1974-02-15 | Troponwerke Dinklage & Co | |
DE2413125A1 (en) * | 1974-03-15 | 1975-10-09 | Schering Ag | INDOLYLACETYLAMINO ACID DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0047358A1 (en) * | 1980-09-10 | 1982-03-17 | A. Nattermann & Cie. GmbH | Indol acetic derivatives, process for producing the same and pharmaceutical compositions comprising the same |
EP0382854A1 (en) * | 1988-07-05 | 1990-08-22 | Zeria Pharmaceutical Co., Ltd. | Indoleacetic acid derivatives, process for their preparation, and medicines containing same as active ingredients |
EP0382854A4 (en) * | 1988-07-05 | 1991-11-13 | Zeria Pharmaceutical Co., Ltd. | Indoleacetic acid derivatives, process for their preparation, and medicines containing same as active ingredients |
US5177223A (en) * | 1988-07-05 | 1993-01-05 | Zeria Pharmaceutical Co., Ltd. | Indoleacetic acid derivatives, process for their preparation, and medicines containing same as active ingredients |
US7718161B2 (en) | 2004-06-09 | 2010-05-18 | Ucb Pharma Gmbh | Method for treating a motoneuron disorder |
Also Published As
Publication number | Publication date |
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JPS5430160A (en) | 1979-03-06 |
DE2860858D1 (en) | 1981-10-29 |
DE2735537A1 (en) | 1979-02-22 |
EP0000741B1 (en) | 1981-07-22 |
EP0000741A3 (en) | 1979-03-07 |
IT7826537A0 (en) | 1978-08-04 |
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