WO1983000146A1 - New derivatives of dipeptides, method for the preparation thereof and utilization thereof as drugs - Google Patents

New derivatives of dipeptides, method for the preparation thereof and utilization thereof as drugs Download PDF

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WO1983000146A1
WO1983000146A1 PCT/FR1982/000116 FR8200116W WO8300146A1 WO 1983000146 A1 WO1983000146 A1 WO 1983000146A1 FR 8200116 W FR8200116 W FR 8200116W WO 8300146 A1 WO8300146 A1 WO 8300146A1
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radical
general formula
residue
acid
acyl
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PCT/FR1982/000116
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French (fr)
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Michel Flork
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Michel Flork
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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
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new dipepti derivatives, their preparation process and their use as a medicament, in particular in the area of the central nervous system.
  • the present invention relates more specifically to N-acyl dipeptides in which the acyl group is a residue of carboxylic acid, aliphatic or aromatic, with or without pharmacodynamic properties.
  • the present invention relates specifically to N-acyl di peptides of general formula I
  • Ac represents the acyl residue of an aliphatic, aromatic or hydroaromatic organic carboxylic acid
  • A is the residue of an amino acid carrying another carboxylic function substituted at ⁇
  • X is the residue of an amino acid
  • Y is hydrogen or the remainder of a mono or disubstituted amine, preferably physiologically active, linear or cyclic.
  • Z is hydrogen or forms with Z 'a lower alkylene radical optionally substituted by a hydroxyl or optionally inte broken by a heteroat ⁇ rne.
  • Z ' is hydrogen, a linear or branched lower alkyl radical, optionally substituted by a hydroxyl radical, a carbamoyl radical, a ureido radical, a guanidino radical, or a sulphonic group; a lower phenylalkyl or indolyl lower alkyl radical, or else Z ′ forms with Z a lower alkyl radical, optionally substituted by a hydroxyl or optionally interrupted by a heteroatom.
  • Y 'and Y distinct from each other, represent hydrogen, an alkyl, aryl, hetero aryl, aralkyl radical, these radicals being able to be substituted by 1 to 3 substituents, with the limitation that Y and Y 'cannot represent hydrogen simultaneously and n is an integer varying from 1 to 3.
  • N-acyl dipeptides referring to the general formula I "
  • Y and Y ' are hydrogen and Ac represents the acyl residue of a organic carboxylic acid in which the hydrocarbon residue is an alkyl radical having from 2 to 18 carbon atoms in a straight or branched chain, a mono, bi- or tricyclic aryl radical having from 5 to 15 carbon atoms, an aralkyl radical in which the alkyl residue has from 1 to 8 carbon atones and where the aryl residue is mono, bi- or tricyclic and has from 5 to 15 carbon atones, a heteroaryl radical mono, bi- or tricyclic, lin hydroaromatic radical having from 3 to 15 atoms of mono, bi- or tricyclic carbon or a (hydroaryl) alkyl radical in which the hydroaryl residue is defined as above and the alkyl residue has from 1 to 8 carbon atoms optionally substituted by a hydroxyl or an oxo radical, or interrupted by an amino group.
  • the hydrocarbon residue is an alkyl radical having from 2 to 18 carbon
  • the group Ac is preferably the acyl residue of a low molecular weight organic carboxylic acid, such as an acetyl, propionyl, butyryl, succinoyl, fumaroyl, glutaroyl, or the acyl residue of an ar ⁇ natic acid such that a benzoyl radical, 2,6 dichloro benzoyl, ⁇ -trifluorobenzoyl, veratroyle, syringoyl, toloyl, durene carbonyle, naphtoyl, indenecarbonyle, fluorenecarbonyle, pramoyl, ni cotinoyl, isonicotinoyl, thiophenecarbonyle (2 or 3), thiaz 2-roethylthiazole 5-oarbonyl ... or a hydro aromatic acid like a dibenzocycloheptene carboxylic acid.
  • a low molecular weight organic carboxylic acid such as an acetyl,
  • the group Ac can also be the acylated residue of a therapeutically usable organic carboxylic acid such as n-propyl acetic acid, acetylsalicylic acid, gentisigue acid, N-phenylanthranilic acids.
  • a therapeutically usable organic carboxylic acid such as n-propyl acetic acid, acetylsalicylic acid, gentisigue acid, N-phenylanthranilic acids.
  • acyl radical the remainder of an aromatic or hydroaromatic acid of mono, bi or tricyclic structure carrying a carboxylic substituent or an alkyl-carboxylic chain such as tricyclic acids carrying an aminepentanoic, aminohexanoic or aminoheptanoic, bicyclic or tricyclic aromatic acids carrying an acetic or ⁇ -methylacetic, oxobutanoxque or hydroxybutanoic chain; N-acylated 3-acetic indolyl acids.
  • the radical A is a carboxylic residue of an ⁇ -amino polycarboxylic acid capable of giving rise to an ⁇ -ismeria in ⁇ .
  • amino acids which meet this definition there may be mentioned more particularly aspartic acid, glutamic acid, ⁇ -hydroxyaspartic acid or N 1 methyl lanthionine.
  • Group X can be any amino acid, and in particular a natural amino acid such as lysine, valine, leucine, isoleucine, alloisoleucine, glycine, serine, proline, 4-hydroxyproline, cysteine, taurine, car ⁇ iitine, citrulline, ornithine, histidine or tryptopbane.
  • a natural amino acid such as lysine, valine, leucine, isoleucine, alloisoleucine, glycine, serine, proline, 4-hydroxyproline, cysteine, taurine, car ⁇ iitine, citrulline, ornithine, histidine or tryptopbane.
  • Group X can also be an artificial amino acid like ⁇ -alanine, the acid -aminobutyric acid -amino ⁇ -hydroxybutyric, N-acylcarnitines.
  • Functional derivatives of natural amino acids can also be used by blocking the terminal carboxylic function in the form of a friend of, for example, prolinamide or glutamine, or in the form of an alcohol such as mathioninol. It is also possible to use, in the case of sulfur-containing amino acids, derivatives whose thiol function is protected in the form of sulfoxide (methionine sulfoxide for example) or sulfone (methionine sulfone for example).
  • the group Y is hydrogen when the terminal carboxylic function of X is blocked or transformed into another functional group which is not reactive under the experimental conditions.
  • the group Y is also, when the carboxylic group is capable of reacting, the radical of an aliphatic or arylaliphatic primary or secondary amine, optionally substituted.
  • the radical Y can be the residue of an amino heterocyclic base such as adenosine, guanine, inosine, N-alkyl glucosamines, tryptamine or tryptamines substituted by one or more substituents selected from the group of halogens, alkoxy, lower alkyl, or trifluoromethyl; phenylalkoylamines such as adrenaline, isopre naline, noradrenaline, dopamine, dihydroxyphenylalamine (DOPA), ⁇ -methyl DOPA, amphetamine, substituted amphetamines such as ⁇ -methylamphetamine, methoxy amphetamine, terbutylphenylamine, (m.trifluorophenyl) ⁇ -methyl ethyl amino, non-substituted or substituted quinolines or iso-quinolines such as 6,7-dimethoxy tetra hydroisoquinoline, 6,7-dimethoxy 1-methyl
  • the principle of this structure is to attach to a dipeptide vector Ac-AX, an amino molecule that the dipeptide will be able to convey to the central nervous system, where it will produce a different or improved physiological effect. It is therefore possible to increase or modify the physiological properties, the metabolic fate or the pharmacokinetics of a very large number of medicinal substances whose properties are limited or insufficient to produce an interesting effect or too fleeting to be used as drug. It is also possible to attach very unstable amino molecules to the vector peptide.
  • the resulting product is itself stable and can therefore find a therapeutic use as is the case for example of S-adenosylmethionine which is easily broken down while the dipeptide according to the invention Acyl-A-methionyl-adenosine e is perfectly resistant to hydrolysis. This is also the case for dyhidroxyphenylalnine (DOPA), dopamine or serotonin which are intense but very fleeting chemical mediators.
  • DOPA dyhidroxyphenylalnine
  • compounds according to the invention are obtained Ac-AX-dihydr ⁇ xvphenylalanine or Ac-AX-dopamine or Ac-AX-serotonin, the duration of action of which makes them usable as a medicament for Parkinson's disease or the states of depression.
  • N-acetyl ⁇ -aspartyl glutamic acid N-acetyl ⁇ -aspartyl glutamic acid
  • This acid is excreted via the urine in the form of ⁇ -aspartyl glutamic acid.
  • the brain in which it binds is therefore capable of using this N-acyl dipeptide by hydrolyzing the N-acetyl group and of using this compound for metabolic purposes by isomerizing the radical ⁇ -aspartyle in ⁇ -aspartyle.
  • the excreted product is completely inactive.
  • N-acetyl ⁇ -aspartyl glutamyl taurine N-butyryl ⁇ -aspartyl glutamyl dopamine N-butyryl ⁇ -aspartyl glutam yl (dihydroxyphenyl) alanine N-butyryl ⁇ -aspartyl histidyl salsolinol N-bu tyryl ⁇ -aspartyl glycyl N-acetyloarnitine N-butyryl ⁇ - aspartyl glycyl glutamine N-acetyl ⁇ -glutamyl -m ethicnyl-S-adenosine N-acetyl ⁇ -glutam yl-glycyl ⁇ -methyl DOPA N- (dibenzocycloheptenyl-5) aminoheptanoyl ⁇ - aspartyl-g
  • the invention also relates to a process for obtaining the compounds of general formula I
  • radicals Ac, A, X and Y have the meanings provided previously, characterized in that an amino acid A - OH is subjected to the action of an acid of formula Ac - OH in which Ac is defined as before or of one of its functional derivatives in the presence of a basic agent to form an acylated derivative of general fotmule II
  • n is equal to 1, 2 or 3 or one of its structural analogues substituted by a methylamino, hydroxy or thio radical, can react this ring in an aqueous medium with an amino acid of formula H - X - CH ( in which X is defined as above), to obtain the N-acyl dipeptide of general formula TV
  • the acylation is carried out in the presence of an alkali metal hydroxide which is not earthy and in particular in the presence of lime
  • the dehydrating agent is a carboxylic or sulfonic acid anhydride and in particular acetic anhydride
  • anhydride from the N-acyl dipeptide of general formula IV is carried out by the action of a carboxylic or sulfonic acid anhydride at a temperature below 10 °
  • the anhydride is opened with the amine YH in water in the presence of a mineral acid.
  • the invention also relates to another process for obtaining the compounds of general formula I which consists in subjecting the dipeptide of general formula III
  • the invention also relates to another process for obtaining the compounds of general formula I, characterized in that the amino function of amino acid A is blocked by the action of formic acid or one of its functional derivatives, form the anhydride of the formylated derivative which is condensed with an amino acid to obtain an N-formyl dipeptide then deformylated it in an acid medium to obtain a dipeptide of formula H - A - X - OH in which A and X are defined like before,
  • Stage A N-acetylaspartic acid.
  • reaction mixture is then percolated on a sulfonic resin capable of fixing the sodium ions (Duolity C-20 resin sold by the company DIA PROSM G, previously treated with clH 2N or 2N sulfuric acid at the rate of 1.2 vol. by resin volure).
  • a sulfonic resin capable of fixing the sodium ions Duolity C-20 resin sold by the company DIA PROSM G, previously treated with clH 2N or 2N sulfuric acid at the rate of 1.2 vol. by resin volure).
  • the percolate is concentrated in vacuo at ordinary temperature (20 - 25 °). A pale yellow limpid oil is collected which crystal reads slowly. The crystals are separated by filtration, drained and then dried under vacuum, first at ordinary temperature, then ending at 45 ° at the end of drying.
  • the yield of acetylated product is 99%.
  • the crystallization yield is 75% of first jet product and 15% of second jet product.
  • N-acetyl L aspartic acid (1 mol) obtained in stage A are loaded into a flask with three tubes. 255 g of acetic anhydride are added. It forms a very fine and fluid porridge. This suspension is heated to 60 ° for 45 min and then allowed to cool with stirring. The reaction mixture is then left 6 hours in a cooler to complete crystallization. The crystals formed are then separated by vacuum filtration or by spin drying. They are washed with trichloro 1,1,1-ettane added in small portions to remove the excess reagent or the acetic acid which may have formed.
  • N-acetylaspartic anhydride is in the form of very large pancake crystals. This anhydride is stable but must be kept away from humidity.
  • STAGE D Activation of N-acetyl ⁇ (or ⁇ ) aspartyl glutamic acid.
  • 1 mol of N-acetyl L-aspartyl glutamic acid (mixture of ⁇ -aspartyl and ⁇ -aspartyl isomers) is dissolved in 500 ml of water.
  • a concentrated solution is obtained which is mixed while cooling approximately 750 g of acetic anhydride ( 7 to 8 mol) then the mixture is heated to 60-70 ° for 6 hours. Then allowed to cool.
  • the crystals of N-acetyl aspartimide glutamic anhydride which have formed are allowed to settle. They are filtered, washed with 1,1,1-trichloroethane, then dried under vacuum.
  • the glutamic N-acetylaspartimido anhydride thus obtained is used as it is for the next stage of the synthesis.
  • the crystallization is made more complete by taking up the residue of the mother liquors with acetone. The crystals are separated, washed and spun under vacuum. N-acetyl ⁇ -aspartyl ⁇ -glutamyl (3,4 - dihydroxyphenyl) alanine is in the form of colorless crystals soluble in water, giving the colored reactions of phenols and browning in alkaline solution. The product does not have of net melting point.
  • the infrared spectrum shows a strong absorption at 1720 cm -1 (carbonyl of the amide) at 1735 cm -1 (carbonyl of the carboxyl) and at 3200 cm -1 (NH band). The infrared spectrum conforms to the structure announced.
  • N-formyl aspartic acid Eh operating according to the procedure of Stage A of Exerple I, starting from 133 g of aspartic acid and a mixture of 113 g. acetic anhydrid and 59.8 g of anhydrous formic acid, prepared in advance, N-formyl aspartic acid is obtained with a yield of 87%.
  • STAGE C N-formyl ⁇ -aspartyl ⁇ dutamioue acid
  • Stage C of Experple I By operating as in Stage C of Experple I, starting from 154.35 g of glutamic acid and 143 g of N-formyl aspartic anhydride, a concentrated solution containing 71% of N-formyl aspartic glutamic acid (mixture of ⁇ and isomers) which is used as it is for the next step.
  • the concentrated solution containing the mixture of isomers of N-formyl ⁇ and ⁇ -aspartyl ⁇ -glutamic acids is treated with acetic anhydride according to the procedure of Stage D of Example I.
  • the anhydride is thus obtained N-formyl aspartimido ⁇ - glutamic acid which is used as it is for the further synthesis.
  • STAGE E ⁇ -aspartyl ⁇ -alutamyl (3,4 - dihydroxypbényl) alanine
  • the procedure is carried out according to the procedure of Stage E of Example I starting from 198 g of dihydroxyphenylalanine and 226 g of N-formylaspartimido glutamic anhydride.
  • the deformylated derivative is obtained after hydrochloric hydrolysis, which is precipitated by adding dioxane to the peroolate.
  • the tripeptide crystals are dried under vacuum at ordinary temperature.
  • STAGE F N-butyryl ⁇ -aspartyl ⁇ -alutamyl (3,4-dihydroxyphenyl) alanine. 44.3 g of ⁇ -aspartyl ⁇ -glutamyl (3,4-dihydroxyphenyl) alanine are dissolved in 450 ml of water previously brought to pH 9 by addition of sodium hydroxide solution. It is poured into this solution while maintaining the temperature in the vicinity of 0 ° and the pH at 9.16.1 g of butyric anhydride with vigorous stirring within 45 minutes.
  • nitrogen can be acylated with propionyl chloride to form an N-propionyl derivative, with benzoyl chloride to form an N-benzoyl derivative or with acid chloride (dibenzocycloheptene 5-yl) heptanoic amino to form the derivative (diberizocyclohepten - 5 yl) corresponding heptanoylated amino.
  • N-butyryl ⁇ -aspartyl ⁇ -qlutamyl dopamine N-butyryl ⁇ -aspartyl ⁇ -qlutamyl dopamine.
  • stage E By operating as in Example II, stage E, starting from 154 g of
  • Butyrylation of 321 g of ⁇ -aspartyl ⁇ -giuta ⁇ rryl dopamine is carried out with butyric anhydride according to the procedure of Experple II, Stage F and 284 g of N-butyryl ⁇ -aspartyl ⁇ are collected after the usual purifications. -glutamyl dopamine.
  • STAGE A N-acetyl glutamic acid
  • STAGE B N-acetyl clutamic anhydride
  • STAGE C N-acetyl ⁇ -glutamyl glycine
  • STAGE D N -acetyl glutarimido glycine anhydride. ⁇ n operating as in Stage D of Example I, starting from 251 g of N-acetyl glutam yl glycine (mixture of ⁇ and ⁇ isomers in concentrated aqueous solution) and 750 g of acetic anhydride, forms N-acetyl glutarimido glycine anhydride.
  • STAGE E N-acetyl ⁇ qlutamyl glycyl ⁇ -methyl (3,4-dihvdroxy phenyl) alanine. 21.5 g of L-3- (3,4-dihydroxy phenyl) 2-methyl alanine are dissolved in 750 ml of water brought to pH 8.5 under a nitrogen atmosphere. The solution is cooled to 0 ° and with vigorous stirring, about 25.5 g of N-acetyl glutarimido glycine anhydride is added in small portions over an hour.
  • the precipitate of closed dicyclohexyl urea is separated by filtration and the dioxane solution of mixed anhydride is gradually added to a solution of 27 g of ⁇ -aspartyl ⁇ -glutamic acid in 125 ml of dimethylformamide. After one hour of contact at ordinary temperature, the precipitate is separated by filtration, then the peptide solution is concentrated in vacuo. It is then diluted with two volumes of ice water and the crystallization is started by scraping. The indole derivative gradually precipitates. It is separated by filtration, washed with water until the washings are neutral and dried under vacuum.
  • N- (5-methoxy 2-methyl N '- (p.chlorobenzoyl) indolyl-3 acetyl- ⁇ -aspartyl ⁇ -glutamic acid is present in the form of a ocher cream powder slightly soluble in water, soluble in pyridine, dimethylforma mide and alkaline solutions.
  • the ⁇ -aspartyl ⁇ -glutamic acid is obtained by hydrochloric hydrolysis of the N-formyl aspartimido ⁇ -glutamic anhydride obtained in Example II, Stage D.
  • N-acetyl ⁇ -glutamyl glycyl (4-amino 5-chloro 2-methoxy) N'N - diethylamino benzamide By operating as in Stage E of Example IV, starting from 30 g of metoclopramide (dihydrochloride) in 250 ml of water, then adjusting the pH to 8.5 and 25 g of N-acetyl glutarimido glycine anhydride, after percolation on Duolite C 20 resin and hydrochloric hydrolysis at 60 °, 26 g of N-acetyl ⁇ -glutamyl glycyl (4-amino 5-chloro 2-methoxy) N'N'-dierythylamino benzamide are obtained which are recrystallized from acetonitri.
  • the product is in the form of crystals with pink reflections which are not very soluble in water and the hydroxylated solvents but which are soluble in alkaline solutions.
  • reaction mixture is passed through a column chromatography loaded with Duolite C 20 resin previously treated with hydrochloric acid.
  • the percolation liquid is collected and then acidified mentally by the addition of hydrochloric acid.
  • the solution is then diluted by adding water and the solution is brought to 45 ° for 2 hours. Then allowed to cool and the solution is concentrated under reduced pressure without exceeding 40 °.
  • the solid mass is taken up in acetone and the crystallization is started by scraping. The mixture is then left to stand by resting in a cooler for 12 hours.
  • N-acetyl ⁇ -aspartyl histidyl ⁇ -methyl N'- (3-trifiuoromethyl phenyl ethyl) N'-ethyl amino occurs in the form of yellowish white crystals, not very soluble in water, soluble in acidic or alkaline medium , poorly soluble in organic solvents. The product shows a decomposition point rather than a specific melting point.

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Abstract

Dipeptide derivatives represented by the general formula Ac - A - X - Y, wherein Ac represents the acyl rest of an organic carboxylic acid. A is an amino acid carrying a carboxylic function at $g(a). X is an amino acid rest and Y is hydrogen or the rest of a mono- or disubstituted amine. They are prepared by acetylation of the amino acid A and then by dihydration of the N-acetyl amino acid into anhydride, coupling with an X amino acid, new dihydration of the dipeptide N-acetyl A-X into anhydride-amide and condensation with a Y amine to form the dipeptide Ac - A - X - Y.

Description

NOUVEAUX DERIVES DE DIPEPTIDES, LEUR PROCEDE DE PREPARATION ET LEUR EMPLOI COMME MEDICSMENT. NOVEL DIPEPTIDE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICS.
La présente invention se rapporte aux nouveaux dérives de dipepti des, leur procédé de préparation et à leur emploi comme médicament, no tamment dans le dαnaine du système nerveux central.The present invention relates to new dipepti derivatives, their preparation process and their use as a medicament, in particular in the area of the central nervous system.
La présente invention se rapporte plus précisément à des N-acyl dipeptides dans lesquels le groupe acyl est un reste d'acide carboxyli que aliphatique ou aromatique, doué ou non de propriétés pharmacodyna miques.The present invention relates more specifically to N-acyl dipeptides in which the acyl group is a residue of carboxylic acid, aliphatic or aromatic, with or without pharmacodynamic properties.
La présente invention se rapporte spécifiquαnent à des N-acyl di peptides de formule générale IThe present invention relates specifically to N-acyl di peptides of general formula I
Ac - A - X - Y (I)Ac - A - X - Y (I)
dans laquelle,in which,
Ac représente le reste acyle d'un acide organique carboxylique aliphatique, aromatique ou hydroaromatique,Ac represents the acyl residue of an aliphatic, aromatic or hydroaromatic organic carboxylic acid,
A est le reste d'un amino acide porteur d'une autre fonction carboxylique substitué en α ,A is the residue of an amino acid carrying another carboxylic function substituted at α,
X est le reste d'un amino acide, et Y est de l'hydrogène ou le reste d'une aminé mono ou disubstituée, physiologiquement active de préférence, linéaire ou cyclique.X is the residue of an amino acid, and Y is hydrogen or the remainder of a mono or disubstituted amine, preferably physiologically active, linear or cyclic.
Parmi les composés de formule générale I, on distinguera plus particulièrement : les N-acyl dipeptides répondant à la formule générale I'Among the compounds of general formula I, a more specific distinction will be made: the N-acyl dipeptides corresponding to the general formula I '
Figure imgf000004_0002
Figure imgf000004_0002
dans laquelle Ac est un radical acétylein which Ac is an acetyl radical
Z est de l'hydrogène ou forme avec Z' un radical alcoylene inférieur éventuellement substitué par un hydroxyle ou éventuellement inte rompu par un heteroatαrne.Z is hydrogen or forms with Z 'a lower alkylene radical optionally substituted by a hydroxyl or optionally inte broken by a heteroatαrne.
Z' est de l'hydrogène, un radical alcoyle inférieur linéaire ou ramifié, éventuellement substitué par utr radical hydrαxyle, un radical carbamoyle, un radical ureido, un radical guanidino, ou un groupe sulfonique ; un radical phenylalcoyle inférieur ou indolyl alcoyle inférieur, ou bien Z' forme avec Z un radical alcoylene inférieur, éventuel lement substitué par un hydroxyle ou éventuellement interrompu par un heteroatome.Z 'is hydrogen, a linear or branched lower alkyl radical, optionally substituted by a hydroxyl radical, a carbamoyl radical, a ureido radical, a guanidino radical, or a sulphonic group; a lower phenylalkyl or indolyl lower alkyl radical, or else Z ′ forms with Z a lower alkyl radical, optionally substituted by a hydroxyl or optionally interrupted by a heteroatom.
Y' et Y", distinctanent l'un de l'autre, représentent de l'hydrogène, un radical alcoyle, aryle, hetero aryle, aralcoyle, ces radicaux pouvant être substitués par 1 à 3 substituants, avec la limitation que Y et Y' ne peuvent représenter simultanènent de l'hydrogène et n est un nombre entier variant de 1 à 3.Y 'and Y ", distinct from each other, represent hydrogen, an alkyl, aryl, hetero aryl, aralkyl radical, these radicals being able to be substituted by 1 to 3 substituents, with the limitation that Y and Y 'cannot represent hydrogen simultaneously and n is an integer varying from 1 to 3.
. les N-acyl dipeptides reportant à la formule générale I". N-acyl dipeptides referring to the general formula I "
Figure imgf000004_0001
dans laquelle les substituants Z, Z' et n sont définis comme précédemment.
Figure imgf000004_0001
wherein the substituents Z, Z 'and n are defined as above.
Y et Y' sont de l'hydrogène et Ac représente le reste acyle d'un acide organique carboxylique dont le reste hydrocarboné est un radical alcoyle ayant de 2 à 18 atones de carbone en chaîne droite ou ramifiée, un radical aryle mono, bi- ou tricyclique ayant de 5 à 15 atones de carbone, un radical aralcoyle dont le reste alooyle possède de 1 à 8 atones de carbone et où le reste aryle est mono, bi- eu tricyclique et possède de 5 à 15 atones de carbone, un radical hétéroarylique mono, bi- ou tricyclique, lin radical hydro aromatique ayant de 3 à 15 atomes de carbone mono, bi- ou tricyclique ou un radical (hydroaryl) alcoyle dans lequel le reste hydroaryle est défini comme précédemment et le reste alcoyle possède de 1 à 8 atomes de carbone éventuellement substi tué par un hydroxyle ou un radical oxo, ou interrompu par un groupe amino.Y and Y 'are hydrogen and Ac represents the acyl residue of a organic carboxylic acid in which the hydrocarbon residue is an alkyl radical having from 2 to 18 carbon atoms in a straight or branched chain, a mono, bi- or tricyclic aryl radical having from 5 to 15 carbon atoms, an aralkyl radical in which the alkyl residue has from 1 to 8 carbon atones and where the aryl residue is mono, bi- or tricyclic and has from 5 to 15 carbon atones, a heteroaryl radical mono, bi- or tricyclic, lin hydroaromatic radical having from 3 to 15 atoms of mono, bi- or tricyclic carbon or a (hydroaryl) alkyl radical in which the hydroaryl residue is defined as above and the alkyl residue has from 1 to 8 carbon atoms optionally substituted by a hydroxyl or an oxo radical, or interrupted by an amino group.
Dans cette formule, le groupe Ac est de préférence le reste acyle d'un acide organique carboxylique de bas poids moléculaire, tel qu'un acétyl, propionyl, butyryl, succinoyl, fumaroyl, glutaroyl, ou le reste acyle d'un acide arαnatique tel qu'un radical benzoyle, 2,6 dichloro benzoyle, β-trifluorobenzoyle, veratroyle, syringoyle, toloyle, durene carbonyle, naphtoyle, indenecarbonyle, fluorenecarbonyle, pramoyle, ni cotinoyle, isonicotinoyle, thiophenecarbonyle (2 ou 3), thiazole 5- carbonyle, 2-roéthylthiazole 5-oarbonyle... ou d'un acide hydro aromatique corme un acide dibenzocycloheptene carboxylique.In this formula, the group Ac is preferably the acyl residue of a low molecular weight organic carboxylic acid, such as an acetyl, propionyl, butyryl, succinoyl, fumaroyl, glutaroyl, or the acyl residue of an arαnatic acid such that a benzoyl radical, 2,6 dichloro benzoyl, β-trifluorobenzoyl, veratroyle, syringoyl, toloyl, durene carbonyle, naphtoyl, indenecarbonyle, fluorenecarbonyle, pramoyl, ni cotinoyl, isonicotinoyl, thiophenecarbonyle (2 or 3), thiaz 2-roethylthiazole 5-oarbonyl ... or a hydro aromatic acid like a dibenzocycloheptene carboxylic acid.
Le groupe Ac peut également être le reste acylé d'un acide organique carboxylique thérapeutiquement utilisable comme l'acide de n-propyl acétique, l'acide acétylsalicylique, l'acide gentisigue, les acides N-phenylanthraniliques . On peut encore utiliser comme radical acyle le reste d'un acide aromatique ou hydro aromatique de structure mono, biou tricyclique porteur d'un substituant carboxylique ou d'une chaîne alcoyl-carboxylique comme les acides tricycliques porteurs d'une chaîne aminepentanoïque, aminohexanoïque ou aminoheptanoique , les acides aromatiques bicycliques ou tricycliques porteurs d'une chaîne acétique ou α -méthylacétique, oxobutanoxque ou hydroxybutanoïque ; les acides indolyl 3-acétiques N-acylés. Le radical A est un reste carboxylique d'un acide α-aminé polycarboxylique susceptible de donner naissance à une iscmérie α en β. Parmi les amino acides qui répondent à cette définition, on citera plus particulièrement l'acide aspartique, l'acide glutamique, l'acide β -hydroxyaspartique ou la N1 méthyl lanthionine.The group Ac can also be the acylated residue of a therapeutically usable organic carboxylic acid such as n-propyl acetic acid, acetylsalicylic acid, gentisigue acid, N-phenylanthranilic acids. It is also possible to use as acyl radical the remainder of an aromatic or hydroaromatic acid of mono, bi or tricyclic structure carrying a carboxylic substituent or an alkyl-carboxylic chain such as tricyclic acids carrying an aminepentanoic, aminohexanoic or aminoheptanoic, bicyclic or tricyclic aromatic acids carrying an acetic or α-methylacetic, oxobutanoxque or hydroxybutanoic chain; N-acylated 3-acetic indolyl acids. The radical A is a carboxylic residue of an α-amino polycarboxylic acid capable of giving rise to an α-ismeria in β. Among the amino acids which meet this definition, there may be mentioned more particularly aspartic acid, glutamic acid, β-hydroxyaspartic acid or N 1 methyl lanthionine.
Le groupe X peut être tout acide aminé et notamment, un acide aminé naturel comme la lysine, la valine, la leucine, l'isoleucine, l'alloisoleucine, la glycine, la serine, la proline, la 4-hydroxyproline, la cystéine, la taurine, la carτiitine, la citrulline, l'ornithine, l'histidine ou le tryptopbane.Group X can be any amino acid, and in particular a natural amino acid such as lysine, valine, leucine, isoleucine, alloisoleucine, glycine, serine, proline, 4-hydroxyproline, cysteine, taurine, carτiitine, citrulline, ornithine, histidine or tryptopbane.
Le groupe X peut être aussi un acide aminé artificiel cαime la β-alanine, l'acide
Figure imgf000006_0001
-aminobutyrique, l'acide
Figure imgf000006_0002
-amino β-hydroxybutyrique, les N-acylcarnitines.Group X can also be an artificial amino acid like β-alanine, the acid
Figure imgf000006_0001
-aminobutyric acid
Figure imgf000006_0002
-amino β-hydroxybutyric, N-acylcarnitines.
On peut également utiliser des dérivés fonctionnels d'acides aminés naturels en bloquant la fonction carboxylique terminale sous forme d'ami de, corme par exemple, la prolinamide ou la glutamine, ou sous forme d'alcool comme le mathioninol. On peut employer également dans le cas d'acides aminés soufrés, des dérivés dont la fonction thiol est protégée sous forme de sulfoxyde (méthionine sulfoxyde par exemple) ou de suifone (méthionine sulfone par exemple).Functional derivatives of natural amino acids can also be used by blocking the terminal carboxylic function in the form of a friend of, for example, prolinamide or glutamine, or in the form of an alcohol such as mathioninol. It is also possible to use, in the case of sulfur-containing amino acids, derivatives whose thiol function is protected in the form of sulfoxide (methionine sulfoxide for example) or sulfone (methionine sulfone for example).
Le groupe Y est de l 'hydrogène lorsque la fonction carboxylique terminale de X est bloquée ou transformée en un autre groupe fonctionnel non réactif dans les conditions ejqpérimentales.The group Y is hydrogen when the terminal carboxylic function of X is blocked or transformed into another functional group which is not reactive under the experimental conditions.
Le groupe Y est aussi, lorsque le groupe carboxylique est susceptible de réagir, le radical d'une aminé primaire ou secondaire aliphatique ou arylaliphatique, éventuellanent substituée.The group Y is also, when the carboxylic group is capable of reacting, the radical of an aliphatic or arylaliphatic primary or secondary amine, optionally substituted.
Le radical Y peut être le resté d'une base hétérocyclique aminée comme l'adénosine, la guanine, l'inosine, les N-alcoyl glucosamines, la tryptamine ou les tryptamines substitués par un ou plusieurs substituants choisis dans le groupe des halogènes, alcoxy, alcoyl inférieur, ou trifluorométhyle ; les phénylalcoylamines comme l'adrénaline, l'isopré naline, la noradrénaline, la dopamine, la dihydroxyphénylalamine (DOPA), l' α -méthyl DOPA, l'amphétamine, les amphétamines substituées comme l' α-méthylamphétamine, la méthoxy amphétamine, la terbutylphénylamine, la (m.trifluorophényl) α-méthyl éthyl aminé, les quinoléines ou iso quinoléines non substitués ou substitués comme la 6,7-diméthoxy tétra hydroisoquinoléine, la 6,7 -diméthoxy 1-méthyl tétrahydroisoquinoléine (Salsolinol), la papavérine, le tétrahydropapavérinol, l'éthavérine ; des dérivés aminés de composés bicycliques ou tricycliques comme les benzodiazepines, les quinoxalines, les benzotriazines ou de composés tricycliques comme les phénothiazines non substituées à l'azote ou substituées à l'azote comme la deméthylprométhazine, la deméthylchlor promazine, la deméthyltrifluoroperazine , la trimepraminé, les dérivés substitués par une chaîne alcoyle ou alcoylene amino des dibenzo azepi nes, des dibenzothiazepines, des dibenzo oxazépines, des azadibenzo azépines ou des azadibenzodiazépines, des thienobenzo azépines.The radical Y can be the residue of an amino heterocyclic base such as adenosine, guanine, inosine, N-alkyl glucosamines, tryptamine or tryptamines substituted by one or more substituents selected from the group of halogens, alkoxy, lower alkyl, or trifluoromethyl; phenylalkoylamines such as adrenaline, isopre naline, noradrenaline, dopamine, dihydroxyphenylalamine (DOPA), α -methyl DOPA, amphetamine, substituted amphetamines such as α-methylamphetamine, methoxy amphetamine, terbutylphenylamine, (m.trifluorophenyl) α-methyl ethyl amino, non-substituted or substituted quinolines or iso-quinolines such as 6,7-dimethoxy tetra hydroisoquinoline, 6,7-dimethoxy 1-methyl tetrahydroisoquinoline (Salsolinol), papaverine tetrahydropapaverinol, ethaverine; amino derivatives of bicyclic or tricyclic compounds such as benzodiazepines, quinoxalines, benzotriazines or tricyclic compounds such as phenothiazines which are not substituted for nitrogen or substituted for nitrogen such as demethylpromethazine, demethylchlor promazine, demethyltrifluoroperazine, trimepramine, derivatives substituted by an alkyl or alkylene amino chain of dibenzo azepines, dibenzothiazepines, dibenzo oxazepines, azadibenzo azepines or azadibenzodiazepines, thienobenzo azepines.
Cette liste n'est pas limitative. Elle vise seulement à donner des informations sur la généralité des radicaux Y qu'il est possible d'accrocher au substituant X.This list is not exhaustive. It only aims to give information on the generality of the radicals Y which it is possible to attach to the substituent X.
Le principe de cette structure est d'accrocher à un dipeptide vec teur Ac-A-X, une molécule aminée que le dipeptide sera capable de véhi culer jusqu'au système nerveux central, où elle produira un effet physiologique différent ou amélioré. Il est donc possible d'accroître ou de modifier les propriétés physiologiques, le devenir métabolique ou la pharmacoci nétique d'un très grand nomber de substances médicamenteuses dont les propriétés sont limitées ou insuffisantes pour produire un effet intéressant ou trop fugaces pour pouvoir être utilisées comme médicament. Il est également possible de fixer sur le peptide vecteur des molécules aminées très instables. Le produit en résultant est lui stable et peut trouver de ce fait un emploi en thérapeutique comme c'est le cas par exemple de la S-adénosylméthionine qui est facilanent décomposée alors que le dipeptide selon l'invention Acyl-A-methionyl-adénosin e est parfaitement résistant à l'hydrolyse. C'est le cas également de la dyhidroxyphénylalnine (DOPA), de la dopamine ou de la sérotonine qui sont des médiateurs chimiques d'action intense mais très fugace. Par couplage avec le vecteur, on obtient des composés selon l'invention Ac-A-X-dihydrαxvphénylalanine ou Ac-A-X-dopamine ou Ac-A-X-sérotonine dont la durée d'action les rend utilisables comme médicament de la maladie de Parkinson ou des états de dépression.The principle of this structure is to attach to a dipeptide vector Ac-AX, an amino molecule that the dipeptide will be able to convey to the central nervous system, where it will produce a different or improved physiological effect. It is therefore possible to increase or modify the physiological properties, the metabolic fate or the pharmacokinetics of a very large number of medicinal substances whose properties are limited or insufficient to produce an interesting effect or too fleeting to be used as drug. It is also possible to attach very unstable amino molecules to the vector peptide. The resulting product is itself stable and can therefore find a therapeutic use as is the case for example of S-adenosylmethionine which is easily broken down while the dipeptide according to the invention Acyl-A-methionyl-adenosine e is perfectly resistant to hydrolysis. This is also the case for dyhidroxyphenylalnine (DOPA), dopamine or serotonin which are intense but very fleeting chemical mediators. By coupling with the vector, compounds according to the invention are obtained Ac-AX-dihydrαxvphenylalanine or Ac-AX-dopamine or Ac-AX-serotonin, the duration of action of which makes them usable as a medicament for Parkinson's disease or the states of depression.
Le principe de cette utilisation thérapeutique découle du fait expérimental constaté par administration de l'acide N-acétyl α -aspartyl glutamique(NAAGA). Cet acide est excrété par voie urinaire sous forme d'acide α-aspartyl glutamique. Le cerveau où il se fixe, ainsi qu'il a été montré par autoradiographie, est donc capable d'utiliser ce N- acyl dipeptide en hydrolysant le groupe N-acétyl et d'utiliser à des fins métaboliques ce composé en isomérisant le radical α -aspartyle en β-aspartyle. Le produit excrété est totalement inactif.The principle of this therapeutic use stems from the experimental fact observed by administration of N-acetyl α-aspartyl glutamic acid (NAAGA). This acid is excreted via the urine in the form of α-aspartyl glutamic acid. The brain in which it binds, as has been shown by autoradiography, is therefore capable of using this N-acyl dipeptide by hydrolyzing the N-acetyl group and of using this compound for metabolic purposes by isomerizing the radical α -aspartyle in β-aspartyle. The excreted product is completely inactive.
Sur la base de ce principe, on a constaté qu'en remplaçant le radical acétyle par tout autre reste acyle et notamment le reste acyle d'un acide carboxylique thérapeutiquement actif et/ou en condensant l'acide glutamique avec un dérivé aminé actif ou non physiologiquement, on peut disposer d'un dérivé de dipeptide susceptible de se fixer sur un centre cérébral et de produire des effets plus sélectifs, améliorés ou différents par rapport à ceux produits par la molécule physiologiquenent active fixée au dipeptide vecteur.On the basis of this principle, it has been found that by replacing the acetyl radical with any other acyl residue and in particular the acyl residue of a therapeutically active carboxylic acid and / or by condensing glutamic acid with an active or non-active amino derivative physiologically, it is possible to have a dipeptide derivative capable of binding to a cerebral center and of producing more selective, improved or different effects compared to those produced by the physiologically active molecule fixed to the vector dipeptide.
Parmi les composés peptidigues selon l'invention, on pourra citer plus particulièranent comme composés actuellement préférés : la N-acétyl α -aspartyl glutamyl taurine la N-butyryl α -aspartyl glutamyl dopamine la N-butyryl α -aspartyl glutam yl (dihydroxyphényl) alanine le N-butyryl α -aspartyl histidyl salsolinol la N-bu tyryl α -aspartyl glycyl N-acétyloarnitine la N-butyryl α- aspartyl glycyl glutamine la N-acétyl α-glutamyl -m ethicnyl-S-adénosine la N-acétyl α -glutam yl-glycyl α -méthyl DOPA la N-(dibenzocycloheptenyl-5) aminoheptanoyl α - aspartyl-glycine le l- [ (dibenzocycloheptenyl-5) amino] 3-méthyl 3- (N-acétyl α- aspartyl) glycyl propane l 'acide N (3, 4, 5, 6-tétrahydro 2-oxacyclohexyl) pyroglutamyl aspartyl glutamique la N-(5-methoxy 2-méthyl N (p.chlorobenzoyl indolyl 3-acétyl) α- aspartyl glycine le N-prppionyl α-glutamyl glycyl (4-amino 5-chloro 2 méthoxy)Among the peptide compounds according to the invention, there may be mentioned more particularly as currently preferred compounds: N-acetyl α -aspartyl glutamyl taurine N-butyryl α -aspartyl glutamyl dopamine N-butyryl α -aspartyl glutam yl (dihydroxyphenyl) alanine N-butyryl α -aspartyl histidyl salsolinol N-bu tyryl α -aspartyl glycyl N-acetyloarnitine N-butyryl α- aspartyl glycyl glutamine N-acetyl α-glutamyl -m ethicnyl-S-adenosine N-acetyl α -glutam yl-glycyl α -methyl DOPA N- (dibenzocycloheptenyl-5) aminoheptanoyl α - aspartyl-glycine l- [(dibenzocycloheptenyl-5) amino] 3-methyl 3- (N-acetyl α- aspartyl) glycyl propane N (3, 4, 5, 6-tetrahydro 2-oxacyclohexyl) pyroglutamyl aspartyl glutamic acid N- (5-methoxy 2-methyl N (p.chlorobenzoyl indolyl 3-acetyl) α- aspartyl glycine N-prppionyl α-glutamyl glycyl (4-amino 5-chloro 2 methoxy)
N' N'-diethylamino éthyl benzamide la l-(N-benzoyl α -aspartyl glycyl) 7-chloro 2,3-dihydro 5-phénylN 'N'-diethylamino ethyl benzamide la l- (N-benzoyl α -aspartyl glycyl) 7-chloro 2,3-dihydro 5-phenyl
[IH] benzodiazépine-1, 42-one.[1H] benzodiazepine-1, 42-one.
L'invention concerne également un procédé d'obtention des composés de formule générale IThe invention also relates to a process for obtaining the compounds of general formula I
Ac - A - X - Y (I)Ac - A - X - Y (I)
dans laquelle, les radicaux Ac, A, X et Y ont les significations fournies antérieurement, caractérisé en ce que l'on soumet un acide aminé A - OH à l'action d'un acide de formule Ac - OH dans laquelle Ac est défini comme précédemment ou d'un de ses dérivés fonctionnels en présence d'un agent basique pour former un dérivé acylé de fotmule générale IIin which the radicals Ac, A, X and Y have the meanings provided previously, characterized in that an amino acid A - OH is subjected to the action of an acid of formula Ac - OH in which Ac is defined as before or of one of its functional derivatives in the presence of a basic agent to form an acylated derivative of general fotmule II
Ac - A - OH (II)Ac - A - OH (II)
dans laquelle, les restes Ac et A sont définis cαime précédemment, soumet celui-ci à l'action d'un agent déshydratant pour former un anhydride de fannule générale IIIin which the residues Ac and A are defined above, submits the latter to the action of a dehydrating agent to form an anhydride of general formula III
Figure imgf000009_0001
dans laquelle,
Figure imgf000009_0001
in which,
Ac est défini comme précédemment n est égal à 1, 2 ou 3 ou un de ses analogues de structure substitué par un radical méthylamino, hydroxy ou thio, feit réagir ce cernier en milieu aqueux avec un acide aminé de formule H - X - CH (dans laquelle X est défini comme précédamment), pour obtenir le N-acyl dipeptide de formule générale TVAc is defined as above n is equal to 1, 2 or 3 or one of its structural analogues substituted by a methylamino, hydroxy or thio radical, can react this ring in an aqueous medium with an amino acid of formula H - X - CH ( in which X is defined as above), to obtain the N-acyl dipeptide of general formula TV
(N) Ac - A - X - OH (IV)(N) Ac - A - X - OH (IV)
dans laquelle, Ac, A et X sont définis came précédemment, soumet celui-ci à l'action d'un agent de déshydratation à basse température pour former l'anhudride correspondant qui, par réaction avec une aminé primaire ou secondaire de formule générale XH, permet d'obtenir le N-acyl dipeptide de formule générale Iin which, Ac, A and X are defined above, subjects it to the action of a dehydrating agent at low temperature to form the corresponding anhudride which, by reaction with a primary or secondary amine of general formula XH , makes it possible to obtain the N-acyl dipeptide of general formula I
N - Ac - A - X - Y (I)N - Ac - A - X - Y (I)
Dans un mode d'action préféré du procédé selon l'inventicai, celuici peut être caractérisé par les points suivants :In a preferred mode of action of the method according to the invention, this can be characterized by the following points:
- l'acylation de l'amino acide AH est effectuée à pH 9 et à 20°- the acylation of the amino acid AH is carried out at pH 9 and at 20 °
- l'acylation est effectuée en milieu aqueux- the acylation is carried out in an aqueous medium
- l'acylation est effectuée en présence d'un hydroxyde de métal alcali no terreux et notamment en présence de chauxthe acylation is carried out in the presence of an alkali metal hydroxide which is not earthy and in particular in the presence of lime
- l'agent déshydratant est un anhydride d'acide carboxylique ou sulfo nique et notamment l'anhydride acétiquethe dehydrating agent is a carboxylic or sulfonic acid anhydride and in particular acetic anhydride
- la réaction entre l'anhydride de formule III et l'amino acide XH s'effectue en milieu aqueux- the reaction between the anhydride of formula III and the amino acid XH takes place in an aqueous medium
- la réaction entre l'anhydride de formule III et l'amino acide XH s'effectue à une température voisine de 0°- the reaction between the anhydride of formula III and the amino acid XH takes place at a temperature close to 0 °
- la réaction entre l'anhydride de formule III et l'amino acide XH s'effectue à un pH compris entre 8 et 9- the reaction between the anhydride of formula III and the amino acid XH takes place at a pH between 8 and 9
- la formation d'anhydride à partir du dipeptide N-acyle de formule gé nérale IV s'effectue par action d'un anhydride d'acide carboxylique ou sulfonique à une température inférieure à 10°the formation of anhydride from the N-acyl dipeptide of general formula IV is carried out by the action of a carboxylic or sulfonic acid anhydride at a temperature below 10 °
- l'ouverture de l'anhydride par l'aminé YH s'effectue dans l'eau en présence d'un acide minéral.- The anhydride is opened with the amine YH in water in the presence of a mineral acid.
L'invention concerne encore un autre procédé d'obtention des composés de formule générale I qui consiste à soumettre le dipeptide de formule générale IIIThe invention also relates to another process for obtaining the compounds of general formula I which consists in subjecting the dipeptide of general formula III
(N) Ac - A - X - OH (IV)(N) Ac - A - X - OH (IV)
dans laquelle,in which,
Ac, A et X ont les significations fournies antérieurement. à l'action d'un agent de déshydratation à chaud pour former l'imi de-anhydride de formule générale VAc, A and X have the meanings previously provided. to the action of a hot dehydrating agent to form the imi-anhydride of general formula V
Figure imgf000011_0002
Figure imgf000011_0002
dans laquelle Ac, n et X ont les mêmes significations que précédemment, traite celui-ci par une aminé primaire ou secondaire en milieu acide pour former un imide de formule générale VIin which Ac, n and X have the same meanings as above, treats the latter with a primary or secondary amine in an acid medium to form an imide of general formula VI
Figure imgf000011_0001
Figure imgf000011_0001
qui, par action d'un agent acide, fournit un composé de formule générale I Ac - A - X - Y (I)which, by the action of an acid agent, provides a compound of general formula I Ac - A - X - Y (I)
dans laquelle la signification des radicaux Ac, A, X et Y demeure inchangée.in which the meaning of the radicals Ac, A, X and Y remains unchanged.
L'invention concerne aussi un autre procédé d'obtention des composés de formule générale I caractérisé en ce qu'on bloque la fonction aminé de l'amino acide A par action de l'acide formique ou d'un de ses dérivés fonctionnels, forme l'anhydride du dérivé formylé que l'on condense avec un amino acide pour obtenir un N-formyl dipeptide puis déformyle celui-ci en milieu acide pour obtenir un dipeptide de formule H - A - X - OH dans laquelle A et X sont définis comme précédémment,The invention also relates to another process for obtaining the compounds of general formula I, characterized in that the amino function of amino acid A is blocked by the action of formic acid or one of its functional derivatives, form the anhydride of the formylated derivative which is condensed with an amino acid to obtain an N-formyl dipeptide then deformylated it in an acid medium to obtain a dipeptide of formula H - A - X - OH in which A and X are defined like before,
que l'on fait réagir avec un dérivé fonctionnel, de l'acide Ac OH (Ac ayant les significations fournies antérieurement) et isole le dérivé N-acylé correspondant de formule (N) Ac - A - X - OH (IV) que l'on transforme en anhydride correspondant, puis condense avec une aminé primaire ou secondaire pour obtenir le N-acyl dipeptide de formule générale I. which is reacted with a functional derivative, Ac OH acid (Ac having the meanings provided previously) and isolates the corresponding N-acylated derivative of formula (N) Ac - A - X - OH (IV) that l 'is converted into the corresponding anhydride, then condensed with a primary or secondary amine to obtain the N-acyl dipeptide of general formula I.
EXEMPLE IEXAMPLE I
N-acétyl α -aspartyl α -glutamyl (3, 4-dihydroxyphenyl) alanineN-acetyl α -aspartyl α -glutamyl (3, 4-dihydroxyphenyl) alanine
Stade A : Acide N-acetylaspartique.Stage A: N-acetylaspartic acid.
133 g d'acide aspartique (Imol) sont dissouts dans 500 ml d'eau préalablement amenée à pH 9 par addition ménagée de lessive de soude 10 N. On coule dans la solution tout en maintenant la tempé rature en-dessous de 20° et le pH à 9, 113 g d'anhydride acétique133 g of aspartic acid (Imol) are dissolved in 500 ml of water previously brought to pH 9 by gentle addition of 10 N sodium hydroxide solution. It is poured into the solution while maintaining the temperature below 20 ° and the pH at 9, 113 g of acetic anhydride
(soit, 1,1 mol) sous agitation en une heure. Le mélange reactionnel est ensuite percolé sur une résine sulfonique capable de fixer les ions sodium (résine Duolité C-20 commercialisée par la firme DIA PROSM G, préalablement traitée par clH 2N ou de l'acide sulfurique 2N à raison de 1,2 vol. par volure de résine).(i.e., 1.1 mol) with stirring in one hour. The reaction mixture is then percolated on a sulfonic resin capable of fixing the sodium ions (Duolity C-20 resin sold by the company DIA PROSM G, previously treated with clH 2N or 2N sulfuric acid at the rate of 1.2 vol. by resin volure).
Le percolat est concentré sous vide à la teirpérature ordinaire (20 - 25°). On recueille une huile limpide jaune pâle qui cristal lise lentement. On sépare les cristaux par filtration, on les essore puis on les sèche sous vide d'abord à température ordinai re, puis en terminant à 45° en fin de séchage.The percolate is concentrated in vacuo at ordinary temperature (20 - 25 °). A pale yellow limpid oil is collected which crystal reads slowly. The crystals are separated by filtration, drained and then dried under vacuum, first at ordinary temperature, then ending at 45 ° at the end of drying.
Le rendement en produit acétylé est de 99 %. Le rendement de la cristallisation est de 75% de produit de premier jet et de 15 % de produit de second jet.The yield of acetylated product is 99%. The crystallization yield is 75% of first jet product and 15% of second jet product.
Dosage de l'azote par protométrie (C104H) : O % Dosage de la fonction acide par méthylate de sodium : 99% de la théorie (2 eq/faole).Determination of nitrogen by protometry (C10 4 H): O% Determination of the acid function by sodium methylate: 99% of theory (2 eq / faole).
STADE B : Anhydride N-acétylaspartiqueSTAGE B: N-acetylaspartic anhydride
175 g d'acide N-acétyl L aspartique (1 mol) obtenus au stade A sont chargés dans un ballon à trois tubulures . On ajoute 255 g d'anhydride acétique. Il se forme une bouillie très fine et fluide. On chauffe cette suspension à 60° pendant 45 mn puis laisse refroidir sous agitation. Le mélange reactionnel est laissé ensuite 6 heures en glacière pour achever la cristallisation. On sépare ensuite les cristaux formés par filtration scus vide ou par esso rage. On les lave par du trichloro 1,1,1-éttane ajouté par petites portions pour éliminer l'excès de réactif ou l'acide acétique qui a pu se former.175 g of N-acetyl L aspartic acid (1 mol) obtained in stage A are loaded into a flask with three tubes. 255 g of acetic anhydride are added. It forms a very fine and fluid porridge. This suspension is heated to 60 ° for 45 min and then allowed to cool with stirring. The reaction mixture is then left 6 hours in a cooler to complete crystallization. The crystals formed are then separated by vacuum filtration or by spin drying. They are washed with trichloro 1,1,1-ettane added in small portions to remove the excess reagent or the acetic acid which may have formed.
Le rendement en produit cristallisé est de 95%. Titre acidimétrique (Me ONa ) 100 %.The yield of crystallized product is 95%. Acidimetric titer (Me ONa) 100%.
L'anhydride N-acétylaspartique se présente sous forme de très gros cristaux en galettes. Cet anhydride est stable nais doit être conservé à l'abri de l'humidité.N-acetylaspartic anhydride is in the form of very large pancake crystals. This anhydride is stable but must be kept away from humidity.
STADE C : Acide N-acétyl α -asnartyl α -qlutamioue.STAGE C: N-acetyl α -asnartyl α -qlutamioue acid.
On dissout 154,35 g (soit, 1 mol 05) d'acide glutamique dans un litre d'eau préalablement ajusté à pH 8,5 et à une température voisine de 0°. La mise en solution est rapide à ce pH. On maintient la température de la solution à 0° par immerxion dans un bain de glace, puis sous une agitation très énergique et tout en régulant le pH très exactement à pH 8,5 par addition de lessive de soude ION, on ajoute l'anhydride N-acétyl α - L - aspartique sous forme solide (1 mole).154.35 g (ie, 1 mol 05) of glutamic acid are dissolved in a liter of water previously adjusted to pH 8.5 and at a temperature in the region of 0 °. The dissolution is rapid at this pH. The temperature of the solution is maintained at 0 ° by immersion in an ice bath, then with very vigorous stirring and while regulating the pH very exactly at pH 8.5 by addition of sodium hydroxide solution ION, the anhydride is added N-acetyl α - L - aspartic in solid form (1 mole).
Une fois l'addition terminée on maintient l'agitation quelques minutes encore, puis on effectue une percolation sur résine Duolite C 20 préalablement traitée à l'acide chlorhydrique 2N. Le liquide de percolation est ensuite concentré sous vide à 20 - 25°. On obtient ainsi une solution épaisse sirupeuse jaune, limpide qui ne cristallise pas.Once the addition is complete, stirring is continued for a few more minutes, then percolation is carried out on Duolite C 20 resin previously treated with 2N hydrochloric acid. The percolation liquid is then concentrated under vacuum at 20 - 25 °. This gives a thick, syrupy yellow, clear solution which does not crystallize.
L'analyse montre qu'elle renferme 75 X d'acide N-acétyl α -aspartyl α -glutamique/et 25 % d'acide N-acétyl β -aspartyl glutamique. Rendement de couplage par rapport à l'anhydride = 99 %. Rendement de couplage par rapport à l'acide glutamique mis en jeu: 94 %.Analysis shows that it contains 75 X of N-acetyl α -aspartyl α -glutamic acid / and 25% of N-acetyl β -aspartyl glutamic acid. Coupling yield relative to the anhydride = 99%. Coupling yield relative to the glutamic acid used: 94%.
STADE D : Activation de l'acide N-acétyl α (ou β) aspartyl glutamique. On dissout 1 mol d'acide N-acétyl L-aspartyl glutamique (mélange d'isomères α -aspartyl et β-aspartyl)dans500ml d'eau.On obtientunesolution concentrée à laquelle on mélange tout en refroidissant 750 g environ d'anhydride acétique (7 à 8 mol) puis on chauffe le mélange à 60 - 70° pendant 6 heures. On laisse ensuite refroidir . On laisse décanter les cristaux d'anhydride N-acétyl aspartimide glutamique qui se sont formés. On les filtre , les lave au 1,1,1- trichloroéthane, puis le fait sécher sous vide. L'anhydride N- acétylaspartimido glutamique ainsi obtenu est utilisé tel quel pour l'étape suivante de la synthèse.STAGE D: Activation of N-acetyl α (or β) aspartyl glutamic acid. 1 mol of N-acetyl L-aspartyl glutamic acid (mixture of α-aspartyl and β-aspartyl isomers) is dissolved in 500 ml of water. A concentrated solution is obtained which is mixed while cooling approximately 750 g of acetic anhydride ( 7 to 8 mol) then the mixture is heated to 60-70 ° for 6 hours. Then allowed to cool. The crystals of N-acetyl aspartimide glutamic anhydride which have formed are allowed to settle. They are filtered, washed with 1,1,1-trichloroethane, then dried under vacuum. The glutamic N-acetylaspartimido anhydride thus obtained is used as it is for the next stage of the synthesis.
STADE E : N-acétyl α -aspartyl α -alutamyl (3,4-dihydroxyphényl) alanine.STAGE E: N-acetyl α -aspartyl α -alutamyl (3,4-dihydroxyphenyl) alanine.
On dissout sous atmosphère d'azote 198 g de dihydroxy phenyl ala nine dans un litre d'eau dont le pH a été alcalinisé à 8,5 sous agitation et à une température de 0°. On ajoute à cette solution par petites portions en environ une heure, 240 g d'anhydride N- acétyl aspartimido glutamique sous forme solide en maintenant strictement la température à 0e et le pH à 8,5 (par addition de soude 5N) . Après achevèrent de l'addition' le mélange reactionnel est passé sur une colonne chargée de résine Duolite C 20 et on recueille le liquide de percolation. Le percolat est acidifié par addition d'acide chlorhy drique (1 mole) puis dilué par addition d'eau jusqu'à obtention d'un volume total de 10 litres.198 g of dihydroxy phenyl ala nine are dissolved under a nitrogen atmosphere in a liter of water, the pH of which has been basified to 8.5 with stirring and at a temperature of 0 °. 240 g of N-acetyl aspartimido glutamic anhydride in solid form are added to this solution in small portions over approximately one hour, strictly keeping the temperature at 0 ° and the pH at 8.5 (by addition of 5N sodium hydroxide). After the addition is complete, the reaction mixture is passed through a column loaded with Duolite C 20 resin and the percolating liquid is collected. The percolate is acidified by addition of hydrochloric acid (1 mole) then diluted by addition of water until a total volume of 10 liters is obtained.
On chauffe alors cette solution pendant une heure à 45° ce qui provoque l'ouverture de l'aspartimide en dérivé α-aspartique. On concentre ensuite sous vide et obtient la cristallisation du tripeptide du milieu.This solution is then heated for one hour at 45 °, which causes the opening of the aspartimide to the α-aspartic derivative. It is then concentrated under vacuum and the crystallization of the tripeptide from the medium is obtained.
La cristallisation est rendue plus complète par reprise du résidu des eaux mères par l'acétone. On sépare les cristaux, les lave et les essore sous vide. La N-acétyl α -aspartyl α -glutamyl (3,4 - dihydroxyphenyl) alanine se présente sous forme de cristaux incolores solubles dans l'eau, donnant les réactions colorées des phénols et brunissant en solution alcaline. Le produit ne possède pas de point de fusion net. Le spectre infrarouge montre une forte absorption à 1720 cm-1 (carbonyle de l 'amide) à 1735 cm-1 (carbonyle du carboxyle) et à 3200 cm-1 (bande NH) . Le spectre infrarouge est conforme à la structure annoncée.The crystallization is made more complete by taking up the residue of the mother liquors with acetone. The crystals are separated, washed and spun under vacuum. N-acetyl α -aspartyl α -glutamyl (3,4 - dihydroxyphenyl) alanine is in the form of colorless crystals soluble in water, giving the colored reactions of phenols and browning in alkaline solution. The product does not have of net melting point. The infrared spectrum shows a strong absorption at 1720 cm -1 (carbonyl of the amide) at 1735 cm -1 (carbonyl of the carboxyl) and at 3200 cm -1 (NH band). The infrared spectrum conforms to the structure announced.
EXEMEI-E II :EXEMEI-E II:
N-butyryl α aspartyl α -glutamyl (3 ,4-dihydroxyphényl) alanine.N-butyryl α aspartyl α -glutamyl (3, 4-dihydroxyphenyl) alanine.
STADE A : Acide N-formyl aspartique Eh opérant selon le mode opératoire du Stade A de l 'Exerple I, au départ de 133 g d'acide aspartique et d'un mélange de 113 g . d'anhydrid acétique et 59, 8 g d'acide formique anhydre, préparé à l 'avance, on obtient avec un rendement de 87 % l 'acide N-formyl aspartique.STAGE A: N-formyl aspartic acid Eh operating according to the procedure of Stage A of Exerple I, starting from 133 g of aspartic acid and a mixture of 113 g. acetic anhydrid and 59.8 g of anhydrous formic acid, prepared in advance, N-formyl aspartic acid is obtained with a yield of 87%.
STADE B : Anhydre N-formylaspartiqueSTAGE B: N-formylaspartic anhydrous
En opérant selon le mode opératoire du Stade B de l'Exerple I, au départ de l'acide N-formyl aspartique, on obtient avec un rendement quantitatif l'anhydride N-formylaspartique.By operating according to the procedure of Stage B of Exercple I, starting from N-formyl aspartic acid, the N-formylaspartic anhydride is obtained in quantitative yield.
STADE C : Acide N-formyl α -aspartyl α dutamioue En opérant comme au Stade C de l'Exerple I, au départ de 154,35 g d'acide glutamique et de 143 g d'anhydride N-formyl aspartique, on obtient une solution concentrée renfermant 71 % d'acide N-formyl aspartique glutamique (mélange d'isomères α et)que l'on utilise telle quelle pour l'étape suivante .STAGE C: N-formyl α-aspartyl α dutamioue acid By operating as in Stage C of Experple I, starting from 154.35 g of glutamic acid and 143 g of N-formyl aspartic anhydride, a concentrated solution containing 71% of N-formyl aspartic glutamic acid (mixture of α and isomers) which is used as it is for the next step.
STADE D :STAGE D:
La solution concentrée renfermant le mélange d'isomères d'acides N-formyl α et β-aspartyl α -glutamiques,est traitée par l'anhydride acétique selon le mode opératoire du Stade D de l'Exemple I. On obtient ainsi l'anhydride de l'acide N-formyl aspartimido α - glutamique qui est utilisé tel quel pour la poursuite de la synthèse.The concentrated solution containing the mixture of isomers of N-formyl α and β-aspartyl α -glutamic acids is treated with acetic anhydride according to the procedure of Stage D of Example I. The anhydride is thus obtained N-formyl aspartimido α - glutamic acid which is used as it is for the further synthesis.
STADE E : α -aspartyl α-alutamyl (3,4 - dihydroxypbényl) alanine On opère selon le mode opératoire du Stade E de l'Exemple I au départ de 198 g de dihydroxyphénylalanine et de 226 g d'anhydride N-formylaspartimido glutamique.STAGE E: α -aspartyl α-alutamyl (3,4 - dihydroxypbényl) alanine The procedure is carried out according to the procedure of Stage E of Example I starting from 198 g of dihydroxyphenylalanine and 226 g of N-formylaspartimido glutamic anhydride.
On obtient après hydrolyse chlorhydrique le dérivé déformylé que l'on précipite par addition de dioxane au peroolat. Les cristaux du tripeptide sont séchés sous vide a temperature ordinaire.The deformylated derivative is obtained after hydrochloric hydrolysis, which is precipitated by adding dioxane to the peroolate. The tripeptide crystals are dried under vacuum at ordinary temperature.
STADE F : N-butyryl α-aspartyl α-alutamyl (3,4-dihydroxyphényl) alanine. On dissout 44,3 g d' α -aspartyl α-glutamyl (3,4-dihydroxyphényl) alanine dans 450 ml d'eau préalablement amenée à pH 9 par addition de lessive de soude. On coule dans cette solution tout en mainte nant la température au voisinage de 0° et le pH à 9, 16,1 g d'anhy dride butyrique sous forte agitation en l'espace de 45 mn. Après achevèment de l'addition on maintient l'agitation à 0° pendant une heure, puis on percole le mélange reactionnel sur une colonne de chromatographie chargée de résine Duolite C 20 préalablenent lavée à l'acide chlorhydrique. Par traitement habituel du perco lat, on obtient le dérivé N-tutytylé avec un rendement de 67 %.STAGE F: N-butyryl α-aspartyl α-alutamyl (3,4-dihydroxyphenyl) alanine. 44.3 g of α -aspartyl α-glutamyl (3,4-dihydroxyphenyl) alanine are dissolved in 450 ml of water previously brought to pH 9 by addition of sodium hydroxide solution. It is poured into this solution while maintaining the temperature in the vicinity of 0 ° and the pH at 9.16.1 g of butyric anhydride with vigorous stirring within 45 minutes. After the addition is complete, stirring is continued at 0 ° for one hour, then the reaction mixture is percolated on a chromatography column loaded with Duolite C 20 resin previously washed with hydrochloric acid. By usual treatment of perco lat, the N-tutytylated derivative is obtained with a yield of 67%.
Dosage de l 'azote par protomètrie : 0 % Dosage de la fonction acide : 98 - 99 %Determination of nitrogen by protometry: 0% Determination of the acid function: 98 - 99%
De la même façon, on peut acyler l'azote par le chlorure de propionyle pour former un dérivé N-propionylé, par le chlorure de benzoyle pour former un dérivé N-benzoylé ou par le chlorure de l 'acide (dibenzocycloheptene 5-yl) amino heptanoïque pour former le dérivé (diberizocyclohepten - 5 yl) amino heptanoylé correspondant.Likewise, nitrogen can be acylated with propionyl chloride to form an N-propionyl derivative, with benzoyl chloride to form an N-benzoyl derivative or with acid chloride (dibenzocycloheptene 5-yl) heptanoic amino to form the derivative (diberizocyclohepten - 5 yl) corresponding heptanoylated amino.
EXEMPLE III :EXAMPLE III:
N-butyryl α -aspartyl α -qlutamyl dopamine.N-butyryl α -aspartyl α -qlutamyl dopamine.
En opérant comme à l'Exemple II, stade E, au départ de 154 g deBy operating as in Example II, stage E, starting from 154 g of
(3, 4-dihydroxyphényl) éthylamine et de 226 g d'anhydride N-formyl aspartimido glutamique, on obtient après hydrolyse chlorhydrique 321 g de α -aspartyl α -glutairyl dopamine.(3,4-dihydroxyphenyl) ethylamine and 226 g of N-formyl aspartimido glutamic anhydride, after hydrochloric hydrolysis, 321 g of α -aspartyl α -glutairyl dopamine.
On procède à la butyrylation de 321 g d' α-aspartyl α-giutaιrryl dopamine par l'anhydride butyryque selon le mode opératoire de l'Exerple II, Stade F et on recueille après les purifications usuelles 284 g de N-butyryl α -aspartyl α-glutamyl dopamine.Butyrylation of 321 g of α-aspartyl α-giutaιrryl dopamine is carried out with butyric anhydride according to the procedure of Experple II, Stage F and 284 g of N-butyryl α -aspartyl α are collected after the usual purifications. -glutamyl dopamine.
Dosage de l'azote aminé par protométrie : 0 % Dosage des fonctions arides : 98 %Determination of amino nitrogen by protometry: 0% Determination of arid functions: 98%
EXEMPTA IV :EXEMPTA IV:
N-acétyl α -glutamyl glycyl α -méthyl (3 ,4-dihydroxyphényl) alani ne.N-acetyl α -glutamyl glycyl α -methyl (3, 4-dihydroxyphenyl) alani ne.
STADE A : Acide N-acétyl glutamigue En opérant comme au Stade A de l 'Exemple I, au départ de 147, 5 g d'acide L-glutamique et purification par percolation sur une résine echangeuse d'ions forme acide, on obtient avec un rendement de 87 % le produit N-acétylé.STAGE A: N-acetyl glutamic acid By operating as in Stage A of Example I, starting from 147.5 g of L-glutamic acid and purification by percolation on an ion exchange resin in acid form, we obtain with an 87% yield of the N-acetylated product.
STADE B : Anhydride N-acétvl clutamigue En opérant comme au Stade B de l 'Exeiple I, au départ de 189 g de dérivé N-acétylé, en obtient avec un rendement de 90 % l 'anhydride N-acétyl glutamique.STAGE B: N-acetyl clutamic anhydride By operating as in Stage B of Example I, starting from 189 g of N-acetylated derivative, obtained therewith a N-acetyl glutamic anhydride with a yield of 90%.
STADE C : N-acétyl α -glutamyl glycine En opérant comme au Stade C de l 'Exemple I, au départ de l 'anhydride N-acétyl glutamique et de 75 g de glycine, on obtient une solution concentrée renfermant environ 70 % de N-acétyl α -glutamyl glycine et 30 % de N-acétyl β -glutarryl glycine que l 'on utilise pour le stade suivant de la synthèse sans séparation supplémentaire.STAGE C: N-acetyl α -glutamyl glycine By operating as in Stage C of Example I, starting from the N-acetyl glutamic anhydride and 75 g of glycine, a concentrated solution containing approximately 70% of N is obtained. -acetyl α -glutamyl glycine and 30% of N-acetyl β -glutarryl glycine which is used for the next stage of the synthesis without additional separation.
STADE D : Anhydride de N -acétyl glutarimido glycine. Εn opérant comme au Stade D de l 'Exemple I, au départ de 251 g de N-acétyl glutam yl glycine (mélange d'isomères α et β) en solution aqueuse concentrée) et de 750 g d'anhydride acétique, on forme l'anhydride de N-acétyl glutarimido glycine.STAGE D: N -acetyl glutarimido glycine anhydride. Εn operating as in Stage D of Example I, starting from 251 g of N-acetyl glutam yl glycine (mixture of α and β isomers in concentrated aqueous solution) and 750 g of acetic anhydride, forms N-acetyl glutarimido glycine anhydride.
STADE E : N-acétyl α qlutamyl glycyl α -méthyl (3,4-dihvdroxy phényl) alanine. On dissout 21,5 g de L-3-(3,4-dihydroxy phényl) 2-méthyl alanine dans 750 ml d'eau amenée à pH 8,5 sous atmosphère d'azote. On refroidit la solution à 0° et sous forte agitation on ajoute par petites portions en une heure environ 25,5 g d'anhydride de N- acétyl glutarimido glycine.STAGE E: N-acetyl α qlutamyl glycyl α -methyl (3,4-dihvdroxy phenyl) alanine. 21.5 g of L-3- (3,4-dihydroxy phenyl) 2-methyl alanine are dissolved in 750 ml of water brought to pH 8.5 under a nitrogen atmosphere. The solution is cooled to 0 ° and with vigorous stirring, about 25.5 g of N-acetyl glutarimido glycine anhydride is added in small portions over an hour.
Après percolation du milieu reactionnel sur résine Duolite C 20 et hydrolyse chlorhydrique du percolat, on obtient 33,4 g de N-acétyl α -glutarryl glycyl α -méthyl (3,4-dihydroxyphényl) alanine, que l'on précipite par addition d'acétone.After percolation of the reaction medium on Duolite C 20 resin and hydrochloric hydrolysis of the percolate, 33.4 g of N-acetyl α -glutarryl glycyl α -methyl (3,4-dihydroxyphenyl) alanine are obtained, which is precipitated by addition of 'acetone.
Titrage protométrique : 97 - 97,5 %Protometric titration: 97 - 97.5%
EXEMPLE V :EXAMPLE V:
Acide N-(5-méthoxy 2-méthyl N-p.chlorobenzoyl indolyl-3 acétyl) α -aspartyl α -glutamique.N- (5-methoxy 2-methyl N-p. Chlorobenzoyl indolyl-3 acetyl) α -aspartyl α -glutamic acid.
On dissout 18 g d'indométhacine dans 150 ml de dioxane et 4,5 ml de triéthylamine. On ajoute à cette solution 22 g de dicyclohexyl carbodiimide et on maintient la solution sous agitation pendant18 g of indomethacin are dissolved in 150 ml of dioxane and 4.5 ml of triethylamine. 22 g of dicyclohexyl carbodiimide are added to this solution and the solution is stirred for
45 mn. Le précipité de dicyclohexyl urée fermée est séparé par filtration et on ajoute progressivement la solution dioxanique d'anhydride mixte à une solution de 27 g d'acide α -aspartyl α - glutamique dans 125 ml de diméthylformamide. Après une heure de contact à température ordinaire, on sépare le précipité par filtra tion, puis on concentre sous vide la solution de peptide. On dilue ensuite avec deux volumes d'eau glacée et on amorce la cristallisation par grattage. Le dérivé indolique précipite progressivement. On le sépare par filtration, le lave à l'eau jusqu'à neutralité des eaux de lavage et le sèche sous vide.45 mins. The precipitate of closed dicyclohexyl urea is separated by filtration and the dioxane solution of mixed anhydride is gradually added to a solution of 27 g of α-aspartyl α-glutamic acid in 125 ml of dimethylformamide. After one hour of contact at ordinary temperature, the precipitate is separated by filtration, then the peptide solution is concentrated in vacuo. It is then diluted with two volumes of ice water and the crystallization is started by scraping. The indole derivative gradually precipitates. It is separated by filtration, washed with water until the washings are neutral and dried under vacuum.
L'acide N-(5-méthoxy 2-méthyl N'-(p.chlorobenzoyl) indolyl-3 acétyl- α -aspartyl α-glutamique se présente sous forme d'une poudre ocre crème peu soluble dans l'eau, soluble dans la pyridine, le diméthylforma mide et les solutions alcalines. L'acide α -aspartyl α -glutamique est obtenu par hydrolyse chlorhydrique de l'anhydride N-formyl aspartimido α-glutamique obtenu à l'Exemple II, Stade D.N- (5-methoxy 2-methyl N '- (p.chlorobenzoyl) indolyl-3 acetyl- α -aspartyl α-glutamic acid is present in the form of a ocher cream powder slightly soluble in water, soluble in pyridine, dimethylforma mide and alkaline solutions. The α -aspartyl α -glutamic acid is obtained by hydrochloric hydrolysis of the N-formyl aspartimido α-glutamic anhydride obtained in Example II, Stage D.
EXEMPLE VI :EXAMPLE VI:
N-acétyl α -glutamyl glycyl (4-amino 5-chloro 2-méthoxy) N'N - diéthylamino benzamide. En opérant comme au Stade E de l'Exemple IV, au départ de 30 g de métoclopramide(dichlorhydrate)dans 250 ml d'eau, puis ajustement du pH à 8,5 et de 25 g d'anhydride N-acétyl glutarimido glycine, on obtient après percolation sur résine Duolite C 20 et hydrolyse chlorhydrique à 60°, 26 g de N-acétyl α -glutamyl glycyl (4-amino 5-chloro 2-méthoxy ) N'N'-diérthylamino benzamide que l'on recristallise de l'acétonitri .N-acetyl α -glutamyl glycyl (4-amino 5-chloro 2-methoxy) N'N - diethylamino benzamide. By operating as in Stage E of Example IV, starting from 30 g of metoclopramide (dihydrochloride) in 250 ml of water, then adjusting the pH to 8.5 and 25 g of N-acetyl glutarimido glycine anhydride, after percolation on Duolite C 20 resin and hydrochloric hydrolysis at 60 °, 26 g of N-acetyl α -glutamyl glycyl (4-amino 5-chloro 2-methoxy) N'N'-dierythylamino benzamide are obtained which are recrystallized from acetonitri.
Le produit se présente sous forme de cristaux à reflets rosés peu solubles dans l'eau et les solvants hydroxylés mais solubles dans les solutions alcalines.The product is in the form of crystals with pink reflections which are not very soluble in water and the hydroxylated solvents but which are soluble in alkaline solutions.
EXEMPLE VII :EXAMPLE VII:
N-acétyl α -aspartyl histidyl α -méthyl N' -(3-trifluorométhyl phényl) éthyl N'-éthyl aminé. STADE A :N-acetyl α -aspartyl histidyl α -methyl N '- (3-trifluoromethyl phenyl) ethyl N'-ethyl amino. STAGE A:
N-acétyl α -aspartyl histidine .N-acetyl α -aspartyl histidine.
Au départ de 156 g de L-histidine en solution dans l'eau à pH 8,5, on ajoute selon le mode opératoire de l'Exemple I, Stade C, 1 mole d'anhydride de N-acétyl α-L-aspartique sous forme solide. Après purification sur résine Duolite C 20 et concentration de la solution aqueuse, on obtient une masse sirupeuse dent l'analyse montre qu'elle contient 80 % de N-acétyl α-aspartyl histidine etStarting from 156 g of L-histidine in solution in water at pH 8.5, 1 mole of N-acetyl α-L-aspartic anhydride is added according to the procedure of Example I, Stage C in solid form. After purification on Duolite C 20 resin and concentration of the aqueous solution, a syrupy tooth mass is obtained, the analysis shows that it contains 80% of N-acetyl α-aspartyl histidine and
20 % de N-acétyl β-aspartyl histidine.20% N-acetyl β-aspartyl histidine.
Rendement de couplage par rapport à l'anhydride = 81 %. STADE B : Anhydride de la (N-acétyl aspartimido) histidine. En opérant selon le mode opératoire de l'Exemple I, Stade D, au départ de la solution concentrée de N-acétyl α (et β ) aspartyl histidine et de 750 g d'anhydride acétique on forme l'anhydride de la N-acétyl aspartimido histidine que l'on utilise tel quel pour l'étape suivante de la synthèse.Coupling yield with respect to the anhydride = 81%. STAGE B: (N-acetyl aspartimido) histidine anhydride. By operating according to the procedure of Example I, Stage D, starting from the concentrated solution of N-acetyl α (and β) aspartyl histidine and 750 g of acetic anhydride, the N-acetyl anhydride is formed. aspartimido histidine which is used as is for the next step of the synthesis.
STADE C : N-acétyl α-aspartyl histidyl α-méthyl N'-(3-trifluo rome thylphényl éthyl) N'-éthyl aminé. On dissout 269 g de chlorhydrate de 2-(3-trifluorométhyl phényl propyl) N-éthyl aminé dans 1000 ml d'eau dont le pH a été amené à 8,5 et dont la température est abaissée à 0°. On ajoute à cette solution sous très forte agitation, par petites fractions, en une heure environ, 240 g d'anhydride de la N-acétyl α -aspartyl histi dine sous forme solide. On maintient pendant tout la durée de l'ad dition la température du mélange reactionnel au voisinage de 0° et le pH du milieu à 8,5.STAGE C: N-acetyl α-aspartyl histidyl α-methyl N '- (3-trifluorome thylphenyl ethyl) N'-ethyl amino. 269 g of 2- (3-trifluoromethyl phenyl propyl) N-ethyl amino hydrochloride are dissolved in 1000 ml of water, the pH of which has been brought to 8.5 and the temperature of which is lowered to 0 °. 240 g of N-acetyl α-aspartyl histidine anhydride in solid form are added to this solution with very vigorous stirring, in small fractions, in about one hour. The temperature of the reaction mixture is kept close to 0 ° for the entire duration of the addition and the pH of the medium is 8.5.
Après achèvement de l'addition, le mélange reactionnel est passé sur une colonne à chromatographie chargée de résine Duolite C 20 préalablement traitée à l'acide chlorhydrique. Le liquide de percolation est recueilli puis acidifié franchement par addition d'acide chlorhydrique. On dilue ensuite la solution par addition d'eau et on porte la solution à 45° pendant 2 heures. On laisse ensuite refroidir et on concentre la solution sous pression réduite sans dépasser 40°. La masse solide est reprise par l'acétone et on amorce la cristallisation par grattage. On laisse ensuite reposer le mélange par repos en glacière pendant 12 heures.After completion of the addition, the reaction mixture is passed through a column chromatography loaded with Duolite C 20 resin previously treated with hydrochloric acid. The percolation liquid is collected and then acidified frankly by the addition of hydrochloric acid. The solution is then diluted by adding water and the solution is brought to 45 ° for 2 hours. Then allowed to cool and the solution is concentrated under reduced pressure without exceeding 40 °. The solid mass is taken up in acetone and the crystallization is started by scraping. The mixture is then left to stand by resting in a cooler for 12 hours.
on sépare ensuite les cristaux, les lave à l'acétone, les essore, puis les sèche sous vide. La N-acétyl α -aspartyl histidyl α -méthyl N'- (3-trifiuorométhyl phényl éthyl) N'-éthyl aminé se présente sous forme de cristaux blancs jaunâtres,peu solubles dans l'eau, solubles en milieu acide ou en milieu alcalin, peu solubles dans les solvants organiques. Le produit montre un point de décomposition plutôt qu'un point de fusion précis. the crystals are then separated, washed with acetone, wrung out, then dried in vacuo. N-acetyl α -aspartyl histidyl α -methyl N'- (3-trifiuoromethyl phenyl ethyl) N'-ethyl amino occurs in the form of yellowish white crystals, not very soluble in water, soluble in acidic or alkaline medium , poorly soluble in organic solvents. The product shows a decomposition point rather than a specific melting point.

Claims

REVENDICATIONSL'invention a pour objet : The object of the invention is:
1. Les nouveaux N - acyl dipeptides de formule générale1. The new N - acyl dipeptides of general formula
Ac - A - X - Y dans laquelle Ac représente le reste acyle d'un acide organique carboxylique, aliphatique, aromatique ou hydroaroraatique. A est le reste d'un amino acide porteur d'une autre fonction carboxylique, substitué en α X est le reste d'un amino acide etAc - A - X - Y in which Ac represents the acyl residue of an organic carboxylic, aliphatic, aromatic or hydroaroraatic acid. A is the remainder of an amino acid carrying another carboxylic function, substituted at α X is the remainder of an amino acid and
Y est de l'hydrogène ou le reste d'une aminé mono ou disubstituée, linéaire ou cyclique.Y is hydrogen or the remainder of a mono or disubstituted, linear or cyclic amine.
2. Les N- acyl dipeptides selon la revendication 1° répondant à la formule générale I'2. The N-acyl dipeptides according to claim 1, corresponding to the general formula I '
Figure imgf000022_0001
dans laquelle Ac est un radical acétyle
Figure imgf000022_0001
in which Ac is an acetyl radical
Z est de l'hydrogène ou forme avec Z' un radical alcoylene inférieur éventuellement substitué par un hydroxyle ou éventuellement interrompu par un hétéroatome.Z is hydrogen or forms with Z 'a lower alkylene radical optionally substituted by a hydroxyl or optionally interrupted by a heteroatom.
Z' est le l'hydrogène, un radical alcoyle inférieur linéaire ou ramifié éventuellèsent substitué par un radical nydroxyle, un radical carbamoyle, un radical ureido, un redical guanidino, ou un groupe sulfonique; un redical phénylalcoyle inférieur ou indolyl alcoyle inférieur, ou bien Z1 forme avec Z un radical alcoylene inférieur, éventuellement substitué par un hydroxyle ou éventuellement interrompu par un hétéroatome. Y' et Y", distinctement l'un de l'autre, représentent de l'hydrogène, un radical alcoyle, aryle, hétéro aryle, aralcoyle, ces radicaux pouvant être substitués par 1 à 3 substituants, avec la limitation que Y et Y' ne peuvent représenter simultanément de l'hydrogène et n est un nombre entier variant de 1 à 3. Z 'is hydrogen, a linear or branched lower alkyl radical optionally substituted by a hydroxyl radical, a carbamoyl radical, a ureido radical, a guanidino redical, or a sulphonic group; a lower phenylalkyl or indolyl lower alkyl redical, or else Z1 forms with Z a lower alkyl radical, optionally substituted by a hydroxyl or optionally interrupted by a heteroatom. Y 'and Y ", distinctly from each other, represent hydrogen, an alkyl, aryl, hetero aryl or aralkyl radical, these radicals being able to be substituted by 1 to 3 substituents, with the limitation that Y and Y 'cannot simultaneously represent hydrogen and n is an integer varying from 1 to 3.
3. Les N - acyl dipeptides selon la revendication 1° répondant à la formule générale I " .3. The N - acyl dipeptides according to claim 1, corresponding to the general formula I ".
Figure imgf000023_0001
dans laquelle les substituants Z, Z' et n sont définis comme précédemment. Y et Y' sont de l'hydrogène et Ac représente le reste acyle d'un acide organique carboxylique dont le reste hydrocarboné est un redical alcoyle ayant de 2 à 18 atomes de Carbone en chaine droite ou ramifiée, un radical aryle mono, bi- ou tricyclique ayant de 5 à 15 atomes de Carbone, un radical aralcoyle dont le reste alcoyle possède de 1 à 8 atomes de Carbone et où le reste aryle est mono, bi- ou tricyclique et possède de 5 à 15 atomes de Carbone, un radical hétéroarylique mono, bi- pu tricyclique, un radical hydro aromatique ayant de 3 à 15 atomes de Car bone mono, bi- ou tricyclique ou un radical (hydroaryl) alcoyle dans lequel le reste hydroaryle est défini corn ne précédemment et le reste alcoyle possède de 1 à 8 atomes de Carbone éventuellement substitué par un hydroxyle ou un radical oxo, ou interrompu par un groupe amino.
Figure imgf000023_0001
wherein the substituents Z, Z 'and n are defined as above. Y and Y 'are hydrogen and Ac represents the acyl residue of an organic carboxylic acid, the hydrocarbon residue of which is an alkyl radical having from 2 to 18 carbon atoms in straight or branched chain, a mono, bi- or tricyclic having 5 to 15 carbon atoms, an aralkyl radical in which the alkyl residue has from 1 to 8 carbon atoms and where the aryl residue is mono, bi- or tricyclic and has from 5 to 15 carbon atoms, a radical heteroaryl mono, bi- or tricyclic, a hydro aromatic radical having 3 to 15 carbon atoms mono, bi- or tricyclic or a (hydroaryl) alkyl radical in which the hydroaryl residue is defined above and the alkyl residue has 1 to 8 carbon atoms optionally substituted by a hydroxyl or an oxo radical, or interrupted by an amino group.
4. Les nouveaux N -acyl dipeptides selcn la revendication 1° dans lesquels le reste A est un reste α - aspartyl eu α - glutamyl.4. The new N-acyl dipeptides according to claim 1 in which the residue A is an α-aspartyl or α-glutamyl residue.
5. Les nouveaux N -acyl dipeptides selon la revendication 1° dans lesquels X est un reste d'acide aminé naturel de configuration L.5. The new N-acyl dipeptides according to claim 1 in which X is a natural amino acid residue of configuration L.
6. Les nouveaux N- acyl dipeptides selon la revendication 1° dans lesquels le reste Y est une base azotée eu une phénylalcoylaminé ou une indolyl alcoylamine .6. The new N-acyl dipeptides according to claim 1 in which the residue Y is a nitrogenous base having a phenylalkylamine or an indolylalkylamine.
7. Un procédé d'obtention des composés de formule générale I7. A process for obtaining the compounds of general formula I
Ac - A - X - Y (I) dans laquelle les radicaux Ac, A, X et Y ont les significations fournies antérieurement, caractérisé en ce que l'on soumet un acide aminé A - C à l'action d'un acide de formule Ac - CH dans laquelle Ac est défini comme précédem-αent, ou d'un de ses dérivés fonctionnels, en présence d'un agent basique pour former un dérivé N - acylé, de formule générale II Ac - A - OH ( II) dans laquelle les restes Ac et A sont définis comme précédemment, soumet celui-ci à l'action d'un agent deshydratant pour former un anhydride de formule générale IIIAc - A - X - Y (I) in which the radicals Ac, A, X and Y have the meanings previously supplied, characterized in that an amino acid A - C is subjected to the action of an acid of formula Ac - CH in which Ac is defined as above, or one of its functional derivatives, in the presence of a basic agent to form an N - acylated derivative, of general formula II Ac - A - OH (II) in which the residues Ac and A are defined as above, subjects it to the action of a dehydrating agent to form an anhydride of general formula III
Figure imgf000024_0002
dans laquelle Ac est défini comme précédemment, n est égal à 1, 2, ou 3, ou un de ses analogues de structure, substitué par un radical méthyl - amino, hydroxy ou thio, fait réagir ce dernier en milieu aqueux avec un acide aminé de formule
Figure imgf000024_0002
in which Ac is defined as above, n is equal to 1, 2, or 3, or one of its structural analogs, substituted by a methylamino, hydroxy or thio radical, reacts the latter in an aqueous medium with an amino acid of formula
H - X - OH dans laquelle X est défini comme précédemment, pour obtenir le N-acyl dipeptide de formule générale IVH - X - OH in which X is defined as above, to obtain the N-acyl dipeptide of general formula IV
Ac - A - X - OH (IV) dans laquelle Ac, A et X sont définis comme précédemment, soumet celui-ci à l'action d'un agent de déhydratation à casse température pour former l'anhydriαe correspondant, qui par réaction avec une aminé primaire ou secondaire de formule générale YH permet d'obtenir le N-acyl dipeptide de formule générale IAc - A - X - OH (IV) in which Ac, A and X are defined as above, subjects it to the action of a dehydration agent at temperature breaks to form the corresponding anhydriαe, which by reaction with a primary or secondary amine of general formula YH makes it possible to obtain the N-acyl dipeptide of general formula I
Ac - A - X - Y (I)Ac - A - X - Y (I)
8. Un autre procédé d'obtention des composés de formule générale I selon la revendication 1° qui consiste à soumettre le dipeptide de formule σénérale IV8. Another process for obtaining the compounds of general formula I according to claim 1 which consists in subjecting the dipeptide of formula σeneral IV
Ac - A - X - CH (IV) dans laquelle Ac, A et X ont les mêmes significations que celles fournies antérieurement, à l'action d'un agent ce dénydratation, à chaud pour former l'imideanhydride de formule générale VAc - A - X - CH (IV) in which Ac, A and X have the same meanings as those supplied previously, to the action of an agent for this dehydration, when hot to form the imideanhydride of general formula V
Figure imgf000024_0001
Figure imgf000024_0001
PCT/FR1982/000116 1981-07-09 1982-07-08 New derivatives of dipeptides, method for the preparation thereof and utilization thereof as drugs WO1983000146A1 (en)

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FR2546407A1 (en) * 1983-05-24 1984-11-30 Therapeutique Applic Sa DRUG WITH ANTI-ALLERGIC ACTIVITY FOR LOCAL ADMINISTRATION BASED ON N-ACETYL ACID (A, B) -ASPARTYL GLUTAMIC
EP0353565A1 (en) * 1988-07-29 1990-02-07 ELLEM INDUSTRIA FARMACEUTICA S.p.A. Immunostimulating peptides, a process for their preparation and pharmaceutical commpositions containing them
WO1995014033A1 (en) * 1993-11-19 1995-05-26 Aktiebolaget Astra Novel dipeptide derivatives
WO2004020394A1 (en) * 2002-08-27 2004-03-11 Asahi Kasei Chemicals Corporation Novel composition containing acyl group

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DE69125216T2 (en) * 1990-07-19 1997-09-25 Nippon Zoki Pharmaceutical Co Aminoalkanesulfonic acid derivatives and pharmaceutical compositions thereof for the prevention or treatment of heart diseases
JP2002537307A (en) * 1999-02-19 2002-11-05 ベー・エル・アー・ハー・エム・エス・ディアグノスティカ・ゲーエムベーハー Use of blocking anti-TSH receptor antibodies in the treatment of hyperthyroidism and monoclonal antibodies for such uses
JP4847113B2 (en) * 2005-11-30 2011-12-28 柳井紙工株式会社 Assembled paper box

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2546407A1 (en) * 1983-05-24 1984-11-30 Therapeutique Applic Sa DRUG WITH ANTI-ALLERGIC ACTIVITY FOR LOCAL ADMINISTRATION BASED ON N-ACETYL ACID (A, B) -ASPARTYL GLUTAMIC
EP0131477A1 (en) * 1983-05-24 1985-01-16 THEA (Thérapeutique et Applications) S.A. Use of a salt of the acid N-acetyl (alpha, beta) aspartylglutamic for the manufacture of a drug having an anti-allergic activity for local administration
EP0353565A1 (en) * 1988-07-29 1990-02-07 ELLEM INDUSTRIA FARMACEUTICA S.p.A. Immunostimulating peptides, a process for their preparation and pharmaceutical commpositions containing them
WO1995014033A1 (en) * 1993-11-19 1995-05-26 Aktiebolaget Astra Novel dipeptide derivatives
WO2004020394A1 (en) * 2002-08-27 2004-03-11 Asahi Kasei Chemicals Corporation Novel composition containing acyl group
US7488841B2 (en) 2002-08-27 2009-02-10 Asahi Kasei Chemicals Corporation Composition containing acyl group

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