FR2671971A1 - New serotonin derivatives, use as medicaments and compositions containing them - Google Patents

Abstract

The serotonin derivatives of general formula I in which R1 represents an amino residue or an alcohol residue,R2 represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon atoms or an acyl radical, R3 represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon atoms, R4 represents a hydrogen or halogen atom and n represents an integer from 1 to 10, their salts, use as medicaments and compositions containing them.

Description

 The present invention relates to new derivatives of serotonin, their application as a medicament and the compositions containing them.

French patent application no 90 06292 has described derivatives of biologically active molecules comprising a primary amine function and a hydroxylated nucleus, characterized in that they correspond to the general formula
R'R "-NABO-CH2-CO-NH-R in which
A represents a linear or branched alkylene chain containing from 1 to 5 carbon atoms and preferably 2, the branching being able to comprise a sulphide group;
B represents an aromatic ring comprising from 6 to 10 carbon atoms, optionally substituted and optionally a heteroatom, or a group -B1-X-B2-, in which B1 and B2 have the meaning of B above and
X represents an oxygen atom or an alkylene chain containing from 1 to 4 carbon atoms,
- NH-R represents an amino residue, and
- Rt and R "represent an alkyl radical containing 1 d 5 carbon atoms, a hydrogen atom or a hydrophobic radical, as well as their addition salts with mineral or organic acids.

Application N 90 06292 also relates to a process for the preparation of the derivatives described above, characterized in that a derivative of formula (II) is reacted:
R'R "NAB-OH (II)
in which R ', R ", A and B have the meaning already indicated, with a derivative comprising a protective group for the amine functions in the case where R' = R" = H, to obtain a derivative of formula (III)
Y-HN-AB-OH (III) in which A and B have the meanings already indicated and
Y represents an easily cleavable protective group of amine functions, which lion reacts with a haloacetic acid to obtain a derivative of formula (IV):
Y-HN-ABO-CH2COOH (IV)
in which A, B and Y have the meaning already indicated, which is reacted with an amino derivative to obtain the expected derivative of the formula as defined above, where appropriate in the form of a dimer in the case of a diamine, that it is isolated and, if desired, salified,
The derivative capable of grafting a protective group of the amine functions onto the derivative of formula (II) may, for example, title an acid chloride [9-fluorenylmethyl oxycarbonyl (FmooCl), benzyloxycarbonyl (BzCl)] and preferably an anhydride Ele di-t-butyldicarbonate, (BOC) 2O, or citraconic anhydride].

 The preparation of the derivative of formula (IV) is preferably carried out at alkaline pH in the presence of a metal oxide such as magnesium oxide and a haloacetic acid, the latter possibly being a chloride but preferably being a bromide.

 The reaction of the derivative of formula (IV) with the amino derivative (R) is preferably carried out after activation of the carboxylic group in the form of mixed anhydride with an alkyl chlorocarbonate such as ethyl chloroforate. Acid chlorides, carbodiimides or the prior formation of a hydrolysable ester of N-hydroxysuccinimide can also be used as activators.

The cleavage of the protective group of the amine is carried out if necessary by acid hydrolysis, in particular using an acid such as trifluoroacetic acid, or alkaline, in particular using piperidine
The above derivatives, optionally labeled for example using a radioactive element, in particular 125 I, or fluorescent or also using an enzyme, have been described as useful in particular for imaging both in vivo and in vitro endogenous mediator binding sites or as a marker for a protein carrying colloidal gold or a contrast agent.

 The above application has also described the application of the above derivatives to the purification of endogenous mediator receptors.

 The aforementioned application has also described the application of the above derivatives and in particular the O-carboxymethyl thyroxine derivatives to the inhibition of binding to transport proteins, for the determination of total hormone.

 The above application has also described the application of the above derivatives to the imaging of endogenous mediator binding sites as well as the application of said derivatives to the preparation of antibodies directed against endogenous mediators.

 This application does not describe any therapeutic activity for these products.

The subject of the present invention is the serotonin derivatives corresponding to the general formula I

 in which R1 represents an amino residue or an alcohol residue, R2 represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon or acyl atoms, R3 represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon atoms, R4 represents a hydrogen or halogen atom and n represents an integer from 1 to 10, as well as their addition salts with pharmaceutically acceptable acids, for their use in a method of therapeutic treatment of the human or animal body, that is to say as a medicament.

 In the general formula I and in what follows, the term "amino residue is a mono or polyamine residue and represents a diamine, a protein, an amino acid or a polypeptide consisting of at most 5 amino acids, or derivatives of said amino acids or polypeptides. Said amino acids will preferably be natural amino acids (in L form) or in D form, or their amide derivatives; C t is thus for example only if the radical R1 is a dipeptide consisting of a glycyl residue and of a tyrosyl residue, it is possible, for example, to replace the tyrosyl residue with a tyrosynamide or tyrosine ester residue.

 n will preferably take the values 2 (dimeric form) or 1 (monomeric form), in particular 1.

 The term "residue of an alcohol" is a residue of a monoalcohol or of a polyol and represents, for example, a fatty alcohol and preferably dodecanol.

The term "linear or branched alkyl radical containing 1 to 5 carbon atoms" denotes, for example, an n-pentyl, n-butyl, n-propyl, 2,2dimethylpropyl radical or, preferably, an isopropyl, ethyl or methyl. The halogen atom can be a chlorine, bromine or iodine atom,
The term "acyl radical" designates a radical of the R'2-CO- type which represents an amino acid or a polypeptide whose amine function is protected, for example, by an acetyl or benzoyl radical;
R'2-CO- acetyl-L-tyrosyl or benzoyl-L-arginyl radicals.

These acyl radicals must be hydrolyzable by proteolytic enzymes, such as those found in the digestive tract or the human body such as chymotrypsin or alphachymotrypsin.

 The addition salts with pharmaceutically acceptable acids may, for example, be salts formed with hydrochloric, hydrobromic, nitric, sulfuric, acetic, formic, propionic, benzoic, malic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic acids. , aspartic, alkane sulfonic such as methane or ethane sulfonic, arylsulfonic, such as benzene or paratoluene sulfonic or carboxylic acids. The salts of chactropic anions which are suitable for facilitating dissolution in an aqueous medium, such as citrate or succinate ions, are more particularly retained.

Among the derivatives described above, there are in particular the derivatives of formula I for which R1 represents a diamine, a protein, an amino acid or a polypeptide consisting of at most 5 amino acids or derivatives of said amino acids or polypeptides, and in particular the tryptamine 5-O-carboxymethylglycyltyrosinamide [S-CM GTNHZ] as well as their addition salts with pharmaceutically acceptable acids.
The above derivatives are more particularly retained for which R2 and R3 represent a linear or branched alkyl radical containing from 1 to 5 carbon atoms, preferably a methyl radical, as well as their addition salts with pharmaceutically acceptable acids.

Among the products of the invention, there may also be mentioned the derivative of formula (I) as defined above, characterized in that R1 represents a radical Gly
Tyr-NH2, R2, R3 and R4 representing a hydrogen atom, as well as its addition salts with pharmaceutically acceptable acids.

 The hydrolysis of the derivatives of formula I in which R2 represents an acyl radical makes it possible to obtain other derivatives of formula I.

 The derivatives which are the subject of the present invention have very advantageous pharmacological properties. They are endowed in particular with a remarkable affinity for the serotonin receptors, particularly 5HTlD.

These properties are illustrated later in the experimental part. They justify the use of the mediator derivatives described above as well as their addition salts with pharmaceutically acceptable acids as medicaments.
The medicaments according to the present invention find their use for example in the curative and preventive treatment of diseases linked to a dysfunction of the 5HTlD receptors, their deregulation or to modifications of the endogenous ligand (generally serotonin). they find in particular their use in the treatment of migraine.

 The usual dose, which varies according to the subject treated and the problem in question, can be, for example, from 0.1 to 10 mg per day orally in humans for the derivative of Example 1.

 A subject of the invention is also pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active principle.

 As medicaments, the derivatives corresponding to general formula I as well as their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.

 These pharmaceutical compositions can be, for example, solid or liquid and are presented in the pharmaceutical forms commonly used in human medicine, such as for example simple or coated tablets, capsules, granules, caramels, suppositories, preparations for instillations nasal preparations, injections: they are prepared according to the usual methods. The actff principle (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic glycol derivatives, the various wetting agents, dispersants or emulsifiers, preservatives.

The present application finally relates to the derivatives corresponding to the general formula I

in which R1 represents an amino residue or residue of an alcohol, R2 represents a hydrogen atom or a linear or branched alkWle radical containing from 1 to 5 carbon or acyl atoms, R3 represents a hydrogen atom or an alkyl radical linear or branched containing from 1 to 5 carbon atoms, R4 represents a hydrogen or halogen atom and n represents an integer from 1 to 10, as well as their addition salts with mineral or organic acids, a l except derivatives of formula I in which R2 = R3 = R4 = H, and R1 represents hydrogen or a group Gly-Tyr, His, Gly-
Tyr-OH, Tyr-Gly-NH2, Gly-Gly-OH or Gly-Cys.

 Among the derivatives described above, there are in particular the derivatives of formula I for which R1 represents a diamine, a protein, an amino acid or a polypeptide consisting at most of S amino acids or derivatives of said amino acids or polypeptides, as well as their addition salts with mineral or organic acids.

 The above derivatives are more particularly retained for which k2 and R3 represent a linear or branched alkyl radical containing from 1 to 5 carbon atoms, preferably a methyl radical, as well as their addition salts with mineral or organic acids.

 The derivatives of general formula I have a basic character. It is advantageous if appropriate to prepare salts of the derivatives of general formula, by reacting in substantially stoichiometric proportions a mineral or organic acid with said derivative of general formula I. the salts can optionally be prepared without isolating the corresponding bases.

 The examples which follow illustrate the present application without however limiting it.

EXPERIMENTAL PART
EXAMPLE 1
Synthesis of serotonin derivatives
Series of examples corresponding to the general formula T in which R2 = R3 = Rq = H.

1. Synthesis of N-tertiobutyl carbamate, 5-O-carboxymethyl tryptamine [BOC-S-CM]
Derivative of type formula (IV) Y-HN-ABO-CH2-COOH
1.1. Protection of the amine group
The amino group protection of 5-HT is carried out with di-t-butyldicarbonate [(BOC) 20] (Tarbell et al., 1972). Mixing equal volumes of 50 mM serotonin oxalate and 50 mM (BOC) 2O in dimethyl sulfoxide (DMSO) in the presence of triethylamine (TEA) is carried out. The reaction is immediate at room temperature.

1.2. Carboxymethylation of the hydroxyphenyl group
Protection by BOC is not useful for certain derivatives of serotonin which, like bufotenin, have a tertiary amine, the residues R2 and R3 of the general formula being methyl groups. The rest of the molecule (residues A and B) being identical to serotonin, it is possible to proceed directly to the O-carboxymethylation of bufotenine under the same conditions as those described below for BOC-S.

 The solution obtained in 1.1. is mixed volume h volume with a 500 mM aqueous bromoacetic acid solution, the adjusted pK 8 12 in the presence of magnesium oxide and nitrogen gas. The pH, the absence of oxygen and light are kept constant for 24 hours. The medium is centrifuged for 5 min at 10,000 rpm.

1.3. Purification by high performance liquid chromatography (HPLC)
The separation of the carboxymethyl-0-5-tryptamine-BOC derivative (BOc-S-CM) from the serotonin BOC (BoC-S) and the oxidation products is carried out by HPLC.

 The supernatant is diluted in two volumes of a 1% aqueous solution of trifluoroacetic acid. 1.8 ml of this mixture is injected into a HPLC on a silica column grafted with Ultrasound ODS C18 (5 m, diameter 4.6 mm, length 15 cm), by isocratic elution (H20-TFA 0.05%, 55 vol, methanol 45 vol). Elution is followed by spectrophotometry.

 The separation of the carboxymethylation products from bufotenine takes place on a Bondapack Cl8 column, in isocratic solution TFA 0.05% 93 vol, acetonitrile 7 vol.

 The fractions collected are analyzed by spectrophotometry. The absorption spectra in basic and acidic medium are compared in order to determine whether the substitution has indeed taken place on the hydroxyl group (Korman Clarke, J. Biol. Chem. 221, 1956, p. 113-131).

 The fractions containing the BOC-S-CM derivative are evaporated and lyophilized.

 2. Conjugation of O-carboxymethylated derivatives with the radical R-NH2.

 2.1. Extension of the newly created side chain.

 An amide bond can be created with a peptide chain after activation of the acid group of BOC-S-CM by ethyl chloroformate (ECF).

 The activation solution is composed of 5 ml of dimethylformamide (DMF), 7 μl of TEA and 7 μl of ECF. A volume of this solution such that the ECF is equimolar with the BOC-S-CM is poured onto the lyophilized BOC-S-CM derivative.

 After 5 minutes of activation at 4 ° C., an equal volume of aqueous glycyl-tyrosinamide solution (or dthistamine, or of Tyr-Gly, Gly-Tyr, Gly-Gly, Gly-Cys in the form of free or amidated acids) is added. S a concentration 50 times higher than that of BOC-S-CM.

The reaction products are separated by
HPLC on ODS C18 Ultrasound column, by isocratic elution (H2O, pH 6 60 vol, methanol 40 vol).

 The fractions containing the serotoninpeptide derivative (BOc-S-cM-GTNH2) are evaporated and lyophilized.

2.2. Preparation of macromolecular derivatives
2.2.1. BOC-S-CM-R derivative graft on protein
The derivatives obtained in 1.3. or 2.1. or in free acid form are activated by ethyl chloroformate (see 2.1.) and grafted onto a native (BSA) or modified (Gly-BSA) protein.

 The BOC-S-CM-R derivatives are separated by dialysis from the coupled derivatives & BSA of the BOC-S-CM-R-BSA type.

The amine group of these derivatives can be deprotected according to 3 below,
2.2.2. Transplant of S-CM-Gly-Cys derivatives onto proteins.

 The proteins are modified by adding a heterobifunctional crosslinking agent of the Nhydroxysuccinimide type, for example succinimidyl-4- (Nmaleimidomethyl) cyclohexane-1-carboxylate (SMCC) reaction (Ishikawa et al ,, 1983, J. Immunoassay 4, 209 327) takes place at pH 7.3 in the phosphate buffer. The protein whose NH2 residues are thus activated is separated by dialysis.

 The S-CM-Cly-Cys derivative is grafted onto the preceding proteins by the sulfhydryl group h pH = 6.5.

 The products are separated by dialysis, derivatives of the S-CM-Gly-Cys-S-SMCC-BSA type are obtained.

3. Deprotection of the amine group
200 l of TFA (200 mg) are poured onto the BOC-S-CO-NHR derivative (with R = H, Gly-TyrNH2, His, Gly-Tyr
OH, Tyr-GlyNH2, Gly-GlyOH, Gly-Cys) lyophilized and cooled to 9-20 C. After one minute of action, the TFA is evaporated under nitrogen gas.

The reaction products are separated by
HPLC on ODS C18 Ultrasound column, by isocratic elution (TFA 0.05% in water 65 vol, methanol 35 vol).

 The fractions containing the derivative having the free amine group (S-CM-GTNH2) are evaporated and lyophilized.

Pharmacological study
1) Affinity for serotonergic receptors.

A. Biological preparation
An 8 kg male monkey (Macacca mulatta n.) Was sacrificed with an overdose of barbiturates and exsanguination. Once the death of the animal has been observed, the skull is removed and the brain exposed. The right hemicerveau is cut and frozen by isopentane cooled in liquid nitrogen. The block is stored at -20 C. Sections 10 m thick are made with a cryostat A 200, C, and placed on gelatinized slides (Ségu. Et al. 1990, J.

Neurosci. meth. 31.197). They are stored at -20 C until use.

- Incubation with the radioactive probe
The sections are preincubated for 1 hour at 4 ° C. in a Krebs solution (mM: NaCl, 118; KCl 4.5; CaCl2, 1.2; MgCl2, 1.2; Tris, 15 t pH 7.4) in order to eliminate endogenous ligands. They are then incubated at 208 ° C. for 60 minutes in a solution containing 10-5M pargyline, 57 mM ascorbic acid, 10 g (1 of bovine serum albumin and S-CM-G [125I] TNSa 0, 02 nM alone or in the presence of increasing concentrations of serotonin.

Certain sections are incubated under identical conditions, but the radioactive probe is replaced either by [H] 5-HT 2 nM, or by [H] 5-HT 2 nM in the presence of 100 nM of 8-hydroxy-2- [di -N-propylamino] tetralin (8-OH
DPAT) and 100 nM of mesulergin, i.e. per [H] 8-OH-DPAT 1 nM. After ringing 2 x 1 minute in distilled water, they are dried.

- Radioautography:
The slides are affixed to a tritium-sensitive film for 8 days. The film is developed for 6 minutes in the b1a, rinsed and fixed. The autoradiograms are quantified with a video image analysis system (Ségu.

et al, 1990).

B. Results
Incubation in the presence of [3 H] 5-HT 2 nM (Fig.

1A) shows a large margin of the hippocampus and the black substance. Under these conditions, all types of 5-HT1A sites are marked.

 Incubation in the presence of 1 nM [H] 8-OH-DPAT (FIG. 1B) which only marks the 5-HT1A sites, shows intense labeling of the hippocampus and not of the substantia nigra.

 In the case of incubation in [H] 5-HT in the presence of 100 nM 8-OH-DPAT and mesulergin (FIG. 1C), only the 5-HT1D sites are marked. Autoradiograms show a strong reaction on the substantia nigra.

 Incubation in S-CM-G [125I] TNH2 0.02 nM alone (Fig. 1D) shows an almost exclusive labeling of the substantia nigra, as in the previous case. This O-carboxymethylated derivative of serotonin binds to 5-HT1D sites.

 If the binding of the S-CM-G [125I] TNH2 0.02 nM is displaced by serotonin, Oh obtains an IC50 (concentration of 5-HT1D inhibiting 50% of the binding) of the order of 5 nM, thus showing that the binding of the derivative is specific for 5-HT1D sites.

Conclusion
S-CM-G [125I] TNH2 is a marker for 5-HT1D.

Any analogous molecule will therefore have this property of binding to 5-HT1X sites.

 2) Crossing the blood-brain barrier.

 When the molecules pass the blood-brain barrier, they are likely to act on the preceptors of the central nervous system, an effect sought in many cases.

In the case where the receptors exist both in the periphery and in the central nervous system, it may be desirable to have derivatives which do not cross the heinatoencephalic barrier. These derivatives will then have an effect on the peripheral receptors, without predominant central action,
A. Experimental protocol
2 mice and 2 guinea pigs are deeply anesthetized with chloral hydrate (intraperitoneal injection of 0.12 ml per 100 g of weight of a 35% solution). The rib cage is open, the heart is exposed.

An intracardiac injection of S-CM-G [125I] -
TNH2 of 200 l for the mouse and 1.5 ml for the guinea pig is produced.

 After 10 minutes, the animals, still under deep anesthesia are decapitated, the brains frozen and preserved as indicated in example 1.

 We carry out cuts and autoradiography as described in Example 1.

B. Results
The examination of sections passing through various levels of the brain does not show any marking, in particular in the substantia nigra, anatomical structure which is well marked when one proceeds to an incubation in vitro in the same tracer.

Conclusion:
The serotonin derivative tested, does not pass the blood-brain barrier, allowing to relieve the most painful effects of migraine. No toxicity was observed at the injected dose.

EXAMPLE 2
Tablets corresponding to the formula 5-O-carboxymethylglycyltyrosinamide (S-CM-GTNH2) were prepared. 0.5 mg excipient qs for a tablet finished at ..l00 mg (detail of the excipient: lactose, starch, talc , magnesium stearate)
EXAMPLE 3
Breakable tablets were prepared corresponding to the formula 5-o-carboxymthylglycyltyrosinamide (S-CM-GTNH2) .. 2 mg excipient qs for a tablet finished at ...... 100 mg detail of the excipient: lactose, starch , talc, magnesium stearate).

EXAMPLE 4
An injectable preparation corresponding to the formula 5-O-carboxymethylglycyltyrosinamide (S-CM-GTNH2) was prepared. 2 mg

<tb> -at: <SEP> up: tin ...... <SEP> 21d
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EXAMPLE 5
A nasal aerosol corresponding to the formula 5-O-carboxymethylglycyltyrosinamide (S-CM-GTNH2) was prepared. 30 mg excipient: aqueous solution: sodium chloride, trisodium citrate, citric acid, distilled water ....... 15 ml
EXAMPLE 6
An oral aerosol corresponding to the formula has been prepared; 5-O-carboxymethylglycyltyrosinamide (S-CM-GTNH2) .. 60 mg excipient: aqueous solution: citric acid, ethyl alcohol, sweetener, flavoring, polysorbate 80, propylene glycol, purified water.Propellant: nitrogen
................................................. 50 ml
FIGURE a
Detection of 5-HT1 receptors on sections of monkey brain (Macacca mu latta n),
The sections (10 m) of frozen tissue are incubated with various probes and radioautographed.

 A. Incubation in [3H] 5-HT 2 nM showing the total 5-HT1 sites in the hippocampus (H), the substantia nigra (SN).

 B. Incubation in 1 nM [3H] 8-OH-DPAT showing the 5-HT1A sites exclusively located in the hippocampus.

 C. Incubation in [3H) 5-HT 2 nM of 100 nM 8 OH-DPAT and 100 nM mesulergin, showing the 5-HT1B sites almost exclusively located in the substantia nigra.

 D. Incubation [125] S-CM-GTNH2 0.02 nM, showing exclusive labeling of the substantia nigra, similar to that shown in C.

 B. Same incubation as D but supplemented with 10-5 M 5HT showing non-specific binding (scale - 1 cm).

 F. Diagram of the anatomical structures, taken at level A11.5 from the Atlas Riche et ai. 1968.

Claims (10)

 1. Serotonin derivatives characterized in that they correspond to general formula I

 in which R1 represents an amino residue or an alcohol residue, R2 represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon or acyl atoms, R3 represents a hydrogen atom or an alkyl radical linear or branched containing from 1 to 5 carbon atoms, R4 represents a hydrogen or halogen atom and n represents an integer from 1 to 10, as well as their addition salts with pharmaceutically acceptable acids, for their use as a medicine.  2. The serotonin derivatives as defined by formula I according to claim 1 characterized in that R1 represents a diamine, a protein, an amino acid or a polypeptide consisting of at most 5 amino acids or derivatives of said amino acids or polypeptides, as well as their addition salts with pharmaceutically acceptable acids.  3. The serotonin derivatives as defined by formula I according to claim 1 characterized in that R2 and R3 represent a linear or branched alkyl radical containing from 1 to 5 carbon atoms, as well as their addition salts with the pharmaceutically acceptable acids.  4. The derivative of formula (I) as defined in claim 1, characterized in that R1 represents a radical Gly-Tyr-NH2, R2, R3 and R4 representing a hydrogen atom, as well as their addition salts with pharmaceutically acceptable acids.  5. Pharmaceutical compositions characterized in that they contain, as active principle, at least one of the medicaments as defined in claim 1.  6. Pharmaceutical compositions characterized in that they contain, as active principle, at least one of the medicaments as defined in any one of claims 2 or 3.  7. Pharmaceutical compositions characterized in that they contain, as active principle, at least one of the medicaments as defined in claim 4.  8. Derivatives corresponding to general formula I

Tyr-OH, Tyr-Gly-NH2, Gly-Gly-OH or Gly-Cys.  in which R1 represents an amino residue or an alcohol residue, R2 represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon or acyl atoms, R3 represents a hydrogen atom or an alkyl radical linear or branched containing from 1 to 5 carbon atoms, R4 represents a hydrogen or halogen atom and n represents an integer from 1 to 10, as well as their addition salts with mineral or organic acids, at l except derivatives of formula I in which n = 1, R2 = R3 = R4 = H and R1 represents hydrogen or a Gly-Tyr, His, Gly group  9. The derivatives of formula I as defined in claim 8 characterized in that R1 represents a diamine, a protein, an amino acid or a polypeptide consisting of at most 5 amino acids or derivatives of said amino acids or polypeptides, as well as their addition salts with mineral or organic acids.  10. The derivatives of formula I as defined in claim 8 or 9 characterized in that R2 and R3 represent a linear or branched alkyl radical containing from 1 to 5 carbon atoms, as well as their addition salts with mineral acids or organic.