WO2002024192A1 - Dipeptide ligands of the npff receptor for treating pain and hyperalgesia - Google Patents

Abstract

The invention concerns compositions and methods for treating or managing pain, for prevention or cure. The invention is characterised in particular in that it consists in using ligand compounds of the NPFF receptor for treating pain, and methods and compositions therefor. The invention further concerns novel compounds, ligands of the NPFF receptor, exhibiting advantageous pharmacological properties for treating pain. The invent is useful for controlling hypersensitivity to pain, chronic or acute, persistent or temporary, of surgical, traumatic, or pathological origin.

Description

NPFF RECEPTOR DIPEPTIDE LIGANDS FOR THE TREATMENT OF PAIN AND HYPERALGIA

The present invention relates to compositions and methods for the treatment or management of pain, for preventive or curative purposes. The invention resides in particular in the use of ligands of the NPFF receptor for the treatment of pain, as well as in methods and compositions which can be used for this purpose. The invention further describes novel compounds, ligands for the NPFF receptor, which have advantageous pharmacological properties for the treatment of pain. The invention can be used for the management of hypersensitivity to pain,

10 chronic or acute, persistent or temporary, of surgical, traumatic, or pathological origin.

Despite recent advances in neurophysiology and neuropharmacology, treatment of pain is often insufficient. Among the therapeutic agents used to manage severe pain, whether acute or chronic,

15 opioid analgesics, especially morphine and morphinomimetics (fentanyl, sufentanil, etc.) represent the most used pharmacological class because of the high efficacy of these drugs. However, this effectiveness is sometimes limited due to a partial or total "resistance" of certain pains to their analgesic effects. This is the case for certain neurogenic pain (pain linked to lesions

20 central or peripheral nerves) or post-operative pain due to persistent pain sensitization clinically manifested by the onset of hyperalgia, allodynia or spontaneous pain which may last or recur very long after the surgical act. On the other hand, the therapeutic use of these substances is accompanied by undesirable effects, such as respiratory depression, slowing down of the

25 intestinal peristalsis, etc., and also of a tolerance process resulting in a decrease in the analgesic effect.

There is therefore a real need for compounds and therapeutic strategies capable of preventing the processes of pain awareness and resistance to opioid analgesics. The prevention and treatment of these two processes could be

30 all the more important since the administration of analgesics itself induces sensitization to long-term pain in animals (Célérier et al., 2000).

These elements therefore suggest that following treatment with opioid analgesics (of the hino-mimetic type), as may be encountered occasionally. of surgical procedures, a patient could be particularly sensitive to pain in the post-surgical period, not only because of the tissue aggressions linked to the surgical act, but also because of an exacerbated sensitivity to pain, induced by the analgesic treatment.

The present invention now provides new therapeutic approaches for the preventive or curative treatment of pain, in particular of increased pain sensitivities, in particular of sensitivities consecutive to the taking of analgesic compounds such as opiates. The present invention is based in particular on the use of ligands of the receptor for the neuropeptide FF (“NPFF”) to inhibit the phenomena of sensitization to pain. The inventors have in fact shown that, surprisingly, such compounds are capable of effectively and lastingly inhibiting the appearance of hyperalgesia following the taking of opioid analgesics. The results observed show that different synthetic ligands of the NPFF receptor have this property, and can be used for the management of hyperalgia induced by different analgesics, in particular morphine or morphino-mimetics.

An object of the invention therefore lies in the use of a synthetic ligand for the NPFF receptor for the preparation of a pharmaceutical composition intended to inhibit the hyperalgia induced by the opioid analgesic compounds.

The invention also relates to compositions, in particular pharmaceutical compositions, solutes, anesthesia products, comprising an opioid analgesic compound and a synthetic ligand for the NPFF receptor.

The invention also relates to methods of treating hyperalgia comprising the administration to a subject (in particular human) of synthetic ligands of the NPFF receptor, preferably of antagonists of the NPFF receptor. The invention is particularly intended for the inhibition of hyperalgia induced by opioid analgesics, and advantageously comprises the administration of synthetic ligands of the NPFF receptor, preferably antagonists of the NPFF receptor, beforehand, concomitant or subsequent to taking the pain reliever. The invention also relates to novel synthetic receptor ligands.

NPFF, usable in the implementation of the methods, uses and compositions according to the invention and, more generally, in the treatment or management of pain. The synthetic ligands are more particularly chemical derivatives of the C-terminal region of the neuropeptide FF.

The invention can be used for the management of hypersensitivity to pain, of chronic or acute nature, persistent or temporary, of surgical, traumatic or pathological origin, in humans as in other mammalian species.

As indicated, the invention is based, in general, on the use of ligands of the NPFF receptor for the treatment of hyperalgia.

NPFF appears to be an antiopioid peptide (for review, see Simonnet 1997). The

NPFF can be considered as a neurotransmitter (Devillers et al; 1995a), capable of opposing the analgesic effects of morphine (Yang et al., 1985, Oberling et al., 1993), and of being released at the level of central nervous system following administration of morphine in rats (Devillers et al. 1995b). On the pharmacological level, it has already been reported by the inventors that certain synthetic molecules possessing the terminal sequence of NPFF were capable of potentiating the analgesic effects of morphine (Bourguignon et al., 1997). However, no previous results describe an approach for the treatment of pain hypersensitization using the NPFF receptor.

The inventors have now demonstrated that, unexpectedly, NPFF receptor ligand compounds are capable of preventing hypersensitivity to the pain of several days appearing following the administration of Fentanyl or heroin. This is, to our knowledge, the first evidence that an NPFF receptor ligand prevents the hyperalgesic effects (of long duration) induced by the administration of opioid analgesics. The mechanism of action that can render such a pharmacological effect so long-lived is still unknown since a single administration of RF2 or RF3 (synthetic ligands of the NPFF receptor), just before Fentanyl or heroin, did not allow us to envisage such lasting effects. This unexpected result could not be considered on the basis of the data already reported (Bourguignon et al., 1997) and opens up a very particular path of pharmacological interest. It is indeed unlikely that a dipeptide (even modified) like RF2 or RF3, rapidly degradable in vivo like any peptide, can act for several days to counter the effect of a possible release of NPFF (not demonstrated to be durable after a single administration of opioid analgesic) following administration of Fentanyl or heroin. It is therefore also, to our knowledge, the first evidence that a receptor antagonist of an antiopioid peptide prevents long-term (days) long-lasting hyperalgesic effects induced by the administration of opioid analgesics. Our hypothesis, which remains to be verified, is that the NPFF system would exert a permissive role on the expression of the systems facilitating the nociception induced by the administration of an opioid analgesic.

The invention therefore proposes a new therapeutic approach for the preventive or curative management of hyperalgia.

The term “hyperalgia” designates, within the meaning of the invention, any state of increased awareness of pain, in particular any hyper-awareness of pain as well as the perception of pain in response to a stimulus perceived as painless under normal circumstances ( allodynia). It can be prolonged, brief, severe or moderate hyperalgia. Detection, measurement and characterization of the presence of hyperalgia can be carried out by standard clinical tests (observation, etc.). In general, it seems that the administration of opioid analgesics to mammalian subjects is always accompanied by hyperalgia, so that the invention can be used whenever an opioid analgesic is administered to a subject .

For the purposes of the present invention, the term "inhibit" means to reduce or eliminate, partially or completely, transient or prolonged. The ability to inhibit hyperalgia and the degree of this inhibition can be determined according to various tests known to those skilled in the art. Furthermore, the term inhibit denotes both the inhibition of the onset (for example for a preventive treatment) and the inhibition of the development or duration (for a curative treatment) of hyperalgia. Preferably, in the context of the present invention, synthetic ligands are used which have the capacity to inhibit by at least 30%, more preferably by at least 50%, even more preferably by at least 80%, the hyperalgia induced by the compounds. opioid analgesics. In a particular embodiment, the invention resides in the use of synthetic ligands of the NPFF receptor for the preparation of a pharmaceutical composition intended to inhibit in the long term (preferably over 1 day, more preferably over 1 to 3 days). hyperalgia induced by opioid analgesic compounds.

Synthetic Ligands

The term synthetic ligand designates within the meaning of the invention any compound capable of binding the NPFF receptor, different from the endogenous ligand (that is to say NPFF). They are therefore generally compounds obtained by synthesis, whether it is a chemical, biological, genetic, enzymatic synthesis, etc., or a combination of these production routes. The synthetic ligands according to the invention are preferably selective for the NPFF receptor, that is to say have a higher affinity for the NPFF receptor than for other neurotransmitter receptors. Even more preferred ligands are NPFF antagonists. However, as will be demonstrated in the following text, synthetic ligands according to the invention may exhibit activity with respect to different receptors, in particular a duality of action, that is to say an important affinity for the NPFF receiver and also for one (or more) other type (s) of receiver (s). Thus, the invention describes compounds having a significant affinity for the NPFF receptor and also for an opioid receptor (of the mu type). Such an action profile is advantageous insofar as such compounds can have an analgesic effect by themselves.

Particular ligands within the meaning of the invention are compounds of peptide nature, derived from the structure of the neuropeptide FF. In particular, synthetic ligands according to the invention are peptide derivatives comprising a part of the C-terminal region of the neuropeptide FF, preferably the C-terminal amino acids Arg-Phe, on which various structural modifications can be introduced. The results presented in the examples thus show that compounds derived from di- Arg-Phe peptide have the ability to bind the NPFF receptor and to inhibit hyperalgia induced by analgesics. Specific examples of such compounds include compounds RF2 (Hydrochloride of N ^α -benzoyl-L-Arginine L-Phe-NH2) and RF3.

Furthermore, the present application also describes the development, synthesis and characterization of new compounds, ligands of the NPFF receptor, which can be used for the applications mentioned above. Thus, the present invention also relates to compounds of general formula (I) as defined below. The invention also relates to compositions, in particular pharmaceutical compositions, comprising a compound of general formula (I) and a pharmaceutically acceptable vehicle. The compounds can be in the form of salts, in racemic form, or of isolated or mixed enantiomers. The invention further relates to the use of compounds of formula (I) for the preparation of pharmaceutical compositions for the treatment of pain or hyperalgia. The invention also relates to methods of treating pain or hyperalgia comprising administering to a subject a compound of general formula (I).

The compounds according to the invention therefore preferably correspond to the general formula (I), in L, D or L / D form,

in which :

. -L- represents either (CH) _m , m being able to represent 2, 3 or 4; either a group of formula

in which n is 0 or 1;

. A is a sulfur atom or a group N i in which Rj represents a hydrogen atom, a methyl group or a group

in which n is 0 or 1 and Xi represents a hydrogen or halogen atom or a hydroxyl, carboxamide, trifluoromethyl, alkoxy, amino or acylamino group;

. R ₂ and R ₁₂ , independently of one another, represent a hydrogen atom or an alkyl or aralkyl group,

. R ₃ is (i) either a group - (CH) _P -W in which p is 1, 3 or 6 and W is chosen from

- a hydrogen atom,

- a group

in which R _Ô is an alkyl, aryl or aralkyl group, - a group

in which R is a hydrogen atom or a methyl group and R ₈ is a hydrogen atom, an alkyl or an aralkyl,

- an -OH or -OMe group,

- a group

in which Y is an oxygen or sulfur atom, or - a phenyl, substituted phenyl or heteroaryl group, (ii) either a group

in L, D or L / D conformation, wherein R ₉ is an alkyl group or a group

with n having a value of 0 or 1 and X] being as defined above, and R] o is a hydrogen atom, an alkyl or an aralkyl;

(iii) either an arylcycloalkyl group, optionally substituted,

(iv) either R ₂ and R ₃ together form a ring having from 3 to 9 carbon atoms, saturated or unsaturated, optionally aromatic, and optionally comprising a link NR _ll5 Rπ being an alkyl, aryl or aralkyl group;

. R ₄ represents a hydrogen atom, a methyl group or a group

in which n is 0 or 1 and Xj is as defined above, and

. R ₅ is a group of formula -CO (CH ₂ ) _q Ar or -SO ₂ (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar comprises an aromatic group, substituted or not, advantageously comprising from 4 to 15 links of which 0 to 4 heteroatoms or R ₅ is a group of formula -CO-R _{] 3} in which R ₁₃ is a group (C] -C ₆ ) alkyl or (C ₃ -C] ₂ ) cycloalkyl, optionally substituted.

According to the invention, the term "alkyl" denotes a linear or branched hydrocarbon radical having from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl . Cι-C groups are preferred. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.

"Aryl" groups are mono or bicyclic aromatic hydrocarbon systems having 6 to 12 carbon atoms. Heteroaryl groups are aryl groups comprising one or more cyclic heteroatoms, preferably 1 to 4 cyclic heteroatoms.

An aromatic group is typically a group comprising from 4 to 15 links of which 0 to 4 heteroatoms, preferably from 4 to 12 links of which 0 to 3 heteroatoms.

An aromatic group can be mono- or multi-cyclic. In addition, an aromatic group can include one or more aromatic rings condensed to a non-aromatic ring.

The term "aralkyl" (or "arylalkyl") designates an aryl group as defined above linked to the nucleus of the molecule by an alkyl group as defined above.

The term "arylcycloalkyl" denotes an aryl group as defined above linked to the molecule by a cycloalkyl group as defined above, in particular in condensed form, such as for example the tetralin group.

The term "acyl" denotes an alkyl, aryl or heteroaryl group as defined above, linked to the nucleus of the molecule by a -CO- group.

The alkoxy groups correspond to the alkyl groups defined above linked to the nucleus via an -O- (ether) bond.

By "halogen" is meant a fluorine, chlorine, bromine or iodine atom.

By “heteroatom” is meant an atom chosen from O, N and S.

Furthermore, the above groups may carry one or more substituents chosen, for example, from halogen, nitro, cyano, carboxy, (Cι-C ₆ ) -alkoxycarbonyl, mono- or di- (C ₁ -C ₆ ) -alkylaminocarbonyl, aminocarbonyl, mono- or di- (C ₆ -C ₁₂ ) -aryl- or hetero- (C ₆ - C ₁₂ ) -arylaminocarbonyl, mono- or di- (C ₆ -C ₁₂ ) -aryl- or hetero- (C ₆ -C ₁₂ ) -aryl- (Cι-C ₆ ) - alkylaminocarbonyl. hydroxy, (Cι-C6) -alkoxy, (Cj-C ₆ ) -alkyl, amino optionally substituted by one or more groups chosen from (C] -C ₆ ) -alkyl, (-C _ό ) - alkylcarbonyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₆ -C _{] 2} ) -aryl, hetero- (C ₆ -C ₁₂ ) -aryl, (C ₆ -Cι ₂ ) -aryl- (CrC ^ -alkyl, hetero- (C ₆ -C ₁₂ ) -aryl- (C ₁ -C ₆ ) -alkyl, (Cj-C ₇ ) -alkanoyl, cyclo- (C ₃ -C ₈ ) - alkanoyl, (C ₆ -C ₁₂ ) -aroyl, or (C ₆ -Cι ₂ ) -aryl- (C ₁ -C ₇ ) -alkanoyl. Particular compounds within the meaning of the invention are those of formula (I) in which Ar represents an aromatic group chosen from cyclic groups with 1, 2 or 3 following condensed cyclic rings:

in which Z is a CX ₅ group or a nitrogen atom, it being understood that for the same cycle, Z cannot take more than three times the meaning nitrogen, Y is a sulfur or oxygen atom or an NX ₅ group , n is 0, 1 or 2, X], X ₂ , X ₃ , X and X ₅ , identical or different, being chosen from a hydrogen atom, a halogen atom, or a carboxamide, trifluoromethyl, alkoxy group , amino or acylamino.

Preferably, in the compounds of the invention _t is a hydrogen atom and R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2, preferably 0 or 1, and Ar comprises an aromatic group, substituted or not, optionally comprising one or more heteroatoms. Even more preferably, R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar represents an aromatic group chosen from

in which Z is a CX ₅ group or a nitrogen atom, it being understood that for the same cycle, Z cannot take more than three times the meaning nitrogen, Y is a sulfur or oxygen atom or an NX ₅ group , n is 0, 1 or 2, Xj, X ₂ , X ₃ and X ₅ , identical or different, being chosen from a hydrogen atom, a halogen atom, or a carboxamide, trifluoromethyl, alkoxy, amino or acylamino.

Specific and preferred examples of implementation are the compounds in which R ₅ is a substituted benzoyl group, or an indol-2-carbonyl group, optionally substituted. Preferred compounds are therefore those of formula (I) in which R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2, preferably 0, and Ar represents an aromatic group:

in which X ₁₃ X ₂ , X ₃ , Y and Z are as defined above.

On the other hand, in the general formula (I), the compounds in which R3 is a group are preferred.

in L, D or L / D conformation, in which

. R ₉ is a group

in which n is 1 and Xi is as defined above, and . R ₁₀ is a hydrogen atom, an alkyl or an aralkyl, preferably a hydrogen atom.

Preferred compounds of general formula (I) above are also compounds in which:

- R ₂ is a hydrogen atom, and / or

- Rι ₂ is a hydrogen atom, and / or

- L is - (CH ₂ ) ₃ -, and / or

- A is the NH group.

A preferred family of compounds is represented by the compounds of formula (I) in which

. R ₄ is a hydrogen atom,. R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar represents an aromatic group chosen from

in which Z is a CX ₅ group or a nitrogen atom, it being understood that for the same cycle, Z cannot take more than three times the meaning nitrogen, Y is a sulfur or oxygen atom or an NX ₅ group , n is 0, 1 or 2, Xj, X ₂ , X ₃ and X ₅ , identical or different, being chosen from a hydrogen atom, a halogen atom, or a carboxamide, trifluoromethyl, alkoxy, amino or acylamino. . R ₂ is a hydrogen atom,

. Rι ₂ is a hydrogen atom,. R ₃ is a group

in L, D or L / D conformation, in which R ₉ is a group

wherein n is 1 and Xj is as defined in claim 1, and Rio is a hydrogen atom. L is - (CH ₂ ) ₃ -, and. A is the NH group.

The compounds according to the invention are particularly advantageous insofar as they have a significant affinity for the NPFF receptor, and are capable of modulating the response to pain. Unexpectedly, the compounds of the invention also have an affinity for other receptors, in particular the opoid receptor Mu. Thus, the examples presented show in particular that, unexpectedly, the presence of an indole group in position R5 makes it possible to increase by a factor of 10 the affinity of the compounds for the Mu receptor. The compounds of the invention also have improved pharmacological properties. Thus, the presence of the RI group or of a sulfur atom makes it possible to lower the basicity of the guanidine group and thus to improve the penetration of the compounds and their bioavailability. The biological, physical and pharmacological properties of the compounds give these molecules significant advantages and new applications, as described in the present application.

Preferred compounds within the meaning of the invention are described in the examples, in particular compounds 4, 7, 13, 18, 24-45.

Particularly preferred compounds are the following compounds:

N ^α acetate -Benzoyl-L-Arg-Atc-NH ₂ N ^α acetate -Adamantan- 1 -yl-L-Arg-L-Phe-NH ₂

N ^α -Benzoyl-L-Arg-D-Phe-NH ₂ acetate

N ^α hydrochloride - [(1H) -Indole-2-carbonyl] -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (4-chloro-Benzoyl) -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (4-chloro-Benzoyl) -L-Arg-D-Phe-NH ₂ N ^α hydrochloride - (3-chloro-Benzoyl) -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (3-chloro-Benzoyl) -L-Arg-D -Phe-NH ₂ N ^α hydrochloride - (3,4-dichloro-Benzoyl) -L-Arg-D, L-Phe-NH ₂ N ^α hydrochloride - (2-chloro-Benzoyl) -L-Arg-D, L-Phe- NH ₂ Trifluoroacetate of N ^α - (4-acetylaminobutanoyl) -L-Arginine-N-phenethylamide Trifluoroacetate of N- (3 -bromo-benzoyl) -L-arginine-N-phenethylamide Trifluoroacetate of N ^α - [(1H) -Indole -2-carbonyl] -L-Arg-D-Phe-NH ₂

N ^α diphenylacetyl N ^γ benzyl (D, L) -Arginine-N-benzylamide trifluoroacetate

The compounds of formula (I) can be prepared according to techniques known to those skilled in the art. The present invention describes in this regard different synthetic routes, which are illustrated in FIGS. 4-8 and can be implemented by a person skilled in the art, as indicated in the examples. The starting compounds can be obtained commercially or synthesized according to usual methods. It is understood that the present application is not limited to a particular synthetic route, and extends to other methods allowing the production of the indicated compounds.

Analgesic compounds

The analgesic compounds used in the context of the present invention are generally opiate compounds, that is to say compounds acting on the opoid receptors. They are preferably morphine compounds, in particular morphine or morphino-mimetics, that is to say compounds derived from morphine and / or acting on one or more receptors of morphine and / or recruiting one or more common metabolic pathways with morphine. By way of particular examples, the following compounds may be mentioned: morphine, fentanyl, sufentanil, alfentanyl, heroin, hydromorphone, levoφhanol, methadone, buprenoφhine, butoφhanol, meperidine, etc.

The invention is particularly suitable for inhibiting hyperalgia induced by mo lahine, fentanyl or heroin.

The ligands or compositions according to the invention can be administered in different ways and in different forms. Thus, they can be injected systemically or orally, preferably systemically, such as for example intravenous, intramuscular, subcutaneous, trans-dermal, intra-arterial, etc., the intravenous, intramuscular and subcutaneous routes being preferred. For injections, the compounds are generally packaged in the form of liquid suspensions, which can be injected using syringes or infusions, for example. In this regard, the compounds are generally dissolved in saline, physiological, isotonic, buffered solutions, etc., compatible with pharmaceutical use and known to those skilled in the art. Thus, the compositions can contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles which can be used in liquid and / or injectable formulations are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, etc.

According to a particular variant, the ligand according to the invention is administered by the same route as the analgesic compound, for example in the form of an infusion.

The compounds can also be administered in the form of gels, oils, tablets, suppositories, powders, capsules, capsules, etc., optionally by means of dosage forms or devices ensuring sustained and / or delayed release. For this type of formulation, an agent such as cellulose, carbonates or starches is advantageously used.

It is understood that the flow rate and / or the dose injected can be adapted by a person skilled in the art depending on the patient, the pain observed, the analgesic concerned, the mode of administration, etc. Typically, the compounds are administered in doses which can vary between 0.1 μg and 10 mg μg / kg of body weight, more generally from 1 to 1000 μg / kg. In addition, repeated injections can be given, if necessary. The results presented in the examples nevertheless indicate that repeated injections are not necessary in many cases to obtain a significant inhibition of hyperalgia.

On the other hand, for chronic treatments, delayed or prolonged systems can be advantageous, ensuring that subjects receive effective and lasting pain management. The present invention can be used for the preventive or curative management of hyperalgia in multiple situations, such as occurring or associated with acute, chronic treatments, of surgical, traumatic or pathological origin.

It is applicable to any mammal, in particular the human being, but also to animals, in particular domestic or breeding, in particular horses, dogs, etc.

It is particularly suitable for the prevention or treatment of the sensitization processes induced by the punctual administration of opioid analgesics, such as powerful moφhinomimetics (for example moφhine or Fentanyl or their derivatives), carried out during acts surgical or trauma. It can also be used for the prevention or treatment of chronic pain in patients with pathologies such as cancer, burns, etc., for which analgesics (such as moφhine) can be administered permanently, possibly in delayed form. .

NPFF receptor ligands can also be used to prevent or reduce, in a very significant way, tolerance processes, thus making it possible to reduce daily doses of moφhine thereby improving the clinical picture of patients (side effects of moφhinomimetics such, for example example, that intestinal disorders).

The compounds according to the invention also have the advantage of better "maneuverability" from a therapeutic point of view (fewer side effects) than the NMDA receptor antagonists, also capable of preventing the hyperalgia induced by opioid analgesics, insofar as their targets in the central nervous system are much more limited than that of NMDA receptors (see mapping of NPFF receptors in Allard et al., 1992). The compounds of formula (I) according to the invention can also be used for the treatment or the treatment, preventive or curative, of pain.

Other aspects and advantages of the present invention will appear on reading the examples which follow, which should be considered as illustrative and not limiting.

Legend of Figures Figure 1: Evolution of the value of the nociceptive threshold evaluated by the Randall-Sellitto test (evocation of the animal's cry in response to a mechanical nociceptive stimulus, the pressure exerted on a paw, expressed in grams in rats receiving serum physiological (NaCl group) or RF _2. Each experimental group is made up of 10 animals. The nociceptive threshold values are represented on average +/- SEM. The analysis of variance (ANOVA) with 2 factors indicates neither time effect, neither group effect.

Figure 2: The administration of RF ₂ (5mg / kg) potentiates the analgesic effect of Fentanyl and prevents long-term hyperalgia induced by the administration of Fentanyl. Figure 3: The administration of RF ₃ (5 mg / kg) potentiates the analgesic effect of Fentanyl and prevents long-term hyperalgia induced by the administration of Fentanyl. Figure 4: Synthetic pathway (1) of synthetic ligands from N ^α -tert- Butyloxycarbonyl-N ^ω -Nitro-L-Arginine 1.

Figure 5: Synthetic route (2) of synthetic ligands from N ^α -tert butyloxycarbonyl- L- Arginine 5. Figure 6: Synthetic route (3) of synthetic ligands from N ^α ' ^ω -bis-

Benzyloxycarbonyl-L-Ornithine 8.

Figure 7: Synthetic pathway (4) of synthetic ligands from N ^α -tert- Butyloxycarbonyl-N ^α -Methyl-N ^{ω, ω3} -bis-Benzyloxycarbonyl- L-Arginine 15 (Xue et al, Tetrahedron Letters 1995,1 , 55-58). Figure 8: Synthetic pathway (5) of synthetic ligands from N ^α -tert-

Butoxy-3-Nitro-L-Phenylglycine 19 (Lee et al, Bioorg; Med. Chem.; EN; 7; 6; 1999; 1097-1104).

Figure 9: Synthetic route (6) of synthetic ligands. Figure 10: Synthetic route (7) of synthetic ligands. Figure 11: Long-term effects of RF ₂ on fentanyl potentiation of hyperalgesia induced by inflammatory pain

A - IN VIVO ANTI-HYPERALGIC PROPERTIES OF NPFF RECEPTOR LIGANDS Materials and methods

1. Products used

Fentanyl and Naloxone come from Sigma-Aldrich (Saint Quentin Fallavier, France). Compounds RF2 and RF3 are dipeptide analogs of the carboxylic end (Arg-Phe-NH2) of NPFF onto which a phenyl group has been grafted. All of these molecules were dissolved in physiological saline solution (0.9%) and administered subcutaneously (100 μl / 100 g of body weight). Control subjects received an equal volume of saline.

2. Animals

All the experiments were carried out on male Sprague-Dawley rats weighing 300 to 350 grams (Iffa Credo, France). The rats are grouped at a rate of 5 per cage; water and food are provided to them at will. All the animals are reared under identical temperature conditions (23 ± 1 ° C) in a pet store alternately with light periods (7h to 19h) and darkness (19h to 7h). Each experiment comprises two batches of 10 rats whose daily maintenance is ensured by the experimenter in order to avoid as much as possible any disturbance of the animals. Pharmacological tests and animal care followed the rules of ethics established by the Committee of the International Pain Control Association (IAPS, 1993).

3. Experimental measurement carried out: Measurement of the nociceptive threshold

The nociceptive threshold was determined by the minimum weight supported by the animal's left hind paw until a cry was emitted, according to the modified Randall-Selitto method (Kayser and Guibaud, 1990). Randall-Selitto's apparatus allows increasing and regular pressure to be exerted on the animal's paw; the value of the pressure intensity (expressed in grams) exerted on the leg is read when the cry is emitted on a graduated scale along which an index moves. In order to avoid any damage to the paw tissue, the maximum pressure (cut-off) is set at 600g. We have retained this test for our experimentation because it involves a stimulus of a mechanical nature, with a supra-spinal integrated response (cry), while the withdrawal test of the tail (involving a thermal stimulus) involves a response with a purely reflex component.

4. Experimental protocol 4.a. Familiarization of animals with experimentation

The experiments must be carried out on non-stressed animals, in order to avoid any release of endogenous opioid peptides capable of modifying their basic nociceptive threshold. For this reason animals must be familiar with:

- their new environment: as soon as they arrive at the animal facility, the rats are placed in collective cages (5 per cage) and left to rest for 2 days.

- the experimenter: he handles them one hour a day for the following two weeks (from 1 p.m. to 2 p.m.).

- the experimental conditions: the animals are weighed daily. At least one hour before the start of handling, the animals are transferred from the animal facility to the experimental room (12 noon) and are then put in the presence of the Randall-Selitto device without undergoing any nociceptive stimulus.

4.b. Experimentation

Following this habituation period, the animals are subjected to the experimental protocol. Two days before the actual testing (D-2 and D-i) and the same day (D) two daily measurements are made at 30-minute intervals, in order to check the stability of the animals' nociceptive threshold.

For each experiment, 20 animals are paired at random in two groups of 10 rats and a measurement of the basic nociceptive threshold is carried out for all the rats. The first group receives a subcutaneous injection of RF2 or RF3 (2.5; 5 or 10 mg / kg) and the second group (control animals) receives a subcutaneous injection of physiological saline. The experiments are carried out blind (the experimenter does not know which syringes contain RF2 / RF3 or physiological saline). Thirty minutes after this pre-treatment (time To), all the animals receive: - either 4 injections of Fentanyl (60 μg / kg, sc) at the rate of one injection every 15 minutes, - or 4 injections of physiological saline at the same rate of one injection every 15 minutes (control).

The nociceptive threshold is then measured every thirty minutes until the return to the basal value.

The five days following (Jι-J ₅ ) this experiment, the nociceptive threshold of the animals is evaluated daily by two measurements separated by a time interval of thirty minutes. If the nociceptive threshold is returned to its basic value on D ₅ , an injection of naloxone (lmg / kg, sc) is applied in order to assess the level of functioning of the endogenous opioid systems which could mask, on the other hand, a possible reaction prolongation of the activity of the systems facilitating the nociception, among which the antiopioid systems that they are NPFFergic or other (CCK, Nociceptine ....).

5. Statistical analysis

The results, expressed in mean value (± standard error) are compared using an analysis of variance (ANOVA) with one or two factors (influence of time and / or treatment on the evolution of the nociceptive threshold). In each experiment and for the two groups of rats, the stability of the basal nociceptive threshold at J_2, Jl, Jθ was determined by a one-factor ANOVA in each batch and two factors between the two batches (time and / or treatment) .

When ANOVA detects intra-batch and / or inter-batch differences, a post-hoc statistical test is performed. The Dunnett test is used to specify the differences in the evolution of the nociceptive thresholds of animals. The amplitudes of the analgesia induced by Fentanyl, alone or combined with a pretreatment with RF2 or RF3 were characterized by the determination of the areas under the curve and were statistically compared using the "t" test from Suident. A difference is considered to be significant for a probability P <0.05.

6. Validation of the experimental procedure

For each of the experiments carried out, the ANOVA carried out on the values obtained before any administration of pharmacological substances (control) did not never revealed significant differences in the nociceptive threshold between the 2 groups of animals (no group effect), nor significant variations in the nociceptive threshold in animals over time (no time effect), nor in their interaction (ANOVA 2 factors, P> 0.05), for each of the days preceding the experiment. This suggests that the nociceptive threshold of the animals is identical for the two groups of animals and that it is stable over time. These results suggest that these experimental conditions are adequate to allow rigorous study of the influence of various drugs on the value of the nociceptive threshold.

For these same experiments, the value of the first measurement of the nociceptive threshold (chosen as being the reference value, see Figures) evaluated on the day of the experiment, before the drug administration, in the control rats is not significantly different from that of the second group of animals (Student's "t" test, P> 0.05). It is therefore possible to compare the nociceptive threshold between the two groups of animals after drug administration for each experiment.

Example 1: The synthetic ligand of the NPFF receptor, RF2, inhibits the hyperalgia induced by Fentanyl.

This example illustrates the capacity of synthetic ligands of the NPFF receptor to inhibit hyperalgia induced by opioid analgesics.

The experiments were carried out under the conditions described in the materials and methods. The results obtained are presented in FIGS. 1 and 2. The results obtained show (1.) that the synthetic ligand RF2 alone does not cause analgesia and (2.) that the synthetic ligand RF2 at a dose of 2, 5 mg / kg does not potentiate the analgesic effect of fentanyl, and that the administration of RF ₂ (5mg / kg) potentiates the analgesic effect of Fentanyl and prevents the long-term hyperalgia induced by the administration of Fentanyl.

L_The results presented in Figure 1 show that the administration of RF ₂ at doses of 2.5, 5 or 10 mg / kg, sc, alone does not cause any change in the value of the nociceptive threshold (see Figure 1, for the dose of 5mg / kg). 2. The results presented in FIG. 2 show that the administration of RF ₂ at the dose of 2.5 mg / kg (sc) does not modify either the amplitude or the duration of the analgesic effect of

Fentanyl (4 x 60μk / kg). On the other hand, the administration of RF ₂ at a dose of 5 mg / kg (see

Figure 2) or 10 mg / kg potentiates the analgesic effect of Fentanyl and prevents long-term hyperalgia induced by the administration of Fentanyl.

More particularly, Figure 2 shows the evolution of the value of the nociceptive threshold evaluated by the Randall-Sellitto test (evocation of the cry of the animal in response to a mechanical nociceptive stimulus, the pressure exerted on a paw, expressed in grams ) in rats treated with Fentanyl (4 injections of fentanyl 15 minutes apart; 60 μg / kg per injection, sc). Measurements are taken every 30 minutes on the day of drug administration and then daily on the following days. Each experimental group is made up of 10 animals. The 2 groups of rats were treated, 30 minutes before the injection of fentanyl, either with physiological saline (NaCl group) or with RF ₂ (5 mg / kg, sc) in the RF ₂ group. The nociceptive threshold values are represented on average +/- SEM. On day 5 (D ₅ ), an injection of naloxone is carried out (lmg / kg, sc) and the nociceptive threshold measured 5 minutes after this injection of the opioid antagonist, then every 30 minutes until the return to the value of basis of the nociceptive threshold. The analysis of variance (ANOVA) with 2 factors shows a time effect and a group effect. Post-hoc analysis (Dunnet test) indicates a significant difference between the 2 groups (p <0.05) for measurements made up to 5 hours after the first administration of Fentanyl. During the days following that of Fentanyl administration, the 2-factor ANOVA shows a time effect and a group effect in rats of the NaCl group. Post-hoc analysis (Dunnett test) indicates a significant difference between the 2 groups (p <0.05) for 3 days as well as following the administration of naloxone on D ₅ . During the days following that of the administration of Fentanyl, the animals pre-treated with RF ₂ do not show any modification of the value of their nociceptive threshold with reference to the base value of their nociceptive threshold (Student test).

Example 2: The synthetic ligand of the NPFF receptor, RF3, inhibits the hyperalgia induced by Fentanyl. This example illustrates the capacity of synthetic ligands of the NPFF receptor to inhibit hyperalgia induced by opioid analgesics.

The experiments were carried out under the conditions described in the materials and methods. The results obtained are presented in FIG. 3. The results presented show that the administration of RF ₃ at a dose of 5 mg / kg or 10 mg / kg potentiates the analgesic effect of Fentanyl and prevents long-term hyperalgia induced by the administration of Fentanyl.

In particular, Figure 3 represents the evolution of the value of the nociceptive threshold evaluated by the Randall-Sellitto test (evocation of the cry of the animal in response to a mechanical nociceptive stimulus, the. Ression exerted on a paw, expressed in grams) in rats treated with Fentanyl (4 injections of fentanyl 15 minutes apart; 60 μg / kg per injection, sc). Measurements are taken every 30 minutes on the day of drug administration and then daily on the following days. Each experimental group is made up of 10 animals. The two groups of rats were treated 30 minutes before the injection of fentanyl, or with saline (NaCl group) or the RF ₃ (5 mg kg, sc) in the RF group _3. The nociceptive threshold values are represented on average +/- SEM. On day 5 (D5), an injection of naloxone is carried out (lmg / kg, sc) and the nociceptive threshold measured 5 minutes after this injection of the opioid antagonist, then every 30 minutes until the return to the basic value of the nociceptive threshold. The analysis of variance (ANOVA) with 2 factors shows a time effect and a group effect. Post-hoc analysis (Dunnet test) indicates a significant difference between the 2 groups (p <0.05) for the measurements made up to 4 hours after the first administration of Fentanyl. During the days following that of Fentanyl administration, the 2-factor ANOVA shows a time effect and a group effect. Post-hoc analysis (Dunnett's test) indicates a significant difference between the 2 groups (p <0.05) the day following that of administration of Fentanyl as well as following administration of naloxone on D ₅ in the animals of the group NaCl. During these days following that of the administration of Fentanyl, the animals pre-treated with RF ₂ do not show any modification of the value of their nociceptive threshold with reference to the base value of their nociceptive threshold (Student test).

B - SYNTHESIS OF SYNTHETIC LIGANDS OF THE NPFF RECEPTOR Example 3: Preparation of the diacetate of N ^α -Phenylacetyl-L-Arginine-L- Phenylalaninamide (4) from N ^α -tert-Butyloxycarbonyl-N ^ω -Nitro-L-Arginine l (Method 1)

3.1. Preparation of N ^α -tert-Butyloxycarbonyl-N ^ω -Nitro-L-Arginine-L-Phenylalanine- amide 2

Dissolve 0.87 g (2.75 mmol) of N ^α -tert-Butyloxycarbonyl-N ^ω -Nitro-L-Arginine 1 in 60 ml of anhydrous tetrahydrofuran and cool to -40 ° C in an acetone / dry ice bath , the reaction medium under argon. Add 0.38 ml (2.75 mmol) of triethylamine and then drop 0.36 ml (2.75 mmol) of isobutyl chloroformate. Leave to stir for 2 minutes (formation of a white precipitate) then quickly add 500 mg (2.5 mmol) of phenylalaninamide hydrochloride and 0.38 ml (2.75 mmol) of triethylamine. Let the medium return to room temperature and keep stirring for 4 hours.

Evaporate to dryness and take up in dichloromethane and a saturated aqueous solution of sodium chloride.

Then wash the organic phase with a saturated aqueous solution of sodium hydrogencarbonate. Dry over sodium sulfate, filter and then evaporate. Obtaining 800 mg of a yellow oil. Purification on a silica column: eluent: acetic acid / methanol (9/1). Obtaining 650 mg of off-white product.

Yid: 50%

TLC: eluent: acetic acid / methanol (9/1): Rf = 0.62

F = 97 ° C 1H NMR (200 MHz, DMSO-d ₆ + D ₂ O): δ 1.31 (s, 9H, C (CH ₃ ) ₃ ); 1.43 (m, 2H,

CH ₂ -CH ₂ -CH ₂ ); 1.68 (m, 2H, CH ₂ - CΗ (NΗ ₂ ) -CO); 2.76 (m, 2H, NH-CH ₂ -CH ₂ -

CH ₂ ); 3.01 (d, 2H, C ₆ H ₅ -CH ₂ ); 3.93 (t, 1Η, CΗ ₂ -CH (NΗ ₂ ) CO); 4.62 (t, 1H,

C ₆ H ₅ -CH ₂ -CH); 7.10-7.40 (m, 5Η, Harom.).

3.2. Preparation of N ^α -phenylacetyl-N ^ω -Nitro-L-Arginine-L-Phenylalaninamide 3

Dissolve 650 mg (1.40 mmol) of the dipeptide previously formed in 18 ml of an acetic acid / hydrochloric acid mixture (2/1) and allow to react for 3 hours at temperature room. Evaporate to dryness. Several azeotropes are carried out successively with ethanol and then cyclohexane. 560 mg of hydrochloride are obtained.

Yield: 100% ^l U NMR (200 MHz, D ₂ O): δ 1.46 (m, 2H, CH ₂ -CH ₂ -CH ₂ ); 1.70 (m, 2H, CH ₂ - CΗ (NΗ ₂ ) -CO); 2.99 (m, 2H, NH-CH ₂ -CH ₂ -CH ₂ ); 3.10 (d, 2H, C ₆ H ₅ -CH ₂ ); 3.83

(t, 1Η, CΗ ₂ -CH (NΗ ₂ ) -CO); 4.85 (t, 1H, C ₆ H ₅ -CH ₂ -CH); 7.10-7.40 (m, 5Η, H arom.).

In a two-necked flask under argon, dissolve 200 mg (0.498 mmol) of the hydrochloride obtained in 10 ml of anhydrous tetrahydrofuran and cool the reaction medium to -20 ° C. Add 0.15 ml (0.55 mmol) of triethylamine and leave to stir for 10 minutes. Then add 0.072 ml (0.55 mmol) of phenylacetyl chloride dropwise. Leave to return to room temperature for 3 hours. Evaporate to dryness and resume with ethyl acetate and a saturated aqueous solution of sodium chloride. Extract 4 times with ethyl acetate, dry the organic phase over sodium sulfate, filter and evaporate to dryness.

Obtaining 140 mg of a yellow oil. Purification on a silica column: eluent: ethyl acetate / methanol (9/1). Obtaining 100 mg of pure product in the form of white powder. YId: 42%

TLC: eluent: Ethyl acetate / Methanol (9/1): Rf = 0.63 F = 203 ° C

* H NMR (200 MHz, DMSO-d ₆ + D ₂ O): δ 1.45 (m, 2H, CH ₂ -CH ₂ -CH ₂ ); 1.60 (m, 2H, CH ₂ -CH- (NH-CO) -CO); 2.95-3.15 (m, 4H, NH-CH ₂ -CH ₂ -CH ₂ and C ₆ H ₅ - CH ₂ ); 3.50 (d, 2Η, NH-CO-CH ₂ -C ₆ H ₅ ); 4.20 (t, 1H, CH ₂ -CH- (NH-CO -) - CO);

4.40 (m, 1H, CH-CH ₂ -C ₆ H ₅ ); 7.18-7.22 (m, 10H, Harorn.).

3.3. Preparation of N ^α -Phenylacetyl-L-Arginine-L-Phenylalaninamide 4 Diacetate

Hydrogenate overnight 100 mg (0.2 mmol) of the product 3 obtained above, dissolved in methanol containing 10% glacial acetic acid, to 40 psi in the presence of 10% Pd / C. Filter and concentrate under vacuum. Obtaining 70 mg of brown powder. Yid: 95% F> 220 ° C

1H NMR (200 MHz, DMSO-d ₆ + D ₂ O): δ 1.45 (m, 2H, CH ₂ -CH ₂ -CH ₂ ); 1.60 (m, 2H, CH ₂ -CH- (NH-CO -) - CO); 2.95-3.15 (m, 4H, NH-CH ₂ -CH ₂ -CH ₂ and C ₆ H ₅ -! CH ₂ ); 3.50 (d, 2Η, NH-CO-CH ₂ -C ₆ H ₅ ); 4.10 (t, 1H, CH ₂ -CH- (NH-CO -) - CO);

4.36 (m, 1H, CH-CH ₂ -C ₆ H ₅ ); 7.18-7.22 (m, 10H, Harorn.).

Example 4 Preparation of N ^α ~ hydrochloride [(lΗ) -Indole-2-carbonyl] -L- Arginine-L-Phenyl alaninamide (7) from Nα-Cbz-L-Arginine 5 (Method 2)

4.1. Preparation of N ^α hydrochloride -Carboxy-L-Arginine Anhydride 6

Place 300 mg (0.87 mmol) of Nα-Cbz-L-Arginine 5 hydrochloride in 12 ml of anhydrous tetjahydrofuran, under argon. Add 0.3 ml (3.2 mmol, 3.6 eq) of phosphorus tribromide and bring the mixture to reflux (outside temperature = 60 ° C) until the starting material is completely dissolved (about 4 hours). Evaporate the tetrahydrofuran to dryness. Put on the vacuum pump for 1 hour to dry the oil obtained well. The oil crystallizes in chloroform. Decant the chloroform and then quickly triturate with ether, decant it. Take up again in ether, decant and dry under vacuum. A very hygroscopic white solid is obtained.

1H NMR (300 MHz, DMSO-d ₆ ): δ 1.50-1.80 (m, 4H, -CH-CH ₂ -CH ₂ ); 2.90-3.00 (m, 2Η, CH ₂ -NH); 4.40-4.50 (m, 1H, CH-CH ₂ -CH ₂ ).

4.2. Preparation of N ^α hydrochloride - [(1H) -Indole-2-Carbonyl] -L-Arginine-L- Phenylalanineamide 7

To the hydrochloride of N ^α -carboxy-L-arginine anhydride 6 obtained previously is added 0.142 g (8.7.10 ^"4 moles) of L-Phenylalaninamide then 10 ml of water. Leave overnight at 60 ° C (outside temperature) After cooling the reaction medium, add 0.1 g (8.7.10 ^"4 moles) of sodium bicarbonate to obtain a pH of 9-10. Then add 0.1 ml (8.7.10 ^"4 moles) of indoloyl chloride. Leave to stir for 3 hours, ensuring that the pH is maintained at 9-10. Acidify to pH = 1 with a solution of 'acid hydrochloric acid IN. Extract three times with ethyl acetate then evaporate to dryness the aqueous phase. The crude reaction product is purified by high performance liquid chromatography. Vydac C ₁₈ reverse phase column Flow rate 10 ml / min Water gradient + 0.1% TFA-MeOH (98: 2 to 60: 40 in 5 min then 48: 52 in 26 min).

T _R HPLC: 28.7 min., Lyophilized product Yield: 10% H NMR (300 MHz, MeOD): δ 1.57-1.64 (m, 2H, CH-CH ₂ -CH ₂ ); 1.77-1.89 (m, 2H, CH ₂ -CH-NH); 2.90-2.97 (m, 2H, CH ₂ -C ₆ H ₅ ); 3.15-3.32 (m, 2H, NH-CH ₂ );

4.52-4.57 (m, 1Η, CΗ ₂ -CH-NΗ); 4.66-4.79 (m, 1H, CH-CH ₂ -C ₆ H ₅ ); 7.02-7.22 (m, 7H, H arom.); 7.45-7.50 (d, J = 7.5, 1Η, Harom.); 7.57-7.63 (d, J = 7.5, 1Η, H arom.)

Example 5; Preparation of N ^α hydrochloride -Benzoyl-N ^ω -Methyl-L-

Arginine-L-Phenylalanine amide (13) from N ^{α, ω} -bis-BenzyloxycarbonyI-L- Ornithine 8 (Method 3)

5.1. Preparation of N ^α -Carboxy-N ^ω -Benzyloxycarbonyl-L-Ornithine Anhydride 9

Dissolve 17.2 g (43 mmol) of N ^α ' ^ω -bis-Benzyloxycarbonyl-L-Ornithine 8 in 150 ml of anhydrous tetrahydrofuran, under argon, and cool the solution to 10 ° C (outside t °). Add 9.8 g (47 mmol, 1.1 eq) of phosphorus pentachloride. Shake for 1:30. Evaporate the tetrahydrofuran to dryness. Take up the syrupy residue in a minimum of ethyl acetate and crystallize the N-carboxyanhydride by adding ether. Filter, wash with ether and dry under vacuum. Obtaining 11.9 g of an off-white powder.

YId: 95%

F = 102 ° C

IR: 2 characteristic bands 1790 and 1852 cm ^{"1 !} Η NMR (300 MHz, DMSO-d ₆ ): δ 1.4-1.8 (m, 4H, -CH-CH ₂ -CH ₂ -); 3, 01 (q, 2Η,

J = 6.0, -CHrNH-); 4.44 (t, 1H, 3 = 6.1, -CH-CH ₂ ); 5.01 (s, 2H, -O-CH ₂ -Ph-); 7,3-

7.4 (m, 6Η, Harom. Et-NHCbz); 9.10 (s, 1Η, -NH-CΗ- exchangeable D ₂ O). ¹³ C NMR (300 MHz, DMSO-d ₆ ): 25.58 (-CH-CH ₂ -CH ₂ -); 29.05 (-CH-CH ₂ -CH ₂ -); 57.32 (-CH-CH ₂ -); 65.77 (-CH ₂ -Ph); 128.87 and 128.25 (-CH arom.); 137.78 (- C quaternary arom.); 152.46 (-NH-C (O) O-); 156.72 (BnO-C (O) O-); 172.04 (- CH-C (O) O-).

5.2. Preparation of N ^α -Benzoyl-L-Ornithine-L-Phenylalanineamide Hydrochloride 10

Dissolve 0.5 g (1.71 mmol) of anhydride 9 in 3 ml of dry dimethylformamide. Cool the mixture to - 40 ° C (outside temperature). Add a solution of L-phenylalanineamide 0.35 g (1.71 mmol) in 3 ml of chloroform containing 0.19 ml (1.7 Immoles) of N-methylmoφholine. Let rise to room temperature then heat to 60 ° C (outside temperature) for 30 minutes. After the solution has cooled, add 0.19 ml (1.71 mmol) of benzoyl chloride dissolved in 1 ml of chloroform. Abandon the reaction medium for 12 hours with stirring. Evaporate the chloroform on a rotary evaporator. Pour the remaining dimethylformamide in 50ml of water and stir for 1 hour. Then cool the reaction medium to 0 ° C for 4 hours and filter. Wash the crystals obtained several times with ether. 0.75 g of a white powder is obtained which is dissolved in 25 ml of methanol and 0.15 ml of concentrated hydrochloric acid. 70 mg of Pd / C at 10% are added thereto and the reaction medium is hydrogenated at 60 psi for 18 hours. After filtration of the catalyst on diatomaceous earth, it is evaporated to dryness. 420 mg of a white powder are obtained after trituration in ether and filtration.

Yield: 95% F = 233 ° C [α _D ]: - 18 ° C (c = 5 mg / ml, methanol)

1H NMR (200 MHz, CD ₃ OD): δ 1.55-1.95 (m, 4H, CH ₂ -CH (NH) -CO and CH ₂ - CH ₂ -CH ₂ ); 2.85-3.25 (m, 4H, C ₆ H ₅ -CH ₂ and NΗ ₂ -CH ₂ ); 4.55 (m, 2Η, CH ₂ - CH (NH) -CO and C ₆ H ₅ -CH ₂ -CH); 6.95 (m, 5Η, C ₆ H ₅ -CH ₂ ); 7.35 (m, 3H, CeH CO); 7.80 (d, J = 7.0, 2H, C ₆ H ₅ -CO). Centesimal analysis: Analysis calculated from C ₂ ιΗ ₂₆ NO ₃ , HC1: C%:

60.21; H%: 6.50; N%: 13.37. Found: C%: 60.20; H%: 6.48; N%: 13.32. 5.3. Preparation of N ^α -Benzoyl-N ^ω -thioureido-L-Norvaline-Phenylalaninamide 11

Add 0.5 g (1.2 mmol) of N ^α -benzoyl-L-Ornithine-L- Phenylalaninamide hydrochloride 10 to a mixture of chloroform (100 ml) and water (100 ml) containing 0.4 g ( 4.0 mmol, 3.3 eq) of calcium carbonate and 0.1 g (1.2 mmol) of sodium hydrogen carbonate. Leave to stir for 5 minutes then add 0.12 ml (1.5 mmol, 1.2 eq) of thiophosgene. Maintain vigorous agitation for 2 hours. Filter and separate the organic phase and the aqueous phase. Wash the precipitate (mineral salts) with ethanol to recover the reaction product which is relatively insoluble in chloroform. Collect the organic phases and concentrate under vacuum. Take up the residue in 100 ml of methanol, cool to 0 ° C and bubble with ammonia for 10 minutes. Leave to stir for 2 hours then concentrate in vacuo. Chromatograph the residue on a silica column (eluent ethyl acetate-methanol 9/1) to obtain 0.35 g of a white solid. YId: 66%

F = 183 ° C

[year]: -25.6 ° (c = 5 mg / ml, methanol)

1H NMR (200 MHz, CD ₃ OD): δ 1.45-1.85 (m, 4H, CH ₂ -CH (NH) -CO and CH ₂ - CH ₂ -CH ₂ ); 2.85-3.20 (m, 4H, C ₆ H ₅ -CH ₂ and NΗ ₂ -CS-NΗ-CH ₂ ); 4.45 (m, 2Η, CH ₂ -CH (NH) -CO and C ₆ H ₅ -CH ₂ -CH); 7.00 (m, 5Η, H arom.); 7.35 (m, 3H, aromatic H); 7.80 (m, 2H, Harom.)

5.4. Preparation of N ^α -Benzoyl-N ^ω -tert-butyloxycarbonyl-N ^{ω '} -Methyl-L-Arginine-L- Phenylalaninamide 12

Dissolve 0.55 g (1.24 mmol) of the thiourea 11 obtained above and 0.15 ml (2.48 mmol, 2 eq) of iodomethane in 20 ml of acetonitrile and leave to stir for 16 hours. Concentrate under vacuum to obtain 0.71 g of white product. Take up in a mixture of 10 ml of a saturated aqueous solution of sodium hydrogencarbonate and 10 ml of 1,4-dioxane. Add 0.32 g of di-tert-butyl dicarbonate to this mixture and leave to stir for 24 hours. Concentrate the dioxane and extract with 100 ml of ethyl acetate. Wash the organic phase with a saturated aqueous solution of sodium chloride. Dry over sodium sulfate, filter and concentrate in vacuo to obtain 0.55 g of yellow-colored isothiourea S-Me. Yield: 80% F = 105 ° C 1H NMR (200 MHz, CDC1 ₃ + D ₂ O): δ 1.49 (s, 9H, C (CH ₃ ) ₃ ); 1.60-2.00 (m, 4H,

CH ₂ -CH (NH) -CO and CH ₂ -CH ₂ -CH ₂ ); 2.42 (s, 3H, S-CH ₅ ); 3.05 (m, 2Η, C ₆ H ₅ - CH ₂ ); 3.25 and 3.45 (m, 2Η, C (CH ₃ S) -NH-CH ₂ ); 4.65 (m, 2Η, CH ₂ -CH (NH) -CO and C ₆ H ₅ -CH ₂ -CH); 7.05 (m, 5Η, C ₆ Hj-CH ₂ ); 7.35 (m, 3H, Harom.); 7.80 (m, 2Η, H arom.)

Dissolve 0.55 g (0.98 mmol) of isothiourea S-Me obtained in 100 ml of acetonitrile and cool the solution to 0 ° C. Then add 0.16 ml (1.17 mmol) of triethylamine, 1 ml (1.96 mmol) of a 2N methylamine / tetrahydrofuran solution, then 0.25 g (1.47 mmol) of silver nitrate. Leave to stir for 12 hours at room temperature. Filter through celite to remove the silver salts and concentrate under vacuum. Chromatograph the residue on a silica column (eluent 9/1 ethyl acetate-methanol + 5% triethylamine) to obtain 0.20 mg of white solid. YId: 38%

Rf (AcOEt-MeOH 9/1 + 5% TEA): 0.54 F = 124 ° C

1H NMR (200 MHz, DMSO-d ₆ + D ₂ O): δ 1.32 (s, 9H, C (CH ₃ ) ₃ ); 1.38-1.55 (m, 4H, CH ₂ -CH (NH) -CO and CH ₂ -CH ₂ -CH ₂ ); 2.67 (s, 3H, NH-CHj); 2.75 (m, 1Η, C (CΗ ₃ NΗ) -NΗ-CH ₂ ); 2.95 (, 3Η, C (CH ₃ NH) -NH-CH ₂ and C ₆ Η ₅ -CH ₂ ); 4.32-4.45 (m, 2Η, CH ₂ -CH (NH) -CO and C ₆ H ₅ -CH ₂ -CH); 7.05 (m, 5Η, C ₆ H ₅ -CH ₂ ); 7.35 (m, 3H, aromatic H); 7.80 (m, 2Η, H arom.)

5.5. Preparation of N ^α -Benzoyl-N ^ω -Methyl-L-Arginine-L-Phenylalanine Hydrochloride amide 13

In a two-necked tube fitted with a guard tube containing calcium chloride, dissolve 0.18 g of the protected amine obtained previously in 8 ml of anhydrous ethyl acetate and make bubbling HCl gas for 5 minutes. Monitor the disappearance of the starting material by TLC (ethyl acetate). Filter the white precipitate formed (0.14 g). Yield: 90% F = 127 ° C [<χ _D ]: -28 ° (c = 5 mg / ml, MeOH)

1H NMR (200 MHz, CD ₃ OD): δ 1.45-1.75 (m, 4H, CH ₂ -CH (NH) -CO and CH ₂ - CH ₂ -CH ₂ ); 2.75 (s, 3H, NH-CH ₅ ); 2.95 (m, 1Η, C (CΗ ₃ NΗ) -NΗ-CH ₂ ); 3.15 (m, 3Η, C (CH ₃ NH) -NH-CH ₂ and C ₆ Η ₅ -CH ₂ ); 4.45-4.75 (m, 2Η, CH ₂ -CH (NH) -CO and C ₆ H ₅ -CH ₂ -CH); 7.00 (m, 5Η, CgHj-CHs); 7.35 (m, 3H, Harom.); 7.80 (m, 2Η, H arom.).

Example 6 Preparation of N ^α -Benzoyl-N ^α hydrochloride-Methyl-L-Arginine-L- Phenylalanine amide (18) from N ^α -tert-ButyloxycarbonyI-N ^α -

Methyl-N ^w ' ^w di-benzyloxycarbonyl-L-Arginine 15 (method 4)

Starting from N ^α -tert-Butyloxycarbonyl-N ^α -Methyl- N ^w ' ^w di-benzyloxycarbonyl-L- Arginine 15 and following the procedure of coupling with L-Phenylalaninamide described in Example 3 (method 1) , the dipeptide amide 16 is obtained with a yield of 53%. This dipeptide amide 16 is then deprotected in an acid medium and acylated with benzoyl chloride, still under the conditions of the reactions described in Example 3 (method 1). Compound 17 is thus obtained. The deprotection of the benzyloxycarbonyl groups is carried out by hydrogenation as described in Example 3 (method 1), replacing acetic acid with hydrochloric acid concentrated in stoichiometric quantity. The overall yield for training of 18 is 35%. F = 90 ° C

1H NMR: (300 MHz, DMSO-d ₆ ): δ 1.48 (m, 2H, CH ₂ -CH ₂ -CH ₂ ); 1.70 (m, 2H, NH-CH ₂ -CH (NH ₂ ) -CO); 1.70 (s, 3H, NCH ₃ ); 2.80-3.12 (m, 4Η, C ₆ H ₅ -CH ₂ and NΗ-CH ₂ -CΗ ₂ -CΗ ₂ ); 4.30-4.37 (m, 1H, CH ₂ -CH-NH); 4.42-4.47 (m, 1H, CH-CΗ ₂ -C ₆ Η ₅ ); 7.11-8.05 (m, 10H, Harom.) Example 7 Preparation of the hydrochloride of N ^α -Benzoyl-3-guanidino-N- Phenethyl-L-Phenyl glycinamide 24 from N ^α -fert-ButyIoxycarbonyl-3-Nitro-L- Phenylglycine 19 (method 5)

7.1. Preparation of N ^α -tert-Butyloxycarbonyle-3-Nitro-N-Phénéthyl-L-

Phenylglycinamide 20

Dissolve 12.7 g (43.0 mmol) of N ^α -tert-Butyloxycarbonyle-3-Nitro-L-Phénylglycine 19 and 7.4 g (64.5 mmol, 1.5 eq) of N-hydroxysuccinimide in 400 ml 1,4-dioxane. Add dropwise 9.7 g (47.3 mmol, 1.1 eq) of DCC dissolved in 100 ml of 1,4-dioxane and keep stirring for 12 hours. Separate the DCU formed by filtration and concentrate under vacuum. Take up the residue in 400 ml of ethyl acetate and wash with 300 ml of a saturated aqueous solution of sodium chloride. Dry the organic phase over sodium sulfate, filter and concentrate in vacuo to obtain 16.1 g of a yellow oil used as it is for the following.

Dissolve the yellow oil previously obtained in 600 ml of 1,4-dioxane and add 6.2 ml (49.2 mmol) of Phenethylamine drop by drop. Keep stirring for 2 hours then concentrate in vacuo. Take up the residue in 750 ml of ethyl acetate and wash with 500 ml of a 5% aqueous citric acid solution. Dry the organic phase over sodium sulfate, filter and concentrate in vacuo. Triturate in ether and filter to obtain 13.6 g of white solid.

YId: 79%

F = 175 ° C

1H NMR (200 MHz, CDC1 ₃ ): δ 1.43 (s, 9H, C (CH ₃ ) ₃ )); 2.73 (t, J = 7.5, 2H, CH ₂ - CH ₂ -C ₆ H ₅ ); 3.41-3.64 (m, 2H, CH ₂ -CH2-C ₆ H ₅ ); 5.15 (s, 1H, CH-NH-C (CH ₃ ) ₃ );

5.70 and 5.95 (two exchangeable s D ₂ O, 2H, CO-NH-C (CH ₃ ) ₃ and CO-NH-CH ₂ );

6.98-7.01 (m, 2H, Harom.); 7.19-7.23 (m, 3Η, Harom.); 7.50 (t, J = 8.0, 1Η, H _b );

7.63 (d, XI., 1Η, H _c ); 8.17-8.19 (m, 2Η, H _{a and} H _d )

7.2. Preparation of N ^α -Benzoyl-3-Nitro-N-Phenethyl L- Phenylglycinamide 21

In a bicol fitted with a guard tube containing calcium chloride, dissolve 1.2 g (3.0 mmol) of the product 20 previously obtained in 20 ml of ethyl acetate. Cool to 0 ° C and bubble HCl gas for 5 minutes. Follow the disappearance of the starting material on TLC (ethyl acetate). Filter the white precipitate that has formed. Add ether to the filtrate, allow to cool to 0 ° C and filter again to obtain a total of 1.0 g of white solid in the form of the hydrochloride.

YId: 95%

F = 220 ° C

^! H NMR (200 MHz, CD ₃ OD): δ 2.64 (t, J = 7.5, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 3.20 to 3.46

(m, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 5.15 (s, 1H, CH-NH ₂ ); 7.01-7.03 (m, 2H, H arom.); 7.10-7.13 (m, 3H, H arom.); 7.73 (t, J = 8.0, 1H, H _b ); 7.96 (d, XI.6, 1H, H _c ); 8.26

(d, J = 8.4, 1H, H _a ); 8.43 (s, 1H, H _d ); 8.94 (s large exchangeable D ₂ O, 3H, NH ₂ and

HCl)

In a bicol under argon, dissolve 3.0 g (8.93 mmol) of the hydrochloride previously obtained in 50 ml of anhydrous tetrahydrofuran and bring the reaction medium to -20 ° C. Add 3.0 ml (21.4 mmol, 2.4 eq) of triethylamine and leave to stir for 10 minutes. Then add dropwise 1.3 ml (10.7 mmol, 1.2 eq) of benzoyl chloride. Let the medium return to room temperature and maintain stirring for 3 hours. Concentrate in vacuo and resume with ethyl acetate and a saturated aqueous solution of sodium chloride. Extract with ethyl acetate, dry the organic phase over sodium sulfate, filter and concentrate in vacuo. Triturate with ether to obtain 3.1 g of white solid. Yield: 83% F = 174 ° C 1H NMR (200 MHz, CDC1 ₃ ): δ 2.70 (t, J-7.5, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 3.30 to 3.66

(m, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 5.96 (d, J = 7.5, 1H, CH-NH-CO); 6.10 (exchangeable D ₂ O, 1H, CO-NH-CH ₂ ); 6.95-7.10 (m, 5H, CH ₂ -CH ₂ -C ₆ Hj); 7.45-7.60 (m, 5Η, CO-C ₆ H ₅ ); 7.75-7.85 (m, 2Η and 1Η exchangeable D2O, H _b and CH-NH-CO); 7.95 (d, 1 = 1.6, 1Η, H _c ); 8.16 (d, J = 8.4, 1Η, H _a ); 8.30 (s, 1Η, H _d )

7.3. Preparation of N ^α -Benzoyl-3-Arnino-N-Phenethyl L-Phenylglycinarnide 22 Hydrogenate at 70 psi for 7 hours 3.0 g (7.45 mmol) of the product 21 previously obtained dissolved in 60 ml of ethanol in the presence of 0.3 g of Pd / C at 10%. Filter and concentrate under vacuum. Chromatograph the residue on a silica column (eluent: ethyl acetate - Hexane 2/1) to obtain 2.1 g of white solid. YId: 75%

F = 124 ° C

1H NMR (200 MHz, CDC1 ₃ ): δ 2.65 (t, J = 7.5, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 3.35 and 3.50 (m, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 3.60 (s exchangeable widened D ₂ O, 2H, CH-C ₆ H ₄ -NH ₂ ); 5.50 (d, 1 = 7.5; 1Η, CH-NΗ-CO); 6.15 (s, exchangeable D ₂ O, 1Η, CO-NH-CΗ ₂ ); 6.60 (d, J = 8.3, 1H, H arom.); 6.70 (m, 2H, H arom.); 7.00 (d, 1 = 8.5, 2H, H arom.); 7.10-7.30 (m, 4H, H arom.); 7.40-7.55 (m, 3H, H arom.); 7.65 (exchangeable D ₂ O, J = 8.0, 1H, CH-NH-CO); 7.79-7.82 (m, 2Η, Harom.).

7.4. Preparation of N ^α -Benzoyl-3- (N, N'-di (tert-Butyloxycarbonyl) guanidino) -N- Phenethyl-L-Phenylglycinamide 23

Dissolve 0.80 g (2.14 mmol) of the product obtained above in 30 ml of dimethylformamide and add 0.98 ml (7.08 mmol, 3.3 eq) of triethylamine and 1.37 g (4.70 mmol, 2.2 eq) of N, N'-di (tert-butyloxycarbonyl) -S-methylisothiourea. Cool to 0 ° C and add 0.62 g (2.35 mmol, 1.1 eq) of mercury chloride. Shake for 3 hours. Dilute in 50 ml of ethyl acetate and filter through diatomaceous earth. Rinse with 100 ml of ethyl acetate, then wash with 100 ml of a saturated aqueous solution of sodium chloride. Recover the filtrate and separate the two phases. Wash the organic phase with 100 ml of a saturated aqueous solution of sodium chloride. Dry over sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a silica column (eluent: ethyl acetate) to obtain 0.78 g of white solid. Yid: 60% F = 103 ° C

1H NMR (200 MHz, CDC1 ₃ ): δ 1.45 (s, 18H, C (CH ₅ ) ₅ ); 2.65 (t, J-7.5, 2Η, CH ₂ - CH C ₆ H ₅ ); 3.35-3.50 (m, 2H, CH ₂ -CH ₂ -C ₆ H _S ); 5.55 (d, 1 = 1.5, 1H, CH-NH-

CO); 6.20 (s, exchangeable D ₂ 0, 1H, CO-NH-CH ₂ ); 7.00-7.90 (m, 2 p.m., Harom.) 7.5. Preparation of N ^α -Benzoyl-3-guanidino-N-Phenethyl-L-Phenyl glycinamide Hydrochloride 24

In a two-necked flask fitted with a calcium chloride guard tube, dissolve 0.60 g (0.97 mmol) of the product 23 previously obtained in 15 ml of ethyl acetate. Cool to 0 ° C and bubble HCl gas for 5 minutes. Follow by TLC (eluent: ethyl acetate) the disappearance of the starting product. Filter the white precipitate that has formed. Add ether to the filtrate, allow to cool to 0 ° C and filter again to obtain a total of 0.42 g of white solid. YId: 90%

F = 128 ° C

[OC _D ]: -28 ° (c = 2 mg / ml, methanol)

Centesimal analysis: Analysis calculated from C ₄ H ₂₆ N ₅ θ ₂ Cl: C%: 61.33;

H%: 6.00; N%: 14.90; Cl%: 7.54. Found: C%: 60.79; H%: 5.87; N%: 14.85; Cl%: 7.82

^] H NMR (200MHz, D ₂ O): δ 2.71 (t, 1 = 1.5, 2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 3.35-3.51 (m,

2H, CH ₂ -CH ₂ -C ₆ H ₅ ); 5.42 (s, 1H, CH-NH-CO); 7.05-7.12 (m, 6H, H arom.);

7.21-7.25 (m, 2H, H arom.); 7.38-7.43 (m, 3H, H arom.); 7.50-7.56 (m, 1H, H arom.); 7.64-7.67 (m, 2H, Harom.)

EXAMPLE 8 Preparation of the Trifluoroacetate of N ^α - (4-acetylaminobutanoyl) - L-Arginine-N-phenethylamide 28 from N ^α -fe / --'- butyloxycarbonyl-N ^CD 2,2,5,7,8 pentamethylchroman -6-sulfonyl (Pmc) -L-Arginine 25 (method 6)

8.1. Preparation of N ^α -tert-Butyloxycarbonyl-N ^0> 2,2,5,7,8 pentamethylchroman-6-sulfonyl (Pmc) -L-Arginine-N-phenethylamide 26.

Dissolve 0.640g (1.18mmol) of N ^α -tert-Butyloxycarbonyl N ^ω (Pmc) Arg 25 in 20 ml of acetonitrile. Add 0.32 g of hydroxybenzotriazole and 0.28 mg (0.3 ml) of phenethylamine. Then add at 0.2 ° C. and dropwise 0.27 g of DCC in 8 ml of acetonitrile. Leave to return to ambient temperature, then leave the reaction medium overnight. Filter the precipitate obtained. Evaporate the acetonitrile then take up the reaction crude with ethyl acetate. Wash the organic phase with an IN HCl solution then with a saturated NaHCO ₃ solution then with a saturated sodium chloride solution. Dry over sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a silica column (eluent: AcOEt / Hexane, 3/1) to obtain 0.6g of a beige powder.

'H NMR (300MHz, CDC1 ₃ ): δ 1.25 (s, 6H, 2xPmc CH ₃ ); 1.39 (s, 9H, C (CH ₃ ) ₃ ) 1.43-1.80 (m, 6Η, CH ₂ -C (CH ₃ ) ₂ -O- and CH ₂ -CH ₂ -CH (NHBOC) -CO-); 2.15 (s, 3H CH ₃ m to ..SO ₂ ); 2.55 (2s, 6Η, 2xCH3 o to ... SO ₂ ); 2.57 (t, 2H, CH ₂ -CH ₂ -C (CH ₃ ) ₂ - O-); 2.75 (t, 2H, CH ₂ -Ph); 3.25 (m, 2Η, CH ₂ -N-Guanidine); 3.55 (m, 2Η, CH ₂ - NΗ-CO-CΗ-); 4.15 (m, 1H, BOCNH-CH-CO-); 7.10-7.40 (m, 5Η, Harom).

8.2. Preparation of N - (4-acetylaminobutanoyl) -N ^ω 2,2,5,7,8 pentamémylchroman-6-sulfonyl (Pmc) L-Arginine-N-phenethylamide 27.

Dissolve 0.55 g (0.86 mmol) of product 26 previously prepared in 6 ml of ethyl acetate. Add 4 ml of a 2.4 N gas / AcOEt ΗCl solution and leave overnight. Evaporate the reaction mixture to dryness. Resume with dichloromethane then wash the organic phase with a saturated NaΗCO ₃ solution. Dry over sodium sulfate, filter and concentrate in vacuo. Take up the crude product obtained in 10 ml of acetonitrile. Add 0.125g (0.86mmol) of 4-acetamidobutyric acid and 0.128g (0.86mmol) of hydroxybenzotriazole. Add at 0 ° C, drop by drop 0.2g of DCC and leave overnight. Filter the DCU formed. Evaporate to dryness then dissolve the residue obtained in 20ml of dichloromethane. Wash the organic phase with 20ml of IN HCl solution, then 20ml of saturated NaHCO ₃ solution and finally with saturated sodium chloride solution. Dry over sodium sulfate, filter and evaporate to dryness. Triturate for 1 hour in ether then filter to obtain 0.24 g of a white powder (Yield: 41%).

1H NMR (300MHz, CDC1 ₃ ): δ 1.25 (s, 6H, 2xPmc CH ₃ ); 1.43-1.80 (m, 8H, CH ₂ -C (CH ₃ ) ₂ -O- and CH ₂ -CH2-CH (NHCO -) - CO- and CH ₂ -CH ₂ -NHCOCH ₃ ); 1.90 (s, 3H, NHCO-CH ₃ ); 2.15 (s, 3Η CH ₃ m to ... SO ₂ ); 2.25 (t, 2Η, CH ₂ -CO-NΗ) 2.55 (2s, 6H, 2xCH3 o to ... SO ₂ ); 2.56 (t, 2H, CH ₂ -CH ₂ -C (CH ₃ ) ₂ -O-); 2.63 (t, 2H,

CH2-CONH-CH); 2.80 (t, 2H, CH ₂ -Ph); 3.25 (m, 2Η, CH ₂ -N-Guanidine); 3,40- 3.55 (m, 4H, CH ₂ -NH-CO-CH- and CH ₂ -NHCOCH ₃ ); 4.45 (m, 1H, -CONH-CH-CO-); 7.20-7.40 (m, 5Η, Harom).

8.3. Preparation of N ^α trifluoroacetate - (4-acetylaminobutanoyl) -L-Arginine-N- phenethylamide 28

Dissolve 0.12 g of product 27 obtained previously in 2 ml of trifluoroacetate acid and leave overnight with stirring. Evaporate the TFA then add pentane which is evaporated. This operation is repeated 3 times. Dry for one hour with a paddle pump, then crush in ether. After filtration, 0.08 g of an ocher solid is obtained.

1H NMR (300MΗz, DMSO-D ₆ ): δ 1.20-1.7 (m, 6H, and CH ₂ -CH ₂ -CH (NHCO -) - CO- and CH ₂ -CH ₂ -NHCOCH ₃ ); 1.85 (s, 3H, NHCO-CH ₃ ); 2.15 (t, 2Η, CH ₂ -CO- NH); 2.75 (t, 2H, CH ₂ -Ph); 3.15 (m, 4Η, CH ₂ -N-Guanidine and CH ₂ -NΗCOCΗ ₃ ); 3.35 (t, 2H, CH ₂ -NH-CO-CH-); 4.45 (m, 1H, -CONH-CH-CO-); 7.20-7.40

(m, 5Η, Harom).

EXAMPLE 9 Preparation of the trifluoroacetate of N diphenylacetyl N ^ω benzyl (D, L) -Arginine-N-benzyIamide 32 starting from N ⁷ benzyloxycarbonyl (D, L) ornithine 29 (method 7)

9.1. Preparation of N ^α - diphenylacetyl D, L-ornithine N-benzylamide 30

Mix 5.5g (19.6mmol) of N ^γ benzyloxycarbonyl (D, L) ornithine 29 with 9.57ml (68.6mmol, 3.5 eq.) Of TEA, 5.11g (47.0mmol, 2.4 eq .) of trimethylsilane chloride in 110 ml of CΗ ₂ C1 ₂ . After 30 min, the solution not being clear, addition of 20% of TEA (1.91 ml, 13.72 mmol) and 20% of trimethylsilane chloride (1.02 ml, 9.4 mmol). Leave to stir at room temperature for 4 hours. Wash the organic phase with saturated NaHCO ₃ solution (2 times), IN HCl solution, then evaporate under reduced pressure. Chromatograph the product on a silica column (eluent: CH ₂ Cl ₂ / MeOH 98/2). To obtain 5.2 g of a colorless viscous product. Yld. 55%. Rf (AcOEt / Hexane 1/1): 0.28 MS: 483.3 (M + 23)

1H NMR (MeOD, 300MHz) δ: 1.40-1.70 (m, 4H, (CH ₂ ) ₂ ); 3.15 (t, J = 6.84, 2Η, CH ₂ -CH ₂ - ^~ NH); 4.4 (m, 1H, NH-CEr (CH ₂ ) ₂ -CO); 5.0-5.1 (m, 3H, CO-Gfifc-Ph + (C ₆ H ₅ ) ₂ -CH-CO)); 7.3-7.45 (m, 15H, Harom).

Dissolve 4.5g (9.77mmol, 1 eq.) Of the acid obtained above in 45ml of DMF.

Add 1.67 g (10.25 mmol, 1.05 eq.) Of DIC and leave to stir at room temperature for 1 h 30 min, under Argon. Then add 1.17 ml (10.74 mmol, 1.1 eq.) Of benzylamine and heat at 80 ° C for 4 hours. Evaporate the DMF under reduced pressure, take up the white residue in a 10% Na ₂ CO ₃ solution and leave to stir for 10 minutes.

Filter and recover the white solid after washing it with water. Dry at the pump.

Dissolve the residue in 250ml of MeOΗ. Add 0.8g of Pd / C (10%) and hydrogenate to

70psi for 30 hours. Filter through celite, evaporate under reduced pressure. Triturate with ether twice, then evaporate under reduced pressure. Obtaining 3.9 g of a white powder. Yld. 72%.

Rf (AcOEt / Ηexane 1/1): 0.25 F: 160-164 ° C MS: 416.26 (M + 23)

1H NMR (DMSO + D ₂ O, 300MΗz) δ: 1.50-1.70 (m, 4H, (CH ₂ ) ₂ ); 3.10 (t, J = 6.42, 2Η, CH2-CH ₂ -NH); 4.38-4.5 (m, 3H, NH-CH ₂ -Ph + NΗ-CH (CΗ ₂ ) ₂ -CO); 5.04 (s, 2H, CO-CH ₂ -Ph); 5.16 (s, 1Η, CO-CH-Ph ₂ ); 7.2-7.40 (m, 15Η, Harom).

9.2. Preparation of N ^α- diphenylacetyl N ^{ffl, ω} [benzyl-bis (tert-butyloxycarbonyl)] D, L- arginine N-benzylamide 31

Dissolve 100 mg (0.24 mmol) of amine 30 in 4 ml of DMF, with 84 μl (0.6 mmole) of TEA. Add 183 mg (0.48 mmol.) Of N-benzyl-1,3-bis (tert-butyloxycarbonyl) -2-methyl-thiopseudourea. Agitate at room temperature overnight, under argon. Evaporate under reduced pressure, dissolve the mixture in AcOEt, wash with water, then with saturated NaCl solution and dry the organic phase over Na ₂ SO ₄ . Chromatograph the product on a silica column (eluent: CH ₂ Cl ₂ / MeOH 97/3) to obtain 94 mg of a colorless viscous solid. Yld. 52%.

Rf (CH ₂ Cl ₂ / MeOH 95/5): 0.30> MS: 770.44 (M + 23)

'H NMR (DMSO + D ₂ O, 300MHz) δ: 1.3-1.7 (m, 22H, (CH ₂ ) ₂ + OC (CH ₃ ) ₃ ); 2.99 (t, J = 7.12, 2Η, CH ₂ -CH ₂ -NH); 4.3-4.5 (m, 3H, NH-CH ₂ -Ph + NΗ- CH (CΗ ₂ ) ₂ -CO); 4.65 (m, 2H, N = C-CH ₂ -Ph); 5.09 (s, 1Η, CO-CH-Ph ₂ ); 7.25- 7.40 (m, 20Η, H arom.).

9.2. Preparation of N ^α- diphenylacetyl trifluoroacetate N ^ω benzyl- D, L-arginine N- benzylamide 32

Dissolve 94 mg (0.126 mmol) of compound 31 in 5 ml of a CH ₂ C1 ₂ / TFA mixture (1/1). Leave to stir at room temperature for 9 hours. Evaporate under reduced pressure and triturate with ether. Lyophilize to obtain 50 mg of a beige powder. Yld. 60%.

MS: 548.34 (M + l)

1H NMR (MeOD, 300MHz) δ: 1.4-1.8 (m, 4H, (CH ₂ ) ₂ ); 3.12 (t, J = 6.35, 2Η, CH ₂ - CH2-NH); 4.3-4.5 (m, 5H, NH-CH ₂ -Ph + C = N-CH ₂ -Ph + NΗ-CH (CΗ ₂ ) ₂ -CO);

5.08 (s, 1H, CO-CH-Ph ₂ ); 7.25-7.40 (m, 20Η, # aromatics).

¹³ C NMR (MeOD, 200MHz) δ: 27.21 (C5); 31.1 (C4); 42.9 (C6); 44.94 (C10);

46.75 (C35); 55.32 (C2); 59.56 (C18); 129.08-130.76 (C aromatics); 138.58

(C36 or Ci l); 140.44 (C36 or C11); 141.74 (C20 and C19); 158.32 (C32); 174.49 (Cl 7); 175.7 (C3).

Example 10 Synthesis of Synthetic Ligands

Following the synthetic methods described in Examples 3-7, the following compounds were prepared. N ° Métho product name of

4 N ^α acetate -Phenylacetyl-L-Arg-L-Phe-NH ₂ 33 N ^α acetate -Benzoyl-L-Arg-Tic-NH ₂ (Tic-NH ₂ ≈ 1,2,3,4- tetrahydroisoquinoline- 3 carboxamide)

34 N ^α -Benzoyl-L-Arg-Atc-NH ₂ acetate (Atc-NH ₂ = 2-amino tetralin-2-carboxamide)

35 N ^α acetate -Adamantan-l-yl-L-Arg-L-Phe-NH ₂ 36 N ^α acetate -Benzoyl-L-Arg-D-Phe-NH ₂ 37 N ^α acetate -Cyclohexoyl-L- Arg-L-Phe-NH ₂ 38 N ^α acetate -Acetyl-L-Arg-L-Phe-NH ₂ 39 N ^α acetate -Pivaloyl-L-Arg-L-Leu-NH ₂ 40 N ^α acetate - Pivaloyl-L-Arg-OMe-L-Tyr-NH ₂ 41 N ^α acetate -Pivaloyl-L-Arg -L-Tyr-NH ₂ 42 N ^α acetate -Pivaloyl-L-Arg -L-Tφ-NH ₂ 7 N ^α hydrochloride - [(1H) -Indole-2-carbonyl] -L-Arg-L-Phe-NH ₂ 2 43 N ^α hydrochloride - (4-chloro-Benzoyl) -L-Arg-L-Phe -NH ₂ 2 44 N ^α hydrochloride - (4-chloro-Benzoyl) -L-Arg-D-Phe-NH ₂ 2 45 N ^α hydrochloride - (3-chloro-Benzoyl) -L-Arg-L-Phe -NH ₂ 2 46 N ^α hydrochloride - (3-chloro-Benzoyl) -L-Arg-D -Phe-NH ₂ 2 47 N ^α hydrochloride - (3,4-dichloro-Benzoyl) -L-Arg-D , L-Phe-NH ₂ 2 48 N ^α (- 2-chloro-Benzoyl) -L-Arg-D hydrochloride, L-Phe-NH ₂ 2 49 N - (4-methyl-Benzoyl) -L- hydrochloride Arg-L-Phe-NH ₂ 2 50 N ^α hydrochloride - (4-methoxy-Benzoyl) -L-Arg-L-Phe-NH ₂ 2 51 N ^α hydrochloride - (4-ni tro-Benzoyl) -L-Arg-D, L-Phe-NH ₂ 2 52 N ^α sulfonate -Benzenesulfonyl-L-Arg-L-Phe-NH2 2

13 N ^α hydrochloride -Benzoyl-N ^ω -Me-L-Arg-L-Phe-NH ₂ 3 10 Hydrochloride N ^α -benzoyl-L-Orn-L-Phe-NH ₂ 3 11 N ^α - Benzoyl-N ^ω - thiouréido-L-Nor-Val-L-Phe-NH ₂ 3 18 N ^α hydrochloride -Benzoyl-N ^α -Me-L-Arg-L-Phe-NH ₂ 4 24 N ^α acetate -Benzoyl-3- guanidino-N-Phenethyl-L-phenyl-Gly-NH ₂ 5 28 Trifluoroacetate of N ^α - (4-acetylaminobutanoyl) -L-Arginine-N- 6 phenethylamide

54 N- (3-bromo-benzoyl) -L-arginine-N- 6 phenethylarnide trifluoroacetate

55 N- (quinoline-3-carbonyl) -L-arginine-N- 6 phenethylamide trifluoroacetate

56 N ^α trifluoroacetate - [(1H) -Indole-2-carbonyι] -L-Arg-D-Phe-NH ₂ 6

32 N ^α diphenylacetyl N ^ω benzyl (D, L) -Arginine-N- 7 benzylamide trifluoroacetate

57 N ^α diphenylacetyl N ^Tri methyl (D, L) -Arginine-N- benzylamide trifluoroacetate 58 N ^α benzoyl N ^ω methyl (D, L) -Arginine-N- benzylamide trifluoroacetate

RF2 N ^α hydrochloride -Benzoyl L-Arginine-L-Phe-NH ₂ EXAMPLE 11 Binding of the ligands to the NPFF receptor

This example demonstrates that the in vivo administration of synthetic ligands of the invention i) potentiates the analgesic effect of fentanyl and ii) prevents sensitization to pain induced by fentanyl in painful animals (pain of inflammatory type).

In order to better study the pharmacological efficacy of synthetic ligands of the NPFF receptor (for example of the compound RF2), we carried out a complementary study of the properties of this compound on rats (strain Sprague-Dawley as in the whole study) affected by '' pain induced by the injection of a pro-inflammatory agent (carrageenan) into a hind leg (unilateral injection). This model is particularly interesting from a methodological point of view since the evoked pain (measured by the Randall and Sellito test) appears quickly within an hour after the injection and lasts 2-3 days (Figure 11, section A). This inflammatory pain model can be considered as a widely encountered clinical pain model and has been widely used as such in international literature in the context of pre-clinical trials in animals.

A. The rats (male Sprague-Dawley, 300-400g) receive an injection of carrageenan (0.2 ml of a 1% solution) in the plantar pad of the left hind paw

(indicated by Λ). Four injections of fentanyl, separated by 15 minutes (60 μg / kg each) or physiological saline are given subcutaneously (indicated by _). The first injection is made 5 minutes after that of carrageenan. The nociceptive threshold, measured by the vocalization test in response to a mechanical stimulus (Randall-Selitto test), is evaluated 2h, 4h, 5h30 and 10h30 after the administration of carrageenan (Jo) as well as the following days (Dd to J ₇ ). B. The rats receive an injection of carrageenan according to the protocol previously indicated (see A). They also receive 3 RF ₂ injections

(5 mg kg) or physiological saline (indicated by ->) according to the following protocol: a first injection is carried out 30 minutes before the injection of carrageenan, then 4:30 and 9:30 after the injection of this pro-inflammatory agent. The nociceptive threshold of the injected paw is measured 2h, 4h, 5h30 and 10h30 after the administration of carrageenan (D ₀ ) as well as the following days (Dd to D ₇ ) using the Randall-Sellito test. C. The rats receive an injection of carrageenan (see A). The RF ₂ (5 mg / kg) is administered in the form of 3 injections as before (see B). The animals also receive 4 injections of fentanyl (60 μg / kg each according to the protocol indicated in A). The nociceptive threshold of the injected paw is measured 2 h, 4 h, 5 h 30 and 10 h 30 after the administration of carrageenan (D ₀ ) as well as the following days (Ji to D ₇ ) using the Randall-Sellito test. * P <0.05; ANOVA two-way, intergroup comparison.

The results obtained are as follows:

1. Interestingly, this study shows, for the first time, that the acute administration of a powerful opioid analgesic such as fentanyl, if it provokes, as expected, a powerful immediate analgesic effect, potentiates both in duration and amplitude hyperalgesia induced by inflammatory type nociceptive impulses (See Figure 11, section A). 2. The administration of RF2, at a dose of 5 mg / kg (3 successive subcutaneous injections: 30 min before, then 4 h 30 and 9 h 30 after that of the pro-inflammatory agent), was carried out in rats having received or not fentanyl:

- in animals not receiving fentanyl: the administration of RF2 only causes per se a modest analgesic effect observable only during the first 2 hours following the injection of carrageenan

(see Figure 11, section B),

- in animals receiving fentanyl: the administration of RF2 very strongly potentiates the analgesic effect of fentanyl during the first 4 hours (see Figure 11, section C) and completely prevents the potentiation of hyperalgesia for 24 hours; this preventive effect gradually fades and disappears after 72 hours.

These data show, for the first time in painful animals, that synthetic ligands of the invention, such as RF2, even if they are not or little analgesic per se (in agreement with the previous data given in 2000) are particularly effective in preventing the potentiation of sensitization to pain induced by an opioid analgesic agent such as fentanyl, widely used in human clinics during surgical procedures. These results therefore confirm the advantageous use of Synthetic ligands according to the invention to improve the management of post-operative pain by preventing pain awareness processes potentiated by the administration of opioid analgesics (4.5 million patients in France per year).

BIBLIOGRAPHICAL REFERENCES

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Célérier et al., Anesthesiology, 2000, 92, 465-472.

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Devillers et al, J. Brain Research, 1995b, 700, 173-180. Hwa-Ok kim, Felix M, Cyprian O. Synlett 1999; 2; 193-194

Kayser and Guilbaud, Pain (1990) 353.

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Claims

1. Use of a synthetic ligand for the NPFF receptor for the preparation of a pharmaceutical composition intended for inhibiting hyperalgia induced by opioid analgesic compounds.

2. Use according to claim 1, for inhibiting hyperalgia induced by moφhine and moφhinomimétiques.

3. Use according to claim 1 or 2, for inhibiting hyperalgia induced by an opioid analgesic compound chosen from moφhine, fentanyl, sufentanil alfentanyl, heroin, hydromorphone, levoφhanol, methadone, buprenoφhine, butoφhanol, meperidine.

4. Use according to any one of the preceding claims for the treatment or management of hypersensitivity to pain, of chronic or acute nature, persistent or temporary, of surgical, traumatic or pathological origin, in humans. human.

5. Use according to claim 1, characterized in that the synthetic ligand is an antagonist of the NPFF receptor.

6. Use according to any one of the preceding claims, characterized in that the synthetic ligand is a compound derived from the C-terminal region of the neuropeptide FF.

7. Use according to any one of the preceding claims, characterized in that the synthetic ligand is a compound of general formula (I) as defined in one of claims 11 to 21.

8. Use according to any one of the preceding claims, characterized in that the synthetic ligand is administered systemically, preferably intravenously, subcutaneously or intramuscularly.

9. Use according to any one of the preceding claims, for the treatment of hyperalgia in patients with cancer or burned.

10. Use according to any one of claims 1 to 8, for the treatment of postoperative hyperalgia.

.

11. Compounds of general formula (I), in L, D or L / D form,

in which :

. -L- represents either (CH ₂ ) _m , m being able to represent 2, 3 or 4; either a group of formula

in which n is 0 or 1;

. A is a sulfur atom or an NRj group in which Ri represents a hydrogen atom, a methyl group or a group

in which n is 0 or 1 and Xi represents a hydrogen or halogen atom or a hydroxyl, carboxamide, trifluoromethyl, alkoxy, a ino or acylamino group;

. R2 and Rj ₂ , independently of one another, represent a hydrogen atom or an alkyl or aralkyl group,

. R ₃ is either a group - (CH2) _P -W in which p is 1, 3 or 6 and W is chosen from

- a hydrogen atom,

- a group

in which R ₅ is an alkyl, aryl or aralkyl group, - a group

in which R ₇ is a hydrogen atom or a methyl group and R ₈ is a hydrogen atom, an alkyl or an aralkyl, - a group -OH or -OMe,

- a group

in which Y is an oxygen or sulfur atom, or

- a phenyl, substituted phenyl or heteroaryl group,

either a group

in the L, D or L / D conformation, wherein R is an alkyl group or a group

with n having a value of 0 or 1 and Xi being as defined above, and Rio is a hydrogen atom, an alkyl or an aralkyl;

either an arylcycloalkyl group, optionally substituted either R2 and R ₃ together form a ring having from 3 to 9 carbon atoms, saturated or unsaturated, optionally aromatic, and optionally comprising a link NRn, Rπ being an alkyl, aryl or aralkyl group;

. } represents a hydrogen atom, a methyl group or a group

in which n is 0 or 1 and Xj is as defined above, and

. R ₅ is a group of formula -CO (CH ₂ ) _q Ar or -SO ₂ (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar comprises an aromatic group, substituted or not, optionally comprising one or more heteroatoms or R ₅ is a group of formula -CO-R ₁₃ in which Rj ₃ is a group (C! -C ₆ ) alkyl or (C ₃ -Ci2) cycloalkyle, optionally substituted.

12. Compounds according to claim 11, characterized in that Ar represents an aromatic group chosen from the cyclic groups with 1, 2 or 3 following condensed cyclic rings:

in which Z is a CX ₅ group or a nitrogen atom, it being understood that for the same cycle, Z cannot take more than three times the meaning nitrogen, Y is a sulfur or oxygen atom or an NX ₅ group , n is 0, 1 or 2, Xi, X ₂ , X ₃ , and X ₅ , identical or different, being chosen from a hydrogen atom, a halogen atom, or a carboxamide, trifluoromethyl, alkoxy, amino group or acylamino.

13. Compounds according to claim 11 or 12, characterized in that R ₄ is a hydrogen atom and R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar comprises an aromatic group, substituted or not, optionally comprising one or more heteroatoms.

14. Compounds according to claim 13, characterized in that R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar represents an aromatic group chosen from

in which Z is a CX ₅ group or a nitrogen atom, it being understood that for the same cycle, Z cannot take more than three times the meaning nitrogen, Y is a sulfur or oxygen atom or an NX ₅ group , n is 0, 1 or 2, Xj, X ₂ , X ₃ and X ₅ , identical or different, being chosen from a hydrogen atom, a halogen atom, or a carboxamide, trifluoromethyl, alkoxy, amino or acylamino.

15. Compounds according to claim 14, characterized in that R ₅ is a substituted indole-2-carbonyl or benzoyl group.

16. Compounds according to any one of claims 11 to 15, characterized in that R3 is a group

in L, D or L / D conformation, in which

. R ₉ is a group

- (CH ₂ ) n - ^^

wherein n is 1 and Xj is as defined in claim 1, and

. Rio is a hydrogen atom, alkyl or aralkyl.

17. Compounds according to claim 16, characterized in that Rio is a hydrogen atom.

18. Compounds according to any one of claims 11 to 17, characterized in that R ₂ and Ri ₂ represent a hydrogen atom.

19. Compounds according to any one of claims 11 to 18, characterized in that L is - (CH ₂ ) 3-.

20. Compounds according to any one of claims 11 to 19, characterized in that A is the group NH.

21. Compounds according to claim 11, characterized in that:

. R _t is a hydrogen atom,

. R ₅ is a group of formula -CO (CH ₂ ) _q Ar in which q is 0, 1 or 2 and Ar represents an aromatic group chosen from

in which Z is a CX ₅ group or a nitrogen atom, it being understood that for the same cycle, Z cannot take more than three times the meaning nitrogen, Y is a sulfur or oxygen atom or an NX ₅ group , n is 0, 1 or 2, X], X ₂ , X ₃ and X ₅ , identical or different, being chosen from a hydrogen atom, a halogen atom, or a carboxamide, trifluoromethyl, alkoxy, amino group or acylamino.

. R ₂ and R ₁₂ represent a hydrogen atom,

. R ₃ is a group

in L, D or L / D conformation, in which R ₉ is a group

wherein n is 1 and Xi is as defined in claim 1, and Rio is a hydrogen atom

. A is the NH group.

22. Composition comprising a compound of general formula (I) according to one of claims 11 to 21 and a pharmaceutically acceptable vehicle.

23. Process for the preparation of a compound according to one of claims 11 to 21, comprising the chemical transformation of a starting compound chosen from N ^α -tert-

Butyloxycarbonyl-N ^ω -Nitro-L-Arginine 1, N ^α -tert butyloxycarbonyl- L- Arginine 5, la

N ^{α, ω} -bis-Benzyloxycarbonyl-L-Ornithine 8, N ^α -tert-Butyloxycarbonyl-N ^α -Methyl- N ^ω ' ^ω3 -bis-Benzyloxycarbonyl- L-Arginine 15 and N ^α -tert-Butoxy-3-Nitro-L- Phenylglycine 19.

24. Use of a compound chosen from

N ^α -Phenylacetyl-L-Arg-L-Phe-NH ₂ acetate

N ^α -Benzoyl-L-Arg-Tic-NH ₂ acetate

N ^α -Benzoyl-L-Arg-Atc-NH2 acetate

N ^α -Adamantan-l-yl-L-Arg-L-Phe-NH2 acetate

N ^α -Benzoyl-L-Arg-D-Phe-NH ₂ acetate

N ^α acetate -Cyclohexoyl-L-Arg-L-Phe-NH ₂

N ^α acetate -Acetyl-L-Arg-L-Phe-NH ₂

N ^α -Pivaloyl-L-Arg-L-Leu-NH ₂ acetate

N ^α -Pivaloyl-L-Arg-OMe-L-Tyr-NH ₂ acetate

N ^α acetate -Pivaloyl-L-Arg -L-Tyr-NH ₂

N ^α -Pivaloyl-L-Arg -L-Tφ-NH ₂ acetate

N ^α hydrochloride - [(1H) -Indole-2-carbonyl] -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (4-chloro-Benzoyl) -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (4-chloro-Benzoyl) -L-Arg-D-Phe-NH ₂

N ^α hydrochloride - (3-chloro-Benzoyl) -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (3-chloro-Benzoyl) -L-Arg-D -Phe-NH ₂

N ^α hydrochloride - (3,4-dichloro-Benzoyι) -L-Arg-DL-Phe-NH

N ^α hydrochloride - (2-chloro-Benzoyl) -L-Arg-D, L-Phe-NH ₂

N ^α hydrochloride - (4-methyl-Benzoyl) -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (4-methoxy-Benzoyl) -L-Arg-L-Phe-NH ₂

N ^α hydrochloride - (4-nitro-Benzoyl) -L-Arg-D, L-Phe-NH ₂

N ^α sulfonate -Benzenesulfonyl-L-Arg-L-Phe-NH ₂

N ^α hydrochloride -Benzoyl-N ^ω -Me-L-Arg-L-Phe-NH ₂

Hydrochloride N ^α -benzoyl-L-Ora-L-Phe-NH ₂

N ^α - Benzoyl-N ^m -thiouréido-L-Nor-Val-L-Phe-NH ₂

N ^α -Benzoyl-N ^α -Me-L-Arg-L-Phe-NH ₂ hydrochloride

N ^α -Benzoyl-3-guanidino-N-Phenethyl-L-phenyl-Gly-NH ₂ acetate

N ^α trifluoroacetate - (4-acetylaminobutanoyl) -L-Arginine-N- phenethylamide

N- (3-bromo-benzoyl) -L-arginine-N-phenethylamide trifluoroacetate

N- (quinoline-3-carbonyl) -L-arginine-N- phenethylamide trifluoroacetate

N ^α trifluoroacetate - [(1H) -Indole-2-carbonyl] -L-Arg-D-Phe-NH ₂

Trifluoroacetate of N ^α diphenylacetyl N ^γ benzyl (D, L) -Arginine-N- benzylamide

N ^α diphenylacetyl ⁷ methyl trifluoroacetate (D, L) -Arginine-N- benzylamide

N ^α benzoyl N ⁷ methyl trifluoroacetate (D, L) -Arginine-N- benzylamide

N ^α -Benzoyl L-Arginine-L-Phe-NH ₂ hydrochloride for the preparation of a pharmaceutical composition intended to inhibit hyperalgia induced by opioid analgesic compounds.