MX2008005303A - Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors - Google Patents

Abstract

The invention relates to novel compounds of formula (I):H2N-CH(R1)-CH2-S-S- CH2-CH(R2)-CONH-R5, wherein R1is a hydrocarbon chain, phenyl or benzyl radical, methylene radical substituted by a 5 or 6 atom heterocycle;R2is a phenyl or benzyl radical, a 5 or 6 atom aromatic heterocycle, methylene group substituted by a 5 or 6 atom heterocycle;R5is a CH(R3)-COOR4radical, wherein R3is hydrogen, an OH or OR group, a saturated hydrocarbon group, a phenyl or benzyl radical and OR4is hydrophile ester, or 5 or 6 membered heterocycle comprising several heteroatoms selected from a group consisting of nitrogen, sulphur and oxygen, with at least two nitrogene atoms, wherein said heterocycle is substitutable by an alkyl C1-C6, phenyl or benzyl radical. The use of the inventive compounds in the form of drugs, a pharmaceutical composition comprising said compounds, a pharmaceutically acceptable excipient, the use in conjunction of at least one type of cannabinoid derivative for potentiating the analgesic and antidepressant effect of the novel compounds of formula (I) and/or morphine or the derivatives thereof are also disclosed.

Description

DERIVATIVES OF AMINO ACIDS CONTAINING A GROUP BISULFANILO IN THE FORM OF BISULFANILO INHIBITORS AND AMINOPEPTIDASA N MIXED DESCRIPTIVE MEMORY The invention relates to novel mixed inhibitors of neprilysin and aminopeptidase N. It is known that natural opioid peptides or enkephalins - (Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu) - are degraded mainly by two zinc metallopeptidases, neprilysin (EC 3.4.24.11) which dissociates the Gly3-Phe4 bond (Nature 276 (1978) 523) and aminopeptidase N (EC 3.4.11.2) which cleaves the Tyr1-Gly2 bond of these peptides (Eur.J .Farmacol 117 (1985) 233, reviewed in Pharmacological review., 1993, 45, 87-146). The mixed inhibitors of these two enzymes are known, by completely protecting the endogenous enkephalins from enzymatic degradation, they reveal the pharmacological activities, in particular analgesic and antidepressant activities, of enkephalins. The mixed inhibitors, described in the prior art, of these two enzymatic activities are compounds with a hydroxamate function (FR 2 518 088 and FR 2 605 004), aminophosphinic compounds (FR 2 755 135 and FR 2 777 780) and amino acid derivatives (FR 2 651 229). The compounds disclosed in these patent applications exhibit excellent in vitro and in vivo activity after administration by route intracerebroventricular; this was particularly demonstrated in the case of the hydroxamates (Eur. J. Pharmacol., 102, (1984), 525-528; Eur.J. Pharmacol., 165, (1989), 199-207; Eur.J. Pharmacol , 192, (1991), 253-262), for which significant activity could also be demonstrated after intravenous (IV) administration in a rat arthritis model (Brain Research, 497, (1989), 94-101) . In the case of phosphine derivatives and amino acid derivatives, a good activity was demonstrated in vivo after administration by IV route when the molecules studied were solubilized in a mixture of oil, ethanol and water (J. Med. Chem., 43 , (2000), 1398-1408; J.Med Chem., 44, (2001), 3523-3530; J.Pharm.Exp.Ther., 261, (1992), 181-190). However, even if one of the compounds belonging to the series of amino acid derivatives proved to be relatively soluble in water (Pain, 73, (1997), 383-391), none of the previously disclosed molecules exhibit solubility in an aqueous phase. and sufficient bioavailability to be administered orally and provide advantageous analgesic responses at sufficiently low doses in animals to adapt to man. Similarly, none of the previously cited molecules allows intravenous administration because in animal tests they require solubilization in mixtures incompatible with administration by this route in man. One of the objects of the invention is to provide novel water-soluble compounds capable of jointly inhibiting the two enzymatic activities responsible for the degradation of enkephalins and to manifest its pharmacological properties after dissolution in an aqueous solvent and intravenous, subcutaneous, percutaneous, intrathecal or intra-articular injection and by oral or nasal route. It is generally understood that the hemtaoencephalic barrier is more easily crossed by hydrophobic and non-polar molecules. However, unexpectedly, the hydrophilic molecules that have been synthesized exhibit powerful responses in central tests indicating the existence of a good capacity to reach the brain structures by numerous routes of administration (except for the local route). Another object of the invention is to provide novel compounds that exhibit the properties of morphine substances, in particular analgesia, beneficial effects on behavior (reduction in the emotional component of pain and antidepressant responses) and peripheral effects (antidiarrheal, antitussive, anti-inflammatory). without its main disadvantages (tolerance, physical and psychological dependence), respiratory depression, constipation, nausea). Moreover, inflammatory and neurogenic pain, whose peripheral component is significant, are reduced or even eliminated by the compounds according to the invention, administered by oral route and then without said compounds being restricted from reaching the central nervous system. This result, highly advantageous but unexpected, was formally demonstrated by the use of an antagonist unable to enter the brain. This completely reduces all the effects due to the stimulation of the cerebral opioid receptors by the compounds according to the invention, without altering the analgesic effects of the compounds in these types of pain, in particular neurogenic pain. More remarkably, the invention relates to compounds of the following formula (I): H2N-CH (R?) -CH2-SS-CH2-CH (R2) -CONH-R5 Where: R1 represents: - A hydrocarbon chain , saturated or unsaturated, linear or branched, comprising from 1 to 6 carbon atoms, optionally substituted by: * An OR, SR or S (0) R radical, wherein in each of these radicals R represents a hydrogen, a straight or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl or benzyl radical, * A phenyl or benzyl radical, - A phenyl or benzyl radical optionally substituted by: * 1 to 5 halogens, notably fluorine, * an OR radical , SR or S (0) R, wherein each of these radicals R is as defined above, - a methylene radical substituted by a 5- or 6-atom, aromatic or saturated heterocycle, having one atom as a hetero atom of nitrogen or sulfur, optionally oxidized in the form of N oxide or S oxide; R2 represents: - A phenyl or benzyl radical, optionally substituted by: * 1 to 5 halogen atoms, notably fluorine, * an OR or SR radical, wherein each of these radicals R is as defined above, * an optionally mono- or di- substituted by an aliphatic, cyclic or linear group of 1 to 6 carbon atoms, * an aromatic ring of 5- or 6- atoms, - a heterocycle of 5- or 6- atoms, the heteroatom is oxygen, nitrogen or sulfur, - a methylene group substituted by a 5- or 6-atom heterocycle, aromatic or saturated, the heteroatom is oxygen, nitrogen or sulfur, the nitrogen and sulfur atoms possibly oxidized in the form of N-oxide or S. R 5 represents: a) a radical CH (R 3) -COOR 4 wherein R 3 represents: - hydrogen, - an OH or OR group, with R as defined above, - a straight or branched saturated hydrocarbon chain (alkyl) , which comprises from 1 to 6 carbon atoms, optionally substituted by an OR or S radical R, wherein in each of these radicals R is as defined above, - a phenyl or benzyl radical, optionally substituted by: * 1 to 5 halogens, notably fluorine, * an OR or SR radical, with R as defined above. Y OR represents - an OCH2COOR'-glycolate radical or OCH (CH3) COOR'-lactate, wherein each of these radicals R 'represents * a chain of saturated hydrocarbon (alkyl) with 1 to 6 carbon atoms, linear or branched and optionally substituted by a C1 to C3 alkoxy group, preferably a C1-C4 alkyl group optionally substituted by a methoxy group, * a C5-C8 cycloalkyl group, preferably a C5-C6 cycloalkyl group, * a phenyl, benzyl, heteroaryl group, alkylheteroaryl, - a group OCH (R ") 0 (CO) OR 'or OCH (R") 0 (CO) R', wherein in each of these radicals R 'is as defined above and R "represents * a hydrogen atom, * a linear or branched C 1 -C 6 alkyl chain, optionally substituted by a C 1 -C 3 alkoxy group, preferably a C 1 -C 4 alkyl group optionally substituted by a methoxy group, * a C 5 cycloalkyl group -C8, preferably a C5-C6 cycloalkyl group, * a phenyl, benzyl, heteroaryl, alkyl group heteroaryl, - a triglyceride radical OCH (CH2OCOR ') 2 or OCH2-CH (OCOR') - CH2OCOR ', wherein in each of these radicals R' is as defined above, - a glycoside radical such as D-glucose, β- D-glucopyranose, α- or β-galactopyranose, - a sulfonate radical OCH 2 CH 2 (S 0 2) CH 3, - a radical OCH (CH 2 OH) 2; b) a 5- or 6- bond heterocycle comprising numerous heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, of which 2 atoms are nitrogen, said heterocycle possibly being substituted by a C 1 -C 6 alkyl, phenyl radical or benzyl; as well as the addition salts of the aforementioned compounds (I) with pharmaceutically acceptable mineral or organic acids. The invention also has as an object the acquisition salts of the compounds of the formula (I), obtained with pharmacologically acceptable organic or mineral acids such as phosphates, hydrochloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate and nicotinate. Within the general framework of the present invention, the expression "hydrocarbon chains" refers to alkanes, alkenes or alkynes.

Notably, the term "saturated hydrocarbon chains" designates alkyl radicals comprising from 1 to 6 carbon atoms (C1-C6) or from 1 to 4 carbon atoms (C1-C4), linear or branched. Examples of alkyl radicals comprising 1 to 4 carbon atoms include methyl, ethyl, propyl, butyl, sopropyl, 1-methyl-ethyl, 1-methyl-propyl and 2-methyl-propyl radicals. Examples of alkyl radicals comprising 1 to 6 carbon atoms further include pentyl, hexyl, 1-7-methyl-butyl, 1-methyl-pentyl, 2-methyl-butyl, 2-methyl-pentyl, 3-methyl-butyl, methyl-pentyl, 4-methyl-pentyl or 1-ethyl-propyl, 1-ethy-butyl and 2-ethyl-butyl. The term "unsaturated hydrocarbon chains" designates alkenyl radicals (at least one double bond), for example vinyl, allyl or the like, or alkynyl (at least one triple bond) comprising from 2 to 6 carbon atoms, or to 4 carbon atoms, linear or branched. The term "halogen" used herein designates chlorine, bromine, iodine or fluorine. As a non-limiting example of heterocyclic nuclei with 5 or 6 atoms, aromatic or saturated, having as a heteroatom a nitrogen or sulfur atom, the following radicals may be mentioned: thienyl, pyrrolyl, imidazole, pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, pipehdyl, piperazinyl, thiadiazolyl, the nitrogen and sulfur atoms optionally are oxidized in the form of N oxide or S oxide.

As a non-limiting example of heterocyclic nuclei with 5 or 6 atoms, aromatic or saturated, having as one heteroatom an oxygen atom, the following radicals can be mentioned: furyl, pyranyl, isoxazolyl, morpholinyl, furazanyl, oxazolyl, oxazolidinyl and oxazolinyl. The radical R- \ advantageously represents an alkyl radical having from 1 to 4 carbon atoms, optionally substituted by an OR, SR or S (0) R radical, wherein in each of these radicals R is as defined above. R1 represents still more advantageously an alkyl radical having 1 to 4 carbon atoms substituted by an SR radical, with R as defined above, notably with R representing a straight or branched saturated hydrocarbon chain, with 1 to 4 carbon atoms. carbon. The radical R2 advantageously represents: - A benzyl or phenyl radical, - A methylene radical substituted by a 5- or 6-atom heterocycle, aromatic or saturated, having as a heteroatom a nitrogen or sulfur atom, optionally oxidized in the form of N oxide or S oxide. Remarkably, the radical R2 represents a benzyl radical or a methylene radical substituted by a 5- or 6- atom, aromatic or saturated heterocycle, having as a hetero atom a sulfur or nitrogen atom, optionally oxidized in the form of N-oxide or S-oxide, still more advantageously a benzyl radical or a methylene radical substituted by a thiophenyl radical (thienyl).

The radical R5 is a radical that increases the hydrophilic character of the complete molecule, which is usually rather a hydrophobic molecule. According to a first embodiment of the invention, the radical R5 represents a radical CH (R3) -COOR. In this first embodiment, the radical R3 advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, even more advantageously from 1 to 4 carbon atoms, optionally substituted by an OR or SR radical, wherein each of these radicals R is as defined above. The radical R3 even more advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, even more advantageously 1 to 4 carbon atoms, substituted by an OH or SH radical. The radical OR 4 advantageously represents: - an OCH 2 COOR 'glycolate radical, with R' as defined above (notably R 'represents a C 1 -C 4 alkyl group optionally substituted by a methoxy group or a C 5 -C 6 cycloalkyl group), - a radical OCH (R ") 0 (CO) OR' or OCH (R") 0 ( CO) R ', with R "and R" as defined above (notably R' and / or R "represent a C1-C4 alkyl group optionally substituted by a methoxy group or a C5-C6 cycloalkyl group or R" represents a hydrogen atom), - a triglyceride radical OCH (CH2OCOR ') 2 or OCH2-CH (OCOR') - CH2OCOR ', wherein in each of these radicals R' is as defined above, - a glycoside radical such as D-glucose, - a sulfonate radical OCH2CH2 (S02) CH3, - a radical OCH (CH2OH) 2. Notably, the radical OR4 represents a group OCH (R ") 0 (CO) OR 'or OCH (R") 0 (CO) R \ the radical R' represents a C1-C4 alkyl chain (notably an ethyl radical) and the radical R "represents a methyl radical, CH (CH3) 2, cyclohexyl or phenyl. According to a second embodiment of the invention, the radical R5 represents a heterocycle, of 5 or 6 bonds, comprising numerous heteroatoms, selected from the group comprising nitrogen, sulfur and oxygen, of which 2 atoms are nitrogen, said heterocycle is possibly substituted by an alkyl radical C1-C6 alkyl or a phenyl or benzyl radical. in this second embodiment, the heterocilco is advantageously a heterocycle 5 bonds comprising 2 nitrogen atoms, optionally substituted by a C 1 -C 4 alkyl chain, notably 2-ethyl-1, 3,4-thiadiazole The invention notably relates to the following compounds: 1- (2- (1- (2,3- diacetoxipropoxicarbonil) - ethylcarbamoyl) - 3- -thiophene 3-ilpropilbisulfanilmetil) -3-amino-metilsulfanilpropil, 1- (2- (1- (2-metanosulfoniletoxicarboníl) ethylcarbamoyl) -3-thiophen-3-¡lpropilbisulfanilmetil) -3-amino-metilsulfanilpropil, 1- (2- (1- (1-etoxicarboniloxietoxicarbonil)) - ethylcarbamoyl) -3-thiophen-3-yl-propilbisulfanilmetil) -3-metilsulfanilpropil- amino, 1- (2- (1-etoxicarbonilmetiloxicarboniletilcarbamoil) -3-thiophen-3-yl-propilbisulfanilmetil) -3-amino-metilsulfanilpropil, 1 - (2- (1 - (1 -etoxicarboniloxietoxicarbonil) -2-hydroxypropylcarbamoyl) - 3 - -thiophene 3- ilpropilbisulfanilmetil) - 3- etilsulfanilpropii- amino, 1- (2- (1- (2-acetoxy-1-acetoximetiletoxicarbonil) ethylcarbamoyl) -3-thiophen-3-ilpropilbisulfanilmetil) -3-amino-metilsulfanilpropil, 1- (2- (1- (2-hydroxy-1-hydroxymethyletoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1- (3, 4,5 , 6 - tetrahydroxytetrahydropyran-2-ylmethoxycarb onyl) ethylcarbamoyl) -3-thiophen-3-¡l-propilbisulfanilmetil) -3-amino-metilsulfanilpropil, 1- (2- (1- (1-ethoxycarbonyloxy-ethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3-fenilpropilbisulfanilmetil) - 3-methylsulfanylpropyl-amino, 1- (2- (1- (2-acetoxy-1-acetoxymethyl-ethoxycarbonyl) -2-hydroxypropylcarbamoyl) - 3- fenilpropilbisulfanilmetil) - 3- amino metilsulfanilpropil-, 1- (2 - ((1-ethoxycarbonyloxy-ethoxycarbonylmethyl) - carbamoyl) -3-phenyl-propilbisulfanilmetil) -3-amino-metilsulfanilpropil, 3- (2-amino-4-methylsulfanyl-butilbisulfanil) -2-benzyl-N- (5-ethyl- (1, 3,4) thiadiazole -2-yl) -prop¡onamida, 1- (2 - ((1-ethoxycarbonyloxy-2-methyl-propoxicarbonilmetil) carbamoyl) -3-phenyl-propilbisulfanilmetil) -3-methylsulfanyl-propyl-amino, 1- (2 - ((cyclohexyl-ethoxycarbonyloxy-methoxycarbonylmethyl) carbamoyl) -3-fen¡l-prop¡lbisulfanilmetil) -3-methylsulfanyl-propyl-amino, 1- (2 - ((ethoxycarbonyloxy-phenyl-methoxycarbonylmethyl) carbamoyl) -3 -phenyl-propilbisulfanilmetil) -3-methylsulfanyl-propyl-amino, 3-methylsulfanyl-1- (3-phenyl-2 - ((1-propionyloxy-ethoxycarbonylmethyl) -carbamoyl) -propilbisulfanilmetil) -propyl-amino, 1- (2 - ((2-methyl-1-propionyloxy-propoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-amino, 1- ( 2 - ((cyclohexyl-propionyloxy-methoxycarbonylmethyl) carbamoyl) -3-phenyl-propilbisulfanilmetil) -3-methylsulfanyl-propyl-amino, 3- methylsulfanyl- 1 - (3- phenyl- 2- ((phenyl- propioniloxi- methoxycarbonylmethyl) -carbamoyl) -propylbisulfanylmethyl) -propyl-amino. The compounds of formula (I) potentially have from 2 to 9 centers of asymmetry. The radicals R1 t R2 and R3 will be introduced in such a way to obtain optically pure chains corresponding to the stoichiometry recognized by the enzymatic activities. The radicals R4 optionally contain an unresolved center of asymmetry. The compounds of formula (I) are obtained: 1) By condensation of a beta-aminothiol protected in the amino function by a t-butyloxycarbonyl group (Boc) (II) with a mercaptoalkanoic acid (III) by means of methoxycarbonylsulfonyl chloride in solution in THF (tetrahydrofuran), leading to IV.

J SH + HS and,. ^ x ^ ^ S__S ' "iv iv Boc beta-aminothiol II is prepared from the corresponding commercial amino acid Boc of absolute configuration S with retention of the configuration according to a method well known to those skilled in the art (J. Med.Chem., 35, (1992 1259). Mercaptoalkanoic acid III is obtained from the corresponding methyl malonate monoester V, which, according to a method well known to those skilled in the art (Ber., 57, (1924), 1116) is transformed into acrylate VI Boc HN COOH Boc HN ^ OH Bo HN. ^ SCOCH? Boc HN SH II HOOC COOCH, ^^ COOCH, / \ "COOCH, COOH I _ T H .CCOS? H.CCOS R *« ":" V VI vil VIII The addition of thioacetic acid to acrylate VI leads to the racemic Vil derivative (Biochemistry, 16, (1977), 5484). Resolution by alpha-chymotrypsin isolates acetyl thioacid VIII optically pure (Bioorg, Med. Chem. Let, 3, (1993), 2681). The alkaline hydrolysis of the thioester leads to compound III. 2) The compounds of formula (I), wherein the radical R5 represents a radical CH (R3) -COOR4, can be obtained by the following synthetic trajectories. 2.1) The dissymmetric IV bisulfide is coupled, under conventional peptide coupling conditions, to the amino ester IX, leading to the protected X inhibitor.

IX According to an alternative method, the compounds X can be obtained by condensation, by means of a methoxycarbonyl sulfenyl chloride, of Boc-β-aminothiol II with a mercaptoacylamino ester of formula XI. The mercaptoaxylamino ester XI is prepared from compound III. It is oxidized by a solution of ethanolic iodide in bisulfide XII. Compound XII is coupled under conventional peptide coupling conditions with amino ester IX, leading to XIII. Treatment of XIII with a reducing agent such as the mixture of Zn + HCl 3 N releases compound XI.

XII XIII II XI The terminal Boc group in N of X is cut by the action of formic acid, releasing XIV. The XIV counter-ion is quantitatively changed by treatment with an equivalent of 0.1 M NaHCO 3, extraction in an organic medium (EtOAc) of the compound having a free amino function, then the addition of one equivalent of the organic or mineral acid selected for take to I. 2.2) The amino ester IX is obtained by condensation of Boc amino acid XII with alcohol R4OH, then deprotection by trifluoroacetic acid (TFA) and neutralization by soda. If the alcohol R OH is a primary alcohol, coupling with XII is carried out under conventional conditions (1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole hydrate (HOBt) or ester activated). If alcohol R OH is a secondary alcohol, the condensation is effected through a Mitsunobu reaction (Synthesis (1981) 1-28), using the diethyl azodicarboxylate / triphenyl phosphine mixture (DEAD / PPhe3). Boc H N. .COO H 4 O H BOÍ: H N.; O O R. R2 Alcohols R4OH are in most cases commercial compounds. When R4OH is an alcohol that leads to an ester "cascade", it is synthesized from the methods described in the literature. 2a) The compounds of formula (I), wherein the radical R5 represents a heterocycle radical as defined above, can be obtained by the following synthetic trajectories. 2.a.1) The dissymmetric IV bisulfide is coupled under conventional peptide coupling conditions with the amino heterocycle XV to carry XVI. The deprotection of the Boc group is carried out as in the foregoing, leading to the derivative XVII.

X I XVI I The amino heterocycle XV is synthesized according to the methods described in the literature. For example, 2-amino-5-ethyl- (1, 3,4) thiadiazole is obtained as described (Takatori et al., Yakugaku Zasshí 79.1959.913) by condensation of thiosemicarbazide XVIII and propionyl chloride XIX. . 2. a.2) According to an alternative method, the compounds of formula (1), wherein the radical R5 represents a heterocycle, can be obtained by the condensation of heterocycle XV in compound XII, leading to XX. After cutting the bisulfide bridge, as previously described, the obtained compound XXI is condensed in II to carry XVI.

The invention also has as an object the pharmaceutical compositions comprising as an active ingredient at least one compound of the general formula (I) or a salt thereof or hydrates of the salt thereof in combination with one or more inert pharmaceutically acceptable carriers or other vehicles. These compounds exhibit the properties of morphine substances, notably analgesia, including peripheral components (inflammatory, neurogenic), beneficial effects on behavior, notably in the case of depression and / or anxiety, without exhibiting their main disadvantages (tolerance, dependence, respiratory depression, constipation). Then, contrary to exogenous opioid agonists that interact with the delta receptors, the inventive mixed inhibitors have antidepressant effects without the risk of triggering epileptiform activity or seizures, and are of rapid action (Baamonde A. et al., 1992, Jutkiewicz EM et al., 2005). These compounds can pass the blood-brain barrier. The main application of the compounds according to the invention is then in the field of analgesia, antidepressants and anxiolytics. The inventive pharmaceutical compositions can be, for example, compositions administered orally, nasally (administration by aerosols) sublingual (administration by perlingual diffusion), rectal, parenteral, intravenous and percutaneous. Examples of compositions administered by the oral route include tablets, gelatin capsules, granules, microspheres, powders and oral solutions or suspensions. The radical R5 confers sufficient hydrophilicity in the compounds according to the invention, which are then soluble in water and hydrophilic solvents in the presence of the absence of various surfactants. Notably, they are soluble in alcohol / polysorbate / water solvents, notably in ethanol / Tween® / water and mannitol / water or with the aid of cyclodextrins suitable for administration in man, which are frequently used for intravenous administration. The compositions according to the invention can then be administered by the intravenous route. They can also be administered orally or nasally, notably through an aerosol or by perlingual diffusion or within a suitable galenic preparation (microemulsions). Similarly, these compositions can be used for transdermal administration. These compositions can be used remarkably as major analgesics, potent analgesics for inflammatory and neurogenic pain, and as antidepressants. It is very advantageous that the compositions according to the invention can be administered in any of the form of aerosols (microemulsions) by oral or nasal route or by intravenous route. These administration routes then allow the administration of the inventive composition by a non-digestive route. This is particularly advantageous when the composition comprises complementary compounds, which may exhibit undesired effects on the digestive system (notably the intestines), such as, for example, cannabinoid derivatives. It also increases the cerebral bioavailability of the compounds or combinations.

Another object of the invention is the use as a drug of the compounds as defined above or obtained by a method as defined above. Surprisingly, it was also noted that the combination of the novel compounds according to the present invention with the cannabinoid derivatives leads to even stronger analgesic effects (higher than the sum of each effect observed for each compound, ie for the compounds according to the invention). with the invention or the cannabinoid derivatives). Until 1954, hemp was considered a medicinal plant that exhibits multiple properties: analgesic, antispasmodic, anticonvulsant, anti-inflammatory, antivomitive, bronchodilator, vasodilator, relaxing and soporific. Recently, the antiproliferative and antineurodegenerative properties have been demonstrated. Numerous harmful effects of hemp have been described, usually related to overdose: anxiety attacks for depressive patients and hallucinations when the product is consumed in beverages (tea) or food (cakes). The effects of hemp are explained by its action on cannabinoid receptors. These receptors are present in many brain structures and an endogenous molecule naturally related to them, anandamide, has been identified.

Two types of receptors have been characterized: the CB1 receptors found in both the central and peripheral nervous systems and the CB2 receptors that are mainly peripheral. CB1 receptors seem involved in the modulation of the neuronal release of neurotransmitters of excitation or inhibition in the brain. The function of the CB2 receptors is less clear, but it seems that they intervene in the modulation of the immune system. Endogenous molecules related to CB1 and CB2 receptors, called "endocannabinoids", such as anandamide, interact with cannabinoid receptors in the brain and in the periphery by inducing various pharmacological effects. The most abundant psychotropic compound present in hemp (Cannabis sativa) is? 9 tetrahydrocannabinol (? 9 THC). The? 9 THC induces numerous pharmacological responses such as analgesia, hypothermia, reduced locomotor activity and a loss of alertness and attention due to interactions with CB1 receptors in the brain. Some of these properties have advantageous therapeutic applications for the treatment of pain and glaucoma, as well as to attenuate nausea and to stimulate the appetite of patients treated with antitumor and antiviral compounds that have severe side effects. The? 9 THC, and more generally the CB1 receptor agonists, are also capable of reducing the painful effects associated with multiple sclerosis while reducing the progress of the disease. However, this leads to the development of SATIVEX, which is a preparation that comes directly from the plant (Cannabis sativa) and that contains a mixture in equal parts of? 9 THC and cannabidiol (another substance present in the plant). This preparation is currently at the end of the clinical trials. However, the doses administered by the orobucal route are high and side effects have been observed (Current Opinion in Investigational Drugs 2004, 5, 748). Another characteristic of the endocannabinoid endogenous system (anandamide) refers to the mode of synthesis and secretion of this specific neurotransmitter. Formed by enzymatic pathway from phospholipids of the organelle membrane, anandamide is secreted by a transporter from a post-synaptic neuron to interact with CB1 receptors located in a presynaptic terminal (retrograde neurotransmission) (Piomelli et al., TIS, 2000, 21, 218-224). However, numerous behavioral effects, such as a loss of consciousness and attention, sedation, ataxia, problems with vision, tachycardia, hypothermia and behavioral disturbances such as hallucinations, anxiety, panic attacks and memory problems, produced by chronic exposure to natural or synthetic cannabinoids, limit their clinical use (reviewed in EA Carlini, The good and the bad effects of (-) trans-delta-9-tetrahydrocannabinol? 9THC on humans, Toxicon, 2004, 44, 461 -467). Moreover, in man, the analgesic effects of? 9 THC are obtained at high doses close to the quantities that cause the adverse effects mentioned above (Campbell F.A. et al., Are cannabinoids an effective and safe treatment option in management of pain? A quantitative systemic review, Br.Med.J., 2001, 323, 12-16). Surprisingly, it has been noted that the coadministration (simultaneous or with time) of low doses of cannabinoid derivatives (notably? 9 THC) enhances the analgesic effect and the antidepressant effect of the derivatives according to the invention (formula (I)) without significantly inducing harmful effects of said cannabinoids, which by IV route seem to start at 4-5 mg / kg (sedation). In the present invention, the expression "very low concentrations of cannabinoids" means concentrations of cannabinoids below those that induce such undesirable side effects. In the present invention, the expression "cannabinoid" means? 9 THC, synthetic agonists of the CB1 receptor or inhibitors of anandamide degradation. The cannabinoids introduced into the compositions according to the invention are preferably? 9 THC. The invention also has as an object a pharmaceutical composition comprising at least one compound of formula (I) as defined above, at least one cannabinoid derivative, notably? 9 THC, or a protector of its metabolism (reviewed in Piomelli et al. al., TIPS, 2000), and a pharmaceutically suitable excipient, in particular a suitable excipient for administration by oral, nasal, intravenous or transcutaneous route.

The invention also relates to the use of at least one cannabinoid derivative, in particular? 9 THC, in a pharmaceutical composition for enhancing the analgesic and / or antidepressant effect of the compounds of formula (I) as defined above. The invention also relates to the use of a combination of at least one compound of formula (I) as defined above and at least one cannabinoid derivative, in particular? 9 THC, for the preparation of a drug designed for the treatment of depression and pain. Another object of the invention is a pharmaceutical composition comprising: i) at least one compound of formula (I) as defined above, ii) at least one cannabinoid derivative as combination products for simultaneous, separate or staged use. Similarly, the invention also has as an object the use of a pharmaceutical composition comprising i) at least one compound of formula (I) as defined above, ii) at least one cannabinoid derivative as combination products for use simultaneous, separate or in stages, for the manufacture of a drug to treat depression and pain.

Within the general framework of the present invention, the term "pain" means the various types of pain, such as acute pain, inflammatory pain and neurogenic pain, including pain associated with multiple sclerosis. The compounds according to the invention, optionally in combination with a cannabinoid derivative, are also suitable for the treatment of glaucoma. The invention also has as an object the combination of the novel compounds according to the invention with morphine or a derivative thereof. Actually, morphine is also capable of enhancing the analgesic effect introduced by the compounds according to the invention. The invention then has as a subject a pharmaceutical composition comprising at least one compound of formula (I) as defined above, of morphine or a derivative thereof and a pharmaceutically acceptable excipient, notably a suitable excipient for administration by route oral, nasal, intravenous or transcutaneous. The composition may additionally comprise at least one cannabinoid derivative, notably? 9 THC, or a protector of its metabolism. This composition can be used as a drug, notably in the treatment of depression and pain. The various compounds can be used as combination products in a simultaneous, separate or staged manner.

It is the good solubility in water of the compounds of the invention of formula I that greatly facilitates the constitution of the preparation (microemulsions, in solution in the presence of surfactants, etc.) suitable for therapeutic use by intravenous, nasal, pulmonary routes ( spray) or transcutaneous. The effective dose of the inventive compounds varies according to a number of parameters, such as, for example, the selected administration route; the weight, age and sex of the patient; the stage of the pathology to be treated; and the sensitivity of the patient. Consequently, the optimal dosage will be determined, according to the parameters considered relevant, by the relevant specialist. The invention will be further illustrated, without limiting it in any way, in the following examples. The list of compounds prepared according to example 12 is given in table 1. For all the compounds disclosed in those examples: Ri represents the radical -CH2-CH2-S-CH3, -CH2- (C: CH.S. .CH: CH) represents the radical thiophen-3-ylmethyl-C: CH.CH: CH-CH: CH represents the phenyl radical, - CeHn represents the cyclohexyl radical.

TABLE 1 Radicals for examples 12a-12r Headings of the drawings Figure 1: Dosage / response curve of morphine-induced analgesia or compound 15 injected by IV route in mice (hot plate test, 52 ° C); X axis: dose in mg / kg, axis Y% analgesia.

The black line (upper) corresponds to the results obtained for morphine, the gray line (lower) corresponds to the results obtained for compound 15. Figure 2A and Figure 2B: Figure 2A) Antinociceptive response induced by the compound injected per os 20 min before the hot plate test (52 ° C, jump latency, seconds) in male OF1 mice (n = 10); X axis: dose of compound 15 in mg / kg, axis Y% of analgesia. Figure 2B) Kinetics of the effect of compound 15 after the administration pair (n = 10-17); X axis: time (minutes), Y axis% analgesia. Figure 3: Antinociceptive response induced by the combination of compound 15 and? 9-tetrahydrocannabinol. Hot plate (52 + 1 ° C), jump latency, male OF1 mice. Unleashed 240 sec. *** p < 0.001 against control, ### p < 0.001 against compound 15 and? 9-THC. ANOVA + Newman-Keuls. X axis: dose of compound 15 (0.4 mg / kg), THC (0.375 mg / kg) and compounds 15 / THC (0.4 and 0.38 mg / kg), Y axis:% analgesia.

EXAMPLE 1 Synthesis of Boc-methioninatiol (compound 1) This compound was prepared following the protocol described in J.Med. Chem., 35, 1992, 2473. White solid: mp: 37 ° C; Rf (Cyclohexane (CHex), ethyl acetate (AcOEt) = 1.1) 0.73; aD20 ° c: -21.1 o (c = 1.0 CHCI3).

EXAMPLE 2 Synthesis of (2S) -2-mercaptomethyl-3-phenyl propanoic acid Stage 1: The methyl ester of 2-acetylthiomethyl-3-phenylpropanoic acid, obtained by the reaction of thioacetic acid in the methyl ester of the corresponding acrylate, prepared according to (Ber., 57, 1924, 116), was treated with α-chymotrypsin according to the general protocol described in (Bioor.Med Chem. Let., 3, 1993, 2681). Yield: 71.4%; Enantiomeric excess (ee): 88%, aD20 C: -42.70 Step 2: (2S) -mercaptomethyl-3-phenylpropanoic acid. The compound from step 1 was dissolved in degassed methanol at 0 ° C (MeOH).

Under an inert atmosphere, 3 equivalents (eq) of 1N sodium hydroxide were added.

(NaOH). The mixture was stirred 30 min at room temperature (RT). The mixture was acidified by adding 6 N hydrochloric acid (HCl) (25 ml) and the MeOH was evaporated under reduced pressure. The aqueous phase was extracted by 2 * 125 ml of AcOEt. The organic phase was washed with a saturated solution of sodium chloride (NaCl sat.) Then dried over sodium sulfate (Na2SO4) and evaporated to dryness. A yellow oil was obtained. 100% performance Kromasil C18 HPLC CH3CN / H20 (0.5% TFA trifluoroacetate) 60-40 4.96 min.

EXAMPLE 3 Synthesis of (2RS) 2-mercaptomethyl-3-thiophen-3-ylpropanoic acid (compound 3) Stage 1: A mixture of dimethylmalonate (392 mmol, 45 ml, 1 eq), thiophen-3-yl aldehyde (0.357 mmol), piperidine (1.87 ml, 0.05 eq) and benzoic acid (4.58 g, 0.05 eq) was heated to reflux 12 h, using a Dean-Stark apparatus, in 270 ml of toluene. The organic phase was washed with 2 * 140 ml of 1 N HCl, 2 * 140 ml of 10% sodium carbonate (NaHCO3) and 140 ml of saturated NaCl. The organic phase was dried over Na 2 SO 4 and evaporated to dryness. An oil was obtained. 100% performance Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 60-40: 5.97 min.

Step 2: The compound from step 1 (340 mmol) was solubilized in MeOH (540 ml). The mixture was cooled to 0 ° C and borohydride from sodium (NaBH) little by little. The mixture was stirred 15 min at room temperature. The reaction was quenched by adding 450 ml of 1 N HCl. The methanol was evaporated and the reaction mixture was extracted with 2 * 500 ml of chloroform (CHCl3). The organic phase was washed with sat. NaCl. then it was dried on Na2SO4 and evaporated to dryness. An oil was obtained. Weight = 64.1 g. Performance 82.4%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 60-40: 5.91 min.

Step 3: The above compound (30 mmol) was dissolved in MeOH (27 mL). The mixture was cooled to 0 ° C and a solution of potassium KOH (1.71 g 30.6 mmol) in MeOH (365 ml) was added little by little. The mixture was stirred 48 h at 4 ° C. The methanol was evaporated and the solid obtained was triturated in ethyl ether Et20. The solid obtained was filtered, washed and dried. W = 25.2 g. Yield 71.0%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 60-40: 3.79 min.

Step 4: The above compound (21.9 mmol) was dissolved in THF (30 mL). Diethylamine Et 2 NH (3.0 ml, 2 eq) and 37% formaldehyde (3.7 ml, 1.5 eq) were added. The mixture was heated to reflux overnight. THF was evaporated and the mixture was taken in 90 ml of AcOEt. The organic phase was washed with 3? 30 ml of 1 N HCl, sat. NaCl. it was then dried in Na 2 SO and evaporated to dryness. A colorless oil was obtained. W = 13.1 g. Yield 72.0%.

Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50: 14.75 min.

Step 5: The above compound (72 mmol) was brought to 80 ° C for 5 h in thioacetic acid CH3COSH (10 mL, 144 mmol, 2 eq). The thioacetic acid was evaporated under reduced pressure. The mixture was coevaporated numerous times with cyclohexane. An orange oil was obtained. W = 18.6 g. 100% performance Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50: 17.16 min.

Step 6: The compound from step 5 was dissolved in degassed MeOH at 0 ° C. under an inert atmosphere, 3 eq of 1 N NaOH was added. The mixture was stirred 30 min at RT. The mixture was acidified by adding 6 N HCl (25 mL) and the MeOH was evaporated under reduced pressure. The aqueous phase was extracted with 2 * 125 ml of AcOEt. The organic phase was washed with sat. NaCl. then it was dried on Na2SO4 and evaporated to dryness. A yellow oil was obtained. 100% performance Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50 6.80 min.

EXAMPLE 4 Synthesis of (2S) -2-mercaptomethyl-3-thiophen-3-α-propanoic acid (compound 4) Step 1: The methyl ester of 2-acetylthiomethyl-3-thiophen-3-ylpropanoic acid, described in step 5 of the synthesis of compound 3, was treated with a-chymotrypsin, as described in the synthesis of 2 (step 1 ). Performance 87.3%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50 7.37 min. ee = 76%.

Step 2: The (2S) acetylthiomethyl-3-thiophen-3-ylpropanoic acid, obtained in step 1, was treated as described in step 2 of compound 2. Yield 97.0%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50 6.80 min.

EXAMPLE 5 Synthesis of 2- (2S) -benzyl-3- ((2S) 2-t-butyloxycarbonylamino-4-methylsulfanyl-butylbisulfani-propanoic acid (compound 5) A mixture of 23 ml of MeOH and 23 ml of THF was cooled to 0 ° C under nitrogen and chlorosulfonylchloride (1.3 ml, 15.25 mmol, 1.09 eq) was added. The mixture was stirred 15 min at 0 ° C to give methoxy carbonylsulfenyl chloride. Then, all compound 1 (14.86 mmoles, 1.06 eq) in 16 ml of THF / MeOH. The mixture was returned to room temperature and stirred 30 min. The above solution was added dropwise to a solution of compound 2 (14.02 mmol, 1 eq) in 100 ml of CHCl3 degassed in the presence of Et3N (1 eq). The solution was stirred 1 h at room temperature. The solvent was evaporated under reduced pressure. The mixture was taken in dichloromethane CH2Cl2. The organic phase was washed: 10% citric acid, NaCl sat., Then dried over Na2SO4 to give a crude product, which was chromatographed on silica with a cyclohexane (CHex mixture) / AcOEt 8/2 then 6/4 as eluent . W = 4, 1 g. Yield: 65.9%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 70-30: 8.20 min.

EXAMPLE 6 Synthesis of 3 - ((2S) 2-t.butyloxycarbonylamino- -methylsulfanyl-butylbisulfanyl) - (2RS) 2-thiophen-3-ylmethyl-propanoic acid (compound 6) Following the protocol described for the synthesis of 5 and replacing compound 2 with compound 3, compound 6 was obtained. Yield: 77.0%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 70-30: 7.36 min.

EXAMPLE 7 Synthesis of 3 - ((2S) 2-t.butyloxycarbonylamino-4-methylsulfanyl-butylbisulfanyl) - (2S) 2-thiophen-3-ylmethyl-propanoic acid (compound 7) Following the protocol described for the synthesis of 5 and replacing compound 2 with compound 4, compound 7 was obtained. Yield 77% Kromasil C18 HPLC CH3CN / H20 (0 5% TFA) 70/30: 7.36 min EXAMPLE 8 Synthesis of alanine esters Compound 8a 2-methylene sulphonylethyl alanine ester, TFA A solution of 1 eq of BocAlaOH, HOBt (1.2 eq, 879 mg), EDCI (1 2 eq, 1 93 g), Et3N (tetylamine) (3 eq , 2.9 ml) in 10 mL of CH2Cl2 was stirred 12 h at room temperature in the presence of 1.2 eq of 2-methylsulfonylethanol in CH 2 Cl 2 solution The solvent was evaporated under reduced pressure. The reaction mixture was taken in AcOEt / H20 The organic phase was washed with 10% citric acid (2 * 15 mL), 10% NaHCO3 (2x15 mL), saturated NaCl, dried in Na2SO4 and evaporated under reduced pressure to give a crude product which was chromatographed on silica with a mixture of CHex / AcOEt 8/2 as eluent to give 989 mg of product Yield 61 8% Rf (CHex / AcOEt 6/4) 0 49 435 mg (1488 mmoles) of this product were cold solubilized in 2.5 ml of CH2Cl2 and 1.2 ml of TFA was added. The mixture was stirred 2 h at room temperature. The solvents were evaporated under reduced pressure.

The mixture was coevaporated with cyclohexane. The product 8a was cold precipitated in Et20. Performance: 100%. Rf (CH2Cl2 / MeOH: 9/1): 0.25.

Compound 8b: 2,3-diacetoxypropyl alanine ester A solution of 1026 g (5,428 mmoles, 1 eq) of BocAlaOH, HOBt (1.2 eq, 879 mg), EDCI (1.2 eq, 1.93 g), 25 Et3N (3 eq, 2.9 ml) in 10 ml of CH 2 Cl 2 were stirred 12 h at room temperature in the presence of 2,3-diacetoxypropanol (prepared according to Jensen, Topics in Lipid Chemistry, 1972, 3, 1) in CH 2 Cl 2. The solvent was evaporated under reduced pressure. The reaction mixture was taken in AcOEt / H20. The organic phase was washed with 10% citric acid (2x15 ml), 10% NaHCO 3 (2x15 ml), saturated NaCl, dried over Na 2 SO and evaporated under reduced pressure to give 1.62 g of a crude product. The mixture was chromatographed on silica with a mixture of CHex / AcOEt 8/2 as eluent to give 1.29 g of product. Performance: 68.7%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 70-30: 4.25 min. This product was cold solubilized in 6 ml of CH2Cl2 and 6 ml of TFA was added. The mixture was stirred 2 h at room temperature. The solvents were evaporated under reduced pressure. The mixture was coevaporated with cyclohexane. The product 8b was cold precipitated in Et20. W = 1.33g. Performance: 100%. Rf (CHex, EtOAc: 6.4): 0.14.

Compound 8c: 1,3-diacetoxy-2-propyl alanine ester, TFA 1.23 g of 1,3-diacetyl-2-propanol (prepared in accordance with Bentley and McCrae, J. Org. Chem., 1971, 35, 15 2082) (7 mmoles, 1.1 eq) were solubilized in 50 ml of Et20. Then, diethyl azodicarboxylate (DEAD) (1.2 eq, 1.1 ml), BocAlanine (5.83 mmol, 1 eq) was added followed by triphenylphosphine (PPh3) (1.2 eq, 1.83 g) and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The mixture was chromatographed on silica with a Heptane / AcOEt 8/2 mixture as eluent to give 2.14 g of product. Performance: 84.6%. Rf (Hept / AcOEt: 6/4): 0.42. 2.0 g (4.7 mmoles) of this product were cold solubilized in 6.5 ml of CH2CI2 and 6.5 ml of TFA was added. The mixture was stirred 2 h at room temperature. The solvents were evaporated under reduced pressure. The mixture was coevaporated with cyclohexane and chromatographed on silica with a mixture of CH 2 Cl 2 / MeOH / AcOH 9/1 / 0.5 as eluent to give 1.16 g of compound 8c. Performance: 65%. Rf (CH2Cl2 / MeOH / AcOH: 9/1/0.5): 0.22.

Compound 8d: Ester of 1,3 (t.butyl dimethylsilyl) hydroxy-2-propyl alanine Dihydroxyacetone (2 g, 11.10 mmol) was dissolved in 50 ml of dimethyl formamide (DMF), tert-butyl dimethylsilyl chloride (tBuDMSCI) was added. (4.8 eq, 8.03 g) and imidazole (10 eq, 7.56 g) and the mixture was stirred 12 h at 20 ° C. The mixture was evaporated to dryness, taken up in 150 ml of AcOEt. The organic phase was washed with H2O water (2 * 50 ml), 10% HCl (2 * 50 ml), saturated NaCl, then dried over Na2SO4 and evaporated under reduced pressure to give 20.1 g of crude product. The mixture was chromatographed on silica with CHex / AcOEt 8/2 as eluent to give 5.96 g of product. Performance: 84.5%. Rf (CH2Cl2 / MeOH / AcOH: 9/1 / 0.5): 0.24. This product (8.82 g, 27.73 mmol) was dissolved in THF (74 ml) and H20 (4.8 ml). The mixture was cooled to 5 ° C and NaBH 4 (965 mg, 1 eq) was added little by little. The mixture was stirred 30 min at 5 ° C. The excess NaBH 4 was destroyed by adding acetic acid (1 ml). The THF was evaporated under reduced pressure and the mixture was taken in CHCl3 / H20. The organic phase was washed with H20 (2 * 50 ml), sat. NaHCO3. (2 * 50 ml), saturated NaCl, then dried over Na 2 SO 4 and evaporated under reduced pressure to give 8.24 g of product. Yield: 93.0%. 2.93 g of this compound (9.07 mmol, 1.1 eq) were solubilized in 60 ml of Et20. The mixture was stirred at room temperature and DEAD (1.2 eq, 1.56 ml), amino acid Boc (8.25 mmol, 1 eq) was added followed by PPh3 (1.2 eq, 2.59 g). The solvent was evaporated under reduced pressure. The The mixture was chromatographed on silica with a mixture of CHex / AcOEt 95/5 as eluent to give 4.42 g of product. Yield: 92.9%. Rf (CHex / AcOEt: 9/1): 0.65. 881 mg (1.79 mmoles) of this product were cold solubilized in 3 ml of CH2Cl2 and 1.36 ml of TFA was added. The mixture was stirred 2 h at room temperature. The solvents were evaporated under reduced pressure. The mixture was coevaporated with cyclohexane. The mixture was cold precipitated in Et20 to give 920 mg of compound 8d. Performance: 100%. Rf (CHex / AcOEt: 9/1): 0.1 Compound 8e: Carboxymethyl alanine ester, TFA BocAlaOH (5 g, 26.4 mmole) and Et3N (3.7 ml, 1 eq) were dissolved in 40 ml of AcOEt. The mixture was stirred 10 min at room temperature. Ethylbromoacetate (6.62 g, 1.5 eq) was added and the mixture was heated to reflux for 30 min. The precipitate was filtered and then 30 ml of H20 and 50 ml of AcOEt to filtering. The aqueous phase was extracted with 3 * 30 ml of AcOEt. The organic phase was washed with 10% citric acid (2 * 30 ml), 10% NaHCO 3 (2 * 30 ml), saturated NaCl, then dried over Na 2 SO and evaporated under reduced pressure to give 7.09 g of a product raw. The mixture was chromatographed on silica with a mixture of CHex / AcOEt 6/4 as eluent to give 4.68 g of product. Performance: 64.3%. Rf (CHex / AcOEt: 6.4): 0.35. 500 mg (1.81 mmoles) of this product were cold solubilized in 3 ml of CH2Cl2 and 1.4 ml of TFA was added. The mixture was stirred 2 h at room temperature. The solvents were evaporated under reduced pressure.

The mixture was coevaporated with cyclohexane. The product 8e was cold precipitated in Et20. W = 525 mg. Performance: 100%. Rf (CH2Cl2 / MeOH: 95/5): 0.14.

Compound 8f: Ethylcarbonate-1-ethyl alanine ester, TFA Boc Ala (76.54 mmole) and Et3N (12.27 ml, 1.2 eq) were dissolved in 70 ml of AcOEt. The mixture was stirred 15 min at room temperature. Ethyl-1-chloroethylcarbonate (prepared according to Barcelo et al., Synthesis, 1986, 627) (14.01 g, 1.2 eq) and sodium iodide Nal (926 mg, 0.1 eq) were added and the mixture was heated to reflux by 16 h. The precipitate was filtered and then 200 ml of H20 and 200 ml of AcOEt were added to the filtrate. The aqueous phase was extracted with 3 * 300 ml of AcOEt. The organic phase was washed with 10% citric acid (2 * 150 ml), 10% NaHCO3 (2 * 150 ml), saturated NaCl, then dried over Na2SO4 and evaporated under reduced pressure to give 24.5 g of a product raw. The mixture was chromatographed on silica with a mixture of CHex / AcOEt 9/1 as eluent to give 18.1 g of product. Yield: 77.51%. Rf (CH2Cl2 / MeOH: 9/1): 0.33. 9.15 g (30 mmol) of this product were cold solubilized in 23 ml of CH2Cl2 and 23 ml of TFA were added. The mixture was stirred 2 h at room temperature. The solvents were evaporated under reduced pressure.

The mixture was coevaporated with cyclohexane. The product 8f was cold precipitated in Et20. W = 9.57g. Performance: 77.5% (2 stages). Rf (CHex / AcOEt: 6/4): 0.1.

Compound 8q: Glucosyl alanine ester, TFA Pentachlorophenol (3 eq, 10 g, 37.54 mmol) was solubilized at 0 ° C in 12 ml of AcOEt and N, N'-dicyclohexylcarbodiimide (DCC) (2.58 g, 12.51 mmol) was added. . The mixture was left 12 h at -20 ° C. Cold hexane (10 ml) was added to the mixture and the solid was filtered and washed with cold hexane. The solid was recrystallized from hexane to give 10.3 g of brown solid. Performance: 82.0%. Mp: 115-130 ° C. This complex was added to 120 ml of AcOEt. After total dissolution, BocAlanine (1.0 eq, 10.25 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and then 100 ml of Et20 was added. The suspension was cooled for 1 h and then the solid was filtered. The latter was suspended in 100 ml of dioxane, filtered and washed with 2 * 20 ml dioxane. The filtrate was evaporated to dryness. The residue was treated again with dioxane to remove dicyclohexylurea (DCU). Then it was suspended in 100 ml of Et20 and placed in the freezer overnight. The solid was filtered and then dried to give 1.29 g of a brown solid. Yield: 27.8%.

To a glucose solution (3 eq, 1.54 g) in 57 ml of redistilled pyridine was added the above compound and imidazole. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to give a crude product. The mixture was chromatographed on silica with a 20/1 AcOEt / AcOH mixture as eluent to give 883 mg of product. Yield: 88.3%. Rf (AcOEt / AcOH: 20/1): 0.13. 883 mg (2.51 mmol) of this product was cooled to 0 ° C and 61 ml of TFA was added. The mixture was stirred 5 min at 0 ° C and then 30 min at room temperature. The TFA was evaporated under reduced pressure. The mixture was coevaporated with cyclohexane. The mixture was cold precipitated in Et20 to give 746 mg of a brown compound 8g. Performance: 81.3%. Rf (AcOEt / AcOH: 10/1): 0.10.

EXAMPLE 9 Synthesis of threonine esters Compound 9a: 1,3-diacetyl-2-propyl threonine ester, TFA This compound was obtained following the protocol described for 8c, replacing Boc-alanine with Boc-threonine.

Compound 9b: threonine ethylcarbonate-1-ethyl ester, TFA This compound was obtained following the protocol described for compound 8f, replacing Boc-alanine with Boc-threonine.

Yield: 89.7% Rf (CHex / AcOEt: 6/4): 0.1.

EXAMPLE 10 Synthesis of glycine esters Compound 10a: Ethyl carbonate-1-ethyl glycine ester, TFA This compound was obtained following the protocol described for compound 8f, replacing Boc-alanine with Boc-glycine. Yield: 92% Rf (CHex / AcOEt 8/2) 0.22.

Compound 10b: Ethyl carbonate ester 1 - (- 2-methyl) propyl glycine, TFA This compound was obtained following the protocol described for compound 10a, replacing ethyl-1-chloroethylcarbonate with ethyl-1-chloro-2-methyl- propyl carbonate. Yield: 88% Rf (CHex / AcOEt 8/2) 0.12.

Compound 10c: Ethyl carbonate methylcyclohexyl glycine ester, TFA This compound was obtained following the protocol described for compound 10a, replacing ethyl-1-chloroethyl carbonate with ethyl-chloromethyl cyclohexyl carbonate. Yield: 78%; Rf (CHex / AcOEt 7/3) 0.31.

Compound 10d: Ethyl carbonate methylphenyl glycine ester, TFA This compound was obtained following the protocol described for compound 10a, replacing ethyl-1-chloroethyl carbonate with ethyl chloromethylphenyl carbonate. Yield: 82%; Rf (CHex / AcOEt 7/3) 0.46.

Compound 10e: (Gly-OCH (CH3) 0-COEt) 1- (2-Amino-acetoxy) -ethyl propionic acid ester This compound was obtained by condensation between Boc-Gly and 1- chloroethyl propionate (1.1 eq) in the Presence of Nal (0.2 eq) and Et3N (1.2 eq) in ethyl acetate (10 ml / mmol) under reflux overnight. After cooling, the organic phase was washed with water, 10% citric acid, 10% NaHC03, H20, NaCl sat. and dried on Na2SO4. After evaporation, an oily product was obtained. Performance: 86%. The Boc group was deprotected as described in the previous examples. White solid product, quantitative yield. Rf (CHex / AcOEt 6/4) 0.64.

Compound 10f: (Gly-OCH (CH (CH3)?) Q-COEt) 1- (2-aminoacetoxy) -2-methyl propyl propionic acid ester This compound was obtained following the protocol described in example 10e, replacing the 1 -chloroethyl propionate by 1-chloro-2-methyl Propyl propionate White solid, yield: 78% in two stages. Rf (CHex / AcOEt 15 6/4) 0.56.

Compound 10q: (Glv-OCH (CHex) O-COEt) (2-aminoacetoxy) -cyclohexyl-methyl propionic acid ester This compound was obtained following the protocol described in example 10e, replacing 1-chloroethyl propionate with chloromethyl (cyclohexyl) propionate. White solid. Performance: 72% in two stages. Rf (CHex / AcOEt 6/4) 0.38.

Compound 10h: (Glv-OCH (Ph) O-COEt) (2-amino-acetoxy) -phenyl-methyl propionic acid ester This compound was obtained following the protocol described in example 10e, replacing 1-chloroethyl propionate by chloromethyl (phenyl) propionate. White solid. Performance: 75% in two stages. Rf (CHex / AcOEt 6/4) 0.42.

EXAMPLE 11 Synthesis of 2-amino-5-ethyl- (1,3,4) thiadiazole A mixture of 25 g (0.27 mol) of thiosemicarbazide and 46.6 ml of propanoyl chloride (0.54 mol, 2 eq) was stirred at 40 ° C for 4 h. The excess of propanoyl chloride was then evaporated under vacuum and the residue was triturated in ether. A solid product was obtained. It contains the expected thiadiazole and an impurity that was eliminated by precipitation in ethanol. White solid, 33.6 g (Yield: 83%) Kromasil C18 HPLC Tr 6.32 min in CH3CN at 30%.

EXAMPLE 12 The bisulfide 5, 6 or 7 (0.54 mmoles) was solubilized in 4 ml of DMF. To this was added benzotriazol-1-yl-oxy-ths- (dimethylamino) -phosphonium hexafluorophosphate (BOP) (1.2 eq, 1.0 g) and diisopropyl-ethyl-amine (DIEA) (284 μl) and then amino acid ester 8, 9 or 10 (1.3 eq). The mixture was stirred 20 min at room temperature and then the DMF was evaporated under reduced pressure. The product was taken in AcOEt. The organic phase was washed with H20, 10% citric acid, 10% NaHCO3, NaCl sat. and dried on Na2SO4. The crude product was purified by chromatography on silica. The obtained compound (0.38 mmol) was solubilized in 640 μl of CH 2 Cl 2 and 320 μl of TFA was added. The mixture was stirred 1 h at room temperature ambient. The excess solvent was evaporated under reduced pressure. The mixture was coevaporated with cyclohexane. The mixture was purified by semi-preparative HPLC or precipitated in a mixture of hexane / Et20.

Compound 12a: 1- (2- (1- (2,3-diacetoxipropoxycarbonyl) -etylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8b) W : 176 mg; Yield: 66.9%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 40-60: 9.07 and 10.18 min. ESI: 35 (M + H) + = 581. Log Kow = 1.31 Compound 12b: 1- (2- (1- (2-Methanesulfonyl-ethoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropyl-1,4-sulfinylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8a ) W: 200 mg; Yield: 74.1%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 40-60: 5.0 and 5.35 min. ESI: (M + H) + = 529. Log Kow = -0.13.

Compound 12c: 1- (2- (1- (1-ethoxycarbonoxyethoxycarbonyl)) - ethylcarbamoyl) -3-thiophen-3-yl-propylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8f) W: 232 mg; Yield: 71.3%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50: 3.84 and 4.03 min. ESI: (M + H) + = 509. Log Kow = 1 .63.

Compound 12d: 1- (2- (1-ethoxycarbonylmethyloxycarbonylethylcarbamoyl) -3-thiophen-3-yl-propylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8e) W: 261 mg; Yield: 83.9%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50: 4.90 and 5.18 min. ESI: (M + H) + = 539. Log Kow = 1 .35.

Compound 12e: 1- (2- (1- (1-ethoxycarbonyloxyethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 9b) W: 285 mg; Performance: 47.8%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 40-60: 10.55 and 11.09 min. ESI: (M + H) + = 594. Log Kow = 0.76.

Compound 12f: 1- (2- (1- (2-Acetoxy-1-acetoxymethylethoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8c) W : 171 mg; Yield: 70.1%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 40-60: 7.35 and 8.09 min. ESI: (M + H) + = 581. Log Kow = 1.31.

Compound 12g: 1- (2- (1- (2-Hydroxy-1-hydroxymethyletoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8d) W: 166 mg; Yield: 67.2%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 40-60: 2.94 and 3.27 min. ESI: (M + H) + = 497. Log Kow = -0.29.

Compound 12h: 1 - (2- (1 - (3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-yl-propylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8g) W: 85 mg; Yield: 93.2%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50: 2.34 min. ESI: (M + H) + = 585. Log Kow = -1.15.

Compound 12i: 1 - (2- ((1- (1-ethoxycarbonyloxy-ethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3-phenylpropylldisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 5 + compound 9b) W: 1.88g; Yield: 83.8% Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 45-55: 7.0 min. ESI: (M + H) + = 563. Log Kow = 0.76.

Compound 12: 1- (2- (1- (2-Acetoxy-1-acetoxymethyl-ethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3-phenylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 5 + compound 9a) W: 532 mg; Yield: 53.6%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 40-60: 6.16 min. ESI: (M + H) + = 605. Log Kow = 0.44.

Compound 12k: 1- (2- (1-ethoxycarbonyloxy-ethoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 5 + compound 10a) W: 1.76g; Rendmiento: 89.5%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50-50: 5.33 min. ESI: (M + H) + = 519. 10 Log Kow = 1.39.

Compound 121: 1- (2 - ((1-Ethoxycarbonyloxy-2-methyl-propoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-ammonium trifluoroacetate (compound 5 + compound 10b ) W: 1.2g; Rendmiento: 82.3%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 9.33 min, ESI: (M + H) + = 547.

Compound 12m: 1-2 - ((Cyclohexyl-ethoxycarbonyloxy-methoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-ammonium trifluoroacetate (compound 5 + compound 10c) W: 2.1g; Yield: 65.3%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 12.65 min, ESI: (M + H) + = 587.

Compound 12n: 1- (2 - ((ethoxycarbonyloxy-phenyl-methoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-ammonium trifluoroacetate (compound 5 + compound 10d) W: 0.95 g; Yield: 68.1%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 10.86 min. ESI (M + H) + = 581.

Compound 12o: 3-methylsulfanyl- (3-phenyl-2 - ((1-propionyloxy-ethoxycarbonylmethyl) -carbamoyl) -propylbisulfanylmethyl) -propyl-ammonium trifluoroacetate (compound 5 + compound 10e) W: 1.6 g; Yield: 81.2%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 6.82 min. ESI (M + H) + = 502.

Compound 12p: 1- (2 - ((2-Methyl-1-propionyloxy-propoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmetyl) -3-methylsulfanyl-propyl-ammonium trifluoroacetate (compound 5 + compound 10f ) W: 1.05 g, Yield: 83%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 8.17 min. ESI (M + H) + = 531.

Compound 12q: 1 - (2 - ((cyclohexyl-propionylaxy-methoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-ammonium (compound 5 + compound 10q) W: 1.8 g; Yield: 78.2%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 12.24 min. ESI (M + H) + = 571.

Compound 12r: 3-methylsulfanyl-1- (3-phenyl-2- ((phenyl-propionyloxy-methoxycarbonylmethyl) -carbamoyl) -propylbisulfanylmethyl) -propyl-ammonium trifluoroacetate (compound 5 + compound 10h) W: 0.98 g; Yield: 76.3%. Kromasil C18 HPLC CH3CN / H20 (0.5% TFA) 50/50 11.25 min. ESI (M + H) + = 565.

EXAMPLE 13 Synthesis of mixed inhibitors where R5 = heterocyclic The disulfide of 5, 6 or 7 (0.54 mmol) was dissolved in 5 ml of CH2Cl2 and the aminothiadiazole of example 11 (1.2 eq), TBTU (O-benzotriazol-1-yl-NNN'.N-tetramethyluronotetrafluoroborate) was added successively. ) (3 eq) and DIEA (diisopropylethylamine) (3 eq). The mixture was stirred for 30 minutes at room temperature (approximately 20 ° C). The solvent was evaporated under vacuum and the residue was taken up in ethyl acetate. The organic phase was washed with citric acid, water, saturated NaCl and dried in Na2SO4. After vacuum filtration and evaporation, a white solid was obtained. The obtained compound was dissolved in formic acid and the mixture was stirred 1 h at room temperature. The excess formic acid was evaporated under vacuum. The residue was taken up in ether and gives a white precipitate.

Compound 13a: 3- (2-amino-4-methylsulfanyl-butylbisulfanyl) -2-benzyl-N- (5-ethyl- (1, 3,4) thiadiazol-2-yl) -propionamide W = 256 mg (Yield 75 %).

EXAMPLE 14 Counter-ion change The compounds of example 12 and example 13 (1 mmol) were solubilized in 9 ml of distilled AcOEt. The organic phase was washed with 12 ml of 0.1 N NaHCO 3. The organic phase was then dried and evaporated under reduced pressure. The product was taken in AcOEt (3 ml), cooled to 0 ° C and 1 eq of the selected AH acid in 3 ml of AcOEt was added. The solvent was evaporated and the product was cold precipitated in a mixture of Et20 / hexane. (A = phosphate, hydrochloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate, nicotinate).

EXAMPLE 15 Pharmacological Results - Composed according to the invention The compound 15 of the following formula was tested in the following various biological tests.

Hot plate test: this test refers to the adherence and jump reflex in mice on a plate heated to 52 ° C (measurement of jump latency in the given examples). The results expressed in% of the maximum possible effect (% of MPE), that is, expressed as a percentage of analgesia, using the following equation: (measured lateritic time-control latency time)% MPE = (lateriticum maximum-time of control latericia) Maximum latency time = 240 seconds. The results are expressed in terms of the mean + SEM. The observed differences are considered significant when the p values are less than 0.05. The test used is an ANOVA test with a multiple comparison test. a) Antinociceptive responses observed after intravenous (IV) injection of compound 15 in the hot plate test (52 ° C, jump response) in male mice (n = 10). Compound 15 was dissolved in a water / mannitol mixture (50 mg / ml). The jump latency times were measured 10 min after injections by intravenous route.

TABLE 2 The results (table 2) show that compound 15 exhibits a dose-dependent analgesic action. ** p < 0.01; *** p < 0.001 against the vehicle. The effective dose 50, ED50, is 16.1 mg / kg. ED50 is the dose (in g / kg of body weight) that gives the desired effect in 50% of the population in which it is tested. b) Anti-infective effect of compound 15 (100 mg / kg pair) on the threshold of vocalization where pressure was applied to the rat claw (male Sprague Dawley) with an inflamed claw, inflammation induced by intraplantar injection of carrageenan. Compound 15 and a vehicle (ethanol / polyethylene glycol (PEG) 400 / water, 10/40/50) were administered 180 min after the intraplantar injection of carrageenan (1% in saline).

TABLE 3 The baseline for the vocalization threshold when pressure was applied to the claw was measured before the inflammation (B) and for the inflamed claw 20 min after the injection of compound 15 or the vehicle. The results are given in table 3 and are expressed as the mean + SEM, n = 10. The observed differences are considered significant when the p values are less than 0.05. These results show that compound 15 is effective in the treatment of neurogenic inflammatory pain. *** p < 0.001 against the vehicle. c) Antinociceptive responses observed after IV injection of compound 15 dissolved in ethanol / surfactant / water (10/10/80) in the hot plate test (53 ° C, jump response) in male OF1 mice and comparison of the responses according to the nature of the vehicle. Compound 15 was dissolved in a mixture of ethanol / Cremophor®EL / water. The jump latency times were measured 10 min after the intravenous injection. The results are given in Figure 1. Dose-dependent responses provide an analgesic response at an effective dose of 50 (ED50) of 1.9 + 0.4 mg / kg.

This value is close to that observed with morphine (ED50 = 1.3 + 0.2 mg / kg). ** p <; 0.01 against the vehicle. *** p < 0.001. Compound 15 is also soluble in ethanol / Tween® / water solvents, frequently used for administration by the intravenous route in man. In these solvents, the difference is not significantly different from those observed with Cremophor®EL. This is illustrated in Table 4 (jump latency time of 10 min after injection) at the same concentration of 2.5 mg / kg IV. *** p < 0.001 against the vehicle.

TABLE 4 d) Antinociceptive effect of compound 15 injected per os 20 min after the hot plate test: a) dose-response curve; b) kinetics of the effect after administration per os of 200 m / kg. Compound 15 was dissolved in a mixture of ethanol / PEG400 / water 10/40/50. The results, given in Figures 2a and 2b, show that compound 15 exhibits a dose-dependent analgesic effect (figure 2a), ED50 = 135 mg / kg, and that the analgesic effect of compound 15 is very high immediately after administration and persists, with a minor effect, for at least two hours (figure 2b). * p < 0.05; ** p < 0.01; *** p < 0.001 against the vehicle. #p < 0.05; ### p < 0.001 against compound 15. e) Comparative antinociceptive responses observed after IV injection of compound 15 (n = 14-17) or compound A (n = 8-14), 5 mg / kg, in the hot plate test (52 ° C, jump response) in male mice. Compound A is the compound of the formula: Which was described in the prior patent application WO 91/02718 (example 7). It is a mixed inhibitor of neprilisin and aminopeptidase that exhibits anesthetic properties. It is very poorly soluble in water or hydrophilic solvents. Compound 15 and A were dissolved in a mixture of ethanol / CremophorEL / water 10/10/80. The jump latency times were measured 10 min after the intravenous injection.

TABLE 5 The results given in table 5 show that at identical doses (low for the administration of compound A by route IV), compound 15 is more effective than compound A. ** p < 0.01 against vehicle, ### p < 0.001 against compound A. f) Analgesia induced by morphine or compound 15 induced by IV route in mice (hot plate test, 52 ° C). The analgesia produced by morphine or compound 15 was measured in mice (male OF1) in the hot plate test (52 ° C). Morphine was dissolved in H20 / NaCl, 9/1000) or compound 15 in the vehicle EtOH / Cremophor EL / water (10/10/80) was injected by IV. The results were measured 10 minutes after the injection and the latency time is 240 seconds (the equation given in examples 15 and 17). The results are presented in the following table 6: TABLE 6 *** p < 0.001, ANOVA test It is noted that compound 15 has analgesic effects compared to those obtained with morphine. This is in agreement with the results of another experiment conducted under identical conditions (Figure 1, example 15c).

EXAMPLE 16 Analgesic effect of? 9 THC alone The analgesia produced by? 9 THC in mice (OF1 males) was measured in the hot plate test (52 ° C). The? 9 THC, was dissolved in the EtOH / Cremophor EL / water vehicle (10/10/80), injected by IV route. The results were measured 10 minutes after the injection and the latency time is 240 seconds (equation given in examples 15 and 17). The results are presented in the following table 7: TABLE 7 "p < 0.1; *" p < 0.001 It is noted that? 9 THC produced a dose-dependent analgesic effect. Significant analgesia values were observed for doses of 0.75 mg / kg and 1.5 mg / kg. At lower doses, the percentage of analgesia is not significant.

EXAMPLE 17 Analgesic effects of the compound according to the invention +? 9 THC The experiments described to demonstrate the magnitude of the synergistic action of the compound according to the invention combined with ? 9 THC were performed in rodents (rats and mice) using antinociception tests classically used in the pharmaceutical industry to demonstrate this type of property, namely: - the hot plate test (Eddie and Leimbach, J. Pharmacol. 107, 385-389, 1953) in mice, the tail impulse test in rats (D'Amour and Smith, J. Pharmacol, Exp.Ther.72, 74-79, 1941) - the Porsolt swim test in mice (Porsolt 25 Arch.Int.Pharmacodyn, 229, 327, 1977). For the central tests (hot plate, impulse in the tail), the concentrations: - in cannabinoids (? 9 THC) it will preferably be between 0.3 and 0.5 mg / kg, - in the compound according to the invention (compound 15) it will preferentially be between 1 and 2 mg / kg . The relative concentrations are dependent on nociceptive stimulation. The? 9 THC used in the following examples is a commercial product purchased from Sigma-Aldrich (T2386). The mixed inhibitor used in the following examples is the compound 15 described above (example 15).

Preparation of the solutions of the compounds All the compounds were solubilized in a mixture of ethanol / Cremophor 80 / water = 10/10/80. For potentiation (synergy) experiments, doses of? 9 THC and inhibitors were used which, taken separately, do not induce significant responses.

Mode of administration The various compounds were administered, in a mixture in the same syringe, by route IV in the tail of the rat or mouse.

Animals The mice used in these tests are male OF1 mice. The rats used in these tests are male Sprague-Dawley rats.

Pharmacological tests 0 - Hot plate test: This test refers to the adhesion and jump reflex in mice on a plate heated to 52 ° C. The results are expressed in% of the maximum possible effect (% MPE), that is, expressed as a percentage of analgesia, using the following equation: '* - > (measured latency time-control latency time)% MPE = (maximum latency time-control latency time) Maximum latency time = 240 s. The results are expressed in terms of the mean + SEM. The observed differences are considered significant when 0 the values of p are less than 0.05. - impulse test in the tail: This test refers to the reflection of the impulse in the tail in the rat, stimulated by radiant heat emanating from a light source focused on a given part of the tail. The results are expressed as in the previous experiment by the measurement of a percentage of analgesia according to the same equation. The maximum latency time is set arbitrarily to 15 seconds. - Swimming test: This test measures the immobilization time for a mouse placed in a water bath at 21-23 ° C, from which it can not escape. The immobilization time reflects a form of depression; the mouse does not struggle anymore to escape to the hostile environment. The results express the immobilization time. The maximum immobilization time is 4 min. With the need to demonstrate the synergy of the 15 +? 9 THC combination, a dose-response curve was prepared for compound 15 alone and? 9 THC alone in the solvent ethanol / Cremophor EL / H20 (1/1 / 8) because? 9 THC can be used only by IV route at high concentrations under these conditions (example 16). The histogram (figure 3) of the analgesic responses (hot plate) clearly shows the very high potentiation of the analgesic effect of the combination of? 9 THC plus the compound 15 compared to one of the other single products. a) Antinociceptive response induced by the injection of a mixture of compound 15 and? 9 THC by route IV in male OF1 mouse in the hot plate test (figure 3). The mixture of compound 15 (0.4 mg / kg) and? 9 THC (0.375 mg / kg) was injected into the vehicle ethanol / Tween 80 / water (10/10/80). The rats They weighed 25-30 grams. This mixture of solvent is compatible with administration by IV route in man and animals. Jump latency was measured 10 minutes after the intravenous injection. The results are expressed as a percentage of analgesia, using the equation defined above, and are presented in figure 3. The difference observed is considered significant for p < 0.05 - ONE-way ANOVA followed by a multiple comparison test. ***: p < 0.01 against the control, ###: p < 0.01 against the mixture of compound 15 and? 9 THC. b) Antinociceptive response induced by injection of a mixture of compounds 15 and? 9 THC by route IV in the tail impulse test in male Spraque-Dawley rats. The mixture of compounds 15 (5 mg / kg) and? 9 THC (0.375 mg / kg) were injected into the vehicle ethanol / Tween 80 / water (10/10/80). Impulse latency in the tail was measured before the injection (pre-test) and 10 minutes after the intravenous injection (test). The latency time and 15 seconds. The rats weighed 260-300 9- The results are presented in table 8.

TABLE 8 Pulse test on the tail ***: p < 0.001 against vehicle, **: p < 0.001 against compound 15, #: p < 0.05 against? 9 THC The difference observed is considered significant for p < 0.05.

Two-way ANOVA followed by a mule comparison test: ***: p < 0.001, **: p < 0.01 against the vehicle group; #: p < 0.05 against the group? 9 THC; *** p < 0.001, **: p < 0.01, against the group of compound 15. c) Antidepressant response induced by injection of a mixture of compound 15 and? 9 THC by IV route in the swimming test in male OF1 mice. The mixture of compounds 15 (5 mg / kg) and? 9 THC (0.375 mg / kg) ethanol / Tween 80 / water (10/10/80) per route were injected into the vehicle intravenous 10 minutes before the test. The total immobilization time was measured for 4 minutes. The results are presented in table 9. The mice weighed approximately 25-30 g. The difference observed is considered significant for p < 0.05.

One-way ANOVA followed by a mule comparison test: ***: p < 0.001, *: p < 0.05 against the vehicle group; ###: p < 0.001 against the group of compounds 15 /? 9 THC; and group? 9 THC.

TABLE 9 Depression / swim test compound 15 Conclusion It is noted that the administration of a low dose of cannabinoids,? 9 THC, that is, at concentrations lower than 0.5 mg / kg by IV route in mice, potentiates antinociceptive or antidepressant responses induced by compound 15. Under these conditions, synergism is demonstrated very clearly when the analgesic effects are obtained in the warm plate test in mice when comparing the dose-response curves for? 9 THC and compound 15 with the effects produced by the sub-analgesic doses of these two compounds (Figure 3). It can be noted that the amplification factors of the active dose of? 9 THC alone / active dose of? 9 THC plus compound 15, and, conversely, the active dose of compound 15 alone / active dose of the compound 15 +? 9 THC, in both cases they are much greater than 10 and are not easily calculated exactly because the doses used for compound 15 and? 9 THC are inactive when these two molecules are used alone in these same doses . The intensity of the antinocicpetive response obtained by the combination of the inventive compound (NEP / APN mixed inhibitor, for example compound 15) and the Δ 9 THC, both substances being administered at very low doses to which they would have no activity, indicate the existence of the synergistic action between the endogenous enkephalins (protected by the inventive compound) and the? 9 THC. This is corroborated by an isobolographic analysis of pharmacological responses.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - The compounds of the following formula (I): H2N-CH (R?) - CH2-SS-CH2-CH (R2) -CONH-R5 wherein: Ri represents: - A hydrocarbon chain, saturated or unsaturated, linear or branched, comprising from 1 to 6 carbon atoms, optionally substituted by: * An OR, SR or S (0) R radical, wherein in each of these radicals R represents a hydrogen, a straight or branched hydrocarbon chain 1 to 4 carbon atoms, a phenyl or benzyl radical, * A phenyl or benzyl radical, - A phenyl or benzyl radical optionally substituted by: * 1 to 5 halogens, notably fluorine, * an OR, SR or S radical (0 ) R, wherein each of these radicals R is as defined above, - a methylene radical substituted by a 5- or 6-atom heterocycle, aromatic or saturated, having as a hetero atom a nitrogen or sulfur atom, optionally oxidized in the form of N oxide or S oxide; R2 represents: - A phenyl or benzyl radical, optionally substituted by: * 1 to 5 halogen atoms, notably fluorine, * an OR or SR radical, wherein each of these radicals R is as defined above, * an amino group optionally mono- or di-substituted by an aliphatic, cyclic or linear group of 1 to 6 carbon atoms, * an aromatic ring of 5- or 6- atoms, -a heterocycle of 5- or 6- atoms, the heteroatom is oxygen , nitrogen or

sulfur, - a methylene group substituted by a 5- or 6- atom, aromatic or saturated heterocycle, the heteroatom is oxygen, nitrogen or sulfur, the nitrogen and sulfur atoms possibly being oxidized in the form of N-oxide or S, R5 represents: a) a radical CH (R3) -COOR4 wherein R3 represents: - hydrogen, - an OH or OR group, with R as defined above, - a saturated or linear hydrocarbon chain (alkyl) , which comprises from 1 to 6 carbon atoms, optionally substituted by an OR or SR radical, wherein in each of these radicals R is as defined above, - a phenyl or benzyl radical, optionally substituted by: * 1 to 5 halogens, notably fluorine, * an OR or SR radical, with R as defined above, and OR4 represents - A radical OCH2COOR 'glycolate or OCH (CH3) COOR' lactate, wherein each of these radicals R 'represents * a chain of saturated hydrocarbon (alkyl) with 1 to 6 carbon atoms, linear or branched and optional substituted by a C1 to C3 alkoxy group, preferably a C1-C4 alkyl group optionally substituted by a methoxy group, * a C5-C8 cycloalkyl group, preferably a C5-C6 cycloalkyl group, * a phenyl, benzyl group, heteroaryl, alkylheteroaryl, -an group OCH (R ") 0 (CO) OR 'or OCH (R") 0 (CO) R', wherein in each of these radicals R 'is defined as in the above and R " represents * a hydrogen atom, * a linear or branched C 1 -C 6 alkyl chain, optionally substituted by a C 1 -C 3 alkoxy group, preferably a C 1 -C 4 alkyl group optionally substituted by a methoxy group, * a group C5-C8 cycloalkyl, preferably a C5-C6 cycloalkyl group, *

a phenyl, benzyl, heteroaryl, alkylheteroaryl group, - a triglyceride radical OCH (CH2OCOR ') 2 or OCH2-CH (OCOR') - CH2OCOR \ wherein in each of these radicals R 'is as defined above, - a radical glycoside such as D-glucose, β-D-glucopyranose, α- or β-galactopyranose, - a sulfonate radical OCH 2 CH 2 (S 0 2) CH 3, - a radical OCH (CH 2 OH) 2; b) a 5- or 6- bond heterocycle comprising numerous heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, of which 2 atoms are nitrogen, said heterocycle possibly being substituted by a C 1 -C 6 alkyl, phenyl radical or benzyl; the 5-link heterocycle is selected from the group consisting of imidazolyl, pyrazolyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiadiazolyl and furazanyl; as well as the addition salts of the aforementioned compounds (I) with pharmaceutically acceptable mineral or organic acids.

2. The compounds according to claim 1, further characterized in that Ri represents an alkyl radical having 1 to 4 carbon atoms substituted by an SR radical, with R as defined above, notably with R representing a straight or branched saturated hydrocarbon chain, with 1 to 4 atoms of carbon.

3. The compounds according to any of the preceding claims, further characterized in that the radical R2 represents a benzyl radical or a methylene radical substituted by a 5- or 6- atom heterocyclic, aromatic or saturated, having as a

heteroatom a nitrogen or sulfur atom, optionally oxidized in the form of N-oxide or S-oxide. The compounds according to any of the preceding claims, further characterized in that the radical R3 represents a hydrogen atom or a radical alkyl having 1 to 6 carbon atoms substituted by an OH or SH radical.

5. The compounds according to any of the preceding claims, further characterized in that the radical OR4 represents a group OCH (R ") 0 (CO) OR 'or OCH (R") 0 (CO) R', - the radical R 'represents a C1-C4 alkyl chain, notably an ethyl radical, and -R-radical "represents a methyl radical, CH (CH3) 2, cyclohexyl or phenyl 6. Compounds according to any of the claims above, further characterized in that the radical R5 represents a heterocywith 5 bonds comprising 2 nitrogen atoms, optionally substituted by a C1-C4 alkyl chain or a phenyl or benzyl radical. the preceding claims, further characterized in that said compounds are selected from the following compounds: 1- (2- (1- (2,3-diacetoxypropoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl- amino, 1- (2- (1- (2-methanesulfonylethoxy carbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1- (1-ethoxycarbonyloxyethoxycarbonyl)) - ethylcarbamoyl) -3-thiophene-3-yl-

propylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1-ethoxycarbonylmethyloxycarbonylethylcarbamoyl) -3-thiophen-3-yl-propyl-bisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1- ( 1-ethoxycarbonyloxyethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3-thiophen-3-ylpropylbisulfani [methyl) -3-methylsulfanylpropyl-amino, 1- (2- (1- (2-acetoxy-1-acetoxymethylethylcarbonyl) -ethylcarbamoyl) -3- thiophen-3-1-propylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1- (2-hydroxy-1-hydroxymethyletoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-ylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1 - (3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-yl-propylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2 - (1- (1-ethoxycarbonyloxy-ethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3-phenylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 1- (2- (1- (2-acetoxy-1-acetoxymethyl-ethoxycarbonyl) -2- hydroxypropylcarbamoyl) -3-phenylpropylbisulfanylmethyl) -3-methylsulfanylpropyl-amine no, 1- (2 - ((1-ethoxycarbonyloxy-ethoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanylpropyl-amino, 3- (2-amino-4-methylsulfanyl-butylbisulfanyl) -2-benzyl- N- (5-ethyl- (1, 3,4) -thiadiazol-2-yl) -proponamide, 1- (2 - ((1-ethoxycarbonyloxy-2-methyl-propoxycarbonylmethyl) -carbamoyl) -3-phenyl -propylbisulfanylmethyl) -3-methylsulfanyl-propyl-amino, 1- (2 - ((cyclohexyl-ethoxycarbonyloxy-methoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-amino, 1- (2- ( (ethoxycarbonyloxy-phenyl-methoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-amino, 3-methylsulfanyl-1- (3-phenyl-2- ((1-propionyloxy-ethoxycarbonylmethyl) -carbamoyl) -propylbisulfanylmethyl) -propyl-amino, 1- (2 - ((2-

methyl-1-propionyloxy-propoxycarbonylmethi) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) -3-methylsulfanyl-propyl-amino, 1 - (2- ((cyclohexyl-propionyloxy-methoxycarbonylmethyl) -carbamoyl) -3-phenyl-propylbisulfanylmethyl) 3-methylsulfanyl-propyl-amino, 3-methylsulfanyl-1- (3-phenyl-2- ((phenyl-propionyloxy-methoxycarbonylmethyl) -carbamoyl) -propylbisulfanylmethyl) -propyl-amino.

8. As drugs, the compounds of formula (I) according to any of the preceding claims.

9. A pharmaceutical composition, characterized in that it comprises at least one compound of formula (I), of any of claims 1 to 7, and a pharmaceutically acceptable excipient, notably an excipient suitable for administration by oral, nasal or intravenous route.

10. The pharmaceutical composition according to claim 9, characterized further because it is to treat depression and various types of pain, such as acute pain, inflammatory pain and neurogenic pain.

11. The use of a compound of the formula (I) of any of claims 1 to 7, for preparing a drug for treating depression and pain.

12. The pharmaceutical composition according to claim 9 or 10, further characterized in that it comprises in addition at least one cannabinoid derivative, notably? 9-tetrahydrocannabinol.

13. The use of at least one cannabinoid derivative, notably 9-tetrahydrocannabinol, in a pharmaceutical composition for enhancing the analgesic and / or antidepressant effect of the compounds of formula (I) of any of claims 1 to 7.

14.- The use of a combination of at least one compound of formula (I) of any of claims 1 to 7 and at least one cannabinoid derivative, notably? 9-tetrahydrocannabinol, to prepare a drug for treating depression and pain.

15. A pharmaceutical composition comprising: i) at least one compound of formula (I), of any of claims 1 to 7, ii) at least one cannabinoid derivative as combination products for simultaneous use, separately or in stages.

16. The use of a pharmaceutical composition comprising: i) at least one compound of formula (I), of any of claims 1 to 7, ii) at least one cannabinoid derivative as combination products for simultaneous use, separate or in stages, to prepare a drug to treat depression and pain.

17. The pharmaceutical composition according to claim 9, 10 or 12, further characterized in that it additionally comprises morphine or a derivative thereof.

18. The use of a combination of at least one compound of formula (I) of any of claims 1 to 7 and morphine or a

derived from it, to prepare a drug to treat depression and

pain.