AU2006307938B2 - 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): HN-CH(R)-CH-S-S- CH-CH(R)-CONH-R, wherein R is a hydrocarbon chain, phenyl or benzyl radical, methylene radical substituted by a 5 or 6 atom heterocycle; R is a phenyl or benzyl radical, a 5 or 6 atom aromatic heterocycle, methylene group substituted by a 5 or 6 atom heterocycle; R is a CH(R)-COOR radical, wherein R is hydrogen, an OH or OR group, a saturated hydrocarbon group, a phenyl or benzyl radical and OR is 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 C-C, 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

AMINOACID DERIVATIVES CONTAINING A DISULFANYL GROUP IN THE FORM OF MIXED DISULFANYL AND AMINOPEPTIDASE N INHIBITORS 5 The invention relates to novel mixed inhibiters of the 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 primarily degraded by two zinc 10 metallopeptidases, neprilysin (EC 3.4.24.11) which cleaves the Gly3-Phe4 bond (Nature 276 (1978) 523) and aminopeptidase N (EC 3.4.11.2) which cuts the Tyrl-Gly2 bond of these peptides (Eur.J.Pharmacol. 117 (1985) 233; review in Pharmacological review., 1993, 45, 87 15 146). Mixed inhibiters of these two enzymes are known, by completely protecting endogenous enkephalins from enzymatic degradation, they reveal the pharmacological activities, in particular analgesic and antidepressant activities, of enkephalins. Mixed inhibiters, described 20 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 divulged in these patent 25 applications exhibit excellent in vitro and in vivo activity after administration by intracerebroventricular route; this was particularly demonstrated in the case of the hydroxamates (Eur. J. Pharmacol., 102, (1984), 525-528; Eur.J.Pharmacol., 30 165, (1989), 199-207; Eur.J.Pharmacol, 192, (1991), 253-262), for which significant activity also could be demonstrated after intravenous (IV) administration in a model of rat arthritis (Brain Research, 497, (1989), 94-101). In the case of phosphine derivatives and amino 35 acid derivatives, good in vivo activity was 2 demonstrated 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., 5 261, (1992), 181-190). However, even if one of the compounds belonging to the series of amino acid derivatives proved relatively water soluble (Pain, 73, (1997), 383-391), none the molecules previously divulged exhibits solubility in an aqueous phase and 10 sufficient bioavailability to be administered by oral route and to provide advantageous analgesic responses to sufficiently low doses in animals to be adapted to man. Similarly, none the molecules previously cited allows intravenous administration since in animal tests 15 they require solubilization in mixtures incompatible with administration by this route in man. The present invention provides novel water-soluble compounds capable of jointly inhibiting the two enzymatic activities responsible for 20 the degradation of enkephalins and to manifest their pharmacological properties after dissolution in an aqueous solvent and intravenous, subcutaneous, percutaneous, intrathecal or intra-articular injection and by oral or nasal route. 25 It is generally understood that the hematoencephalic 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 30 indicating the existence of a good capacity to reach cerebral structures by several administration routes (except for the local route). The invention therefore also provides novel compounds that exhibit the properties of morphine substances, in particular 35 analgesia, beneficial effects on behavior (reduction in the emotional component of pain and antidepressant responses) and peripheral effects (antidiarrheal, antitussive, anti-inflammatory) without their major disadvantages (tolerance, physical and psychological 5 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 10 invention administered by oral route and thus without such compounds being constrained from reaching the central nervous system. This result, highly advantageous but unexpected, was formally demonstrated by the use of an antagonist incapable of entering the 15 brain. This completely reduces all of the effects due to stimulation of cerebral opioid receptors by the compounds according to the invention, without altering the analgesics effects of the compounds on these types of pain, in particular neurogenic pain. 20 Most notably, the invention relates to compounds of following formula (I):

H

2 N-CH (R 1 ) -CH 2

-S-S-CH

2 -CH (R 2 ) -CONH-R 5 wherein: 25 R 1 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 30 each of these radicals R represents a hydrogen, a linear 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, SR or S(0)R radical, wherein in 5 each of these radicals R is defined as above, - a methylene radical substituted by a 5- or 6 atom heterocycle, aromatic or saturated, having as a heteroatom an atom of nitrogen or sulfur, 10 optionally oxidized in the form of N-oxide or S-oxide;

R

2 represents: - a phenyl or benzyl radical, optionally substituted by: 15 * 1 to 5 halogen atoms, notably fluorine, * an OR or SR radical, wherein in each of these radicals R is defined as above, * an amino group optionally mono- or di substituted by an aliphatic, cyclic or 20 linear group of 1 to 6 carbon atoms, * a 5- or 6-atom aromatic ring, - a 5- or 6-atom aromatic heterocycle, the heteroatom being oxygen, nitrogen or sulfur, - a methylene group substituted by a 5- or 6-atom 25 heterocycle, aromatic or saturated, the heteroatom being oxygen, nitrogen or sulfur, the nitrogen and sulfur atoms possibly being oxidized in the form of N-oxide or S-oxide.

R

5 represents: 30 a) a CH(R 3

)-COOR

4 radical wherein

R

3 represents: - hydrogen, - an OH or OR group, with R as defined above, - a saturated hydrocarbon chain (alkyl), linear 35 or branched, comprising from 1 to 6 carbon atoms, optionally substituted by an OR or SR radical, wherein in each of these radicals R is defined as above, - a phenyl or benzyl radical, optionally 5 substituted by: * 1 to 5 halogens, notably fluorine, * an OR or SR radical, with R as defined above. and 10 - OR 4 represents - an OCH 2 COOR' glycolate or OCH(CH 3 )COOR' lactate radical, wherein in each of these radicals R' represents * a saturated hydrocarbon chain (alkyl) with 15 1 to 6 carbon atoms, linear or branched and optionally substituted by an alkoxy group at Cl to C3, preferably an alkyl group at C1-C4 optionally substituted by a methoxy group, 20 * a cycloalkyl group at C5-C8, preferably a cycloalkyl group at C5-C6, * a phenyl, benzyl, heteroaryl, alkylheteroaryl group, - an OCH(R")O(CO)OR' or OCH(R")O(CO)R' group, 25 wherein in each of these radicals R' is defined as above and R" represents * a hydrogen atom, * a Cl-C6 alkyl chain, linear or branched, optionally substituted by a Cl-C3 alkoxy 30 group, preferably a Cl-C4 alkyl group optionally substituted by a methoxy group, * a C5-C8 cycloalkyl group, preferably a C5 C6 cycloalkyl group, * a phenyl, benzyl, heteroaryl, 35 alkylheteroaryl group, C.\NRPolhRDCC\RBR\J4 t274_ DOC.Th1W/2W12 -6 - an OCH (CH 2 0COR ') 2 or OCH 2 -CH (OCOR' )-CH 2 0COR' triglyceride radical, wherein in each of these radicals R' is defined as above, - a glycoside radical such as D-glucose, 0-D 5 glucopyranose, a- or P-galactopyranose, - an OCH 2

CH

2 (S0 2

)CH

3 sulfonate radical, - an OCH(CH 2

OH)

2 radical; as well as additive salts of the aforesaid compounds (I) with pharmaceutically acceptable mineral or organic 10 acids. The invention also provides additive salts of compounds of formula (I), obtained with pharmacologically acceptable organic or mineral acids such as phosphates, hydrochloride, acetate, methanesulfonate, borate, lactate, fumarate, 15 succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate and nicotinate. Within the framework of the present invention, the expression "hydrocarbon chains" designates alkanes, alkenes 20 or alkynes. Notably, the expression "saturated hydrocarbon chains" designates alkyl radicals comprising from 1 to 6 carbon atoms (Cl-C6) or from 1 to 4 carbon atoms (Cl-C4), linear or branched. Examples of alkyl radicals comprising from 1 to 4 carbon atoms include methyl, ethyl, propyl, 25 butyl, isopropyl, 1-methyl-ethyl, 1-methyl-propyl and 2-methyl-propyl radicals. Examples of alkyl radicals comprising from 1 to 6 carbon atoms further include pentyl, hexyl, 1methyl-butyl, 1-methyl-pentyl, . 2-methyl-butyl, 2 methyl-pentyl, 3-methyl-butyl, 3-methyl-pentyl, 4 methyl-pentyl or 1-ethyl-propyl, 1-ethyl-butyl and 2 ethyl-butyl radicals. The expression "unsaturated 5 hydrocarbon chains" designates alkenyl radicals (at least one double bond), for example vinyl, allyl or similar, or alkynyl (at least one triple bond) comprising from 2 to 6 atoms of carbon, or 2 to 4 carbon atoms, linear or branched. 10 The term "halogen" used herein designates chlorine, bromine, iodine or fluorine. As non-limiting example of heterocyclic cores with 5 or 6 atoms, aromatic or saturated, having as a heteroatom an atom of nitrogen or sulfur, the following 15 radicals can be cited: thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, thiadiazolyle, the nitrogen and sulfur 20 atoms optionally being oxidized in the form of N-oxide or S-oxide. As non-limiting example of heterocyclic cores with 5 or 6 atoms, aromatic or saturated, having as a heteroatom an atom of oxygen, the following radicals 25 can be cited: furyl, pyranyl, isoxazolyl, morpholinyl, furazanyl, oxazolyl, oxazolidinyl and oxazolinyl. Radical Ri advantageously represents an alkyl radical having from 1 to 4 atoms of carbon, optionally substituted by an OR, SR or S(O)R radical, wherein in 30 each of these radicals R is defined as above. Ri represents even more advantageously an alkyl radical having from 1 to 4 carbon atoms substituted by a SR radical, with R defined as above, notably with R representing a saturated hydrocarbon chain, linear or 35 branched, with 1 to 4 atoms of carbon.

U Radical R 2 advantageously represents: - a benzyl or phenyl radical, - a methylene radical substituted by a 5- or 6 atom heterocycle, aromatic or saturated, having 5 as a heteroatom an atom of nitrogen or sulfur, optionally oxidized in the form of N-oxide or S-oxide. Notably, radical R 2 represents a benzyl radical or a methylene radical substituted by a 5- or 6-atom 10 heterocycle, aromatic or saturated, having as a heteroatom a sulfur or nitrogen atom, optionally oxidized in the form of N-oxide or S-oxide, even more advantageously a benzyl radical or a methylene radical substituted by a thiophenyl radical (thienyl). 15 Radical R 5 is a radical that increases the hydrophilic character of the whole molecule, which normally is a rather hydrophobic molecule. According to a first embodiment of the invention, radical R 5 represents a CH(R 3

)-COOR

4 radical. 20 In this first embodiment, radical R3 advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, even more advantageously 1 to 4 carbon atoms, optionally substituted by an OR or SR radical, wherein in each of 25 these radicals R is defined as above. Radical R 3 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. 30 Radical OR 4 advantageously represents: - an OCH 2 COOR' glycolate radical, with R' as defined above (notably R' represents a Cl-C4 alkyl group optionally substituted by a methoxy group or a C5-C6 cycloalkyl group), - an OCH(R")O(CO)OR' or OCH(R")O(CO)R' radical, with R' and R" as defined above (notably R' and/or R" represent a Cl-C4 alkyl group optionally substituted by a methoxy group or a 5 C5-C6 cycloalkyl group or R" represents a hydrogen atom), - an OCH (CH 2 0COR' )2 or OCH 2 -CH (OCOR' )-CH 2 0COR' triglyceride radical, wherein in each of these radicals R' is defined as above, 10 - a glycoside radical such as D-glucose, - an OCH 2

CH

2

(SO

2

)CH

3 sulfonate radical, - an OCH(CH 2

OH)

2 radical. Notably, radical OR 4 represents an OCH(R")O(CO)OR' or OCH(R")O(CO)R' group, the R' radical representing a 15 Cl-C4 alkyl chain (notably an ethyl radical) and the R" radical representing a methyl, CH(CH 3

)

2 , cyclohexyl or phenyl radical. According to a second embodiment of the invention, radical R 5 represents a heterocycle, of 5 or 6 links, 20 comprising several heteroatoms, selected among the group comprising nitrogen, sulfur and oxygen, of which 2 atoms are nitrogen, said heterocycle possibly substituted by a Cl-C6 alkyl radical or a phenyl or benzyl radical. 25 In said second embodiment, the heterocycle is advantageously a 5-link heterocycle comprising 2 nitrogen atoms, optionally substituted by a Cl-C4 alkyl chain, notably 2-ethyl-1, 3, 4-thiadiazole. The invention notably relates to the following 30 compounds: 1- (2-(l- (2, 3-diacetoxypropoxycarbonyl) ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl) 3-methylsulfanylpropyl-amino, -Lu 1- (2- (1-(2-methanesulfonylethoxycarbonyl) ethylcarbamoyl) -3-thiophen-3-ylpropyldisulfanylmethyl) 3-methylsulfanyipropyl-amino, 1-(2--1- (1-ethoxycarbonyloxyethoxycarbonyl) ) 5 ethylcarbamoyl) -3-thiophen-3-yl propyldisulfanylmethyl) -3-methylsulfanyipropyl-amino, 1- (2- (1-ethoxycarbonylmethyloxycarbonylethyl carbamoyl) -3-thiophen-3-yl-propyldisulfanylmethyl) -3 methylsulfanyipropyl-amino, 10 1- (2- (1- (-ethoxycarbonyloxyethoxycarbonyl) -2 hyciroxypropylcarbamoyl) -3-thiophen-3 ylpropyldisulfanylmethyl) -3-methylsulfanyipropyl-amino, 1- (2- (1-(2-acetoxy-1-acetoxymethylethoxycarbonyl) ethylcarbamoyl) -3-thiophen-3-ylpropyldisulfanylmethyl) 15 3-methylsulfanylpropyl-amino, 1- (2- (1-(2-hydroxy-1-hydroxymethylethoxycarbonyl) ethylcarbamoyl) -3-thiophen-3z-ylpropyldisulfanylmethyl) 3-methylsulfanyipropyl-amino, 1- (2- (1-(3,4,5, 6-tetrahydroxytetrahyciropyran-2 20 ylmethoxycarbonyl) -ethylcarbamoyl) -3-thiophen-3-yl propyldisulfanylmethyl) -3-methylsulfanyipropyl-anino, 1- (2- (1- (-ethoxycarbonyloxy-ethoxycarbonyl) -2 hydroxypropylcarbamoyl) -3 phenylpropyldisulfanylmethyl) -3-methylsulfanyipropyl 25 amino, 1- (2- (1-(2-acetoxy-1-acetoxymethyl ethoxycarbonyl) -2-hydroxypropylcarbamoyl) -3 phenyipropyilisulfanylmethyl) -3-methylsulfanyipropyl amino, 30 1- (2-C(1l-ethoxycarbonyloxy-ethoxycarbonylmethyl) carbamoyl) -3-phenyl-propyldisulfanylmethyl) -3 methyl sul fanyipropyl-amino, 3- (2-amino-4-methylsulfanyl-butyldisulfanyl) -2 benzyl-N- (5-ethyl- (1, 3, 4)-thiadiazol-2-yl) 35 propionamide, 1-(2-((1-ethoxycarbonyloxy-2-methyl propoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amino, 1-(2-((cyclohexyl-ethoxycarbonyloxy 5 methoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amino, 1-(2-((ethoxycarbonyloxy-phenyl methoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amino, 10 3-methylsulfanyl-l-(3-phenyl-2-((1-propionyloxy ethoxycarbonylmethyl)-carbamoyl) propyldisulfanylmethyl)-propyl-amino, 1-(2-((2-methyl-1-propionyloxy propoxycarbonylmethyl)-carbamoyl)-3-phenyl 15 propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amino, 1-(2-((cyclohexyl-propionyloxy methoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amino, 3-methylsulfanyl-1-(3-phenyl-2-((phenyl 20 propionyloxy-methoxycarbonylmethyl)-carbamoyl) propyldisulfanylmethyl)-propyl-amino. The compounds of formula (I) potentially have from 2 to 9 centers of asymmetry. Radicals R 1 , R 2 and R 3 Will be introduced in such a way as to obtain optically pure 25 chains corresponding to stereochemistry recognized by enzymatic activities. Radicals R 4 optionally contain an unresolved center of asymmetry. The compounds of formula (I) are obtained: 1) by condensation of a protected beta-aminothiol 30 on the amino function by a t-butyloxycarbonyl (Boc) group (II) with a mercaptoalcanoic acid (III) by means of methoxycarbonylsulfonyl chloride in solution in THF (tetrahydrofuran), leading to IV.

J-z Boc-HN SH + HS_ <COOH Boc-HN S-S COOH R1 R2 R1 R2 I III IV Boc beta-aminothiol II is prepared from the corresponding commercial Boc amino acid of absolute configuration S with retention of configuration 5 according to a method well-known by those skilled in the art (J.Med.Chem., 35, (1992) 1259). The mercaptoalcanoic acid III is obtained from the corresponding methyl malonate monoester V, which, according to a method well-known by those skilled in 10 the art (Ber., 57, (1924), 1116) is transformed into acrylate VI. Boc'HN COOH Boc-HN OH BocHN SCOCH 3 SH OH Boc HN-SCOCH3 N SH I R R 11 HOOC COOCH 3

COOCH

3

COOCH

3 (S) COOH - H 3 CCOS HCCOS R2 R2 R2 R 2 V VI VII Vill The addition of thioacetic acid to acrylate VI leads to racemic derivative VII (Biochemistry, 16, 15 (1977), 5484). Resolution by alpha-chymotrypsin isolates the optically pure acetylthioacide VIII (Bioorg.Med.Chem.Let, 3, (1993), 2681). Alkaline hydrolysis of the thioester leads to compound III. 2) The compounds of formula (I), wherein radical 20 R 5 represents a CH(R 3

)-COOR

4 radical, can be obtained by the following synthetic pathways. 2.1) Dissymmetrical disulfide IV is coupled, under conventional peptide coupling conditions, with aminoester IX, leading to the protected inhibiter X.

.L R Boc-HNO R S S COOH Boc-HN COOR R, R 2 + H 2 N COOR, R1 R2 H Iv Ix x According to an alternative method, compounds X can be obtained by condensation, by means of methoxycarbonyl sulfenyl chloride, of Boc-p-aminothiol 5 II with a mercaptoacylaminoester of formula XI. Mercaptoacyl aminoester XI is prepared from compound III. It is oxidized by an ethanolic iodine solution into disulfide XII. Compound XII is coupled under conventional peptide coupling conditions with 10 aminoester IX, leading to XIII. Treatment of XIII with a reducing agent such as the mixture 3 N Zn+HCl, releases compound XI. 0 OR 3 COOH COOH ONCOOR] R2 RL R III X11 XIII 0 R Boc-HN SH HS N COOR4 X R1 + R 2 XI O R3 O R3 Boc-HN H H HCOO HCOO H3N S-S N COOR4 R, R2 R, R2 x 0 R A' H 3 N S-S N COOR4 r_*_ H R, R2 The N-terminal Boc group of X is cut by the action 15 of formic acid, releasing XIV. The counter-ion of XIV is changed quantitatively by treatment with one equivalent of 0.1 M NaHCO 3 , extraction in an organic medium (EtOAc) of the compound possessing a free amino function, then addition of one equivalent of the organic acid or mineral chosen to lead to I. 2.2) Aminoester IX is obtained by condensation of Boc amino acid XII with alcohol R 4 0H, then deprotection 5 by trifluoroacetic acid (TFA) and neutralization by soda. If alcohol R 4 0H is a primary alcohol, coupling with XII is carried out under conventional conditions (1-[3-(dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole hydrate 10 (HOBt) or activated ester). If alcohol R 4 0H is a secondary alcohol, condensation is achieved via a Mitsunobu reaction (Synthesis (1981) 1-28), using the mixture diethyl azodicarboxylate/triphenyl phosphine (DEAD/PPhe 3 ) Boc.HN .. <COOH

R

4 0H Boc-HN COOR R "I 15 3 R Alcohols R 4 0H are in most cases commercial compounds. When R 4 0H is an alcohol leading to an ester "cascade," it is synthesized from methods described in the literature. 20 2a) Compounds of formula (I), wherein radical R 5 represents a heterocycle radical such as defined above, can be obtained by the following synthetic pathways. 2.a.1) xv 0 0 H 2 N SoH N BocHN R H R2_ _ _ N-N Iv s xv' 25 Dissymmetrical disulfide IV is coupled under conventional peptide coupling conditions with amino heterocycle XV to lead to XVI. Deprotection of the Boc group is carried out as above leading to derivative

XVII.

BocHN R H A- H3N S N 2 N-N 2) AH N-N XVI XVII Amino heterocycle XV is synthesized according to methods described in the literature. For example, 2-amino-5-ethyl-(1, 3,4) thiadiazole 5 XVa is obtained as described (Takatori et al., Yakugaku Zasshi 79,1959,913) by condensation of thiosemicarbazide XVIII and propionyl chloride XIX. S Ci H NH, A, 4h H 2 N S

NH

2 N 2.a.2) 10 According to an alternative method, compounds of formula (1), wherein radical R 5 represents a heterocycle, can be obtained by condensation of heterocycle XV on compound XII, leading to XX. After cutting the disulfide bridge, as previously described, 15 the compound obtained XXI is condensed on II to lead to XVI. 1 N 1N -2 XII XV XX 0 0 BoctiN(S (S Wt HN RS HS SH --- T- R ,N XXI 11 xvi The invention also has as an object pharmaceutical compositions comprising as active ingredient at least 20 one compound of general formula (I) or a salt of same or salt hydrates of same in combination with one or more pharmaceutically acceptable inert carriers or other vehicles. These compounds exhibit the properties of morphine substances, notably analgesia, including peripheral components (inflammatory, neurogenic), 5 beneficial effects on behavior, notably in the case of depression and/or anxiety, without exhibiting their major disadvantages (tolerance, dependence, respiratory depression, constipation). Thus, contrary to exogenous opioid agonists that 10 interact with delta receptors, the inventive mixed inhibiters have antidepressant effects without the risk of triggering epileptiform activity or convulsions, and they are fast acting (Baamonde A. et al., 1992, Jutkiewicz E.M. et al., 2005). These compounds can pass 15 the blood-brain barrier. The principal application of the compounds according to the invention is thus in the field of analgesia, antidepressants and anxiolytics. The inventive pharmaceutical compositions can be, as example, compositions administered by oral, nasal 20 (administration by aerosol), sublingual (administration by perlingual diffusion), rectal, parenteral, intravenous and percutaneous route. Examples of compositions administered by oral route include tablets, gelatin capsules, granules, microspheres, 25 powders and oral solutions or suspensions. Radical R 5 confers sufficient hydrophily on the compounds according to the invention, which are thus soluble in water and hydrophilic solvents in the presence of absence of various surfactants. Notably, they are 30 soluble in alcohol/polysorbate/water solvents, notably ethanol/Tween@/water and mannitol/water or with the assistance of cyclodextrins suitable for administration in man, which are frequently used for administration by intravenous route. The compositions according to the 35 invention can thus be administered by intravenous route. They can also be administered by oral or nasal route, notably via an aerosol or by perlingual diffusion or within a suitable galenic preparation (microemulsions) . Similarly, these compositions can be 5 used for transdermal administration. These compositions can be used notably as major analgesics, powerful analgesics for inflammatory and neurogenic pain, and as antidepressants. It is very advantageous that the compositions 10 according to the invention can be administered either in the form of aerosols (microemulsions) by oral or nasal route or by intravenous route. These administration routes thus allow administration of the inventive composition by a non-digestive route. This is 15 particularly advantageous when the composition comprises complementary compounds, which can exhibit undesired effects on the digestive system (notably the intestine), such as, for example, of cannabinoid derivatives. This also increases the cerebral 20 bioavailability of compounds or combinations. Another object of the invention is the use as a drug of compounds as defined above or obtained by a method as defined above. Surprisingly, it was also noted that the 25 combination of the novel compounds according to the present invention with cannabinoid derivatives leads to even stronger analgesic effects (superior to the sum of each effect observed for each compound, i.e., for the compounds according to the invention or the cannabinoid 30 derivatives). Until 1954, cannabis was regarded as a medicinal plant exhibiting multiple properties: analgesic, antispasmodic, anticonvulsive, anti-inflammatory, anti vomitive, bronchodilator, vasodilator, relaxant and soporific. Recently, anti-proliferative and anti neurodegenerative properties have been demonstrated. Several harmful effects of cannabis, generally related to overdose, have been described: anxiety 5 attacks for depressed patients and hallucinations when the product is consumed in drinks (tea) or food (cakes). The effects of cannabis are explained by its action on cannabinoid receptors. These receptors are 10 present in many cerebral structures and an endogenous molecule naturally related to it, anandamide, has been identified. Two types of receptors have been characterized: CBl receptors found in both the central nervous system 15 and the periphery and CB2 receptors which are primarily peripheral. CBl receptors appear involved in modulating neuronal release of excitory or inhibitory neurotransmitters in the brain. The role of CB2 receptors is less clear, but it seems that they 20 intervene in the modulation of the immune system. The endogenous molecules related to CBl and CB2 receptors, called "endocannabinoids," such as anandamide, interact with cannabinoid receptors in the brain and in the periphery by inducing various 25 pharmacologic effects. The most abundant psychotropic compound present in cannabis (Cannabis sativa) is A9 tetrahydrocannabinol (A' THC) .

A

9 THC induces numerous pharmacological responses, 30 such as analgesia, hypothermia, reduced locomotor activity and a loss of alertness and attention due to interactions with brain CBl receptors. Some of these properties have advantageous therapeutic applications for the treatment of pain and glaucoma, as well as to 35 attenuate nausea and to stimulate the appetite of patients treated with antitumor and antiviral compounds that have severe side effects. A THC, and more generally CB1 receptor agonists, is also able to reduce painful effects associated with multiple sclerosis 5 while reducing the progress of the disease. Nevertheless, this led to the development of SATIVEX, which is a preparation directly arising from the plant (Cannabis sativa) and which contains a mixture in equal parts of L 9 THC and cannabidiol (another substance 10 present in the plant). This preparation is currently at the end of clinical testing. However, the doses administered by orobuccal route are high and side effects have been observed (Current Opinion in Investigational Drugs 2004, 5, 748). 15 Another characteristic of the endogenous endocannabinoid (anandamide) system relates to the mode of synthesis and secretion of this specific neurotransmitter. Formed by enzymatic route from organelle membrane phospholipids, anandamide is 20 secreted by a transporter from a post-synaptic neuron to interact with CBl receptors located on a presynaptic terminal (retrograde neurotransmission) (Piomelli et al., TIS, 2000, 21, 218-224). However, several behavioral effects, such as a 25 loss of alertness and attention, sedation, ataxia, vision trouble, tachycardia, hypothermia and behavioral disturbances such as hallucinations, anxiety, panic attacks and memory problems, produced by chronic exposure to natural or synthetic cannabinoids, limit 30 their clinical use (reviewed in E.A. Carlini, The good and the bad effects of (-)trans-delta-9 tetrahydrocannabinol A 9 THC on humans, Toxicon, 2004, 44, 461-467) . Moreover, in man, the analgesic effects of L 9 THC are obtained at high doses near to the 35 amounts that cause the adverse effects mentioned above ZLU (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). 5 Surprisingly, it has been noted that the co administration (simultaneous or over time) of low doses of cannabinoid derivatives (notably L 9 THC) potentiates the analgesic effect and the antidepressant effect of the derivatives according to the invention (formula 10 (I)) without significantly inducing harmful effects of said cannabinoids, which by IV route appear beginning at 4-5 mg/kg (sedation). In the present invention, the expression "very low cannabinoid concentrations" means cannabinoid 15 concentrations below those inducing said undesirable side effects. In the present invention, the expression "cannabinoid" means L 9 THC, synthetic CB1 receptor agonists or anandamide degradation inhibiters. The 20 cannabinoids introduced into the compositions according to the invention are preferably t9 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 25 cannabinoid derivative, notably L 9 THC, or a protector of its metabolism (reviewed in Piomelli et al., TIPS, 2000), and a pharmaceutically suitable excipient, in particular an excipient suitable for administration by oral, nasal, intravenous or transcutaneous route. 30 The invention also relates to the use of at least one cannabinoid derivative, in particular A 9 THC, in a pharmaceutical composition to potentiate the analgesic and/or antidepressant effect of compounds of formula (I) as defined above.

LI The invention also relates to the use of a combination of at least one compound of formula (I) as defined above and of at least one cannabinoid derivative, in particular A 9 THC, for preparing a drug 5 intended for the treatment of depression and of pain. Another object of the invention is a pharmaceutical composition comprising: i) at least one compound of formula (I) as defined above, 10 ii) at least one cannabinoid derivative as combination products for simultaneous, separate or staggered use. Similarly, the invention also has as an object the use of a pharmaceutical composition comprising 15 i) at least one compound of formula (I) as defined above, ii) at least one cannabinoid derivative as combination products for simultaneous, separate or staggered use, for manufacture of a drug to treat 20 depression and pain. Within the 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 25 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 30 invention with morphine or a derivative of same. Indeed, morphine is also able to potentiate the analgesic effect induced by the compounds according to the invention. Thus, the invention has as an object a 35 pharmaceutical composition comprising at least one compound of formula (I) as defined above, of morphine or a derivative of same and a pharmaceutically suitable excipient, notably an excipient suitable for administration by oral, nasal, intravenous or 5 transcutaneous route. The composition can in addition comprise at least one cannabinoid derivative, notably

A

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 10 compounds can be used as combination products in a simultaneous, separate or staggered fashion. It is the good aqueous solubility of the compounds according to the invention of formula I that greatly facilitates the constitution of the preparation 15 (microemulsions, in solution in the presence of surfactants, etc.) suitable for therapeutic use by intravenous, nasal, pulmonary (aerosol) or transcutaneous routes. The effective dose of the inventive compound 20 varies according to a number of parameters, such as, for example, the administration route chosen; the patient's weight, age and sex; the stage of the pathology to be treated; and the patient's sensitivity. Consequently, optimal dosing will be determined, 25 according to the parameters considered to be relevant, by the relevant specialist. The invention will be further illustrated, without being limiting in any way, in the examples below. The list of compounds prepared according to example 12 is 30 given in table 1. For all of the compounds divulged in these examples: - Ri represents the -CH 2

-CH

2

-S-CH

3 radical, - CH 2 -(C:CH.S.CH:CH) represents the thiophen-3 ylmethyl radical, 35 - C:CH.CH:CH-CH:CH represents the phenyl radical, - C 6

H

11 represents the cyclohexyl radical. Example R 2 R3 R4 12a -CH 2 -(C:CH.S.CH:CH) -CH 3

-CH

2

-C(OCOCH

3

)(CH

2 0COCH 3 ) 12b -CH 2 -(C:CH.S.CH:CH) -CH 3

-CH

2

-CH

2

-SO

2

-CH

3 12c -CH 2 -(C:CH.S.CH:CH) -CH 3

-CH(CH

3

)-O-CO-()-C

2

H

5 12d -CH 2 -(C:CH.S.CH:CH) -CH 3

-CH

2

-CO-O-C

2

H

5 12e -CH 2 -(C:CH.S.CH:CH) -CH(OH)CH 3

-CH(CH

3

)-O-CO-O-C

2

H

5 12f -CH 2 -(C:CH.S.CH:CH) -CH 3

-CH(CH

2 0COCH 3

)

2 12g -CH 2 -(C:CH.S.CH:CH) -CH 3

-CH(CH

2

OH)

2

-H

2 C 0 H 12h -CH 2 -(C:CH.S.CH:CH) -CH 3 H OH O OH 12i -C:CH.CH:CH-CH:CH -CH(OH)CH 3

-CH(CH

3

)-O-CO-(-C

2 H 12j -C:CH.CH:CH-CH:CH -CH(OH)CH 3

-CH(CH

2

OCOCH

3

)

2 12k -C:CH.CH:CH-CH:CH -H -CH(CH 3

)-O-CO-)-C

2

H

5 121 -C:CH.CH:CH-CH:CH -H -CH(CH(CH 3

)

2 )-(-CO-O-C2H 5 12m -C:CH.CH:CH-CH:CH -H -CH(C 6 H, 1

)-O-CO-O-C

2

H

5 12n -C:CH.CH:CH-CH:CH -H -CH(C:CH.CH:CH-CH:CH)--C(-'-C 2 HS 12o -C:CH.CH:CH-CH:CH -H -CH(CH 3

Y)--CO-C

2

H

5 12p -C:CH.CH:CH-CH:CH -H -CH(CH(CH 3

)

2

)-O-CO-C

2

H

5 12q -C:CH.CH:CH-CH:CH -H

-CH(C

6

H

1 1

)-O-CO-C

2

H

5 12r -C:CH.CH:CH-CH:CH -H -CH(C:CH.CH:CH-CH:CH)-O-CO-C 2 H5 Table 1: radicals for examples 12a-12r. 5 Figure captions: Figure 1: Dose/response curve of analgesia induced by morphine or compound 15 injected by IV route in mice (hot plate test, 52'C); X-axis: dose in mg/kg, Y-axis % analgesia. 10 The black (upper) line corresponds to the results obtained for morphine, the grey (lower) line corresponds to the results obtained for compound 15. Figure 2: A) Antinociceptive response induced by compound 15 injected per os 20 min before the hot plate test (52 0 C, jump latency, seconds) in male OF1 mice (n=10); X-axis: dose of compound 15 in mg/kg, Y-axis % 5 analgesia. B) Effect kinetics of compound 15 after administration par os (n=10-17); X-axis: time (minutes), Y-axis % analgesia. Figure 3: Antinociceptive response induced by the 10 combination of compound 15 and L 9 -tetrahydrocannabinol. Hot plate (52±1 *C), jump latency, male OF1 mice. Cuff off: 240 sec. *** p<0.001 versus control, ### p<0.001 versus compound 15 and L 9 -THC. ANOVA + Newman-Keuls. X-axis: doses of compound 15 (0.4 mg/kg), THC 15 (0.375 mg/kg) and compounds 15/THC (0.4 and 0.38 mg/kg), Y-axis: % analgesia. Example 1: Synthesis of Boc-methioninethiol (compound 1) 20 This compound is 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; D20*C : 2 1 o (c=1.0 CHCl 3 ). 25 Example 2: Synthesis of (2S)-2-mercaptomethyl-3-phenyl propanoic acid (compound 2) Step 1. 2-acetylthiomethyl-3-phenylpropanoic acid methyl ester, obtained by the action of thioacetic acid on the methyl ester of the corresponding acrylate, 30 prepared according to (Ber., 57, 1924, 1116), is treated with a-chymotrypsin according to the general protocol described in (Bioor.Med.Chem.Let., 3, 1993, 2681). Yield: 71.4%; enantiomeric excess (ee): 88%, 35 aD20*C : -42.7.

Step 2. (2S)-mercaptomethyl-3-phenylpropanoic acid. The compound of step 1 is dissolved in 0 0C degassed methanol (MeOH). Under inert atmosphere, 3 equivalents (eq) of 1 N soda (NaOH) are added. The 5 mixture is agitated 30 min at room temperature (RT) . The mixture is acidified by adding 6 N hydrochloric acid (HCl) (25 ml) and MeOH is evaporated under reduced pressure. The aqueous phase is extracted by 2x125 ml AcOEt. The organic phase is washed by a solution of 10 saturated sodium chloride (sat. NaCl) then dried on sodium sulfate (Na 2

SO

4 ) and evaporated to dryness. A yellow oil is obtained. Yield 100%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% trifluoroacetate TFA) 60-40 4.96 min. 15 Example 3: Synthesis of (2RS) 2-mercaptomethyl-3 thiophen-3-ylpropanoic acid (compound 3) Step 1: A mixture of dimethylmalonate (392 mmol, 45 ml, 1 eq), thiophen-3-yl aldehyde (0.357 mmol), 20 piperidine (1.87 ml; 0.05 eq) and benzoic acid (4.58 g; 0.05 eq) is refluxed 12 h, using a Dean-Stark apparatus, in 270 ml of toluene. The organic phase is washed with 2x140 ml of 1 N HCl, 2x140 ml 10% sodium carbonate (NaHCO 3 ) and 140 ml of saturated NaCl. The 25 organic phase is dried on Na 2

SO

4 and evaporated to dryness. An oil is obtained. Yield 100%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 60-40: 5.97 min. Step 2: The compound of step 1 (340 mmol) is 30 solubilized in MeOH (540 ml) . The mixture is cooled to 0 *C and sodium borohydride (NaBH 4 ) is added little by little. The mixture is agitated 15 min at room temperature. The reaction is quenched by adding 450 ml 1 N HCl. Methanol is evaporated and the reaction 35 mixture is extracted with 2x500 ml of chloroform (CHC1 3 ) . The organic phase is washed with sat. NaCl then dried on Na 2

SO

4 and evaporated to dryness. An oil is obtained. Weight=64.1 g. Yield 82.4%. 5 Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 60-40: 5.91 min. Step 3: The preceding compound (30 mmol) is dissolved in MeOH (27 ml). The mixture is cooled to 0 *C and a solution of potash KOH (1.71 g 30.6 mmol) in 10 MeOH (365 ml) is added little by little. The mixture is agitated 48 h at 4 0C. Methanol is evaporated and the solid obtained is triturated in ethyl ether Et 2 0. The solid obtained is filtered, washed and dried. W=25.2 g. Yield 71.0%. 15 Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 60-40: 3.79 min. Step 4: The preceding compound (21.9 mmol) is dissolved in THF (30 ml) . Diethylamine Et 2 NH (3.0 ml; 2 eq) and 37% formaldehyde (3.7 ml; 1.5 eq) are added. 20 The mixture is refluxed overnight. THF is evaporated and the mixture is taken up in 90 ml AcOEt. The organic phase is washed with 3x30 ml 1 N HCl, sat. NaCl then dried on Na 2

SO

4 and evaporated to dryness. A colorless oil is obtained. 25 W=13,1 g. Yield 72.0%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50-50: 14.75 min. Step 5: The preceding compound (72 mmol) is brought to 80 0C for 5 h in thioacetic acid CH 3 COSH 30 (10 ml, 144 mmol, 2 eq) . The thioacetic acid is evaporated under reduced pressure. The mixture is coevaporated several times with cyclohexane. An orange oil is obtained. W=18.6 g. Yield 100%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50-50: 35 17.16 min.

LII Step 6. The compound of step 5 is dissolved in degassed MeOH at 0 *C. Under inert atmosphere, 3 eq of 1 N NaOH are added. The mixture is agitated 30 min at RT. The mixture is acidified by adding 6 N HCl (25 ml) 5 and MeOH is evaporated under reduced pressure. The aqueous phase is extracted with 2x125 ml AcOEt. The organic phase is washed with sat. NaCl then dried on Na 2

SO

4 and evaporated to dryness. A yellow oil is obtained. 10 Yield 100%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50-50 6.80 min. Example 4: Synthesis of (2S)-2-mercaptomethyl-3 thiophen-3-ylpropanoic acid (compound 4) 15 Step 1: 2-acetylthiomethyl-3-thiophen-3 ylpropanoic acid methyl ester, described in step 5 of the synthesis of compound 3, is treated with the a chymotrypsin, as described in the synthesis of 2 (step 1) . Yield 87.3%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 20 50-50 7.37 min. ee=76% Step 2: (2S) acetylthiomethyl-3-thiophen-3 ylpropanoic acid, obtained in step 1, is treated as described in step 2 of compound 2. Yield 97.0%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50-50 6.80 min. 25 Example 5: Synthesis of 2(2S)-benzyl 3((2S) 2t.butyloxycarbonylamino-4-methylsulfanyl butyldisulfanyl)-propanoic acid (compound 5) A mixture of 23 ml MeOH and 23 ml THF is cooled to 30 0 0C under nitrogen and chlorosulfonylchloride (1.3 ml, 15.25 mmol, 1.09 eq) is added. The mixture is agitated 15 min at 0 CC to give methoxy carbonylsulfenyl chloride. Then, compound 1 (14.86 mmol, 1.06 eq) in 16 ml THF/MeOH is added all at once. The mixture is 35 returned to room temperature and agitated 30 min. The zo preceding solution is added drop by drop to a solution of compound 2 (14.02 mmol, 1 eq) in 100 ml of degassed CHCl 3 in the presence of Et 3 N (1 eq) . The solution is agitated 1 h at room temperature. The solvent is 5 evaporated under reduced pressure. The mixture is taken up in dichloromethane CH 2 C1 2 . The organic phase is washed: 10% citric acid, sat. NaCl, then dried on Na 2

SO

4 to give a crude product, which is chromatographed on silica with a cyclohexane 10 (CHex)/AcOEt 8/2 mixture then 6/4 as eluent. W=4, 1 g. Yield: 65.9%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 70-30: 8.20 min. Example 6: Synthesis of 3-((2S)2 15 t.butyloxycarbonylamino-4-methylsulfanyl butyldisulfanyl)-(2RS)2-thiophen-3-ylmethyl-propanoic acid (compound 6) Following the protocol described for the synthesis of 5 and by replacing compound 2 by compound 3, 20 compound 6 is obtained. Yield: 77.0%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 70-30: 7.36 min. Example 7: Synthesis of 3-((2S)2 t.butyloxycarbonylamino-4-methylsulfanyl 25 butyldisulfanyl)-(2S)2-thiophen-3-ylmethyl-propanoic acid (compound 7) Following the protocol described for the synthesis of 5 and by replacing compound 2 by compound 4, compound 7 is obtained. Yield: 77%. Kromasil C18 HPLC 30 CH 3

CN/H

2 0 (0.5% TFA) 70/30: 7.36 min. Example 8: Synthesis of alanine esters Compound 8a: 2-methyl sulfonylethyl alanine ester,

TFA.

A solution of 1 eq of BocAlaOH, HOBt (1,2 eq, 879 mg), EDCI (1. 2 eq, 1. 93 g) , Et 3 N (triethylamine) (3 eq, 2.9 ml) in 10 ml CH2C1 2 is agitated 12 h at room temperature in the presence of 1.2 eq of 2 5 methylsulfonylethanol in solution in CH 2 C1 2 . The solvent is evaporated under reduced pressure. The reaction mixture is taken up in AcOEt/H 2 0. The organic phase is washed with 10% citric acid (2x15 ml), 10% NaHCO 3 (2x15 ml), saturated NaCl, dried on Na 2

SO

4 and 10 evaporated under reduced pressure to give a crude product which is chromatographed on silica with a CHex/AcOEt 8/2 mixture as eluent to give 989 mg of product. Yield: 61.8%. Rf (CHex/AcOEt: 6/4): 0.49. 15 435 mg (1.488 mmol) of this product are cold solubilized in 2.5 ml of CH 2 Cl 2 and 1.2 ml of TFA are added. The mixture is agitated 2 h at room temperature. The solvents are evaporated under reduced pressure. The mixture is coevaporated with cyclohexane. Product 8a is 20 cold precipitated in Et 2 0. Yield: 100%. Rf (CH 2 Cl 2 /MeOH: 9/1): 0.25. Compound 8b: 2,3-diacetoxypropyl alanine ester. A solution of 1.026 g (5.428 mmol, 1 eq) of BocAlaOH, HOBt (1.2 eq, 879 mg), EDCI (1.2 eq, 1.93 g), 25 Et 3 N (3 eq, 2.9 ml) in 10 ml CH 2 Cl 2 is agitated 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 C1 2 . The solvent is evaporated under reduced pressure. The reaction 30 mixture is taken up in AcOEt/H 2 0. The organic phase is washed with 10% citric acid (2x15 ml), 10% NaHCO 3 (2x15 ml), saturated NaCl, dried on Na 2

SO

4 and evaporated under reduced pressure to give 1.,62 g of a crude product. The mixture is chromatographed on silica j U with a CHex/AcOEt 8/2 mixture as eluent to give 1.29 g of product. Yield: 68.7%. Kromasil C18 HPLC CH3CN/H 2 0 (0.5% TFA) 70-30: 4.25 min. 5 This product is cold solubilized in 6 ml of CH 2 C12 and 6 ml of TFA are added. The mixture is agitated 2 h at room temperature. The solvents are evaporated under reduced pressure. The mixture is coevaporated with cyclohexane. Product 8b is cold precipitated in Et 2 0. 10 W=1.33g. Yield: 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 according to Bentley and McCrae, J.Org.Chem., 1971, 35, 15 2082) (7 mmol, 1.1 eq) is solubilized in 50 ml of Et 2 0. Then, diethyl azodicarboxylate (DEAD) (1.2 eq, 1.1 ml), BocAlanine (5.83 mmol, 1 eq) are added followed by triphenylphosphine (PPha) (1.2 eq, 1.83 g) and the mixture is agitated overnight at room temperature. The 20 solvent is evaporated under reduced pressure. The mixture is chromatographed on silica with a Heptane/AcOEt 8/2 mixture as eluent to give 2.14 g of product. Yield: 84.6%. Rf (Hept/AcOEt: 6/4): 0.42. 2.0 g (4.7 mmol) of this product are cold 25 solubilized in 6.5 ml of CH 2 C1 2 and 6.5 ml of TFA are added. The mixture is agitated 2 h at room temperature. The solvents are evaporated under reduced pressure. The mixture is coevaporated with cyclohexane and chromatographed on silica with a CH 2 Cl 2 /MeOH/AcOH 30 9/1/0.5 mixture as eluent to give 1.16 g of compound 8c. Yield: 65%. Rf (CH 2 Cl 2 /MeOH/AcOH: 9/1/0.5): 0.22. Compound 8d: 1,3(t.butyl dimethylsilyl)hydroxy-2 propyl alanine ester.

Dihydroxyacetone (2 g, 11.10 mmol) is dissolved in 50 ml of dimethyl formamide (DMF), tert-butyl dimethylsilyl chloride (tBuDMSCl) (4.8 eq, 8.03 g) and imidazole (10 eq, 7.56 g) are added and the mixture is 5 agitated 12 h at 20 'C. The mixture is evaporated to dryness, taken up in 150 ml AcOEt. The organic phase is washed with water H 2 0 (2x50 ml), 10% HCl (2x50 ml), saturated NaCl, then dried on Na 2

SO

4 and evaporated under reduced pressure to give 20.1 g of crude product. 10 The mixture is chromatographed on silica with CHex/AcOEt 8/2 as eluent to give 5.96 g of product. Yield: 84.5%. Rf (CH 2 Cl 2 /MeOH/AcOH: 9/1/0.5): 0.24. This product (8.82 g, 27.73 mmol) is dissolved in THF (74 ml) and H 2 0 (4.8 ml). The mixture is cooled to 15 5 0C and NaBH 4 (965 mg, 1 eq) is added little by little. The mixture is agitated 30 min at 5 0C. The excess of NaBH 4 is destroyed by adding acetic acid (1 ml) . The THF is evaporated under reduced pressure and the mixture is taken up in CHC1 3

/H

2 0. The organic 20 phase is washed with H 2 0 (2x50 ml), sat. NaHCO 3 (2x50 ml), saturated NaCl, then dried on 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) are 25 solubilized in 60 ml of Et 2 0. The mixture is agitated at room temperature and DEAD (1.2 eq, 1.56 ml), amino BocAcid (8.25 mmol, 1 eq) are added followed by PPh 3 (1.2 eq, 2.59 g). The solvent is evaporated under reduced pressure. The mixture is chromatographed on 30 silica with a CHex/AcOEt 95/5 mixture as eluent to give 4.42 g of product. Yield: 92.9%. Rf (CHex/AcOEt: 9/1): 0.65. 881 mg (1.79 mmol) of this product is cold solubilized in 3 ml of CH 2 C1 2 and 1.36 ml of TFA are 35 added. The mixture is agitated 2 h at room temperature.

The solvents are evaporated under reduced pressure. The mixture is coevaporated with cyclohexane. The mixture is cold precipitated in Et 2 0 to give 920 mg of compound 8d. 5 Yield: 100%. Rf (CHex/AcOEt: 9/1): 0.1. Compound 8e: Carbethoxymethyl alanine ester, TFA. BocAlaOH (5 g, 26.4 mmol) and Et 3 N (3.7 ml, 1 eq) are dissolved in 40 ml of AcOEt. The mixture is agitated 10 min at room temperature. Ethylbromoacetate 10 (6.62 g, 1.5 eq) is added and the mixture is refluxed for 30 min. The precipitate is filtered and then 30 ml

H

2 0 and 50 ml AcOEt are added to the filtrate. The aqueous phase is extracted with 3x30 ml AcOEt. The organic phase is washed with 10% citric acid (2x30 ml), 15 10% NaHCO 3 (2x30 ml), saturated NaCl, then dried on Na 2

SO

4 and evaporated under reduced pressure to give 7.09 g of a crude product. The mixture is chromatographed on silica with a CHex/AcOEt 6/4 mixture as eluent to give 4.68 g of product. 20 Yield: 64.3%. Rf (CHex/AcOEt: 6.4): 0.35. 500 mg (1.81 mmol) of this product is cold solubilized in 3 ml of CH 2 C1 2 and 1.4 ml of TFA are added. The mixture is agitated 2 h at room temperature. The solvents are evaporated under reduced pressure. The 25 mixture is coevaporated with cyclohexane. Product 8e is cold precipitated in Et 2 0. W=525 mg. Yield: 100%. Rf (CH 2 Cl 2 /MeOH: 95/5): 0.14. Compound 8f: Ethylcarbonate-l-ethyl alanine ester, 30 TFA. Boc Ala (76.54 mmol) and Et 3 N (12.27 ml, 1.2 eq) are dissolved in 70 ml of AcOEt. The mixture is agitated 15 min at room temperature. Ethyl-1 chloroethylcarbonate (prepared according to Barcelo et 35 al., Synthesis, 1986, 627) (14.01 g, 1.2 eq) and sodium iodine N'aI (926 mg, 0.1 eq) are added and the mixture is refluxed for 16 h. The precipitate is filtered and then 200 ml H 2 0 and 200 ml AcOEt are added to the filtrate. The aqueous phase is extracted with 3x300 ml 5 AcOEt. The organic phase is washed with 10% citric acid (2x150 ml), 10% NaHCO 3 (2x150 ml), saturated NaCl, then dried on Na 2

SO

4 and evaporated under reduced pressure to give 24.5g of a crude product. The mixture is chromatographed on silica with a CHex/AcOEt 9/1 mixture 10 as eluent to give 18.1 g of product. Yield: 77.51%. Rf (CH 2 Cl 2 /MeOH: 9/1) : 0.33. 9.15 g (30 mmol) of this product are cold solubilized in 23 ml of CH 2 C1 2 and 23 ml of TFA are added. The mixture is agitated 2 h at room temperature. 15 The solvents are evaporated under reduced pressure. The mixture is coevaporated with cyclohexane. Product 8f is cold precipitated in Et 2 0. W=9.57g. Yield: 77.5% (2 steps). Rf (CHex/AcOEt: 6/4): 0.1. 20 Compound 8g: Glucosyl alanine ester, TFA. Pentachlorophenol (3 eq, 10 g, 37.54 mmol) is solubilized at 0 0 C in 12 ml AcOEt and N,N' dicyclohexylcarbodiimide (DCC) (2.58g, 12.51 mmol) is added. The mixture is left 12 h at -20 0 C. Cold hexane 25 (10 ml) is added to the mixture and the solid is filtered and washed with cold hexane. The solid is recrystallized in hexane to give 10.3 g of brown solid. Yield: 82.0%. Mp: 115-130 *C. This complex is added to 120 ml of AcOEt. After 30 total dissolution, BocAlanine (1.0 eq, 10.25 mmol) is added and the mixture is agitated overnight at room temperature. The solvent is evaporated under reduced pressure and then 100 ml of Et 2 0 are added. The suspension is cooled for 1 h and then the solid is 35 filtered. The latter is suspended in 100 ml dioxane, filtered and washed with 2x20 ml dioxane. The filtrate is evaporated to dryness. The residue is treated again by dioxane to eliminate dicyclohexylurea (DCU). It is then suspended in 100 ml Et 2 0 and placed in the freezer 5 overnight. The solid is filtered and then dried to give 1.29 g of brown solid. Yield: 27.8%. To a solution of glucose (3 eq, 1.54 g) in 57 ml of redistilled pyridine is added the preceding compound and imidazole. The mixture is agitated overnight at 10 room temperature. The solvent is evaporated under reduced pressure to give a crude product. The mixture is chromatographed on silica with a AcOEt/AcOH 20/1 mixture as eluent to give 883 mg of product. Yield: 88.3%. Rf (AcOEt/AcOH: 20/1): 0.13. 15 883 mg (2.51 mmol) of this product are cooled to 0 *C and 61 ml of TFA are added. The mixture is agitated 5 min at 0 *C and then 30 min at room temperature. The TFA is evaporated under reduced pressure. The mixture is coevaporated with cyclohexane. 20 The mixture is cold precipitated in Et 2 0 to give 746 mg of brown compound 8g. Yield: 81.3%. Rf (AcOEt/AcOH: 10/1): 0.10. Example 9: Synthesis of threonine esters 25 Compound 9a: 1,3-diacetyl-2-propyl threonine ester, TFA. This compound is obtained following the protocol described for 8c, replacing Boc-alanine by Boc threonine. 30 Compound 9b: Threonine ethylcarbonate-1-ethyl ester, TFA. This compound is obtained following the protocol described for compound 8f, replacing Boc-alanine by Boc-threonine. 35 Yield: 89.7% Rf (CHex/AcOEt:6/4): 0.1.

Example 10: Synthesis of esters of the glycine Compound 10a: ethyl carbonate-l-ethyl glycine ester, TFA. 5 This compound is obtained following the protocol described for compound 8f, replacing Boc-alanine by Boc-glycine. Yield: 92% Rf (CHex/AcOEt 8/2) 0.22. Compound 10b: Ethyl carbonate 1-(-2-methyl) propyl 10 glycine ester, TFA. This compound is obtained following the protocol described for compound 10a, replacing ethyl-l chloroethylcarbonate by ethyl-l-chloro-2-methyl-propyl carbonate. 15 Yield: 88% Rf (CHex/AcOEt 8/2) 0.12. Compound 10c: Ethyl carbonate methylcyclohexyl glycine ester, TFA. This compound is obtained following the protocol described for compound 10a, replacing ethyl-l 20 chloroethyl carbonate by ethyl-chloromethyl cyclohexyl carbonate. Yield: 78%; Rf (CHex/AcOEt 7/3) 0.31. Compound 10d: Ethyl carbonate methylphenyl glycine ester, TFA. 25 This compound is obtained following the protocol described for compound 10a, replacing ethyl-l chloroethyl carbonate by ethyl chloromethylphenyl carbonate. Yield: 82%; Rf (CHex/AcOEt 7/3) 0.46. 30 Compound 10e: 1-(2-amino-acetoxy)-ethyl propionic acid ester (Gly-OCH(CH 3 )O-COEt). This compound is obtained by condensation between Boc-Gly and 1-chloroethyl propionate (1.1 eq) in the presence of NaI (0.2 eq) and Et 3 N (1.2 eq) in ethyl 35 acetate (10 ml/mmol) at reflux overnight. After cooling, the organic phase is washed with water, 10% citric acid, 10% NaHCO 3 , H 2 0, sat. NaCl and dried on Na 2

SO

4 . After evaporation, an oily product is obtained. Yield: 86%. 5 The Boc group is deprotected as described in the preceding examples. Solid white product, quantitative yield. Rf (CHex/AcOEt 6/4) 0.64. Compound 10f: 1-(2-aminoacetoxy)-2-methyl propyl 10 propionic acid ester (Gly-OCH(CH(CH 3

)

2 )0-COEt) . This compound is obtained following the protocol described in example 10e, replacing 1-chloroethyl propionate by 1-chloro-2-methyl propyl propionate. White solid, yield: 78% in two steps. Rf (CHex/AcOEt 15 6/4) 0.56. Compound 10g: (2-aminoacetoxy)-cyclohexyl-methyl propionic acid ester (Gly-OCH(CHex)O-COEt). This compound is obtained following the protocol described in example 10e, replacing 1-chloroethyl 20 propionate by chloromethyl(cyclo hexyl) propionate. White solid. Yield: 72% in two steps. Rf (CHex/AcOEt 6/4) 0.38. Compound 10h: (2-amino-acetoxy)-phenyl-methyl propionic acid ester (Gly-OCH(Ph)O-COEt). 25 This compound is obtained following the protocol described in example 10e, replacing 1-chloroethyl propionate by chloromethyl(phenyl)propionate. White solid. Yield: 75% in two steps. Rf (CHex/AcOEt 6/4) 0.42. 30 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 propanoyle chloride (0.54 mol, 2 eq) is 35 agitated at 40 *C for 4 h. The propanoyle chloride excess is then evaporated under a vacuum and the residue is triturated in ether. A solid product is obtained. It contains the expected thiadiazole and an impurity that is eliminated by precipitation in 5 ethanol. White solid, 33.6 g (Yield: 83%) Kromasil C18 HPLC Tr 6.32 min in 30% CH3CN. Example 12: Synthesis of mixed inhibiters wherein

R

5 =CH (R 3 ) COOR 4 . 10 Disulfide 5,6 or 7 (0.54 mmol) is solubilized in 4 ml of DMF. To it is added benzotriazole-1-yl-oxy tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) (1.2 eq, 1.0 g) and diisopropyl-ethyl-amine (DIEA) (284 pl) and then amino acid ester 8, 9 or 10 15 (1.3 eq). The mixture is agitated 20 min at room temperature and then the DMF is evaporated under reduced pressure. The product is taken up in AcOEt. The organic phase is washed with H 2 0, 10% citric acid, 10% NaHCO 3 , sat. NaCl and dried on Na 2

SO

4 . The crude product 20 is purified by chromatographed on silica. The compound obtained (0.38 mmol) is solubilized in 640 pl CH 2 C1 2 and 320 pl of TFA is added. The mixture is agitated 1 h at room temperature. The solvent excess is evaporated under reduced pressure. 25 The mixture is coevaporated with cyclohexane. The mixture is purified by semi-preparative HPLC or precipitated in a hexane/Et 2 0 mixture. Compound 12a: 1-(2-(1-(2,3 diacetoxypropoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3 30 ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl ammonium trifluoroacetate (compound 6 or 7 + compound 8b). W: 176 mg; Yield: 66.9%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (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 methanesulfonylethoxycarbonyl)-ethylcarbamoyl)-3 thiophen-3-ylpropyldisulfanylmethyl)-3 methylsulfanylpropyl-ammonium trifluoroacetate 5 (compound 6 or 7 + compound 8a). W: 200 mg; Yield: 74.1%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (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 10 ethoxycarbonyloxyethoxycarbonyl))-ethylcarbamoyl)-3 thiophen-3-yl-propyldisulfanylmethyl)-3 methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8f). W: 232 mg; Yield: 71.3%. Kromasil C18 HPLC 15 CH 3

CN/H

2 0 (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-propyldisulfanylmethyl)-3 20 methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8e). W: 261 mg; Yield: 83.9%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 50-50: 4.90 and 5.18 min. ESI: (M+H)*=539. Log Kow=1.35. 25 Compound 12e: 1- (2- (1- (1 ethoxycarbonyloxyethoxycarbonyl)-2 hydroxypropylcarbamoyl)-3-thiophen-3 ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl ammonium trifluoroacetate (compound 6 or 7 + compound 30 9b). W: 285 mg; Yield: 47.8%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (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 35 acetoxymethylethoxycarbonyl)-ethylcarbamoyl)-3thiophen-3-ylpropyldisulfanylmethyl)-3 methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8c). W: 171 mg; Yield: 70.1%. Kromasil C18 HPLC 5 CH 3

CN/H

2 0 (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-l hydroxymethylethoxycarbonyl) -ethylcarbamoyl) -3 thiophen-3-ylpropyldisulfanylmethyl)-3 10 methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8d). W: 166 mg; Yield: 67.2%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 40-60: 2.94 and 3.27 min. ESI: (M+H)*=497. Log Kow=-0.29. 15 Compound 12h: 1-(2-(1-(3,4,5,6 tetrahydroxytetrahydropyran-2-ylmethoxycarbonyl) ethylcarbamoyl)-3-thiophen-3-yl propyldisulfanylmethyl)-3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 6 or 7 + compound 8g). 20 W: 85 mg; Yield: 93.2%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (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 25 phenylpropyldisulfanylmethyl)-3-methylsulfanylpropyl ammonium trifluoroacetate (compound 5 + compound 9b). W: 1.88g; Yield: 83.8%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 45-55: 7.0 min. ESI: (M+H)*=563. Log Kow=0.76. 30 Compound 12j: 1-(2-(1-(2-acetoxy-1-acetoxymethyl ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3 phenylpropyldisulfanylmethyl) -3-methylsulfanylpropyl ammonium trifluoroacetate (compound 5 + compound 9a).

9 U W: 532 mg; Yield: 53.6%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 40-60: 6.16 min. ESI: (M+H)*=605. Log Kow=0.44. Compound 12k: 1-(2-(1-ethoxycarbonyloxy 5 ethoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl) -3-methylsulfanylpropyl-ammonium trifluoroacetate (compound 5 + compound 10a). W: 1.76g; Yield: 89.5%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (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 propyldisulfanylmethyl)-3-methylsulfanyl-propyl ammonium trifluoroacetate (compound 5 + compound 10b). 15 W: 1.2g; Yield: 82.3%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50/50 9.33 min, ESI: (M+H)*=547. Compound 12m: 1-2-((cyclohexyl-ethoxycarbonyloxy methoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl 20 ammonium trifluoroacetate (compound 5 + compound 10c). W: 2.lg; Yield: 65.3%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50/50 12.65 min, ESI: (M+H)*=587. Compound 12n: 1-(2-( (ethoxycarbonyloxy-phenyl methoxycarbonylmethyl) -carbamoyl) -3-phenyl 25 propyldisulfanylmethyl)-3-methylsulfanyl-propyl ammonium trifluoroacetate (compound 5 + compound 10d) W: 0.95 g; Yield: 68.1%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 50/50 10.86 min. ESI (M+H)*=581. Compound 12o: 3-methylsulfanyl-1-(3-phenyl-2-((1 30 propionyloxy-ethoxycarbonylmethyl)-carbamoyl) propyldisulfanylmethyl) -propyl-ammonium trifluoroacetate (compound 5 + compound 10e). W: 1,6 g; Yield: 81,2%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 50/50 6,82 min. ESI (M+H)*=502.

Compound 12p: 1-(2-((2-methyl-1-propionyloxy propoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl ammonium trifluoroacetate (compound 5 + compound 10f). 5 W: 1.05 g, yield: 83%. Kromasil C18 HPLC CH 3

CN/H

2 0 (0.5% TFA) 50/50 8.17 min. ESI (M+H)*=531. Compound 12q: 1-(2-((cyclohexyl-propionylaxy methoxycarbonylmethyl)-carbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanyl-propyl 10 ammonium trifluoroacetate (compound 5 + compound 10g). W: 1.8 g; Yield: 78.2%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 50/50 12.24 min. ESI (M+H)*=571. Compound 12r: 3-methylsulfanyl-1-(3-phenyl-2 ((phenyl-propionyloxy-methoxycarbonylmethyl) 15 carbamoyl) -propyldisulfanylmethyl) -propyl-ammonium trifluoroacetate (compound 5 + compound 10h) W: 0.98 g; Yield: 76.3%. Kromasil C18 HPLC

CH

3

CN/H

2 0 (0.5% TFA) 50/50 11.25 min. ESI (M+H)*=565. 20 Example 13: Synthesis of mixed inhibiters wherein Rs=heterocycle Disulfide 5, 6 or 7 (0.54 mmol) is dissolved in 5 ml of CH 2 C1 2 and the aminothiadiazole of example 11 (1.2 eq), TBTU (0-benzotriazol-1-yl-N,N,N',N' 25 tetramethyluroniumtetrafluoroborate) (3 eq) and DIEA (diisopropylethylamine) (3 eq) are successively added. The mixture is agitated for 30 minutes at room temperature (approximately 20 *C). The solvent is evaporated under a vacuum and the residue taken up in 30 ethyl acetate. The organic phase is washed with citric acid, water, saturated NaCl and dried on Na 2

SO

4 . After vacuum filtration and evaporation, a white solid is obtained. The compound obtained is dissolved in formic acid 35 and the mixture is agitated 1 h at room temperature.

The excess formic acid is evaporated under a vacuum. The residue is taken up ether and gives a white precipitate. 5 Compound 13a: 3-(2-amino-4-methylsulfanyl butyldisulfanyl)-2-benzyl-N-(5-ethyl-(1,3,4)thiadiazol 2-yl)-propionamide W=256 mg (Yield 75%). 10 Example 14: Change of counter-ion The compounds of example 12 and example 13 (1 mmol) are solubilized in 9 ml of distilled AcOEt. The organic phase is washed with 12 ml 0.1 N NaHCO 3 . The organic phase is then dried and evaporated under 15 reduced pressure. The product is taken up in AcOEt (3 ml), cooled to 0 *C and 1 eq of the chosen AH acid in 3 ml of AcOEt is added. The solvent is evaporated and the product is cold precipitated in an Et 2 0/hexane mixture. 20 (A=phosphate, hydrochloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, 25 phenylglyoxylate, nicotinate). Example 15: Pharmacological results - compound according to the invention Compound 15 of the following formula was tested in 30 the various biological tests below.

S O 4 S-S NH O O Ot

H

2

PO

4

H

3 N 1 1 1 lh 0 0 Hot plate test: this test relates to the licking and jumping reflex in mice on a plate heated at 52 0C (measurement of jump latency in the examples given). 5 The results are expressed in % of maximum possible effect (% MPE), i.e., expressed as a percentage of analgesia, using the following equation: (Measured latency time-control latency time) 10 % MPE= (Maximum latency time-control latency time) Maximum latency time=240 seconds. The results are expressed in term of mean ± SEM. 15 The differences observed are considered significant when the values of p are less than 0.05. The test used is an ANOVA test with a multiple comparison test. a) Antinociceptive responses observed after injection by intravenous (IV) route of compound 15 in 20 the hot plate test (52 *C, response per jump) in male mice (n=10). Compound 15 is dissolved in a water/mannitol mixture (50 mg/ml) . Jump latency times are measured 10 min after the injections by intravenous route. 25 Table 2 Dose mg/kg % analgesia 10 33.4 7.5** 20 59.2 9.6*** 40 90.2 7.0*** The results (table 2) show that compound 15 exhibits a dose-dependant analgesic action. **p<0.01; ***p<0.001 versus vehicle. 5 Effective dose 50, ED 5 o, is 16.1 mg/kg.

ED

5 o 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) Antinociceptive effect of compound 15 10 (100 mg/kg par os) on vocalization threshold when pressure is applied to the paw of a rat (male Sprague Dawley) with an inflamed paw, inflammation being induced by intraplantar injection of carrageenan. Compound 15 and a vehicle (ethanol/polyethylene 15 glycol (PEG) 400/water, 10/40/50) are administered 180 min after intraplantar injection of carrageenan (1% in saline solution). Table 3 Vocalization threshold (g) Basal threshold 298.8 ± 18.7 Inflamed paw + vehicle 205.5 ± 17.8 Inflamed paw + compound 15 292.5 ± 20.1*** 20 The baseline for vocalization threshold when pressure is applied to the paw is measured before inflammation (B) and for the inflamed paw 20 min after injection of compound 15 or the vehicle. The results are given in table 3 and are expressed as mean ± SEM, 25 n=10. The differences observed are considered significant when the values of p are less than 0.05. These results show that compound 15 is effective in the treatment of neurogenic inflammatory pain. ***p<0.001 versus vehicle. 30 c) Antinociceptive responses observed after IV injection of compound 15 dissolved in ethanol/surfactant/water (10/10/80) in the hot plate test (52 'C, response per jump) in male OF1 mice and comparison of the responses according to the nature of the vehicle. 5 Compound 15 is dissolved in a ethanol/Cremophor@EL/water mixture. Jump latency times are measured 10 min after intravenous injection. The results are given in figure 1. The dose-dependant response provides an analgesic 10 response at an effective dose 50 (ED 5 o) of 1.9 ± 0.4 mg/kg. This value is close to that observed with morphine (ED 5 o=1.3 ± 0.2 mg/kg). **p<0.01 versus vehicle. ***p<0.001. Compound 15 is also soluble in 15 ethanol/Tween@/water solvents, frequently used for administration by intravenous route in man. In these solvents, the differences are not significantly different from those observed with Cremophor@EL. This is illustrated in table 4 (jump 20 latency time 10 min after injections) at the same concentration of 2.5 mg/kg IV. ***p<0.001 versus vehicle. Table 4 % analgesia Cremophor EL 56.2 ± 6.9*** Tween 80 44.7 ± 6.2*** Tween 20 48.4 ± 10.2*** 25 d) Antinociceptive effect of compound 15 injected per os 20 min before the hot plate test: a) dose response curve; b) effect kinetics after administration per os of 200 m/kg. Compound 15 is dissolved in an 30 ethanol/PEG400/water 10/40/50 mixture. The results, given in the figures 2a and 2b, show that compound 15 exhibits a dose-dependant analgesic effect (2a),

ED

50 =135 mg/kg, and that the analgesic effect of compound 15 is very high right after administration and persists, with a lesser effect, for at least two hours 5 (2b). *p<0.05; **p<0.01; ***p<0.001 versus vehicle. #p<0.05; ###p<0.001 versus compound 15. e) Comparative antinociceptive responses observed after IV injection of compound 15 (n=14-17) or of 10 compound A (n=8-14), 5 mg/kg, in the hot plate test (52 0C, response per jump) in male mice. Compound A is the compound of formula: S 0 S-S NH

H

2 N 0 0 which was described in prior patent application 15 WO 91/02718 (example 7) . It is a mixed inhibiter of neprilysin and aminopeptidase that exhibits analgesic properties. It is poorly soluble in aqueous or hydrophilic solvents. Compounds 15 and A are dissolved in an 20 ethanol/CremophorEL/water 10/10/80 mixture. Jump latency times are measured 10 min after intravenous injection. Table 5 % analgesia Compound 15 87.6 ± 4.6**,### Compound A 51.1 ± 7.6** 25 The results given in table 5 show that at identical doses (low for administration of compound A 4 / by IV route), compound 15 is more active than compound A. **p<0.01 versus vehicle, ###p<0.001 versus compound A. 5 f) Analgesia induced by morphine or compound 15 injected by IV route in mice (hot plate test, 52 CC). The analgesia produced by morphine or compound 15 in mice (male OFl) in the hot plate test (52 0C) was measured. Morphine in H 2 0/NaCl, 9/1000) or compound 15 10 dissolved in the vehicle EtOH/Cremophor EL/water (10/10/80) is injected by IV. The results are measured 10 minutes after injection and latency time is 240 seconds (equation given in examples 15 and 17). The results are presented in table 6 below: 15 Table 6 Dose (mg/kg) 1 2.5 5 % analgesia compound 15 46.4 ±5.6*** 56.3 6.9*** 87.6t4.6*** % analgesia morphine 45.5 i 4.5*** 66 i6.0*** 100*** ***p<0.001, ANOVA test It is noted that compound 15 has analgesic effects 20 comparable with those obtained with morphine. This agrees with the results of another experiment carried out under identical conditions (Figure 1, example 15c). Example 16: Analgesic effect of 8 9 THC alone 25 The analgesia produced by L9 THC in mice (male OF1) in the plate hot test (52 CC) was measured. A9 THC, dissolved in the vehicle EtOH/Cremophor EL/water (10/10/80), is injected by IV route. The results are measured 10 minutes after injection and latency time is 30 240 seconds (equation given in examples 15 and 17). The results are presented in table 7 below: Table 7 Dose (mg/kg) 0.188 0.375 0.75 1.5 % analgesia 0.4 ±3.9 18.2±6.4 41.2±12.7** 57.2±10.9*** **p<0.01; ***p<0.001 It is noted that A 9 THC produced a dose-dependant 5 analgesic effect. Significant analgesia values are observed for doses of 0.75 mg/kg and 1.5 mg/kg. At lower doses, the percentage of analgesia is not significant. 10 Example 17: Analgesic effects of the compound according to the invention + L 9 THC The experiments described to demonstrate the magnitude of the synergistic action of the compound according to the invention combined with A 9 THC were 15 carried out in rodents (rat and mouse) using antinociception tests classically used in the pharmaceutical industry to demonstrate this type of property, namely: - the hot plate test (Eddie and Leimbach, 20 J.Pharmacol.Exp.Ther. 107, 385-389, 1953) in mice, - the tail-flick 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, tail-flick), the concentrations: - in cannabinoids (A 9 THC) will preferentially be between 0.3 and 0.5 mg/kg, 30 - in the compound according to the invention (compound 15) will preferentially be between 1 and 2 mg/kg. The relative concentrations are dependant on nociceptive stimulation.

The A9 THC used in the examples below is a commercial product purchased from Sigma-Aldrich (T2386). The mixed inhibiter used in the following examples 5 is compound 15 described above (example 15). Preparing solutions of the compounds All of the compounds were solubilized in an ethanol/Cremophor 80/water = 10/10/80 mixture. For the potentiation experiments (synergy), doses 10 of L9 THC and inhibiters were used that, taken separately, do not induce significant responses. Mode of administration The various compounds are administered, in a mixture in the same syringe, by IV route in the tail of 15 the rat or mouse. Animals The mice used in these tests are male OFl mice. The rats used in these tests are male Sprague-Dawley rats. 20 Pharmacological tests - Hot plate test: This test relates to the licking and jumping reflex in mice on a plate heated at 52 *C. The results are expressed in % of maximum possible effect (% MPE), 25 i.e., expressed as a percentage of analgesia, using the following equation: (Measured latency time-control latency time) % MPE= 30 (Maximum latency time-control latency time) Maximum latency time=240 s. The results are expressed in terms of mean ± SEM. The differences observed are considered significant 35 when the values of p are less than 0.05. - Tail-flick test: This test relates to the tail-flick reflex in the rat, stimulated by radiant heat emanating from a source of light focused on a given part of the tail. The results are expressed as in the preceding experiment by 5 the measurement of a percentage of analgesia according to the same equation. The maximum latency time is fixed arbitrarily at 15 seconds. - Swim test: This test measures the immobilization time for a 10 mouse placed in a water bath at 21-23 'C, from which it cannot escape. Immobilization time reflects a form of depression; the mice no longer struggle to escape the hostile environment. The results are expressed in immobilization time. Maximum immobilization time is 4 15 min. For the need of demonstrating the synergy of the combination of compound 15 + A 9 THC, a dose-response curve for compound 15 alone and ZO THC alone are prepared in the solvent ethanol/Cremophor EL/H 2 0 20 (1/1/8) because A 9 THC can be used only by IV route at high concentrations under these conditions (example 16). The histogram (figure 3) of analgesic responses (hot plate) clearly shows the very high potentiation of the analgesic effect of the L 9 THC plus compound 15 25 combination compared to one or the other of the products alone. a) Antinociceptive response induced by the injection of a mixture of compound 15 and A 9 THC by IV route in male OF1 mouse in the hot plate test (figure 30 3). The mixture of compounds 15 (0.4 mg/kg) and A 9 THC (0.375 mg/kg) are injected in the vehicle ethanol/Tween 80/water (10/10/80). The mice weigh 25-30 grams. This solvent mixture is compatible with administration by IV 35 route in man and in animals.

Jump latency is measured 10 minutes after intravenous injection. The results are expressed as percentage analgesia, using the equation defined above, and are presented in figure 3. 5 The difference observed is considered significant for p 0.05 - One-way ANOVA followed by a multiple comparison test. ***: p 0.01 versus control, ###: p 0.01 versus the mixture of compounds 15 and L 9 THC. 10 b) Antinociceptive response induced by injection of a mixture of compounds 15 and A9 THC by IV route in the tail-flick test in male Sprague-Dawley rats. The mixture of compounds 15 (5 mg/kg) and L9 THC (0.375 mg/kg) are injected in the vehicle ethanol/Tween 15 80/water (10/10/80). Tail-flick latency is measured before injection (pretest) and 10 minutes after intravenous injection (test). Latency time is 15 seconds. The rats weigh 260-300 grams. 20 The results are presented in table 8. Table 8: Tail-flick test % analgesia Vehicle -3.9±3.3 Compound 15 -4.2±1.9

A

9 THC 23.3±2.4*** Compound 15 and _9 THC 39.2i7.7**,***,# ***: p<0.001 versus vehicle, **:P<0.001 versus compound 15, #: p<0.05 versus A 9 THC. 25 The difference observed is considered significant for p 0.05. Two-way ANOVA followed by a multiple comparison test: ***: p 0.001, **:p 0.01 versus vehicle group; #:p 0.05 versus 8 9 THC group; ***p 0.001, 30 **p 0.01 versus compound 15 group.

c) Antidepressant response induced by injection of a mixture of compound 15 and ZO THC by IV route in the swim test in male OF1 mice. The mixture of compounds 15 (5 mg/kg) and A 9 THC 5 (0.375 mg/kg) are injected in the vehicle ethanol/Tween 80/water (10/10/80) by intravenous route 10 minutes before the test. Total immobilization time is measured for 4 minutes. 10 The results are presented in table 9. The mice weigh approximately 25-30 grams. The difference observed is considered significant for p 0.05. One-way ANOVA followed by a multiple comparison test: ***: p0.001, *:p 0.05 versus vehicle 15 group; ###: p 0.001 versus compounds 15/A 9 THC group; and A9 THC group. Table 9: Depression/swim test. Mobilization Vehicle 230.7±4.5 Compound 15 180±8.4*** L9 THC 206±6.1 Compound 15 / L9 THC 137.4±8.8***,### ***: p<0.001 versus control, ###: p<0.001 versus L9 THC 20 and compound 15. Conclusion: It is noted that the administration of a low dose of cannabinoid, A9 THC, i.e., at concentrations less 25 than 0.5 mg/kg by IV route in mice, potentiates the antinociceptive or antidepressant responses induced by compound 15. Under these conditions, synergy is quite clearly demonstrated when the analgesic effects obtained in the 30 hot plate test in mice by comparing the dose-response 53 curves for A9 THC and compound 15 with the effect produced by sub-analgesic doses of these two compounds (Figure 3). It can be noted that the amplification factors of 5 the active dose of A9 THC alone/active dose of L 9 THC plus compound 15, and conversely, the active dose of compound 15 alone/active dose of compounds 15 + L 9 THC, are in both cases much greater than 10 and are not easily calculable precisely since the doses used of 10 compound 15 and L 9 THC are inactive when these two molecules are used alone at these same doses. The intensity of the antinociceptive response elicited by the combination of the inventive compound (mixed inhibiter NEP/APN; for example compound 15) and 15 of 8 9 THC, both substances being administered at very low doses at which they have no activity, indicate the existence of action synergy between endogenous enkephalins (protected by the inventive compound) and A9 THC. This is corroborated by an isobolographic 20 analysis of pharmacological responses. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (21)

1. A compound of following formula (I): H 2 N-CH (R 1 ) -CH 2 -S-S-CH 2 -CH (R 2 ) -CONH-R 5 5 wherein: R 1 represents: - a hydrocarbon chain, saturated or unsaturated, linear or branched, comprising from 1 to 6 carbon atoms, optionally substituted by: 10 * an OR, SR or S(0)R radical, wherein in each of these radicals R represents a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl or benzyl radical, 15 * a phenyl or benzyl radical, - a phenyl or benzyl radical optionally substituted by: * 1 to 5 halogens, notably fluorine, * an OR, SR or S(O)R radical, wherein in 20 each of these radicals R is defined as above, - a methylene radical substituted by a 5- or 6 atom heterocycle, aromatic or saturated, having as a heteroatom an atom of nitrogen or sulfur, 25 optionally oxidized in the form of N-oxide or S-oxide; R 2 represents: - a phenyl or benzyl radical, optionally substituted by: 30 * 1 to 5 halogen atoms, notably fluorine, * an OR or SR radical, wherein in each of these radicals R is defined as above, * an amino group optionally mono- or di substituted by an aliphatic, cyclic or 35 linear group of 1 to 6 carbon atoms, C:\NRPonb[\DCC\RBRul412n DOC.1rMI12l'12 -55 * a 5- or 6-atom aromatic ring, - a 5- or 6-atom aromatic heterocycle, the heteroatom being oxygen, nitrogen or sulfur, - a methylene group substituted by a 5- or 6-atom 5 heterocycle, aromatic or saturated, the heteroatom being oxygen, nitrogen or sulfur, the nitrogen and sulfur atoms possibly being oxidized in the form of N-oxide or S-oxide. R 5 represents: 10 a CH(R 3 )-COOR 4 radical wherein R 3 represents: - hydrogen, - an OH or OR group, with R as defined above, - a saturated hydrocarbon chain (alkyl), linear or 15 branched, comprising from 1 to 6 carbon atoms, optionally substituted by an OR or SR radical, wherein in each of these radicals R is defined as above, - a phenyl or benzyl radical, optionally substituted 20 by: * 1 to 5 halogens, notably fluorine, * an OR or SR radical, with R as defined above. and OR 4 represents 25 - an OCH 2 COOR' glycolate or OCH(CH 3 )COOR' lactate radical, wherein in each of these radicals R' represents * a saturated hydrocarbon chain (alkyl) with 1 to 6 carbon atoms, linear or branched and 30 optionally substituted by an alkoxy group at C1 to C3, * a cycloalkyl group at C5-C8, * a phenyl, benzyl, heteroaryl, alkylheteroaryl group, C \NRPonblDCC\RBR\4241274_ I DOC-311/03/2012 - 56 - an OCH(R")O(CO)OR' or OCH(R")O(CO)R' group, wherein in each of these radicals R' is defined as above and R" represents * a hydrogen atom, 5 * a Cl-C6 alkyl chain, linear or branched, optionally substituted by a Cl-C3 alkoxy group, * a C5-C8 cycloalkyl group, * a phenyl, benzyl, heteroaryl, alkylheteroaryl group, 10 - an OCH (CH 2 OCOR' ) 2 or OCH 2 - CH (OCOR ')-CH 2 0COR ' triglyceride radical, wherein in each of these radicals R' is defined as above, - a glycoside radical such as D-glucose, -D glucopyranose, a- or -galactopyranose, 15 - an OCH 2 CH 2 (SO 2 )CH 3 sulfonate radical, - an OCH(CH 2 OH) 2 radical; as well as additive salts of the aforesaid compounds (I) with pharmaceutically acceptable mineral or organic acids. 20

2. The compound according to claim 1, wherein R 1 represents an alkyl radical having from 1 to 4 carbon atoms substituted by a SR radical, with R defined as above, notably with R representing a saturated hydrocarbon chain, 25 linear or branched, with 1 to 4 atoms of carbon.

3. The compound according to claim 1 or claim 2, wherein radical R 2 represents a benzyl radical or a methylene radical substituted by a 5- or 6-atom heterocycle, aromatic 30 or saturated, having as a heteroatom an atom of nitrogen or C\NRPonbhDCC\RBR\J24j27 _I I)OC. 1 I124)12 - 57 sulfur, optionally oxidized in the form of N-oxide or S-oxide.

4. The compound according to any one of claims 1 to 5 3, wherein radical R 3 represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms substituted by an OH or SH radical.

5. The compound according to any one of claims 1 to 10 4, wherein radical OR 4 represents an OCH(R")O(CO)OR' or OCH(R")O(CO)R' group, - the R' radical representing a Cl-C4 alkyl chain, and - the R" radical representing a methyl, CH(CH 3 ) 2 , cyclohexyl or phenyl radical. 15

6. The compound according to any one of claims 1 to 5, wherein said compound is selected from the group consisting of: 1-(2-(1-(2,3-diacetoxypropoxycarbonyl)-ethylcarbamoyl) 20 3-thiophen-3-ylpropyldisulfanylmethyl)-3 methylsulfanylpropyl-amino, 1-(2-(1-(2-methanesulfonylethoxycarbonyl) ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3 methylsulfanylpropyl-amino, 25 1-(2-(1-(l-ethoxycarbonyloxyethoxycarbonyl)) ethylcarbamoyl)-3-thiophen-3-yl-propyldisulfanylmethyl)-3 methylsulfanylpropyl-amino, 1-(2-(l-ethoxycarbonylmethyloxycarbonylethyl carbamoyl) 3-thiophen-3-yl-propyldisulfanylmethyl)-3 30 methylsulfanylpropyl-amino, 1-(2-(1-(l-ethoxycarbonyloxyethoxycarbonyl)-2 hydroxypropylcarbamoyl)-3-thiophen-3 ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amino, C xNRpoahlflCCRBRWA1~274_I OOCWAI/I21 - 58 1- (2- (1-(2-acetoxy-l-acetQxymfethylethoxycarbonyl) ethylcarbamoyl) -3-thiophen-3-ylpropyldisufalmethyl) -3 methylsulfaflylpropyl-amilo, 1- (2- (1-(2-hydroxy-1--hydroxymethylethoxycarbofyl) 5 ethylcarbanoyl) -3-thiophen-3-ylpropyldisufalmethyl) -3 methylsulfanylpropyl-amilo, 1- (2- (1-(3, 4,5, 6-tetrahydroxytetrahydropyrafl> ylmethoxycarbolyl) -ethylcarbanoyl) -3-thiophen-3-yl propyldisulfanylmethYl)-3-methylsulfanylpropy1-amilo, 10 1- (2- (1- C1-ethoxycarbonyloxy-ethoxycarboflYl) -2 hydroxypropylcarbamoyl) -3-phenylpropyldisulalylmethyl) -3 methylsulfaflylpropyl-amilo, 1- (2- (1-(2-acetoxy-l-acetoxymethy1-ethQxycarbonyl) -2 hydroxypropylcarbamoyl) -3-phenylpropyldisulfalylmethyl) -3 15 methylsultanylpropyl-amilo, 1- (2- ( (lethoxycarbonyloxy-ethoxycarboflmethyl) carbamoyl) -3-pheny1-propyldisulfalmethyl) -3 methylsulfanylpropyl-amilo, 1- (2- ( (-ethoxycarboloxy-2-methy]l 20 propoxycarbonylmethyl) -carbatnoyl) -3 -phenyl propyldisulfanylmethyl) -3-methylsulfalyl-propy1-amnie, 1- (2- ((cyclohexyl-ethQxycarboflloxy methoxycarbonylmfethyl) -carbamoyl) -3 -phenyl propyldisulfanylmethyl) -3-methylsulfalyl-propyl-amnie, 25 1- (2- ((ethoxycarbonyloxy-phelyl-ethoxycarbonlmethyl) carbamoyl) -3-pheny1-propydisufalmTethy1) -3 methylsulfanyl-propyl- amine, 3-rnethylsulfalyl-l-(3-phenyl-2- ((1-propionyloxy ethoxycarbonylmethyl) -carbamoyl) -propyldisulfanylmethyl) 30 propyl-amine, 1- (2- ((2-methy1-1-propionyloxy-propoxycarbolmethyl) carbamoyl) -3-phenyl-propyldisulfalmethyl) -3 methylsulfanyl-propy1 amine, C:\NRPonbADCCMRBR\J242lJ_ DOC11AWf/2012 - 59 1- (2- ((cyclohexyl-propionyloxy-methoxycarbonylmethyl) carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3 methylsulfanyl-propyl-amine, and 3-methylsulfanyl-l-(3-phenyl-2-((phenyl-propionyloxy 5 methoxycarbonylmethyl) -carbamoyl) -propyldisulfanylmethyl) propyl-amine.

7. A drug comprising a compound of formula (I) according to any one of claims 1 to 6. 10

8. A pharmaceutical composition, comprising at least one compound of formula (I) , according to any one of the claims 1 to 6, and a pharmaceutically suitable excipient. 15

9. The pharmaceutical composition according to claim 8, wherein the excipient is suitable for administration by oral, nasal or intravenous route.

10. The pharmaceutical composition according to claim 20 8 or claim 9, for the treatment of depression and the various types of pain, such as acute pain, inflammatory pain and neurogenic pain.

11. The pharmaceutical composition according to any 25 one of claims 8 to 10, comprising in addition at least one cannabinoid derivative.

12. A pharmaceutical composition comprising: i) at least one compound of formula (I), according to 30 any one of claims 1 to 6, and ii) at least one cannabinoid derivative C \NRPonhiRC RBRu2412 i I DOC-'A1m/2112 -60 as combination products for simultaneous, separate or staggered use.

13. The pharmaceutical composition according to any 5 one of claims 8 to 12, said composition comprising in addition morphine or a derivative of the same.

14. The use of a compound of formula (I) according to any one of the claims 1 to 6, for preparing a drug to treat 10 depression and pain.

15. The use of at least one cannabinoid derivative, in a pharmaceutical composition to potentiate the analgesic and/or antidepressant effect of compounds of formula (I) 15 according to any one of the claims 1 to 6.

16. The use of a combination of at least one compound of formula (I) according to any of claims 1 to 6 and at least one cannabinoid derivative, for preparing a drug to 20 treat depression and pain.

17. The use of a pharmaceutical composition comprising: i) at least one compound of formula (I), according to 25 any one of the claims 1 to 6, and ii) at least one cannabinoid derivative as combination products for simultaneous, separate or staggered use, for preparing a drug to treat depression and pain. 30

18. The use of a combination of at least one compound of formula (I) according to any one of the claims 1 to 6 and C NRPorbl\DCC\RBR\21274_ I DOC.1M)I2012 -61 morphine or a derivative of the same, for preparing a drug to treat depression and pain.

19. A method for the treatment of depression and pain 5 comprising administration of a compound according to any one of claims 1 to 6 to a patient in need thereof.

20. A compound according to claim 1 substantially as hereinbefore described. 10

21. A drug according to claim 7, a pharmaceutical composition according to claim 8 or claim 12, a use according to any one of claims 14 to 18 or a method according to claim 19, substantially as hereinbefore 15 described.