FR2699178A1 - New glycosyl phospho:tri:ester derivs of CNS active agents - Google Patents

Abstract

Glycosyl phospho-triester derivs of formula R1-P(O)(OR2)AM (I) are new. In (I), A = O, N or S; R1 = either 5 or 6C sugar or desoxy sugar which may be substdn in the D or L series; n = 1-6; and the link between the sugar and phosphorus is through OH at position 2,3,4 or 6, or (Ose)x-O-((CH2)y-O)z-, where Ose is 5 or 6 C sugar; D or L configuration, with the indicated chain attached through position 1; x = 1-12; y = 1-16; z = 1-4; R2 = 6-30 C opt. satd alkyl, which may be branched or cyclic; M = gp. which acts on CNS, esp. a psychotrope, this list not being limited and may include any active material having a OH, SH or amino groups that may be esterified or amidified by the phosphate group.

Description

GLYCOSYL PHOSPHOTRIESTERS DERIVATIVES AND THEIR USE
AT THE CENTRAL NERVOUS SYSTEM LEVEL
The subject of the invention is glycosyl phosphotriester derivatives of substances capable of passing the blood-brain barrier (BBB) and having pharmacological activity in the central nervous system (CNS).

 An important problem posed in pharmacology is that of the availability of drugs at the level of their therapeutic target, and in this area, the passage of the BBB. Among these substances, mention may be made of psychotropics (antidepressants, neuroleptics or anxiolytics), analgesics, or even various regulators of the reticuloendothelial system or of the cardiovascular system. A bad passage of the BBB constitutes a major drawback to the administration of substances which must act on the level of the central nervous system.

 These substances are generally administered by peripheral route (oral, intravenous, intramuscular or intraperitoneal) in massive doses with the objective that a minimal fraction reaches the cerebral target. The result is most often the induction of significant and disabling side effects.

 Different strategies have been developed to allow targeting of substances with pharmacological effect in the central nervous system.

One of these, developed by N. Bodor et al. since the early 1980s, the redox-dihydropyridine / pyridinium system has been used (cf. in particular the Bodor patents: US n 4,479,932, n "4,540,564, n" 4,617,298, n "4,727,079, n" 4,824 .850, n "4.829.070, n" 4.863.911, n "4.880.816, n" 4.880.921, n "4.900.837, as well as PCT patent applications W083 / 03968 and
W086 / 00897 on behalf of University of Florida.

 This system, if it has given encouraging results in the laboratory, encounters major drawbacks during the transposition to the conception of a drug: derivatives containing dihydropyridine are unstable, and extremely sensitive to oxidation. In addition, this type of compound is insoluble in an aqueous solution, which makes its systemic administration problematic.

 Other approaches have been developed, also by Bodor in PCT patent application WO92 / 00988.

In this approach, phosphonate derivatives have been developed. These compounds have a residue composed of a pharmacological substance having a functional reactive group, which group is coupled, directly or by a bridging group, and via an -O- link, to the phosphorus atom of the compound; these compounds are hydrolyzed in situ, allowing the release of the pharmacological substance and its active site.

 The present invention aims to develop a new approach and new compounds in order to allow the targeting of molecules at the central level, by a means usable as a drug in humans or animals.

 A pharmacologically active substance which, originally or badly passes the blood-brain barrier at all, is modified by the addition of a phosphate group esterified by a sugar and a lipid chain which allow it to cross this barrier; at the level of the central nervous system (CNS), metabolic reactions make it possible to release the active molecule again in its initial state and this, in the vicinity of its targets.

dans laquelle : A = O, N ou S - R1 représente 1) soit : [sucre ou désoxy sucre en C5 à C6, substitué ou non]n, en serine D ou L ; n = 1 à 6, et la jonction entre le sucre et le phosphore étant sur l'un des hydroxyles des sommets 2, 3, 4, 6, ou 2) soit : (Ose) x - O - [(CH2)y - O]z dans lequel Ose représente un sucre en C5 ou C6, D ou
L, la substitution de la chaîne O - [(CH2)y - O]z se faisant sur le sommet 1 du sucre.The present invention is a new family of compounds exhibiting central pharmacological activity, having the capacity to cross the BBB after administration of said compound by the peripheral route, and exhibiting the general formula I

in which: A = O, N or S - R1 represents 1) either: [C5 to C6 sugar or deoxy sugar, substituted or not] n, in serine D or L; n = 1 to 6, and the junction between sugar and phosphorus being on one of the hydroxyls of vertices 2, 3, 4, 6, or 2) either: (Ose) x - O - [(CH2) y - O] z in which Ose represents a C5 or C6 sugar, D or
L, the substitution of the chain O - [(CH2) y - O] z taking place on the top 1 of the sugar.

- x is an integer from 1 to 12 - y is an integer from 1 to 6 - z is an integer from 1 to 4 - R2 represents an alkyl group of 6 to 30 carbon atoms, saturated or not, which can carry ramifications or cycles - M represents a molecule capable of acting at the central level. Mention may in particular be made of psychotropics, analgesics, regulators of the immune or cardiovascular systems; it can also represent a precursor of said molecules capable of being transformed in the CNS into the active molecule.

 Said molecule can be, for example, a peptide or polypeptide or a glycosylated protein or not, a cyclic or heterocyclic molecule chosen for example from the different families of psychotropics. This list is not exhaustive and may include any active substance having a hydroxyl, thiol or amine radical capable of being esterified or amidified on a phosphate function.

To demonstrate the effectiveness of this methodology, 5-hydroxy N-acetyltryptamine was chosen as a model. This compound is a derivative of serotonin having only a chemically reactive OH function it is a metabolite of serotonin which is transformed in the brain by an O-methyl transferase into melatonin (CT15850). Melatonin is a hormone secreted by the pineal gland; its role is quite complex: it can be considered as a mediator involved in photoperiodicity, thermoregulation, reproduction and locomotor activity in a certain number of animals (L. Tamarkin, CJ Baird and
OFX Almeida, Science (1985), 227: 714-720; SM

Reppert, DR Weaver, SA Rivkees and EG Stopa,
Science (1988), 242: 78-81 and VM Cassone, TINS (1990), 13: 457-467; DN Kranse and ML Dubocovitch, TINS (1990), 13: 464-470. In humans, melatonin has been used to resynchronize circadian rhythms and to combat the physiological and psychological effects of jet lag; on the other hand, recent work seems to indicate in addition an immunomodulatory and anti-stress role (A. Conti and G.

Maestroni, Neuroimmunomodulation in pharmacology, 2nd
Course of the Federation of the European
Pharmacological Societes, 5-7 February 1992, PARIS).

When administered intraperitoneally (IP) melatonin at high concentration (30 mg / kg) has no effect on the locomotion of the mouse (Ducobovitch et al., 1990, Eur. J. Pharmacol. 182: 313-325), whereas a low dose intracerebral injection (0.1 to 100 ng) directly into the accumbens nucleus decreases the locomotor activity (Gaffori and Van Ree, 1985,
Neuropharmacology, 24: 237-244).

 These observations strongly suggest a very weak passage of melatonin across the blood-brain barrier after peripheral administration.

 The present invention illustrates the capacity of glycosylphosphotriester derivatives to cross the blood-brain barrier by measuring the functional effect of the brain on locomotion in mice. This effect has been compared to that of melatonin alone after central or peripheral administration. Hydroxy-N-acetyltryptamine (CT15166) has been tested in the same way.

dans laquelle - R2 a la même définition que dans la formule I cidessus et/ou - R a les signification suivantes R R = H : le sucre est alors un désoxyglucose et la formule II générale est codée sous le n CT15165,
R R = OH : le sucre est un mannose et la formule II générale ci-dessus est codée n CT16729,
R R = OH : le sucre est un glucose et la formule II générale est codée n CT16731, - M est la N-acétyltryptamine. A group of glycosylated phosphotriester derivatives of the invention corresponds to the following formula II

in which - R2 has the same definition as in formula I above and / or - R has the following meanings RR = H: the sugar is then a deoxyglucose and the general formula II is coded under the n CT15165,
RR = OH: the sugar is a mannose and the general formula II above is coded n CT16729,
RR = OH: sugar is glucose and general formula II is coded n CT16731, - M is N-acetyltryptamine.

 The three derivatives CT15165, CT16729 and CT16731 will be used in the experiments below as glycosylated phosphotriester derivatives of melatonin.

 However, any other sweet derivative in which the sugar is a C5 OR C6 D or L sugar also meets the characteristics of the invention. Among these, mention may be made of fructose, fucose, amino hexoses for hexoses, or arabinose, xylose, ribose, deoxyribose for pentoses.

Another compound of the invention can be represented by formula III.

in which R, R2 and M have the same meaning as in formula II.

 The invention also relates to the process for the preparation of compounds of formula I. This process is a three-step process.

 The first step is to phosphorylate a suitably protected sugar with a phosphite which is in situ coupled with N-acetyl hydroxy-5 tryptamine and oxidized to the corresponding phosphotriester.

 The second step consists in removing the protective groups from the sugar and the phosphate to phosphodiester, isolated in the form of tetrabutyl ammonium salt.

 The third step consists of a nucleophilic substitution of an alkyl halide with the phosphodiester salt to give the phosphotriester.

 It is understood that any variant of this reaction scheme is also possible, for example phosphorylation of 5-hydroxy tryptamine and of a long chain aliphatic alcohol and final alkylation with a halogen-sugar derivative. Likewise, the chemistry described here with a derivative of trivalent phosphorus (chlorophosphoramidite) can be carried out with other phosphoric derivatives of the phosphotriester type (cf. oligonucleotide synthesis), phosphonate or phosphorothioate.

A particular example of the synthesis of compounds
CT15165, CT16729 and CT16731 will be given in Example I below.

 All the compounds obtained as well as the intermediate compounds have spectral characteristics (nuclear magnetic resonance, ultra-violet, SM) in accordance with the formulas proposed. The purity was tested by HPLC chromatography (Table I).

 The following examples are intended to show the particularly advantageous effects of the compounds of the invention; a series of hexadecylphosphates glycosyls of hydroxy-5N-acetyltryptamine (CT15165, CT16729 and CT16731) were synthesized. Their effect on locomotor activity in mice was measured and compared with the effects of melatonin alone (CT15850) and the precursor of melatonin 5-hydroxyN-acetyltryptamine (CT15166).

- EXAMPLE I: Synthesis of derivatives CT15165, CT16729 and
CT16731
To this end, we start with a sugar (deoxyglucose, mannose or glucose) which is coupled to a hydroxy-5-Nacetyl tryptamine by a phosphate. The hexadecyl chain is then condensed on this phosphodiester structure by means of a nucleophilic substitution reaction.

 The chemistry of trivalent phosphorus (phosphoramidite) has been used to allow much faster reaction times than that of pentavalent phosphorus.

The different steps are as follows and illustrated in Figure 1
First step: Protection of sugar, and phosphorylation with a phosphyte coupled with Nacetyl hydroxy-5 tryptamine and oxidation to phosphotriester a) Synthesis of Tetra-O-benzoyl-1,3,4,6 deoxy-2-Dglucose (2a):
10 g (61 mmol) of deoxy-2-D-glucose co-evaporated with pyridine are redissolved in 100 ml of anhydrous pyridine, 58 ml (70.24 g; 500 mmol) of benzoyl chloride are added dropwise maintaining the temperature at 0 "C. It is left overnight at 4" C., then methanol is added at 0 C until complete dissolution of the precipitate formed. The solvent is evaporated to dryness and the residue is taken up in dichloromethane, washed twice with saturated NaHCO3 solution, then with water. The organic phase is dried over Na2SO4 and evaporated to dryness to give a residue (32.46 g, 92%) which is washed several times with petroleum ether. Rf = 0.27 (AcOEt-hexane, 1-2). F = 131 "C.

b) Synthesis of Tri-O-benzoyl-3,4,6-benzyloxy-2 ethyl deoxy-2-D-glucopyranoside (3a)
A release of HCl gas is made to arrive in a suspension of 32.26 g of 2a in 12 ml (84.5 mmol) of benzyloxyethanol at room temperature for 2 h 30 min until complete dissolution. The mixture is diluted in dichloromethane, washed twice with saturated NaHCO3 solution, once with water. The residue is chromatographed on a Merck 9385 silica column eluted with dichloromethane to give 78% 3a (oil). Rf = 0.07 (CH2Cl2).

 NMR (CDC13, ppm) = 1H: 5.05 (H1), 2.0 and 2.60 (H2, H2 '), 5.80 (H3), 5.6 (H4), 3.9 (H5) , 4.45 (H6, H6 '), 3.6-3.75 (CH2), 4.55 (CH2).

c) Synthesis of Tri-O-benzoyl-3,4,6-hydroxy-2 ethyl deoxy-2-D glucopyranoside (4a):
18.5 g (30 mmol) of 3a dissolved in 250 ml of ethyl acetate are catalytically hydrogenated in the presence of Pd-C (10%) for 5 h at 30 psi.

 After filtration through Celite, the solvent is evaporated to dryness and the residue chromatographed on a column of silica eluted with dichloromethane to give 19.4 g (86%) of 4a. Rf = 0.49 (MeOH-CH2Cl2, 5-95). F = 42-46OC. MS (IC, NH3) = 538 (M + 18). NMR (CDCl3, ppm): H: 5.1 (H1), 2.05 and 2.55 (H2, H2 '), 5.75 (H3), 5.6 (H4), 4.4 (H6, H6 '), 3.6 (CH2CH2OH), 3.8 (CH2CH2OH).

d) Synthesis of p-cyanoethyl (tri-O-benzoyl 3,4,6 deoxy-2-D-glucopyranosidyl) ethyl-2 (N-acetyl tryptaminyl) -5 phosphate (5a)
To a solution of 2.29 g (4.4 mmol) of 4a in 20 ml of anhydrous acetonitrile and 3.3 ml (2.44 g, 19 mmol) of diisopropyl ethylamine is added under nitrogen atmosphere 975 y1 ( 1.034 g, 4.4 mmol) of Pcyanoethyl N, N diisopropyl chlorophosphoramidite. The mixture is left for 15 minutes at ambient temperature and then a solution of 1.284 g (18.3 mmol) of tetrazole and 800 mg (3.67 mmol) of hydrox-5-Nacetyltryptamine dissolved in 15 ml of anhydrous acetonitrile is added. After 1 h at room temperature, the mixture is oxidized with 30 ml of a 0.1 M iodine solution (H2O-pyridine
THF, 1-10-40) diluted with dichloromethane and washed twice with NaHSO3 solution (5%) and once with water. After evaporation to dryness, the residue is precipitated with petroleum ether and chromatographed on a Merck 7734 silica column eluted with dichloromethane enriched in methanol (0-5%). A second column chromatography on Sephadex LH-20 eluted with a THF-MeOH mixture (95-5) gives 1.78 g 57% of 5a. Rf 0.40 (MeOH-CH2Cl2, 75-92.5).

Second step: Synthesis of CT15164, CT16728 and
CT16730 a) Synthesis of (deoxy-2-D-glucopyranosidyl) ethyl-2 (N-acetyl tryptaminyl) -5 phosphate (6a) (CT15164):
900 mg (1.06 mmol) of 5a are treated with 50 ml of sodium methylate (1%) for 10 min at room temperature. After neutralization with Dowex resin
AG-50WX8, the solvent is filtered and evaporated to dryness to give a residue which is purified on a silica column
Lichroprep RP-18 (Merck 9303) eluted with water gradually enriched in methanol (0-100) to give 457 mg (89%) of 6a in the form of ammonium salt. F = 139 "C. Rf = 0.62 (isopropanol-NH4OH-H2O, 7-1-2).

 Analysis C20H32O10N3P, H2O (C, H, N): Calc. 45.89, 6.50, 8.03; Tr. 45.66, 6.53, 7.92. HPLC: Rt 11.07 min.

 MS (FAB +): 527.3 (M + Na +), 506.2 (M + H) +. UV (MeOH): 222 (27000), 277 (6000). NMR (table).

b) Synthesis of (D-Mannopyranosidyl) ethyl-2 (N-acetyl tryptaminyl) -5 phosphate (6b) (CT16728):
The same sequence of reactions is carried out from 900 mg (1.406 mmol) 2-hydroxyethyl-Da mannopyranoside 4b (Rf = 0.62, CH2Cl2-MeOH, 95-5) (Y.

Hénin et al., J. Med. Chem. 1191, 34: 1830-1837; vs.

Gouyette et al. Tetrahedron Lett. 1989, 30: 6019-6022) to give 40% of 5b. (Rf = 0.57, CH2Cl2-MeOH, 90-10) which is deprotected by the methylate in 6b (95%). This phosphate is exchanged in N (Bu) 4+ form for the rest of the reactions. (Rf = 0.78, isopropranol-NH4OH-H2O, 7-1-2) MS (FAB +): 987.4 (M + N (Bu) 4) +. W (MeOH): 223 (31000), 276 (6800).

 Analysis C36H64011N3P, 1/2 H2O. (C, H, N, P): Calc.

57.29, 8.62, 5.57, 4.11; Tr. 57.27, 8.67, 5.35, 4.28.

HPLC: Rt 11.07 min. NMR (Table I).

c) Synthesis of (D-glucopyranosidyl) ethyl-2 (N-acetyl tryptaminyl) -5 phosphate (6c) (CT16730):
Penta-O-benzoyl-1,2,3,4,6 glucose is transformed into bromo-1 tetra-0-benzoyl-2,3,4,6 glucose according to RK Ness et al. (JACS, 1950, 72: 2200-2205).

 A suspension of 4.6 g of bromo-glucose (7 mmol) with 2.14 g of Hg (CN) 2, 3.05 g of Hg (Br) 2, 670 mg is allowed to rotate at room temperature for 1 hour 30 minutes. of molecular sieve 4 and 1 ml of benzyloxyethanol in 40 ml of a toluene-nitromethane mixture (1/1).

After filtration, the solution is diluted with dichloromethane, washed 3 times with H2O, NaHCO3, H2O.

After chromatography on a Merck 9385 silica column with dichloromethane, 60% of 3c is obtained. (Rf = 0.35, AcEt-Hexane, 1-2) (oil) which is hydrogenated on
Pd / C to give 85% of 4c. (Rf = 0.76, CH2Cl2-MeOH, 95-5).

The sequence of analogous reactions as for the previous series gives 5c (9%) Rf = 0.42 (CHCl2
MeOH, 10-90) which is deprotected in 6c (782s). (Rf = 0.40, isopropranol-NH4 OH-H20, 7-1-2)
Analysis C36H64011N3p, 1/2 H2O (C, H, N): Calc. 57.29, 8.62, 5.57; Tr. 57.20, 8.78, 5.60. HPLC: Rt: 7.05 min.

MS (FAB +): 987.5 (M + N (Bu) 4) +. NMR (table).

Third step: nucleophilic substitution of an alkyl halogen; synthesis of CT15165, CT16729, and
CT16731.

a) Hexadecyl (deoxy-2-D-glucopyranosidyl) ethyl-2 (Nacetyl tryptaminyl) -5 phosphate (7a) (CT15165):
We pass the phosphodiester 6a on a column of
Dowex AG-50WX8, N (Butyl) + to obtain the tetrabutylammonium salt. 260 mg (0.537 mmol) of the phosphodiester in 17 ml of anhydrous CH3CN and 1.7 ml (1.9 g, 5.4 mmol) of iodo-16 hexadecane are heated at 80 "C overnight. After evaporation of the solvent , the residue is precipitated with petroleum ether and chromatographed on a Merck 9385 silica column eluted with dichloromethane gradually enriched in methanol to give 86% of 7a. (Rf = 0.44, CH2C12-MeOH, 80-20).

 Analysis C36H61010N2P, 1/2 H2O; (C, H, N, F): Calc.

59.92, 8.60, 3.88, 4.30; Tr. 60.06, 8.66, 3.89, 3.97.

HPLC: Rt 15.35 min. MS (FAB +): 735.7 (M + Na +). NMR (table).

b) Synthesis of hexadecyl (ar-D-mannopyranosidyl) ethyl-2 (N-acetyl tryptaminyl) -5 phosphate (7b) (CT16729)
The same protocol as for 7a on 250 mg of 6b (0.336 mmol) gives 74% of 7b. (Rf = 0.32, CH2Cl2
MeOH, 80-20).

 Analysis C36H61O11N2P, H2O (C, H, N, P). Calc. 57.91, 8.44, 3.75, 4.16; Tr. 58.51, 8.45, 3.82, 4.59. W (MeOH): 224 (34000), 286 (5700).

 HPLC: Rt 13.19 min. MS (FAB +): 751.6 (M + Na +), 728 (M +). NMR (Table 1).

c) Synthesis of hexadecyl (D-glucopyranosidyl-ethyl-2 (N-acetyl tryptaminyl) -5 phosphate (7c) (CT16731)
The reaction with iodohexadecane on 6c gives 69 of 7c. (Rf = 0.35, CH2Cl2-MeOH, 80-20).

 Analysis C36H61N2 11P, H2O (C, H, N, P). Calc: 57.91, 8.44, 3.75, 4.16; Tr .: 58.45, 8.5, 3.83, 4.12. HPLC: Rt: 13.11 min. MS (FAB +): 751.8 (M + Na +), 729.7 (MH +), 728 (M +). NMR (Table 1).

HPLC chromatographic conditions
TEAA buffer: 10-2 M triethylammonium acetate pH 6.5.

 Acetonitrile Merck (ACN).

 Duration of the gradient: 20 minutes.

CT15164 0 to 25% ACN CT15165 50 to 95% ACN CT16728 0 to 25% ACN
CT16729 50 to 95% ACN
CT16730 5 to 25% ACN
CT16731 50 to 95% ACN.

 Nucleosil 5-C18 column (Macherey-Nagel) (15 cm x 0.46 cm).

 Flow 1 ml / min.

- EXAMPLE II: Measurement of the pharmacological activity of the five products CT15165, CT16729, CT16731, CT15850 and
CT15166 on the locomotor activity of mice
The animals used are Swiss mice weighing 15 to 18 g (Iffa Credo). The mice used are kept in a pet store in a light-dark cycle from 12 noon to 12 noon at 22oC, and having food and drink ad libitum.

 The intraperitoneal (IP) injections are carried out in a volume of 0.5 ml per 20 g of animal, corresponding to 1.10 or 30 mg / kg for melatonin or the equivalent doses for the glycosylated phosphotriester derivatives.

 The animals then remain 15 minutes at rest in their cage before starting the measurement of their motor activity in an activometer, according to a process described below.

 Intracerebroventricular (ICV) injections are performed freehand in the third ventricle of the right cerebral hemisphere in a maximum volume of 5 μl. The injection time is 30 seconds. The doses used vary from 5 to 50 ng / kg of melatonin or their equivalence for glycosylated phosphotriester derivatives.

 The animals are observed and left to rest for 15 minutes in their cage before starting to measure their motor activity.

 The locomotor activity of animals is measured in a six-compartment activometer in which the activity of animals is measured by their passage through two light beams arranged at 90 and directed towards two photoelectric cells. The only horizontal locomotion is recorded for 15, 30, 45 and 60 minutes.

 The results are expressed as a percentage of locomotion measured relative to control mice having received NaCl in an equivalent volume and measured 15, 30, 45 and 60 min after the injection, which results are obtained at variable doses of compound injected.

CT15850 mélatonine

. CT15166 hydroxy-5N-acétyltryptamine

EXAMPLE III Comparison of the Effects of Melatonin, of N-acetyltryptamine and of the Glycosyl Phosphotriester Derivative of N-Acetyltryptamine of the Following Formulas Phosphotriester Derivatives
CT15165 a) R = H deoxyglucose
CT16729 b) R = OH mannose CT16731 c) R = OH glucose

CT15850 melatonin

. CT15166 5-hydroxy-acetyltryptamine

3.1. Intracerebroventricular injection (ICV):
The injection is carried out under the conditions described above.

 Two doses were used 5 or 50 ng / kg of animal weight, in melatonin equivalent.

 Figure 2 shows the results obtained for each of these doses with CT15850, CT15165 and CT15166.

 Each of the three compounds has an effect on locomotion.

 The ICV administration of the products studied made it possible to observe at the dose of 5 ng / kg an inhibiting effect on locomotion progressing over time for the CT15850, as well as the CT15165. The melatonin precursor did not show significant effects under the same conditions.

 At 50 ng / kg, melatonin itself showed a marked inhibitory effect after 60 minutes, its precursor CT15166 also induced an inhibitory effect progressing over time; it was the same with the ester derivative.

3.2. Administration on the outskirts
Intraperitoneal administration was carried out under the conditions described above.

 Four doses were used: 0.01, 1, 10 and 30 mg / kg.

 The results of the locomotion tests obtained are shown in Figure 3a.

 Melatonin itself and its precursor Nacetyltryptamine had no significant effect in increasing or inhibiting animal locomotion during the four time periods analyzed after injection. A slight reduction in activity was observed after 45 and 60 minutes at 10 mg / kg of Nacetyltryptamine, but this effect was not significant and it was not confirmed at the higher dose of 30 mg / kg.

 On the contrary, the ester derivative CT15165 reduced the activity at the three doses studied, moderately to 1 mg / kg and 10 mg / kg and very markedly, to 30 mg / kg.

 Figure 3b indicates that the intraperitoneal administration of the two derivatives CT16729 and CT16731 are as effective, injected at a dose of 30 mg of melatonin equivalent per kg of mouse as CT15165.

 The results obtained in this experimental series showed that by the intraperitoneal route, the only ester derivative was capable of inhibiting locomotor activity in mice at the 3 doses studied (1, 10, 30 mg / kg), while in the same conditions, no significant effect was observed for melatonin itself or its precursor N-acetyltryptamine. These results strongly suggest that the only ester derivative was able to cross the blood-brain barrier to induce locomotor effects.

This hypothesis is supported by the fact that the three substances studied reduce locomotor activity when administered directly at the central level.

 This last observation also indicates that the locomotor effects observed are indeed of central origin since melatonin and its precursor had no effect after their administration at the peripheral level.

 The large difference that can be observed between the active doses of the ester derivative when administered ICV (5 to 50 ng / kg) and PI (1 to 30 mg / kg) is probably due to the fact that this lipophilic product is sequestered extremely significantly in a large number of peripheral compartments despite this inactivation by its sequestration or a rapid metabolism which denatures it in its form of native melatonin, a small but functionally very significant percentage is capable of reaching brain targets. Under the same conditions, melatonin itself does not show any activity at these same doses.

 These results therefore indicate that a molecule active at the central level but whose physicochemical properties prevent the passage of the BBB can receive a chemical group giving it the property of passing this obstacle.

 On the basis of these results, it has not been investigated whether the ester could act as such or as melatonin generated by the degradation of this molecule. However, there is every reason to believe that the molecule is metabolized since the brain probably contains in large numbers the enzymes necessary for this operation.

 This example does not limit the importance of the invention in terms of new means for targeting an effector molecule at specific CNS receptors.

TABLE 1/1
CT 15164 CT 16728 CT 16730 CT 15165 CT 16729 CT 16731
6a (D2O) 6b (D2O) 6c (D2O) 7a (DMSO) 7b (DMSO) 7c (DMSO)
Sugar
H1 4.9 4.9 4.35 4.9 4.8 4.19
H2 1.95 1.9 1.55 1.4
H3 '3.85 4 3.75 3.94
H4 3.3 3
H5 3.3 3
H6H6 '3.25-3.38 2.84-3.18
Sugar O-CH2-CH2-OP 3.65 3.8 3.65 3.69
Sugar O-CH2-CH2-OP 4m1 4.11 4.15 4.22 4.09
Tryptamine
H2 7.2 7.2 7.2 7.2 7.2 7.21
H4 7.42 7.41 7.42 7.33 7.38 7.32
H6 7.39 7.38 7.39 7.3 7.35 7.30
H7 7.05 7.05 7.05 6.95 6.95 6.95
CH2-CH2-NH 3.45 2.91 2.92 2.76 2.78 2.76
CH2-CH2-NH 1.9 3.45 3.44 3.5 3.45 3.44 -CO-CH3 1.87 1.85 1.8 1.8 1.8
Chain - (CH2) n-CH3 - - - 0.85 0.85 0.85 - (CH2) n- 1.23 1.20 1.23
PO-CH2-CH2- (CH2) n- 1.6 1.6 1.59
PO-CH2-CH2 (CH2) 2- 4.08 4.07 4.24
RMN.P31 -2.77 -2.79 -2.6 -2.60; -2.66

Claims (8)

 1. Compounds having pharmacological activity at the level of the CNS, having the capacity to cross the BBB after administration of said compound by the peripheral route, and having the general formula

 in which: A = O, N, or S - R1 represents 1) either: [C5 or C6 sugar or deoxy sugar, substituted or not) n in series D or L: n = 1 to 6, and the junction between the sugar and phosphorus being on one of the hydroxyls of vertices 2, 3, 4 or 6 or 2) either: (Ose) x - O - [(CH2) y - 0] z in which Ose represents a C5 sugar or C6, D or L, the substitution of the chain 0 - [(CH2) y - O] z taking place on the top 1 of the sugar, - x is an integer from 1 to 12 - y is an integer from 1 to 6 - z is an integer from 1 to 4 - R2 represents an alkyl group of 6 to 30 carbon atoms, saturated or not, which can carry ramifications or rings, - M represents a molecule capable of acting at the central level, we can cite in in particular psychotropic drugs, analgesics, cerebral regulators of the immune or cardiovascular systems; it can also represent a precursor of said molecules capable of being transformed in the CNS into the active molecule, said molecule being able to be, for example, a peptide or polypeptide or a glycosylated protein or not, a cyclic or heterocyclic molecule chosen for example in different families of psychotropic drugs, this list not being limiting and can include any active substance having a hydroxyl, thiol or amine radical capable of being esterified or amidified on a phosphate function.  2. Compound according to claim 1, characterized in that the dare motif is chosen from mannose, deoxyglucose, glucose, galactose, fructose and fucose.  3. Compound according to Claims 1 and 2, characterized in that x is equal to 1, y is equal to 2 and z is equal to 1.  4. Compound according to one of claims 1 to 3, characterized in that it is glycosylated phosphotriesters of formula II

 in which - R2 has the same definition as in formula I above and can be, for example, a cholestryl, phytyl radical and / or - R has the following meanings  R = H: the sugar is then a deoxyglucose and the general formula II is coded under the number "CT15165,  R = OH: the sugar is then a mannose and the general formula II above is coded n CT16729,  R = OH: the sugar is then a glucose and the general formula II is coded n "CT16731, - M is N-acetyltryptamine.  5. Compound according to one of claims 1 to 3, characterized in that it is glycosylated phosphotriesters of formula III

 in which R, R2 and M have the same meaning as in formula II.  6. Compound according to one of claims 1 to 4, characterized in that the group R2 represents an alkyl chain containing from 2 to 30 carbon atoms, where appropriate, substituted by a group NH2, -NHR '- or -NR 'R "in which R' and R" represent an alkyl group of 1 to 4 carbon atoms.  7. A method of preparing a compound according to claims 1 to 6 characterized by the following steps a) phosphorylation of a sugar suitably protected with a phosphite which is in situ coupled with Nacetyl hydroxy-5 tryptamine and oxidized to the corresponding phosphotriester; b) removal of the protective groups of the sugar and of the phosphate in phosphodiester, isolated in the form of tetrabutyl ammonium salt c) nucleophilic substitution of an alkyl halide with the salt of the phosphodiester to give the phosphotriester being understood that the different variants allow obtaining the derivatives of formula I, II or III using the conventional chemistry of trivalent phosphorus, are also part of the invention.  8. Pharmaceutical composition for the prevention or treatment of disorders having their origin in the central nervous system, comprising as active ingredient a compound according to one of claims 1 to 5 in association with a pharmaceutically acceptable carrier.