CA2374411A1 - Novel esters derived from nucleosides, preparation methods and pharmaceutical compositions containing them - Google Patents

Abstract

The invention concerns the field of organic chemistry, and more precisely, that of therapeutic chemistry. More particularly, the invention concerns novel esters derived from nucleosides of general formula (I) wherein: A represents a divalent group selected among -(CH¿2?)¿n?-, -(CH¿2?)¿n? -NH-, -(CH¿2?)¿n? -O-; (a); (b); (c); (d); (e); n is an integer ranging between 1 and 12; Z represents an amino, hydroxyl or an alkyl group; and the nucleoside group is the radical of a hydroxylated nucleoside of general formula (1) wherein: R¿1? represents a radical selected among (2) and (3) wherein: R¿4? represents a methyl, trifluoromethyl or halovinyl; R¿2? represents a hydrogen or a hydroxyl; R¿3? represents a hydrogen, a hydroxyl or an azido; and the dotted line represents an optional carbon-carbon double bond. The invention is useful as an antiviral agent.

Description

NOVEL ESTERS DERIVED FROM NUCLEOSIDES, THEIR METHODS OF
PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING
The present invention relates to the field of organic chemistry, and more precisely, to that of therapeutic chemistry.
The subject of the present invention is new esters derived from nucleosides, their processes preparation, and pharmaceutical compositions containing them.
The invention more particularly relates to new compounds of formula general (I) ZACO nucleoside (I) O
in which A represents a divalent group chosen from - (CH2) ~ -, -(CHZ) ~ - NH -, - (CH2) ~ - O -; ~~ - ~ ~ - ~ ~ - (CH2) "~;
NH - O - (CHz) ~ -n is an integer which can vary from 1 to 12;
Z represents an amino group, a hydroxyl or an alkyl, and the group "nucleoside" is the remainder of a hydroxylated nucleoside, of formula general HO OR ~

in which R1 represents a radical chosen from O
N Ra H ~ W
H
NN / \
\ O

2 where R4 represents a methyl, a trifluoromethyl or a halovinyl, R2 represents a hydrogen or a hydroxyl, R3 represents hydrogen, hydroxyl or azido and the dotted line symbolizes a possible carbon-carbon double bond, excluding the compound having a formula in which A is the group -(CH2) ~ - NH -with n equal to l, Z represents a methyl group, R ~ represents the radical O
Ra ~ O
wherein R4 represents a hydroxyl.
The invention preferably relates to the compounds of general formula (I) in which the "nucleoside" group is the remainder of a hydroxylated nucleoside, selected from the nucleoside group hydroxylated including zidovudine, didanosine and stavudine.
The invention particularly relates to compounds of general formula (I) chosen from following compounds - 3'-azido-3'-deoxy- ~ '-O- [~ -amino-a-butanoyl] thymidine - 3'-azido-3'-deoxy-5'-O - [(a, w-diaminopropyl) -a-carbonyl] thymidine - 3'-azido-3'-deoxy-5'-D - [(c ~ -amino-a-hydroxypropyl) -a-carbonyl] thymidine - 3'-azido-3'-deoxy-5'-O - [(a, c ~ -butanedioyl) -a-carbonyl] thymidine - 3'-azido-3'-deoxy-5'-O - [(a-amino-w-hydroxypropyl) -a-carbonyl] thymidine - 3'-azido-3'-deoxy-5'-O - [(a-hydroxybutyl) -a-carbonyl] thymidine - 2 ', 3'-dideoxy -5'-O - [(w-amino-a-butanoyl] inosine - 2 ', 3'-dideoxy -5'-O - [(a, c ~ -diaminopropyl) -a-carbonyl] inosine - 2 ', 3'-dideoxy -5'-O - [(c ~ -amino-a-hydroxypropyl) -a-carbonyl] inosine - 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O- [c ~ -amino-a-butanoyl] thymidine - 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O - [(a, ~ -diaminopropyl) -a-carbonyl] thymidine

3 - 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O - ((c ~ -amino-oc-hydroxypropyl) -a, -carbonyl]
thymidine The invention also relates to a process for the preparation of the compounds of formula (I), characterized in that a hydroxylated nucleoside of the general formula is subjected R3 Ri in which RI represents a radical chosen from O
N Ra H, w H
NN / \
N \ O
where R4 represents a methyl, a trifluoromethyl or a halovinyl, RZ represents a hydrogen or a hydroxyl, R3 represents a hydrogen, a hydroxyl or an azido, and the dotted line symbolizes a possible carbon-carbon double bond, in the presence of an esterification catalyst, such as 4-dimethylaminopyridine (DMAP) in a polar solvent, such as for example dimethylformamide (DMF), acetone, acetonitrile, N-methyl-methanamide, formamide, dimethyl sulfoxide and sulfolane, to the action of an acidic compound of formula (II) Z ~ A ~ OH (II) O
in which A is as defined above and Z, represents a protected amino group, a hydroxyl or an alkyl, in which for example the amino group is protected by a 1,1 dimethyl group ethoxycarbonyl (ter-butyloxycarbonyl) or by a benzyloxycarbonyl group, WO 01/0413

4 PCT / FR00 / 02002 in order to obtain an ester of formula (III) Zi ACO nucleoside (III) O
in which A, Z1 and the "nucleoside" group are as defined previously;
that we possibly subject to a deprotection reaction when Z1 represents a group protected amino, for example by addition of a strong acid such as acid trifluoroacetic acid hydrochloric, or by hydrogenolysis, in order to obtain the compound of formula (I), in which Z is defined as previously.
The invention also relates to a process for the preparation of the compounds of formula (I), characterized in that a hydroxylated nucleoside as defined is subjected previously in action N, N-carbonyldümidazole, in a polar solvent, such as for example dimethylformamide (DMF), acetone, acetonitrile, N-methyl-methanamide, formamide, dimethyl sulfoxide and sulfolane, in order to obtain a functional derivative of formula (IV) CO nucleoside (IV) in which the “nucleoside” group is as defined above, which is subjected to the action of a diamine of formula (V) HZN B NHZ (V) where B is a divalent group - (CHZ) ~ - or ~, n being a number whole can vary from 1 to 12, in order to obtain a compound of formula (I), in which A represents a group divalent - (CHZ) ~ - NH - or ~ and Z represents an amino group.
NH-The invention also relates to a process for the preparation of the compounds of formula (I), characterized in that a hydroxylated nucleoside as defined is subjected previously in a polar solvent, such as for example dimethylformamide, acetone, acetonitrile, N-methyl-methanamide, formamide, dimethylsulfoxide, sulfolane, to the action of N, N-carbonyldümidazole, in order to obtain the product of formula (IV) V
CO nucleoside (IV)

5 in which the “nucleoside” group is as defined above, which is subjected to the action of an alcohol of formula (VII) Z1 B OH (VII) where B is a divalent group - (CHZ) "- or ~, n is a number integer that can vary from 1 to 12, and ZI represents a protected amino group, a hydroxyl or an alkyl, in which for example the amino group is protected by a 1,1 dimethyl group ethoxycarbonyl (ter-butyloxycarbonyl) or by a benzyloxycarbonyl group, in order to obtain an ester of formula (VIII) Z1 BOCO nucleoside (VIII) O
in which B, Z1 and the "nucleoside" group are as defined previously, that we submit to a deprotection reaction when ZI represents a group amino protected, for example by adding a strong acid such as trifluoroacetic acid, hydrochloric acid, or by hydrogenolysis, in order to obtain an ester of formula (I), in which A represents a group divalent - (CHZ) ~ - O - or O-The compounds of formula (I) have the property of inhibiting replication HIV-1-BRU virus, making them suitable for use in the treatment of viral diseases, especially in the treatment of hepatitis A, hepatitis B, AIDS and pathologies associated.

6 The present invention also relates to pharmaceutical compositions containing title of active principle at least one of the compounds as defined previously, mixed or in combination with an inert, non-toxic, pharmaceutically acceptable excipient acceptable.
The pharmaceutical compositions are suitable for administration, especially by way oral, parenteral, rectal, in the form of capsules, tablets, capsules, solutions oral and injectable solutions.
For these purposes, the content of active principle of general formula (I) can vary from 0.1 mg to 100 mg per single dose depending on the route of administration. This administration can be repeated from 1 3 times a day depending on therapeutic needs.
The examples which follow illustrate the present invention without, however, limit.
The abbreviations used in this application have the meanings following AcOEt: ethyl acetate AZT: 3'-azido-2 ', 3'-dideoxy-thymidine or Zidovudine DCC: N, N'-dicyclohexylcarbodümide DCM: Dichloromethane ddI: 2 ', 3' -dideoxyinosine or Didanosine DMAP: 4-dimethylaminopyridine d4T: 2 ', 3'-didehydro-2', 3'-dideoxy-thymidine or Stavudine FAB: "Fast Atomic Bombardment"
SM: mass spectrometry TFA: trifluoroacetic acid HIV: Human immunodeficiency virus HBV: Hepatitis B virus VTLH: Human lymphotropic T cell virus EXAMPLE I
3'-azido-3'-deoxy-5'-O - [c ~ -amino-a-butanoyllthymidine 1 To a solution of 4- (tert-butyloxycarbonyl) amino-1-butanoic acid (342 mg;
1.684 mmol; 3 eq) in dimethylformamide (DMF) (3 ml), with magnetic stirring and nitrogen, cooled to 0 ° C, the DCC is added (255 mg; 1.235 mmol; 2.2 eq). The mixture reactionary is agitated at this temperature for 2 h, then add a solution of AZT (150 mg; 0.561 mmol ; 1 eq) in DMF (2 ml) containing 4-dimethylaminopyridine (DMAP) (69 mg; 0.561 mmol; 1 eq).

7 After 24 hours at room temperature, the reaction mixture is filtered in order to to eliminate N, N'-dicyclohexylurea (DCU) formed, then evaporated under reduced pressure. The residue obtained is diluted in 8 ml of AcOEt and washed with 2x7 ml of an aqueous solution of citric acid 5%, 2x7 ml 5% aqueous NaHCO3 solution and 2x7 ml of H20. The aqueous phases recovered are extracted with 2x7 ml of AcOEt. The combined organic phases are dried over NaZS04, filtered and evaporated under reduced pressure. The residue obtained is purified by flash chromatography on a silica gel column (eluent: 5% methanol in dichloromethane) for lead to the desired compound (228 mg; 90%). Deprotection of function terminal amine is performed using TFA (1 ml) in CHZC12 (2 ml) quantitatively, to lead to compound 1.
Rf (dichloromethane 90 / methanol 10) = 0.14.
[1H] NMR (methanol-d4), b: 7.26 (s, 1H, H-6); 5.94 (t, 1H, H-l ', J = 6.4Hz) ; 4.3-4.1 (m, 3H, H-5 ', 5 ", H-3'); 3.88 (m, 1H, H-4 '); 2.9-2.8 (m, 2H, 2H-9'); 2.5- 2.2 (m, 4H, H-2 ', 2 ", 2H-7');
1.9-1.8 (m, 2H, 2H-8 '); 1.74 (s, CH3 in position 5).
[i3C] NMR (methanol-d4), 8: 171.91 (C-6 '); 164.55 (C-4); 150.39 (C-2);
136.35 (C-6);
110.20 (C-5); 85.14 (C-1 '); 81.21 (C-4 '); 63.22 (C-5 '); 60.40 (C-3 '):
38.26 (C-9 '); 35.78 (C-2 '); 29.72 (C-7 '); 21.86 (C-8 '); 12.29 (CH3 in position 5).
Mass spectrum (GT matrix): FAB +: 353 (M + H) +; 225 (M - (B -)) +; 127 (B + 2H) +.
LR. (KBr, cm-1), v: 3445 (NHZ); 3167 (NH); 2939 (C sp2 and sp3); 2112 (N3) ; 1780 (C = 0);
1686 (C = 0); 1472; 1274; 1190; 793; 708.
EXAMPLE II
3'-azido-3'-deoxy-5'-O -f (a, c ~ -diaminopropyl) -a-carbonyllthymidine 2 To a solution of AZT (150 mg; 0.561 mmol; 1 eq) in DMF (3 ml), under agitation magnetic and nitrogen, add N, N-carbonyldümidazole (100 mg; 0.617 mmol ; 1.1 eq). The reaction mixture is stirred at room temperature for 2 h, then add, to the syringe, the 1, 3-diaminopropane (70 ~ 1; 0.842 mmol; 1.5 eq). After 4h at temperature room, the mixture reaction is evaporated under reduced pressure. The reaction product is taken up in ether

8 then filtered to remove excess diamine. The residue obtained is purified on preparative plate 2 mm thick silica (eluent: 20% dichloromethane in methanol) to drive to compound 2 (116 mg; 78%).
Rf (dichloromethane 45 / methanol 45 / AcOH 10) = 0.43.
('H] NMR (chloroform-d), b: 9.48 (s, 1H, H-3); 7.01 (s, 1H, H-6); 5.88 (m, 2H, H-l ', NH-6'carbamate); 4.2-3.9 (m, 3H, H-5 ', 5 ", H-3'); 3.81 (m, 1H, H-4 '); 3.02 (m, 2H, 2H-7 '); 2.53 (m, 2H, 2H-9 '); 2.3-2.0 (m, 2H, H-2, 2 '); 1.62 (s, CH3 in position 5);
1.39 (m, 2H, 2H-8 ').
('3C] NMR (chloroform-d), 8: 164.51 (C-4); 155.94 (C-6'); 150.67 (C-2);
135.56 (C-6);
111.05 (C-5); 85.50 (C-1); 82.21 (C-4 '); 63.73 (C-5 '); 60.92 (C-3 ');
39.02 (C-7 ', C-9 '); 37.36 (C-2 '); 31.93 (C-8 '); 12.51 (CH3 in position 5).
Mass spectrum (GT matrix): FAB +: 368 (M + H) +; 735 (2M + H) +; 127 (B + 2H) +.
LR. (dichloromethane, cm-1), v: 3353 (NH2); 3067 (NH); 2949 (C sp2 and sp3) ; 2252; 2107 (N3); 1700 (C = 0); 1517; 1469; 1268; 1097; 909; 733.
Log P (n-octanol / H20) _ - 1.19 +/- 0.44 [PAZT log = - 0.88 +/- 0.42]
EXAMPLE III
3'-azido-3'-deoxy-5'-O - [(c ~ -amino- a-hydroxypropyl) -a-carbonyllthymidine 3 To a solution of AZT (150 mg; 0.561 mmol; 1 eq) in DMF (3 ml), under agitation magnetic and nitrogen, add N, N-carbonyldümidazole (100 mg; 0.617 mmol ; 1.1 eq). The reaction mixture is stirred at room temperature for 2 h, then add the 3- (ter-butyloxycarbonyl) -amino-1-propanol (147 mg; 0.842 mmol; 1.5 eq). After 2 p.m.
at 70 ° C, the reaction mixture is evaporated under reduced pressure. The residue obtained is diluted in 5 ml of CHZCI2, then washed with 2x5 ml of a 5% aqueous citric acid solution, 2x5 ml of a 5% aqueous solution of NazSO4 and 2x5 ml of HZO. The aqueous phases are extracted with 2x5 ml of CHZC12. The combined organic phases are dried over Na2SO4, filtered and evaporated under reduced pressure. The residue obtained is purified by flash chromatography on gel column

9 silica (eluent: methanol S% in dichloromethane) to lead to desired compound (228 mg; 90%). The deprotection of the terminal amine function is carried out at using TFA (1 ml) in CHZC12 (2 ml) quantitatively, to yield compound 3.
Rf (dichloromethane 90 / methanol 10) = 0.12.
[1H] NMR (methanol-d4), 8: 7.31 (s, 1H, H-6); 5.96 (t, 1H, H-l ', J = 6.4 Hz) ; 4.3-4.1 (m, 3H, H-5 ', 5 ", H-3'); 4.06 (t, 2H, 2H, 2H-7 ', J = 6.5 Hz); 3.97 (m, 1H, H-4') ;
2.9-2.8 (m, 2H, 2H-9 '); 2.5-2.3 (m, 2H, H-2, 2 '); 2.1-2.0 (m, 2H, 2H-8 '); 1.90 (s, 3H, CH3 in position 5).
[i3C] NMR (methanol-d4), 8: 164.60 (C-4); 154.83 (C-6 '); 150.48 (C-2);
136.02 (C-6);
110.48 (CS); 85.08 (C-1 '); 81.37 (C-4 '); 68.30 (C-S '); 66.12 (C-7 ');
60.31 (C-3 '); 38.21 (C-9 '); 36.05 (C-2 '); 25.14 (C-8 '); 12.10 (CH3 in position 5).
Mass spectrum (GT matrix): FAB +: 369 (M + H) +; 268 (AZT + H) +; 127 (B + 2H) +.
LR. (dichloromethane, cm-1), v: 3380 (NHZ); 3081 (NH); 2942 (C sp2 and sp3);
2107 (N3);
1692 (C = 0); 1471; 1270; 1110; 738.
EXAMPLE IV
3'-azido-3'-deoxy-5'-Of (a, ~ -butanedioyl) -oc-carbonyl ~ thymidine 4 To a solution of AZT (150 mg; 0.561 mmol; 1 eq) in DMF (4 ml), under agitation magnetic and nitrogen, N, N-carbonyldümidazole (100 mg; 0.617 mmol) is added ; 1.1 eq). The reaction mixture is stirred at room temperature for 2 h, then add, to the syringe, 1,4-butanediol (75 q1; 0.842 mmol; 1.5 eq). After 2 p.m. at 70 ° C, the reaction mixture is evaporated under reduced pressure. The residue obtained is diluted in 5 ml of CHZC12 then washed with 2x5 ml of a 5% aqueous citric acid solution and 2x5 ml of HZO. The phases watery are extracted with 2x5 ml of CHZCIZ. The combined organic phases are dried on NaZS04, filtered and evaporated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel column (eluent: 20% hexane in AcOEt) to conduct to compound 4 (182 mg; 85%).
Rf (Ethyl acetate 85 / hexane 15) = 0.23.

[1H] NMR (chloroform-d), 8: 9.14 (s, 1H, H-3); 7.38 (d, 1H, H-6, J = I, OHz) ; 6.18 (t, 1H, H-1, J = 6, 1 Hz); 4.5-4.2 (m, 3H, H-5 ', 5 ", H-3'); 4.23 (t, 2H, 2H-7 ', J =
6.4Hz); 4.07 (m, 1H, H-4 '); 3.68 (t, 2H, 2H-10 ', J = 6, 1Hz); 2.47 (m, 2H, H-2 ', 2 "); 1.90 (s, 3H, CH3 in position 5);
1.80 (m, 2H, 2H-8 '); 1.67 (m, 2H, 2H-9 ').

[13C] NMR (chloroform-d), 8: 164.18 (C-4); 154.61 (C-6 '); 150.42 (C-2);
135.47 (C-6);
111.11 (C-5); 84.96 (C-1); 81.50 (C-4 '); 68.52 (C-5 '); 66.10 (C-7 ');
61.56 (C-10 '); 59.93 (C-3 '); 37.68 (C-2 '); 28.66 (C-8 '); 25.16 (C-9 '); 12.49 (CH3 in position 5).

Mass spectrum (GT matrix): FAB +: 384 (M + H) +; 767 (2M + H) +; 268 (AZT + H) 1; 127 (B + 2H) +.
LR. (dichloromethane, cm-1), v: 3392 (OH); 3188; 3055 (NH); 2950 (C spZ and sp3); 2108 (N3); 1749 (C = O carbonate); 1693 (C = O amide); 1468; 1405; 1266; 1089;
1049 (C-OH);
738.
Log P (n-octanol / H20) _ -0.68 +/- 0.48 [log P, ~ T = -0.88 +/- 0.42]
EXAMPLE V
3'-azido-3'-deoxy- ~ '-O- (a-amino-c ~ -hydroxypropyl) -a-carbonyl thymidine To a solution of AZT (60 mg; 0.225 mmol; 1 eq) in CH3CN (1.5 ml), under agitation magnetic and nitrogen, N, N carbonyldümidazole (40 mg; 0.247 mmol;
1.1 eq). The reaction mixture is stirred at room temperature for 2 h, then add, to the syringe, the 3-amino-1-propanol (25q1; 0.292 mmol; 1.3 eq). After 4h at temperature room, the mixture reaction is evaporated under reduced pressure. The residue obtained is diluted in 5 ml of CHZC12, then washed with 2x5 ml of a 5% aqueous citric acid solution, with 2x5 ml of a solution 5% NaHCO3 aqueous and 2x5 ml H20. The aqueous phases are extracted with 2x5 ml of CHZC12. The combined organic phases are dried over Na2SO4, filtered and evaporated under reduced pressure. The residue obtained is purified on a preparative plate of 1 mm silica thick (eluent: 20% hexane in ethyl acetate) to yield compound 5 (50 mg; 60%).

11 Rf (dichloromethane 90 / methanol 10) = 0.37.
[1H] NMR (chloroform-d), ~: 9.10 (s, 1H, H-3); 7.19 (s, 1H, H-6); 5.99 (t, 1 H, H-l ', J
= 6.1Hz); 5.58 (m, 1H, NH-6 'carbamate); 4.4-4.1 (m, 3H, H-5 ', 5 ", H-3');
3.99 (m, 1H, H-4 ');
3.63 (t, 2H, 2H-9 ', J = 5.2Hz); 3.27 (m, 2H, 2H-7 '); 2.5-2.3 (m, 2H, H-2 ', 2 "); 1.82 (s, 3H, CH3 in position 5); 1.66 (m, 2H, 2H-8 ').
[13Cj NMR (chloroform-d), ~: 164.21 (C-4); 156.38 (C-6 '); 150.30 (C-2);
135.88 (C-6);
111.03 (C-5); 86.05 (C-1 '); 82.37 (C-4 '); 63.95 (C-5 '); 60.79 (C-9 ');
60.04 (C-3 '); 39.11 (C
7 '); 37.23 (C-2 '); 32.34 (C-8 '); 12.53 (CH3 in position 5).
Mass spectrum (GT matrix), FAB +: 369 (M + H) +; 737 (2M + H) +; 127 (B + 2H) +.
LR. (dichloromethane, cm- '), v: 3391 (OH); 3066 (NH); 2947 (C sp2 and sp3);
2105 (N3);
1694 (C = O carbamate and amides); 1520; 1471; 1253; 1095; 1051 (C-OH); 908 ; 733; 650.
Log P (n-octanol / HZO) _ -1.24 +/- 0.44 [log P, e, zT = -0.88 +/- 0.42]
EXAMPLE VI
3'-azido-3 'deoxy- ~' -O - [(a-hydroxybutyl) -a-carbonyllthymidine 6 To a solution of AZT (100 mg; 0.374 mmol; 1 eq) in CH3CN (2 ml), under agitation magnetic and nitrogen, N, N carbonyldümidazole (67 mg; 0.412 mmol;
1.1 eq). The reaction mixture is stirred at room temperature for 2 h, then add, to the syringe, 1-butanol (52 p1; 0.561 mmol; 1.5 eq). After 2 p.m. at 60 ° C, the reaction mixture is evaporated under reduced pressure. The residue obtained is diluted in 5 ml of CHZC12, then washed with 2x5 ml of a 5% aqueous solution of citric acid, with 2x5 ml of a solution aqueous NaHC03 to 5% and 2x5 ml of H20. The aqueous phases are extracted with 2x5 ml of CHZCIz.
The phases combined organics are dried over NazS04, filtered and evaporated under reduced pressure. The residue obtained is purified on a 2 mm thick preparative silica plate (eluent: hexane 20 in ethyl acetate) to yield compound 6 (84 mg; 64%).
Rf (ethyl acetate 80 / hexane 20) = 0.65.

12 [1H] NMR (chloroform-d), 8: 9.32 (s, 1H, H-3); 7.34 (s, 1H, H-6); 6.19 (t, 1H, H-l ', J = 6.2 Hz); 4.4-4.2 (m, 3H, H-5 ', 5 ", H-3'); 4.12 (t, 2H, 2H-7 ', J = 6.6Hz);
4.00 (m, 1H, H-4 '); 2.5-2.2 (m, 2H, H-2 ', 2 "); 1.86 (s, 3H, CH3 in position 5); 1.60 (m, 2H, 2H-8 '); 1.33 (m, 2H, 2H-9 '); 0.87 (t, 3H, 3H-10 ', J = 7.3Hz).
[i3C] NMR (chloroform-d), 8: 163.91 (C-4); 154.89 (C-6 '); 150.43 (C-2);
135.37 (C-6);
111.55 (C-5); 85.04 (C-1 '); 81.81 (C-4 '); 68.82 (C-5 '); 66.26 (C-7 ');
60.11 (C-3 '); 37.91 (C-2 '); 30.73 (C-8 '); 19.01 (C-9 '); 13.75 (C-10 '); 12.63 (CH3 in position 5).
Mass spectrum (GT matrix): FAB +: 368 (M + H) +; 735 (2M + H) +; 127 (B + 2H) +.
LR. (dichloromethane, cm-1), v: 3184; 3051 (NH); 2962 (C sp2 and sp3); 2107 (N3); 1748 (C = O carbonate); 1691 (C = O amides); 1466; 1403; 1271; 1091; 910; 733.
Log P (n-octanol / H20) _ +1.02 +/- 0.48 [log PAT = -0.88 +/- 0.42]
PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF FORMULA (I) The viral strain used in the tests is subtype B of the prototype virus HIV-1-LAV, which is a “standard” strain.
The method of evaluation of antiviral properties, to test molecules susceptible to inhibit the replication of HIV, is the observation of the formation of syncitia.
This method consists in observing the fusogenic effect of the HIV virus on the cell line bet implementation and formation of syncitia over time. The method used involves MT4 lymphocytes infected with the HIV-1-BRU (LAV) viral strain allowing observation optimal formation of syncitia. Experimentally, the method consists to put in culture the MT4 cells in RPMI 1640 medium in the presence of serum from fetal cattle, antibiotics and glutamine. The culture medium is renewed every 3 or 4 days.
Infection with the HIV-1-BRU virus is carried out by incubation of the culture cell MT4

13 for 1 hour at 37 ° C in the presence of this virus. After infection, cells are washed in a buffer solution, centrifuged and then re-cultured in the same medium as the one described previously. The formation of giant multinucleated cells appears from 48 hours and the majority of cells merged into syncitia by day 4. This culture is going serve as a witness. A
same cell culture is incubated at 37 ° C. in the presence of different concentrations of compounds to be tested as soon as the infection has been carried out. The number of syncitia is determined microscopically from the 5th day after infection. With reference to the control culture, we can determine the concentration of the compound that inhibits 50% of the viral replication (ECso).
On the other hand, the determination of cytotoxicity makes it possible to know the action compounds to test on the biology of healthy cells and their ability not to interfere with development of these cells if they are not infected with the virus. The compound cytotoxicity test is measured by incubation of the same healthy MT4 cell line at 37 ° C under atmosphere at 5% CO 2 alone or in the presence of the compound to be tested.
After incubation, cells are suspended and samples are taken and mixed with Trypan Blue to determine the dose corresponding to inhibition 50% of the cell proliferation (CCso).
We can thus determine the Selectivity Index (SI) which is the CCso /
ECSO of a molecule given, knowing that it must be greater than 500 for the molecule to be clinically interesting.
Result The ECso, CCso, and SI of compounds in accordance with the invention are reported in table next

14 ECso CCso SI
(~ M) (~ M) H2N- (CH2) 3-C (O) -OAZT 1 0.1>100> 1000 H2N- (CH2) 3-NH-C (O) -OAZT 0.1>100> 1000 H2N- (CH2) 3-OC (O) -OAZT 0.1>100> 1000 HO- (CHZ) 4-OC (O) -OAZT 4 0.0005>100> 100,000 HO- (CHZ) 3-NH-C (O) -OAZT - - -H3C- (CHZ) 3-OC (O) -OAZT - - -AZT 0.05>100> 2000 d4T 0.1> N / A> 500 ddI 0.1>50> 500 ECso: concentration required to inhibit 50% of syncitia formation on MT4 cells CCso: concentration required to induce the lysis of non MT4 cells by 50%
infected.
5 SI: selectivity index = CCSO / ECSO.
Compared anti-HIV activities of 3'-azido-3'-deoxy-5'-O-ffa, ~ -butanedioyl) -at-carbonyll thymidine 4 and AZT
~ Tests on MT-4 cells and HIV-1 BRU viral strain AZT 3'-azido-3'-dsoxy-S'-O - [(a, w-butanedioyl) -a-carbonyl]
thymidine ECso 25 nM 0.5 nM

CCSO> 100 pM> 50 ~ M

IT>4,000> 100,000 ~ Tests on PBMC cells and HIV-1 IIIB viral strain AZT 3'-azido-3'-dsoxy-5'-O - [(a, c ~ -butanedioyl) -a-carbonyl]
thymidine ECso 7.5 nM 0.78 nM

CCso 8 pM 38 ~ M

IT 1.067 48.333 ~ Tests on PBMC cells and HIV-1 BaL viral strain AZT 3'-azido-3'-dsoxy-5'-O - [(a, w-butanedioyl) -a-carbonyl]
thymidine ECso 11 nM 0.78 nM

CCSO 11 pM 24 ~ M

IT 1.000 30.769 with 5 ECSO: concentration required to inhibit 50% of viral replication on the various strains cellular.
CCso: concentration required to cause 50% lysis of the different uninfected cells.
IT: therapeutic index = CC; o / ECso.
10 We have summarized here the most remarkable results obtained with this composed it is good to note that this prodrug is not always more active than the parent drug (AIT) according to cell and viral strains used in evaluation tests for anti-HIV properties.
However, the virological test performed on PBMC cells is the most representative and the most significant of what is actually happening in vivo in humans. We can moreover note that

15 best results obtained with this prodrug were those achieved on PBMC cells.
3'-azido-3'-deoxy-5'-O - [(a, c ~ -butanedioyl) -a-carbonyl] thymidine present a phenomenon intramolecular cyclization in solution, and more particularly in the human serum.
The intramolecular cyclization mechanism is as follows HO a O
AZT-0H +
OO ~ O
AZT-O- ~~
bb a AZT-OC- O - (CH ~~ -OH
II
O
This phenomenon of intramolecular cyclization leads to in situ regeneration of the prodrug of departure and, therefore, increases its half-life time in serum.
During the intramolecular rearrangement of this compound, the opening according to the pathway led to the formation of a thermodynamically disadvantaged 7-atom ring. This length of arms

16 (- (CHZ) 4-) will thus favor path b, i.e. in situ regeneration from the mother prodrug of start, and increase the half-life of this molecule in solution.
Anti-HIV activities observed with another AZT prodrug:
phosphoramidate 3'-azido-3'-deoxythymidine with structural formula O
H
NH-- p O
...
/ ON ~ O

NOT

~ Tests on PBMC cells and HIV-1 LAV viral strain AZT 3'-azido-3'-dsoxy-S'-O - [(a, w-butanedioyl) -a-carbonyl]
thymidine ECSO 80 nM 10 nM

CCSO> 100 ~ M> 100 ~ .M

IT 1,125 10,000

Claims (8)

1. Compounds of general formula (I) in which A represents a divalent group chosen from - (CH2)n -, -(CH2)n-NH-, - (CH2)n - O -;

n is an integer which can vary from 1 to 12;
Z represents an amino group, a hydroxyl or an alkyl, and the "nucleoside" group is the residue of a hydroxylated nucleoside of the formula general in which R1 represents a radical chosen from:

where R4 represents methyl, trifluoromethyl or halovinyl, R2 represents a hydrogen or a hydroxyl, R3 represents hydrogen. a hydroxyl or an azido, and the dotted line symbolizes a possible carbon-carbon double bond, excluding the compound having a formula wherein A is the group -(CH2)n-NH-with n equal to 1, Z represents a methyl group, R1 represents the radical:

in which R4 represents a hydroxyl R2 represents hydrogen and R3 represents hydroxyl. 2. Compounds of general formula (I) according to claim 1, characterized in what the group "nucleoside" is the residue of a hydroxylated nucleoside selected from the group of nucleosides containing zidovudine, didanosine and stavudine. 3. Compounds of general formula (I) according to one of claims 1 or 2, chosen from the following compounds - 3'-azido-3'-deoxy-5'-O-[.omega.-amino-.alpha.-butanoyl]thymidine - 3'-azido-3'-deoxy-5'-O-[(.alpha., .omega.-diaminopropyl)-.alpha.-carbonyl]thymidine - 3'-azido-3'-deoxy-5'-O-[(.omega.-amino-.alpha.-hydroxypropyl)-.alpha.-carbonyl]thymidine - 3'-azido-3'-deoxy-5'-O-[(.alpha., .omega.-butanedioyl)-.alpha.-carbonyl]thymidine - 3'-azido-3'-deoxy-5'-O-[(.alpha.-amino-.omega.-hydroxypropyl)-.alpha.-carbonyl]thymidine - 3'-azido-3'-deoxy-5'-O-[(.alpha.-hydroxybutyl)-.alpha.-carbonyl]thymidine - 2',3'-dideoxy -5'-O-[(.omega.-amino-.alpha.-butanoyl]inosine - 2',3'-dideoxy -5'-O-[(.alpha.,.omega.-diaminopropyl)-.alpha.-carbonyl]inosine - 2',3'-dideoxy -5'-O-[(.omega.-amino-.alpha.-hydroxypropyl)-.alpha.-carbonyl] inosine - 2',3'-didehydro-2',3'-dideoxy-5'-O-[.omega.-amino-.alpha.-butanoyl]thymidine - 2',3'-didehydro-2',3'-dideoxy-5'-O-[(.alpha., .omega.-diaminopropyl)-.alpha.-carbonyl]thymidine - 2',3'-didehydro-2',3'-dideoxy-5'-O-[(.omega.-amino-.alpha.-hydroxypropyl)-.alpha.-carbonyl]
thymidine 4. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that that we submit a hydroxylated nucleoside of general formula:

in which R1 represents a radical chosen from where R4 represents methyl, trifluoromethyl or halovinyl, R2 represents a hydrogen or a hydroxyl, R3 represents a hydrogen, a hydroxyl or an azido, and the dotted line symbolizes a possible carbon-carbon double bond, in the presence of an esterification catalyst in a polar solvent, to the action of a compound of formula (II):
in which A is as previously defined and Z1 represents a protected amino group, hydroxyl or alkyl in order to obtain an ester of formula (III):
wherein A, Z, and the "nucleoside" group are as defined previously;
which is subjected to a deprotection reaction when Z1 represents a group amino protected, in order to obtain the compound of formula (I), in which Z is as defined previously. 5. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that that a hydroxylated nucleoside as defined previously is subjected to the action N,N-carbonyldiimidazole, in a polar solvent, in order to obtain the functional derivative of formula (IV) wherein the nucleoside group is as previously defined, which is subjected to the action of a diamine of formula (V) H2N-B-NH2 (V) wherein B is a divalent group -(CH2)n- or n being an integer can vary from 1 to 12, in order to obtain a compound of formula (I), in which A represents a group divalent -(CH2)n-NH- or and Z represents an amino group. 6. Process for the preparation of an ester of formula (I) according to claim 1, characterized in that that a hydroxylated nucleoside as defined above is subjected to a polar solvent, to the action of N,N-carbonyldiimidazole, in order to obtain the product of formula (IV) in which the "nucleoside" group is as defined above, which is subjected to the action of a hydroxy compound of formula (VII) Z1-B-OH (VII) wherein B is a divalent group -(CH2)n- or n is a number entire which can vary from 1 to 12, and Z1 represents a protected amino group, hydroxyl or alkyl in order to obtain an ester of formula (VIII) wherein B, Z1 and the "nucleoside" group are as defined previously, which is subjected to a deprotection reaction of the amino group when Z, represents a protected amino group in order to obtain a compound of formula (I), in which A represents a group divalent -(CH2)nO- or 7. Pharmaceutical compositions containing as active ingredient at least one of the compounds defined according to any one of claims 1 to 3, as a mixture or in association with an inert excipient, non-toxic, pharmaceutically acceptable. 8. Pharmaceutical compositions according to claim 7 in which the content in principle active ingredient ranges from 0.1 mg to 100 mg per unit dose.