JP2003504377A - Novel ester obtained from nucleoside, method for producing the same, and pharmaceutical composition containing the same - Google Patents

Abstract

(57) Abstract: A novel ester obtained from a nucleoside, a method for producing the same, and a pharmaceutical composition containing the same. Use as antiviral drug. SOLUTION: A novel ester of the general formula (I) obtained from a nucleoside: (A is _{- (CH 2) n -,} - (CH 2) n-NH -, (CH 2) a bivalent radical selected from n-0-, n is an integer from 1 to 12, Z is amino, A hydroxyl or alkyl group, a `` nucleoside '' group is the residue of a hydroxylated nucleoside of the general formula, R ₁ is a group selected from (2) and (3), R ₄ is methyl, trifluoromethyl or halovinyl, R ₂ represents hydrogen or hydroxyl, R ₃ represents hydrogen, hydroxyl or azide, and the dotted line represents a carbon-carbon double bond).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the field of organic chemistry, in particular to the field of therapeutic chemistry. The present invention particularly relates to a novel ester obtained from nucleoside, a method for producing the same,
And a pharmaceutical composition containing the same.

[0002]

[Problems to be Solved by the Invention and Means for Solving the Problems]

  The subject of the invention is the novel compounds of the general formula (I):

[0003]

[Chemical 19] Here, A is _{- (CH 2) n -,} - (CH 2) n-NH -, (CH 2) n-0-,

[0004]

[Chemical 20] Represents a divalent group selected from among, n represents an integer of 1 to 12, Z represents an amino, hydroxyl or alkyl group, and a “nucleoside” group is a residue of a nucleoside of the following general formula:

[0005]

[Chemical 21] [Wherein R ₁ represents a group selected from:

[0006]

[Chemical formula 22]

(Wherein R 4 represents methyl, trifluoromethyl or halovinyl) R ₂ represents hydrogen or hydroxyl, R ₃ represents hydrogen, hydroxyl or azide The dotted line, if present, is carbon-carbon Represents a double bond] (wherein A represents a group — (CH ₂ ) —NH—, n is 1, Z is a methyl group, R ₁ is a group below, and R ₄ is hydroxyl. Except)

[0008]

[Chemical formula 23]

The compound of the present invention is a compound of the general formula (I) wherein the “nucleoside” group is zidovudine
ovudine), didanosine and stavudine, and particularly preferably selected from the group consisting of hydroxylated nucleosides.

The present invention especially relates to compounds of general formula (I) selected from: 3′-azido-3′-deoxy-5′-O- [ω-amino-α-butanoyl] thymidine, 3'-azido-3'-deoxy-5'-O-[(α, ω-diaminopropyl) -α-carbonyl
] Thymidine, 3'-azido-3'-deoxy-5'-O-[(ω-amino-α-hydroxypropyl) -α- (carbonyl) thymidine, 3'-azido-3'-deoxy-5'- O-[(α, ω-butanedioyl) -α-carbonyl]
Thymidine, 3'-azido-3'-deoxy-5'-O-[(α-amino-ω-hydroxypropyl) -α-carbonyl] thymidine, 3'-azido-3'-deoxy-5'-O- [(Α-Hydroxybutyl) -α-carbonyl] thymidine, 2 ', 3'-dideoxy-5'-O-[(ω-amino-α-butanoyl] inosine, 2', 3'-dideoxy-5'- O-[((α, ω-diaminopropyl) -α-carbonyl] inosine, 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O- [ω-amino-α-butanoyl] thymidine , 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O-[(α, ω-diaminopropyl) -α
-Carbonyl] thymidine, 2 ', 3'-didehydro-2', 3'-dideoxy-5'-O- [ω-amino-α-hydroxypropyl] -α-carbonyl] thymidine

The invention further relates to the process for the preparation of the compounds of formula (I). The method of the present invention comprises a polar solvent such as dimethylformamide (DMF), acetone, acetonitrile, N-
Esterification catalysts such as 4-dimethyl-aminopyridine (DMAP) in methyl-methanantide, formamide, dimethylsulfoxide, sulfolane.
) In the presence of), a hydroxylated nucleoside of the general formula:

[0012]

[Chemical formula 24] [Wherein R ₁ represents a group selected from:

[0013]

[Chemical 25] (Wherein R ₄ represents methyl, trifluoromethyl or halovinyl) R ₂ represents hydrogen or hydroxyl, R ₃ represents hydrogen, hydroxyl or azide and the dotted line, when present, is the carbon-carbon double Represents a bond] is a compound of formula (II) below:

[0014]

[Chemical formula 26] (Wherein A represents the above definition, Z ₁ represents a protected amino group, a hydroxyl group or an alkyl group. In particular, the amino group is, for example, dimethyl-1,1-ethoxycarbonyl (tert-butyloxy). (Protected by a carbonyl) group or a benzyloxycarbonyl group) to give an ester of formula (III):

[0015]

[Chemical 27] (Wherein A, Z ₁ and “nucleoside” groups represent those defined above) In the case where Z ₁ is a protected amino group, a deprotection reaction is carried out to give, for example, a strong acid (eg trifluoroacetic acid, hydrogen chloride Acid) or hydrogenolysis to deprotect,
A compound of formula (I) is obtained, where Z is as defined above.

The present invention further relates to another process for the preparation of the compounds of formula (I). This method is suitable for polar solvents such as dimethylformamide (DMF), acetone, acetonitrile, N-
The hydroxylated nucleoside as defined above is reacted with N, N-carbonyldiimidazole in methyl-methanamide, formamide, dimethylsulfoxide, sulfolane to give the following formula (IV):

[0017]

[Chemical 28] (Wherein the "nucleoside group" is as defined above) and a functional derivative of the following formula (V):

[0018]

[Chemical 29] (Where B is a divalent group-(CH2) n- or

[0019]

[Chemical 30] And n is an integer of 1 to 12), and A is a divalent group:-(CH ₂ ) n-NH- or

[0020]

[Chemical 31] Embedded image wherein Z represents an amino group to obtain a compound of formula (I).

The present invention relates to another method, even for the preparation of compounds of formula (I). This method
The hydroxylated nucleoside as defined above is reacted with N, N-carbonyldiimidazole in a polar solvent such as dimethylformamide, acetone, acetonitrile, N-methyl-methanamide, formamide, dimethylsulfoxide, sulfolane to give the following formula ( IV):

[0022]

[Chemical 32] (Wherein the “nucleoside” group represents as defined above), which is represented by the alcohol of formula (VII):

[0023]

[Chemical 33] (Where B is a divalent group-(CH ₂ ) n- or

[0024]

[Chemical 34] , N represents an integer of 1 to 12, Z ₁ represents a protected amino group, a hydroxyl group or an alkyl group.The amino group is, for example, dimethyl-l, l-ethoxycarbonyl (tert.
-Butyloxycarbonyl) group or protected by benzyloxycarbonyl) to give an ester of formula (VIII):

[0025]

[Chemical 35] (Wherein B, Z1 and the “nucleoside” group represent those defined above) (when Z1 is a protected amino group, a reaction for deprotecting the amino group, for example, a strong acid (for example, trifluoroacetic acid, chloride Hydrogenoic acid) or hydrogenolysis is performed
1) compound (A is a divalent group — (CH ₂ ) n—O— or

[0026]

[Chemical 36] Is obtained). The compound of formula (I) has the property of inhibiting the replication of the HIV-I-BRU virus. Therefore,
This compound is suitable for the treatment of viral diseases, in particular for the treatment of hepatitis A, hepatitis B, AIDS and the pathologies associated therewith.

The present invention further comprises at least one compound as defined above as an active ingredient,
It relates to a pharmaceutical composition which is mixed or combined with an inert, non-toxic pharmaceutically acceptable excipient.

The pharmaceutical composition of the invention is suitable for oral, parenteral or rectal administration in the form of capsules, tablets, beverage solutions and injection solutions. The content of the active ingredient of the general formula (I) can be varied from 0.1 mg to 100 mg / unit dose depending on the administration route. Administration can be carried out 1 to 3 times a day depending on the treatment conditions.

[0029]

【Example】

Examples of the present invention will be shown below, but the present invention is not limited to the following examples. The abbreviations used in the examples have the following meanings: AcOEt: Ethyl acetate AZT: 3'-azido-2 ', 3'-dideoxy-thymidine or zidovudin.
e) DCC: N, N-dicyclohexylcarbodiimide DCM: Dichloromethane ddl: 2 ', 3'-dideoxyinosine or didanosine DMAP: 4-dimethylaminopyridine d4T: 2', 3'-didehydro-2 ', 3' -Dideoxy-thymidine or stavudine (st
avudine) FAB: Fast atom bombardment MS: Mass spectrometry TFA: Trifluoroacetic acid HIV: Human immunodeficiency virus HBV: Hepatitis B virus HTLV: Human T cell lymphotropic virus

Example I 3'- Azido-3'-deoxy-5'-O- [ω-amino-α-butanoyl] thymidine (1) DCC (255 mg; 1.235 mmol; 2.2 eq) under nitrogen Add 4- (tert-butyloxycarbonyl) amino-1-butanoic acid (342 mg, 1.684 mmol, 3 eq) in dimethylformamide (OME) (3 ml) cooled to 0 ° C. with magnetic stirring. The reaction solution was stirred at this temperature for 2 hours and then 4-dimethylaminopyridine (DMAP) (69 mg, 0.561 mmol, 1
AZT (150 mg, 0.561 mmol, 1 eq) solution in DMF (2 ml) containing After standing at ambient temperature for 24 hours, the reaction is filtered to remove the N, N-dicyclohexylurea (DCU) formed and then evaporated under reduced pressure. The residue obtained was diluted with 8 ml AcOEt and washed twice with 5% aqueous citric acid solution x 7 ml,
% NaHCO ₃ twice with an aqueous solution x 7 ml, then twice x 7 ml with H ₂ 0. The recovered aqueous phase is extracted twice with 7 x AcOEt. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue obtained is purified by flash chromatography on a silica gel column (eluent: methanol 5% in dichloromethane). Desired compound (228m
g: 90%). Deprotection of the terminal amino function is quantitatively performed with TEA (1 ml) in CH ₂ Cl ₂ (2 ml) to give compound I. Rf (dichloromethane 90 / methanol 10) = 0.14 [ ¹ H] NMR (methanol-d4) δ: 7.26 (S, 1H, H-6), 5.94 (t, 1H, H-1 ′, j = 6.4 Hz), 4.3-4.1 (m, 3H, H
-5 ', 5 medium, H-3'), 3.88 (m, lH, H-4 '), 2.9-2.8 (m, 2H, 2H-9'), 2.5-2.2 (
m, 4H, H-2 ', 2 media, 2H-7'), 1.9-1.8 (m, 2H, 2H-8 '), 1.74 (s, CH ₃ , 5th place)
[ ¹³ C] NMR (methanol-d4), δ: 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'); 63.9 (C-5 ') 60.40 (C-3'); 38.26 (C-9 '); 35
.78 (C-2 '); 29.72 (C- 7'); 21.86 (C-8 '); 12.29 (CH 3 5 -position) Mass spectrum (CT ^{Matrix): FAB +: 353 (M} + H) +; 225 ( M− (B ⁻ )) ⁺ , 127 (B + 2H) ⁺ IR (KBr, cm ⁻¹ ) ν: 3445 (NH ₂ ); 3167 (NH); 2939 (C sp2 and sp3); 2112 (N ₃ ). 1780 (C = 0
); 1686 (C = 0): 1472; 1474; 1190; 793; 708

Example II 3'- Azido-3'-deoxy-5'-O- (α, ω-diaminopropyl) -α-carbonyl] thio
Midin (2) N, N-carbonyldiimidazole (100 mg, 0.617 mmol, 1.1 eq) is added to a solution of AZT (150 mg, 0.561 mmol, 1 eq) in DMF (3 ml) under nitrogen with magnetic stirring. The reaction was stirred at ambient temperature for 2 hours and then 1,3-diaminopropane (70 μl, 0.842 mmol, 1
.5 eq) with a syringe. After standing at ambient temperature for 4 hours, the reaction is evaporated under reduced pressure. The reaction product is then taken up in ether and the excess diamine is filtered off. The resulting residue is purified on a 2 mm thick preliminary silica plate (eluent: dichloromethane in methanol 20%) to give compound 2 (116 mg, 78%). Rf (dichloromethane 45 / methanol 45 / AcOH 10) = 0.43 [ ¹ H] NMR (chlorohomam-d): δ: 9.48 (s lH, H-3), 7.01 (s, 1H, H-6), 5.88 (m , 2H, H-1, NH-6 ', Carbamate), 4.2-3.9 (m, 3H, HS. 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, CH ₃
5)); 1.39 (m, 2H, 2H-8 ') [ ¹³ C] NMR (chloroform-d) δ: 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 (CH ₃ 5th position) Mass spectrum (GT matrix): FAB ⁺ : 368 (M + H) ⁺ , 735 (2M + H) ⁺ ; 127 (B + 2H) ⁺ . IR (dichloromethane, cm ^-1 ) ν: 3353 (NH ₂ ): 3067 (NH); 2949 (C sp2 and sp3); 2252; 2107 (N ₃ ); 170
0 (C = 0); 1517; 1469; 1268; 1097; 909; 733 Log P (n-octanol / H ₂ 0) = -1.19 ± 0.44 [log P _AZT = -0.88 ± 0.42]

[0032] Example III 3'-azido-2'-deoxy -5'-O - [(ω- amino-.alpha.-hydroxypropyl)-.alpha.-carboxymethyl sulfonyl] thymidine (3) NN- carbonyldiimidazole (100 mg: 0.617 mmol; 1.1 eq) is added to a solution of AZT (150 mg, 0.561 mmol; 1 eq) in DMF (3 ml) under a nitrogen atmosphere with magnetic stirring. After stirring the reaction at ambient temperature for 2 hours, 3- (tert-butyloxycarbonyl) -amino-1-propanol (147 mg, 0.842 mmol, 1.5 eq) is added. The reaction is heated at 700 C for 14 hours and then evaporated under reduced pressure. The residue obtained was diluted with 5 ml of CH ₂ Cl ₂ and washed twice with 5% aqueous citric acid solution x 5 ml, 5
Wash with ₅ % aqueous Na ₂ SO ₄ twice x5 ml, then with H ₂ O twice x5 ml. The aqueous phase is extracted twice with CH ₂ Cl ₂ x 5 ml. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting residue is purified by flash chromatography on a silica gel column (eluent: dichloromethane 5% in methanol) to give the desired compound (228 mg, 90%). Deprotection of the terminal amino function was quantitatively performed with TEA (1 ml) in CH ₂ Cl ₂ (2 ml) to give compound 3. Rf (dichloromethane 90 / methanol 10) = 0.12 [ ¹ H] NMR (methanol-d4) δ: 7.31 (s, 1H, H-6); 5.96 (t, lH, H-1 ′, J = 6.4 Hz); 4.3-4.1 (m, 3H, H
-5 ', 5'';,H-3'); 4.06 (t, 2H, 2H, H-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, CH ₃ 5th place). [ ¹³ C] NMR (methanol-d4) δ: 164.60 (C-4); 154.83 (C-6 '); 150.48 (C-2); 136.02 (C-6); 110.48 (C-5)
85.08 (C-l '): 81.37 (C-4'); 68.30 (C-5 '); 66.12 (C-7'); 60.31 (C-3 ');
38.21 (C-9 '); 36.05 (C2'); 25.14 (C-8 '); 12.10 (CH 3 5 -position) Mass spectrum (GT Matrix): FAB +: 369 (M + H) +; 268 (AZT + H) ⁺ , 127 (B + 2H) ⁺ IR (dichloromethane, cm ^-1 ) ν: 3380 (NH ₂ ); 3081 (NH); 2942 (C sp2 and sp3); 2107 (N ₃ ); 1692 (C = 0
); 1471; 1270; 1110; 738

Example IV 3'-Azido-3'-deoxy-5'-O-[(α, ω-butanedioyl) -α-carbonyl] thymi
Zin (4) NN-carbonyldiimidazole (100 mg, 0.617 mmol, 1.1 eq) is added to a solution of AZT (150 mg, 0.561 mmol, 1 eq) in DN4F (4 ml) under a nitrogen atmosphere under magnetic stirring. The reaction was stirred at ambient temperature for 2 hours and then 1,4-butanediol (75 μl; 0.842 mm
ol, 1.5 eq) with a syringe. After heating at 70 ° C. for 14 hours, the reaction solution is evaporated under reduced pressure. The residue obtained is diluted in 5 ml of CH ₂ Cl ₂ and washed 2 × 5 ml with 5% aqueous citric acid solution, then 2 × 5 ml with H ₂ 0. The aqueous phase is extracted twice with CH ₂ Cl ₂ x 5 ml. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. Purify the resulting residue by flash chromatography on a silica gel column (eluent: hexane 20% in AcOEt).
To give compound 4 (182 mg, 85%). Rf (ethyl acetate 85 / hexane 15) = 0.23 [ ¹ H] NMR (chloroform-d) δ: 9.14 (s, 1H, H-3); 7.38 (d, lH, H-6, J = 1.0 Hz); 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 = 6.4
Hz); 4.07 (m, lH, H-4 '); 3.68 (t, 2H 2H-10', J = 6.1 Hz); 2.47 (m, 2H,
H-2 ', 2 ") ; 1.90 (s, 3H, CH 3 5 -position); 1.80 (m, 2H, 2H-8'); 1.67 (m, 2H, 2H-
9 ') [ ¹³ C] NMR (chloroform-d): δ: 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 (CH ₃ 5th place)
Mass spectrum (GT matrix): FAB ⁺ : 384 (M + H) ⁺ , 767 (2M + H) ⁺ , 268 (AZT + H) ⁺ , 127 (B + 2H) ⁺ IR (dichloromethane, cm ^-1 ): ν; 3392 (OH); 3188; 3055 (NH); 2950 (C sp2 and sp3); 2108 (N ₃ ); 1749
(C = O carbonate); 1693 (C = O amide); 1468; 1405; 1266; 1089; 1049 (CO
H); 738 Log P (n-octanol / H ₂ 0) = -0.68 ± 0.48 [log P _AZT = -0.88 ± 042]

Example V 3'-Azido-3'-deoxy-5'-O- [α-amino-ω-hydroxypropyl) -α-cal
Bonyl] thymidine (5) N, N-carbonyl-diimidazole (40 mg, 0.247 mmol, 1.1 eq) AZT (60 mg, 0.225 mmol, 1 eq) in CH ₃ CN (1.5 ml) under a nitrogen atmosphere with magnetic stirring. ) Add to solution. The reaction was stirred at ambient temperature for 2 hours then treated with 3-amino-1-propanol (25
μl, 0.292 mmol, 1.3 eq) is added by syringe. After standing for 4 hours at ambient temperature, the reaction solution is evaporated under reduced pressure. The residue obtained was diluted with 5 ml of CH ₂ Cl ₂ and diluted with 5% aqueous citric acid.
Wash 2 × 5 ml, 5% NaHCO ₃ aqueous solution × 5 ml, and H ₂ × 2 × 5 ml. The aqueous phase is extracted twice with CH ₂ Cl ₂ x 5 ml. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting residue is purified on a 1 mm thick preparative silica plate (eluent: hexane 20% in ethyl acetate) to give compound 5 (50 mg, 60%). Rf (dichloromethane 90 / methanol 10) = 0.37 [ ¹ H] NMR (chloroform-d): δ: 9.10 (s, 1H, H-3); 7.19 (s, 1H, H-6); 5.99 (t, 1H , H-1 ', J = 6.1 Hz)
5.58 (m, lH, NH-6 'carbonate); 4.4-4.1 (m, 3H, H-5', 5 ", H-3 '); 3.9
9 (m, 1H, H-4 '); 3.63 (t, 2H, 2H-9', J = 5.2 Hz); 3.27 (m, 2H, 2H-7 '); 2
.5-2.3 (m, 2H, H- 2 ', 2 "); 1.82 (s, 3H, CH 3 5 -position); 1.66 (m, 2H, 2H-8') [13 C] NMR ( chloroform -d ) Δ: 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 (CH 3 5 -position) Mass spectrum (GI ^{Matrix): FAB +: 369 (M} + H) +, 737 (2M + H) ⁺ , 127 (B + 2H) ⁺ IR (dichloromethane, cm ^-1 ) ν: 3391 (OH); 3066 (NH); 2947 (C sp2 and sp3); 2105 (N ₃ ; 1694 (C = O
Carbomate and amide); 1520; 1471; 1253; 1095; 1051 (C-OH); 908; 733
650 Log P (n-octanol / H ₂ 0) = -1.24 ± 0.44 [log P _AZT = -0.88 ± 0.42]

Example VI 3'-Azido-3'-deoxy-5'-O-[(α-hydroxybutyl) -α-carbonyl] thymi
Zin (6) NN-carbonyldiimidazole (67 mg, 0.412 mmol, 1.1 eq) is added to a solution of AZT (100 mg, 0.374 mmol, 1 eq) in CH ₃ CN (2 ml) with magnetic stirring under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 2 hours and then 1-butanol (5
2μ1, 0.561mmol, 1.5eq) is added. After heating at 60 ° C. for 14 hours, the reaction solution is evaporated under reduced pressure. The residue obtained was diluted with 5 ml of CH ₂ Cl ₂ and washed twice with 5% aqueous citric acid solution.
Wash x5 ml, wash twice with 5% aqueous NaHCO ₃ solution x5 ml, and wash with H ₂ O twice x5 ml. Water phase to C
Extract twice with H ₂ C ₁₂ x 5 ml. The organic phases are combined, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The resulting residue is purified on a 2 mm thick preparative silica plate (eluent: hexane 20% in ethyl acetate) to give compound 6 (84 mg, 64%). Rf (80 ethyl acetate / 20 hexane) = 0.65. [ ¹ H] NMR (chloroform-d) δ: 9.32 (s, 1H, H-3): 7.34 (s, 1H, H-6); 6.19 (t, lH, H-l ', J = 6.2 Hz) ;
44-4.2 (m, 3H, H-5 ', 5 ", H-3'); 4.12 (t, 2H, 2H-7 ', J = 6.6 Hz); 4,00 (m
, 1H, H-4 '); 2.5-2.2 (m. 2H. H-2'. 2 medium): 1.86 (s, 3H, CH ₃ 5th position); 1.60 (m
2H, 2H-8 '); 1.33 (m, 2H, 2H-9'); 0.87 (t, 3H, 3H-10 ', J = 7.3 Hz) [ ¹³ C] NMR (chloroform-d): δ: 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 (CH ₃ 5th) Mass spectrum (GT matrix): FAB +: 368 ( M + H) ⁺ , 735 (2M + H) ⁺ , 127 (B + 2H) ⁺ IR (dichloromethane, cm ^-1 ): ν: 3184; 3051 (NH), 2962 (C sp2 and sp3); 2107 (N ₃ ); 1748 (C = 0 carbonate); 1691 (C = 0 amide); 1466 1403; 1271; 1091; 910; 733 Log P (n-octanol / H ₂ 0) = -1.02 ± 0.48 [log P _AzT = -0.88 ± 0.42]

Pharmacological study of compounds of formula (I) The virus strain used in this test is the prototype virus HI, which is a standard strain.
It is a subtype B of Vl-LAV. The formation of syncytia was observed as a method of assessing antiviral properties for testing molecules capable of inhibiting HIV replication. In this method, the cell strain used
The fusogenic effect of the HIV virus and the fused cells as a function of time (
formation of syncytia). Here we used MT4 lymphocytes infected with the viral strain HIV-l-BRU (LAV) to allow optimal observation of fused cell formation. In the experiment MT was used in the presence of fetal bovine serum, antibiotics and glutamine.
4 cells were cultured in RPMI 1640 medium. This medium was refreshed every 3 or 4 days. HIV-
Contamination with 1-BRU virus was carried out by culturing MT4 cells at 37 ° C for 1 hour in the presence of this virus. After the contamination, the cells were washed with a buffer solution, centrifuged, and returned to the same medium as above to culture. After 48 hours, formation of multinucleated giant cells was observed, and most of the cells combined after 4 days to form a fused cell (syncytia). This culture served as a control. Immediately after the contamination was carried out, the same cell culture was carried out at 37 ° C. in the presence of various concentrations of the test compound. Counting of the number of fused cells was started microscopically on day 5 after contamination. The concentration of compound that inhibits viral replication by 50% (EC ₅₀ ) can be determined by comparison to control cultures.

Furthermore, the observation of cytotoxicity shows that the compound under test has no biological effect on healthy cells and does not interfere with the growth of these cells in the absence of virus infection. It was The cytotoxicity of the test compound was determined by culturing a healthy MT4 cell line in a 5% CO ₂ atmosphere alone or in the presence of the test compound at 37 ° C. After culturing, suspend the cells, take a sample, mix with Trypan Blue, and
The dose corresponding to the 0% ban (CC ₅₀ ) was determined. Selectivity index (SI) is expressed as the ratio of CC ₅₀ / EC _{50 for} a given molecule. It is known that this ratio of clinically significant molecules should be above 500.

Results The EC ₅₀ , CC ₅₀ and SI values of the compounds of the present invention are shown in [Table 1] below.

[0039]

[Table 1]

3'-azido-3'-deoxy-5'-O-[(α, ω-butanedioyl) -α-carbonyl] thymi
Comparison of anti-HIV activity between gin4 and AZT

[Table 2]

Testing with MT4 cells and the viral strain HIV-1 BRU

[Table 3]

[0042]

[Table 4]

The most notable results obtained with the compounds of the present invention have been summarized above. It should be noted that the prodrugs of the present invention are not always more active than the parent drug (AZT) and depend on the cells and viral strains used to assess anti-HIV properties. However, in understanding what is actually happening in humans (in vivo), P
The viral tests performed on BMC cells are the most representative and the most significant. It can also be emphasized that the best results obtained with the prodrugs of the invention were obtained with PBMC cells. 3'-azido-3'-deoxy-5'-O-[(α, ω-butanedioyl)-
α-Carbonyl] thymidine can be used in solution, especially in human serum.
r cyclization) action. The mechanism of intermolecular cyclization is as follows:

[0044]

[Chemical 37]

This intermolecular cyclization leads to the in situ formation of the starting prodrug, thus increasing the half-life in serum. Upon intramolecular rearrangement of this compound, a thermodynamically unfavorable 7-atom ring is formed (ring opening according to route a). Arm length (-(C
H ₂ ) ₄ —) favors route b, ie in situ production of the starting mother drug, increasing the half-life of this molecule in solution.

Other AZT prodrugs: 3′-azido-3′-deoxythymidine phosphine having the following structural formula
Anti-JIIV activity obtained with acid amides:

[Chemical 38]

[0047]

[Table 5]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 31/18 A61P 31/18 C07D 405/04 C07D 405/04 473/30 473/30 C07H 19/16 C07H 19/16 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), AL, AU, BR, CA, CN, CZ, DZ, HU, IL, IN, JP, KR, LT, LV, MA, MK, MX, NO, Z, PL, RO, RU, SI, US, VN, ZA (72) Inventor Clerque, Thierry France 13007 Marseille Boulevard Road Duban 9, Parc Mermo Numero 1 (72) Inventor Sale, Jean-Pierre France 13510 Egile Schmann de Bergon (No address) F-term (reference) 4C057 AA17 LL10 LL19 LL39 4C063 AA01 BB02 CC73 DD29 EE01 4C086 AA02 AA03 AA04 EA07 EA08 MA01 MA04 MA05 MA17 MA35 MA37 MA52 MA66 NA14 ZB

Claims (8)

[Claims] 1. A compound represented by the following general formula (I): [Where A is-(CH ₂ ) n-,-(CH ₂ ) n- (NH)-, (CH ₂ ) n-0-, and Represents a divalent group (n represents an integer from 1 to 12), Z represents an amino group, a hydroxyl group or an alkyl group, and a “nucleoside” group is a hydroxylated group represented by the following general formula: Represents the residue of a nucleoside: (Wherein R ₁ represents a group selected from the following: (Wherein R ₄ represents methyl, trifluoromethyl or halovinyl), R ₂ represents hydrogen or hydroxyl and R ₃ represents hydrogen, hydroxyl or azide. A heavy bond] (where A is a-(CH ₂ ) n-NH- group, n is 1, Z is a methyl group, R ₁ is
Compounds in which 4 represents a hydroxyl group, R2 represents hydrogen and R3 represents hydroxyl are excluded. 2. A "nucleoside" group is a residue of a hydroxylated nucleoside selected from the group of hydroxylated nucleoside groups including zidovudine, didanosine and stavudine. A compound represented by the general formula (I) according to claim 1. 3. A compound of general formula (I) according to claim 1 or 2 selected from the following compounds: 3'-azido-3'-deoxy-5'-O- [ω-amino- α-butanoyl] thymidine, 3′-azido-3′-deoxy-5′-O-[(α, ω-diaminopropyl) -α-carbonyl] thymidine, 3′-azido-3′-deoxy-5′- O-[(ω-amino-α-hydroxypropyl) -α- (
Carbonyl] thymidine, 3'-azido-3'-deoxy-5'-O-[(α, ω-butanedioyl) -α-carbonyl
] Thymidine, 3'-azido-3'-deoxy-5'-O-[(α-amino-ω-hydroxypropyl) -α-
Carbonyl] thymidine, 3'-azido-3'-deoxy-5'-O-[(α-hydroxybutyl) -α-carbonyl]
Thymidine, 2 ', 3'-dideoxy-5'-O-[(ω-amino-α-butanoyl] inosine, 2', 3'-dideoxy-5'-O-[((α, ω-diaminopropyl) -α-carbonyl] inosine, 2 ′, 3′-didehydro-2 ′, 3′-dideoxy-5′-O- [ω-amino-α-butanoyl] thymidine, 2 ′, 3′-didehydro-2 ′, 3'-dideoxy-5'-O-[(α, ω-diaminopropyl)-
α-carbonyl] thymidine, 2 ′, 3′-didehydro-2 ′, 3′-dideoxy-5′-O- [ω-amino-α-hydroxypropyl] -α-carbonyl] thymidine 4. A hydroxylated nucleoside of the following general formula in the presence of an esterification catalyst in a polar solvent: embedded image [Wherein R ₁ represents a group selected from the following: (Wherein R ₄ represents methyl, trifluoromethyl or halovinyl) R ₂ represents hydrogen or hydroxyl, R ₃ represents hydrogen, hydroxyl or azide and the dotted line, when present, is the carbon-carbon double Is a compound of formula (II) below: (Wherein A represents as defined above and Z ₁ represents an amino group, a hydroxyl group or an alkyl group) to give an ester of formula (III): (Where A, Z ₁ and the “nucleoside” group represent those defined above) (when Z ₁ is a protected amino group, a deprotection reaction is carried out to carry out the reaction of formula (I) (where Z is defined as above). A compound of formula (1) is obtained). 5. A hydroxylated nucleoside as defined above in N in a polar solvent.
By reacting with N, N-carbonyldiimidazole, the following formula (IV): (Wherein the “nucleoside group” is as defined above) and prepare a functional derivative thereof with a diamine of the following formula (V): (Where B is a divalent group-(CH2) n- or And n is an integer of 1 to 12), and A is a divalent group:-(CH ₂ ) n-NH- or And a compound of formula (I) in which Z represents an amino group is obtained, a process for producing a compound of formula (I) according to claim 1. 6. A hydroxylated nucleoside as defined above is reacted with N, N-carbonyldiimidazole in a polar solvent to form formula (IV): (Wherein the “nucleoside” group represents as defined above) is prepared by adding the alcohol of formula (VII): (Where B is a divalent group-(CH ₂ ) n- or Represents an integer of 1 to 12, Z ₁ represents a protected amino group, a hydroxyl group or an alkyl group) to obtain an ester of the following formula (VIII): (Wherein B, Z1 and the “nucleoside” group represent those defined above) (When Z1 is a protected amino group, a reaction for deprotecting the amino group is carried out to carry out the reaction of the formula (1
) (Where A is a divalent group — (CH ₂ ) n—O— or The method for producing an ester of formula (I) according to claim 1, characterized in that 7. A pharmaceutical composition, which is mixed or combined with an inert, non-toxic pharmaceutically acceptable excipient comprising at least one compound according to any one of claims 1 to 3 as active ingredient. object. 8. The pharmaceutical composition according to claim 7, wherein the content of the active ingredient is 0.1 mg to 100 mg per unit dose.