WO1999062921A1 - Antiviral phosphorus derivatives of 4'-thio-5-ethyl-2'-deoxyuridine - Google Patents

Antiviral phosphorus derivatives of 4'-thio-5-ethyl-2'-deoxyuridine Download PDF

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WO1999062921A1
WO1999062921A1 PCT/CA1999/000465 CA9900465W WO9962921A1 WO 1999062921 A1 WO1999062921 A1 WO 1999062921A1 CA 9900465 W CA9900465 W CA 9900465W WO 9962921 A1 WO9962921 A1 WO 9962921A1
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deoxyuridine
hsv
thio
ethyl
formula
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PCT/CA1999/000465
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French (fr)
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Alexandrova Lioudmila Alexandrovna
Krayevsky Alexander Antonovich
Alexander Adani
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S & T Science And Technology Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention relates to novel inhibitors and, more specifically, to novel 4 ' -thio-5-ethyl- 2'-deoxyuridine 5'-phosphonates. which inhibit the reproduction of the human He ⁇ es viruses (HSV- I, HSV-2, TK " HSV-1), Human Cytomegalo virus (HCMV) and Vaccinia virus (VV) in cell cultures.
  • HSV- I, HSV-2, TK " HSV-1 Human Cytomegalo virus
  • VV Vaccinia virus
  • HSV human He ⁇ es viruses
  • TEDU (4'-thio-5-ethyl-2'-deoxyuridine) (Formula I) and as shown below, inhibits HSV (HSV-1, HSV-2) reproduction in cell cultures but it has two negative properties.
  • TEDU has generally unacceptable toxicity in human and cell free systems with DNA polymerases.
  • TEDU does not inhibit thymidine kinase defective (TK ' HSV- 1 ) he ⁇ es viruses [1-3].
  • the present invention is directed to novel compounds exhibiting a selective inhibition of the reproduction of the HSV-1, HSV-2, TK " HSV, HCMV and W and which possess low toxicity.
  • the present compounds are U and HI of the formula as follows:
  • the reaction was mixed at ⁇ 20°C for 20 h, then ice-cold water (5 ml) was added. After mixing during 1 h at +4°C the reaction was diluted with water (150 ml) and applied onto a DEAE-Toyopearl column (2.5 x 12 cm. HCO ; " form), elution was made with a linear gradient of NH4HCO3 (0 -> 0.15M, 1 1). The fractions containing the product were evaporated and coevaporated with water (3 x 10 ml). The residue was dissolved in 25% NH ⁇ OH and kept at +4°C for 20 h, then evaporated, coevaporated with water (2x5ml). Then it was purified on a LiChroprep RP-18 column (2 x 15 cm), elution was made with 0.01M NH4HCO3 to yield 120 mg (63%).
  • the reaction was mixed at +20°C for 20 h, then ice-cold water (5 ml) was added. After mixing during 1 h at +4°C the reaction was diluted with water (150 mi) and applied onto a DEAE- Toyopearl column (2.5 x 12 cm, HC0 3 " form), elution was made with a linear gradient of NH4HCO3 (0 - > 0.15M, 1 l). The contaix ⁇ g e p ⁇ luct were evaporated and coevaporated with water (3 x 10 mi). The residue was purified on a LiChroprep RP-18 column (2 x 15 cm), elution was made with 0.01M
  • Antiviral assays of ⁇ . R-C 2 H,OOC were performed using an adaptation of the plaque reduction assay described in [4]. Twenty- four well plates containing monoiayers of MCR 5 cells (human embryo lung fibroblasts. ATCC CCL 171 ) were used for assay of varicella zostar virus ( VZV strain G31 ), and
  • SUBSTT ⁇ SHEET (RULE 2 ⁇ ) monoiayers of Vero cells (African Green monkey kidney, ATCC CCLB1) were used for he ⁇ es simplex virus type 1 (HSV- 1 ) strain SC 16 and HSV-2 (strain 186). Monoiayers were infected with virus at a multiplicity calculated to produce 60-80 plaques per well. Infected cells were overlaid with liquid growth medium containing various known concen ⁇ a ⁇ ons of the compound under investigation , and, in the case HSV-1 and HSV-2, carboxymethyl cellulose to prevent the formation of secondary plaques. Following a suitable period of incubation, plaques were fixed with formoi saline and stained, and their numbers were determined.
  • IC M detemnnanon For IC M detemnnanon. a dose-response curve was obtained and from this the 50% inhibitory concentianon (IC*) was obtamed. Tables 1 (first testing) and 2 (second independent tesung ) demonstrate these data for different viruses.
  • the well known antiviral drugs are shown as controls: BVDU - 5- bromovinyl-2'-deoxyuridine: ⁇ bovi ⁇ n: ACG - acyciovir, DHPG - gancyclovir.
  • Subconfluet cultures of Vero or MRC-5 ceils were grown in 96-well microtiter plates i n the presence of different dilutions of drug.
  • Cell numbers present at 96h (Varb) and 7 days (MRC-5) were est i ma t ed, on replicate cultures, using uptake of a tetrazolium dye (MTT).
  • MTT tetrazolium dye
  • the concentrauon required for a 50% inhibition of cell growth compared to comroi ceil growth in the absence of compound is t ermed
  • CCID Cv t otoxiciry assays were oe ⁇ ormeo using Vero cells and MRC-5 cells. For 50% cytotoxic concentianon (CC i( ⁇ ) determinanon.
  • the compounds according to the present lnven ⁇ on viz 4'-thio-5-ethyI-2'-deoxyu ⁇ dine 5 1 - phospnonates have shown to be capable of selective inhibinon of the reproducnon of the HSV-1 and HSV-2 viruses in ceil cultures. It is expected that this same selecnve inhibinon of the reproducnon of TK" HSV-1, HSMV and W viruses will be exhibited by the compounds of Formula ⁇ and HJ It is expected that he compounds of Formula ⁇ and Hi will be effecnve m the treatment of these viruses, including prophylactic treatment

Abstract

4'-Thio-5-ethyl-2'-deoxyuridine 5'-phosphonate of formula (II) wherein R=H, CONH2, AlkylOOC, Alkyl, Haloidalkyl, dihaloidalkyls, trihaloidalkyl, HOCH2, AcylOCH2.

Description

ANTIVIRAL PHOSPHORUS DERIVATIVES OF 4 ' -THI0-5-ETHYL-2 ' -DEOXYURIDINE
FIELD OF THE INVENTION
The present invention relates to novel inhibitors and, more specifically, to novel 4'-thio-5-ethyl- 2'-deoxyuridine 5'-phosphonates. which inhibit the reproduction of the human Heφes viruses (HSV- I, HSV-2, TK" HSV-1), Human Cytomegalo virus (HCMV) and Vaccinia virus (VV) in cell cultures.
BACKGROUND OF THE INVENTION
Known in the art are various compounds inhibiting the reproduction of the human Heφes viruses (HSV). The compounds known as TEDU (4'-thio-5-ethyl-2'-deoxyuridine) (Formula I) and as shown below, inhibits HSV (HSV-1, HSV-2) reproduction in cell cultures but it has two negative properties. First, TEDU has generally unacceptable toxicity in human and cell free systems with DNA polymerases. Second. TEDU does not inhibit thymidine kinase defective (TK'HSV- 1 ) heφes viruses [1-3].
Figure imgf000003_0001
(I) SUMMARY OF THE INVENTION
The present invention is directed to novel compounds exhibiting a selective inhibition of the reproduction of the HSV-1, HSV-2, TK" HSV, HCMV and W and which possess low toxicity. The present compounds are U and HI of the formula as follows:
Figure imgf000004_0001
wherein for Formula LL R=H, CONH2, AlkylOOC, Alkyl, Haloidalkyl, dihaloidalkyls, trihaloidalkyls, HOCH2, AcylOCH2 and wherein for Formula HI, R= is as defined in Formula LI and R'=O-alkyl, O-aminoalkyls, O-hydroxyalkyls, O-glycosyl
These compounds of Formula II and HI are capable of inhibiting the reproduction of HSV and are less toxic as compared to the prior art compounds.
DETAILED DESCRIPTION OF THE INVENTION
Synthesis of compounds II and III can be made according to Scheme 1 (one arrow essentially corresponds to one chemical step).
Scheme 1
Figure imgf000005_0001
II III
.Another synthetic pathway which may be used does not invite the preliminary protection of 3 -hydroxyl as set out in Scheme 2 below(here also one arrow essentially corresponds to one chemical step). According to Scheme 2. synthesis of compounds of Formula II and III are developed with essentially one chemical step starting from the compound of Formula I. Selection between Schemes 1 and 2 generally depends on the yield of the desired compound. In some cases, the yield is higher when the desired compound is synthesized according to Scheme 1, but in another cases Scheme 2 produces higher yields. Yieids of II and III ranged from 20-70% with schemes 1 and 2.
Scheme 2
(H) (I) (III) The compounds according to the present invention are white amoφhous powders, readily soluble in water, with low solubility in ethanol and dimethylsulfoxide. They have been found generally to be insoluble in other organic solvents.
The purity and structure of the compounds according to the present invention were proven by chromatography, UV, mass- and NMR-spectroscopy.
EXAMPLE 1
3'-O-Acetyl-I was synthesized according to [3]. Synthesis of 4'-thio-5-ethyI-2'-deoxyuridine 5'-hydrogenphosphonate (II, R=H)
(Scheme 1).
Figure imgf000006_0001
To a solution of phosphite acid (51 mg, 0.8 mmol) in water (2 ml), pyridine (3ml) and tri-π- butylamine (148 mg, 0.8 mmol) was added. The solution was evaporated, coevaporated with pyridine (3x5 ml) and then with dimethylformamide (3x5 ml). The residue was dissolved in pyridine (5 ml), 4'-thio-5-ethyl-2'-deoxy-3'-0-acetyluridine (IV, 180 mg, 0.57 mmol) and N,N'- dicyclohexylcarbodiimide (800 mg, 3.8 mmol) were added. The reaction was mixed at ÷20°C for 20 h, then ice-cold water (5 ml) was added. After mixing during 1 h at +4°C the reaction was diluted with water (150 ml) and applied onto a DEAE-Toyopearl column (2.5 x 12 cm. HCO; " form), elution was made with a linear gradient of NH4HCO3 (0 -> 0.15M, 1 1). The fractions containing the product were evaporated and coevaporated with water (3 x 10 ml). The residue was dissolved in 25% NH^OH and kept at +4°C for 20 h, then evaporated, coevaporated with water (2x5ml). Then it was purified on a LiChroprep RP-18 column (2 x 15 cm), elution was made with 0.01M NH4HCO3 to yield 120 mg (63%).
UV (water) ^ 272nm (6 9800). ΪH'NMR (D,O), ppm, JHz: 7.77s (IH, H-6), 6.69 d (IH, Jw 632, H-P), 6.25dd (lH,J2, J7.5, H-l'), 4.52m (IH. H-3'), 3.86-4.05m, (2H, 5'a, 5'b), 3.55m (IH, H-4'), 2.17-2.40 m (4H, 2'a, 2'b, CH,(Ura)), 1.0 t (3H, J 7.5, CH3CH2 (Ura)). 31P-NMR (D,O) δ 7.2s. Mass: m/z: 336 [M+^l].
EXAMPLE 2 Synthesis of 4'-thio-5-ethyl-2'-deoxyuridine S'-ethoxycarbonylphosphonate (II, R=COOEt)
(Scheme 2)
Figure imgf000007_0001
To a solution of moφholinium ethoxycarbonylphosphonate (59.3 mg, 0.24 mmoi) in water Dowex 50W (Py", 0.5 ml) was added. The precipitate was filtered, washed with water (10 mi), pyridine (5 ml) and tri-Λ-butylamine (44 mg, 0.24 mmol) was added, the resulting solution was evaporated, coevaporated with pyridine (3x5 mi), dissolved in pyridine and 4'-thio-5-ethyl-2'- deoxyuridine I (54 mg, 0.2 mmol) in was added. The solution was evaporated with pyridine (3x5 ml) and dimethylformamide (3x5 ml). The residue was dissolved in dimethylformamide (5 ml) and then N,N'-dicyclohexyicarbodiimide (124 mg, 0.6 mmol) was added, the reaction mixture was kept at +20°C for 20 h, then cold water (5 ml) was added. After mixing for 1 h at +4°C the mixture was diluted with water (150 ml) and applied onto a DEAE-Toyopearl column (2.5 x 12 cm, HCO3'-form), elution was made with a linear gradient of NH4HCO3 (0-> 0.15M, 1 1). The fractions containing the product were evaporated and coevaporated with water (3 x 10 ml). The residue was purified on a LiChroprep RP-8 column (2 x 15 cm), elution being made with a linear gradient of MeOH (0 -> 10%, 1 1) in 0.01M NH4HCO3 to yield 35 mg (43%).
UV (water)
Figure imgf000008_0001
272nm (e 9800), iH'NMR (D2O), δ, ppm, JHz: 7.77s (IH, H-6), 6.25dd (IH,J2, J7.5, H-V), 4.65m (IH, H-3'), 3.9-4.1m (3H, CH3CH2O, 5'a, 5'b), 3.55m (IH, H-4'), 2.37- 2.40 m (IH, 2'a), 2.21-2.28 m (3H, 2'b, CH2(Ura)), 1.18 dt (3H, JCH3J, 1.1, JCH3CH27, CH3CH2O), 0.98t (3H,J7.5, CH3CH2 (Ura)). 31P-NMR (D2O) δ -3.9s. Mass: m/z: 408 [M+].
EXAMPLE 3 Synthesis of 4'-thio-5-ethyl-2'-deoxyuridine 5'-hydrogenphosphonate (II, R=H)
(Scheme 2)
Figure imgf000008_0002
To a solution of phosphite acid (51 mg, 0.8 mmol) in water (2 ml) pyridine (3 ml) and tή-n- butylamine (148 mg, 0.8 mmol) was added. The solution was evaporated, coevaporated with pyridine (3x5 ml) and then with dimethylformamide (3x5 ml). The residue was dissolved in pyridine (5 ml), 4'- tm«>-5-eώyl-2'-deoxyuridine (1, 165 mg, 0.57 mmol) and N,N'-dicyciohexyicarbodiimide (800 mg, 3.8 mmol) were added. The reaction was mixed at +20°C for 20 h, then ice-cold water (5 ml) was added. After mixing during 1 h at +4°C the reaction was diluted with water (150 mi) and applied onto a DEAE- Toyopearl column (2.5 x 12 cm, HC03" form), elution was made with a linear gradient of NH4HCO3 (0 - > 0.15M, 1 l). The
Figure imgf000009_0001
contaixι g e pπκluct were evaporated and coevaporated with water (3 x 10 mi). The residue was purified on a LiChroprep RP-18 column (2 x 15 cm), elution was made with 0.01M
NH4HCO3 to yield 90 mg (47%).
UV (water) λmax 272nm (e 9800). lH-NMR (D:O), ppm, JHz: 7.77s (IH. H-6). 6.69 d (lH.J„, 632. H-P), 62Sάd (IH. J 2. J 7.5. H-D, 4.52m ( IH. H-3'). 3.86-4.05m, (2H. 5'a, 5'b).3.55m ( IH. H- 4»), 2.17-2.40 m (4H.2'a, 2'b, CH2(Ura)). 1.01 (3H, J 7.5, CH,CH2 (Ura)). 3'P-NMR (D:0) δ 72s. Mass: m/z: 336 [M++l].
EXAMPLE 4
Synthesis of 4 hio-5-etbyi-2'-deoxyuridine 5'-(trimethylcarbonyioxymethylene- hydrogenphosphonate) (III. RβH)
|CH^CC00CHp-» — ,
To a solution of trimethylcarbonyloxymethylene hydrogenphosphonate (84 mg, 0.5 mmo pvπdine (5 ml) tπ-n-butyiamme (93 mg, 0.5 mmo!) was added, the resulting solution was evaporated, coevaporated with pyridine (3x5 ml), dissolved in pyridine and 4'-tmo-5-e yl-2'-deoxyuridine I (108 rag, 0.4 mmol) in was added. The solution was evaporated with pyridine (3x5 ml) and dimethylformamide (3x5 ml). The residue was dissolved in dimethylformamide (5 ml) and then N^T- ώcyciohexyicaroodiimide (248 mg, 1.2 mmol) was added, the reaction mixture was kept at +20"C for 20 h, then cold water (5 ml) was added. After mixing for 1 h at +4βC the mixture was diluted with water (150 mi) and applied onto a DEAE-Toyopeari column (2J x 12 cm, HCO3 '-form), elution was made with a linear gradient of NH4HCO3 (0 -> 0.15M, 1 1). The fractions containing the product were evaporated and coevaporated with water (3 x 10 ml). The residue was purified on a LiChroprep RP-8 column (2 x 15 cm), elution being made with a linear gradient of MeOH (0 -> 10%, 1 1) in 0.01 M NH4HCO3 to yield 82J mg (49%).
UV (water) ^ 272nm (e 9800), 'NMR (D,O), δ, ppm,JHz: 7.77s (IH, H-6), 6.69 d (IH, n, 632, H-P), 6 2dd (IH, J2, J 7.5, H-1 *), 5.63d (2H, 14, OCH2O), 4.55m (IH, H-3'), 3.8-4.1m (2H, H-5'a, 5T>), 3.52m (IH, H-4*), 2J7-2.40 m (IH, H-2'a), 2.21-2^8 m (3H, 2'b, CH2(Ura)), 1.18 s (9H,C(CH,)), 0.99t (3H,J7.5. CH,CH2 (Ura)). Mass: m r 421 [M+].
EXAMPLE 5 Viral Plaque Redaction Assays.
Figure imgf000010_0001
Antiviral assays of π. R-C2H,OOC were performed using an adaptation of the plaque reduction assay described in [4]. Twenty- four well plates containing monoiayers of MCR 5 cells (human embryo lung fibroblasts. ATCC CCL 171 ) were used for assay of varicella zostar virus ( VZV strain G31 ), and
SUBSTTΠΠΈ SHEET (RULE 2β) monoiayers of Vero cells (African Green monkey kidney, ATCC CCLB1) were used for heφes simplex virus type 1 (HSV- 1 ) strain SC 16 and HSV-2 (strain 186). Monoiayers were infected with virus at a multiplicity calculated to produce 60-80 plaques per well. Infected cells were overlaid with liquid growth medium containing various known concenπaπons of the compound under investigation, and, in the case HSV-1 and HSV-2, carboxymethyl cellulose to prevent the formation of secondary plaques. Following a suitable period of incubation, plaques were fixed with formoi saline and stained, and their numbers were determined. For ICM detemnnanon. a dose-response curve was obtained and from this the 50% inhibitory concentianon (IC*) was obtamed. Tables 1 (first testing) and 2 (second independent tesung) demonstrate these data for different viruses. The well known antiviral drugs are shown as controls: BVDU - 5- bromovinyl-2'-deoxyuridine: πboviπn: ACG - acyciovir, DHPG - gancyclovir.
EXAMPLE 6
Cytotoxicity assay of II, R=C2H}OOC
Figure imgf000011_0001
Subconfluet cultures of Vero or MRC-5 ceils were grown in 96-well microtiter plates in the presence of different dilutions of drug. Cell numbers present at 96h (Varb) and 7 days (MRC-5) were estimated, on replicate cultures, using uptake of a tetrazolium dye (MTT). The concentrauon required for a 50% inhibition of cell growth compared to comroi ceil growth in the absence of compound is termed CCID Cvtotoxiciry assays were oeπormeo using Vero cells and MRC-5 cells. For 50% cytotoxic concentianon (CCi(^) determinanon. a dose-response curve was obtamed. Tables 1 (first testing) and 2 (second independent tesung) demonstrate these data for ceils. The well known anπviral drugs are shown as controls: BVDU - 5-bromovmyl-2'-deoxvuπdιnε: πboviππ; ACG ■ acyclovir, DHPG - gaπcyclovir.
The compounds according to the present lnvenπon, viz 4'-thio-5-ethyI-2'-deoxyuπdine 51- phospnonates have shown to be capable of selective inhibinon of the reproducnon of the HSV-1 and HSV-2 viruses in ceil cultures. It is expected that this same selecnve inhibinon of the reproducnon of TK" HSV-1, HSMV and W viruses will be exhibited by the compounds of Formula π and HJ It is expected that he compounds of Formula Ω and Hi will be effecnve m the treatment of these viruses, including prophylactic treatment
Figure imgf000013_0001
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Figure imgf000014_0001
REFERENCES
1. Walker R.T., Whale R.F., Dyson M.R., Coe P.L., Alderton W., Collins P., Ertl P., Lowe D., Rahim G., Snowden W.. Liner E. Antiviral properties of 4'-S-WDTU, Nucleic Acids Res , 31 (Symp..Ser.) 9-10.
2. Rahim S.D., Trivedi N., Bogdanovic-Batchelor M.V., Hardy G.W., Mils G., Serway J.W-T., Littler E., Coe P.L., Basnak I., Whale R.F., Walker R.T., Synthesis and antiherpesvirus activity of 2'-deoxy-4'-thiopyrimidine nucleosides, J.Λ βrf. Chem., 1996, 39, 789-795.
3. Alexandrova L.A., Semizarov D.G., Krayevsky A.A., Walker R.T.. 4,-Thio-5-ethyl-2'- deoxyuridine 5'-triphosphate (TEDUTP): synthesis and substrate properties in DNA-symhesizing systems, Antiviral Chem.Chemother. 1996, 7, 237-242.
4. Crumpacker C.S., Schnipper L.E., Zaia J.A., Levene M., Antimicrob. Agents Chemother. 1979, 15, 642-645.

Claims

We claim:
1. 4'-Thio-5-eώyl-2 '-deoxyuridine 5'-phosphonate of the formula:
Figure imgf000016_0001
(π)
wherein R=H, CONH2, AlkylOOC, Alkyl, Haloidalkyl, dihaloidalkyls, trihaloidalkyL HOCH* AcylOCH,
2. 4'-Thio-5-eώyl-2'-deoxyuridine 5'-phosphonate of the formula (IT) of claim 1 fbruse in selectively inhibiting HSV-1HSV-2, TKΗSV-1, HCMV and W:
3. 4 '-Thio-5-ethyl-2 '-deoxyuridine 5'-ρhosphonate of the formula (IT) of claim 1 for use in the prophylactic treatment of HSV-1, HSV-2, TKΗSV-1 , HCMV and W.
4. 4'-Thio-5-ethyl-2 '-deoxyuridine P-substinited 5 '-phosphonates of the formula:
Figure imgf000016_0002
wherein R-H, CONH2, AlkylOOC, Alkyl, Haloidalkyl, dihaloidalkyls, trihaloidalkyi, HOCH,, AcylOCHj and R'=0-alkyl, C^aminoaikyls, O-hydroxyalkyls, O-glycosyl
5. 4'-Thio-5-ethyl-2 '-deoxyuridine P-substimted 5 '-phosphonates of the formula (III) for use in selectively inhibiting HSV- 1 , HSV-2, TKΗSV- 1 , HCMV and W.
6. 4'-Thio-5-ethyl-2 '-deoxyuridine P-substimted 5 '-phosphonates of the formula (HI) for use in the prophylactic treatment of HSV-1, HSV-2, TKΗSV-1, HCMV and W.
PCT/CA1999/000465 1998-06-01 1999-06-01 Antiviral phosphorus derivatives of 4'-thio-5-ethyl-2'-deoxyuridine WO1999062921A1 (en)

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