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WO2006121820A1 - Promedicaments de phosphoramidate pour traitement d'infections virales - Google Patents

Promedicaments de phosphoramidate pour traitement d'infections virales Download PDF

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Publication number
WO2006121820A1
WO2006121820A1 PCT/US2006/017314 US2006017314W WO2006121820A1 WO 2006121820 A1 WO2006121820 A1 WO 2006121820A1 US 2006017314 W US2006017314 W US 2006017314W WO 2006121820 A1 WO2006121820 A1 WO 2006121820A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
methyl
optionally substituted
group
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PCT/US2006/017314
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English (en)
Inventor
Esmir Gunic
Suetying Chow
Frank Rong
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Valeant Research & Development
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Publication of WO2006121820A1 publication Critical patent/WO2006121820A1/fr

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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

Definitions

  • a group of 2' methylribofuranosyl purine nucleoside derivatives were disclosed by An et al in WO 03/062256, which is commonly owned with the present application.
  • the purine derivatives described by An et al. bears substituents at the 6-position, including hydrazino, methylhydrazino and methylsulfonylhydrazino.
  • Modified nucleotides and nucleosides have been widely used to treat not only HCV and other viral infections.
  • the active drug is the nucleotide triphosphate.
  • the compound administered to the patient is a prodrug; the active drug results from intracellular phosphorylation to yield the triphosphate.
  • the native nucleotide is never administered to the patient because it is unstable in plasma and, being charged, does not penetrate the cell membrane.
  • the effectiveness of modified nucleotides as anti-virals thus depends not only on the selectivity and affinity of the active drug for the viral polymerase, but also on the efficiency of the in vivo phosphorylation of the form that is administered.
  • PPA prodrug chemistry is described by McGuigan in U. S. Patent Nos. 6,638,919; 6,455,513; and 6,573,247; and in PCT International Publication No. WO 05/012327. Further developments are described by Uckun and Vig in WO 00/00501.
  • the nucleoside base (or base analogue) is indicated by B.
  • the bracketed moiety is an amino acid residue.
  • R 1 is methyl and R 2 is H
  • the amino acid is L- alanine.
  • the naturally-occurring amino acids such as L-alanine and glycine, are suitable for use in this invention.
  • synthetic amino acid dimethylglycine and synthetic amino acids where R 1 and R 2 are, independently, H or C 1 - C 5 alkyl, or where R 1 and R 2 ; together with the ⁇ carbon, form a ring containing 3 to 6 carbons.
  • R 3 is any group that can be readily removed by intracellular esterases; examples of R are benzyl, trifluoromethyl benzyl, methyl, or Ci-C 6 alkyl, such as methyl or isopropyl.
  • Ar is phenyl, pyridyl, or pyrimidyl and may be unsubstituted or substituted with electron withdrawing groups. Substituents at the para and ortho positions are more effective. Suitable substituents include, but are not limited to, H, F, Cl, Br, CF 3 , SO 2 Me, CN and NO 2 .
  • this invention provides a compound of formula I, in which B is selected from the following bases B-I, B-2, and B-3,
  • Z 2 is H, -NH 2 , -NHMe, or -NMe 2 ;
  • Z 4 is -NH 2 or -OH;
  • Z 6 is H, OH, OMe, OEt, SCH 3 , thienyl, furyl, or -NR 2 R 3 , where R 2 is H, Ci-C 3 alkyl, or cyclopropyl, and R 3 is H or NHR 4 ,
  • R 4 is H, Ci-C 4 alkyl, or SO 2 Rs, and R 5 is Ci-C 4 alkyl;
  • Z 7 is H, halogen, or CN. All tautomeric forms are included in these definitions.
  • this invention provides a compound of formula I, in which B is B-I and is selected from the following bases:
  • this invention provides a compound of formula I, in which B is B-2.
  • this invention provides a compound of formula I, in which B is B-2, where Z 2 is -NHMe, or -NMe 2 . In another more specific embodiment, this invention provides a compound of formula I, in which B is B-2, where Z 2 is H or -NH 2 .
  • this invention provides a compound of formula I, in which B is selected from the following bases:
  • this invention provides a compound of formula I, in which B is B-3, selected from the following bases:
  • this invention provides or contemplates a compound of formula I-B2
  • Ar is phenyl, pyridyl, or pyrimidyl, optionally substituted with one or two groups selected independently from halo, nitro, cyano, Ci-C 3 alkyl, or CpC 3 alkoxy, wherein said Q- C 3 alkyl group, and the Ci-C 3 alkyl moiety of said C]-C 3 alkoxy group are optionally substituted with one, two, or three chlorine or fluorine atoms;
  • R] and R 2 are, independently, H, Ci -C 5 alkyl, or C 2 -C 5 alkenyl, or Ri and R 2) together with the ⁇ -carbon, form a 3- to 6- membered saturated ring;
  • R 3 is Ci-Ce alkyl, C 3 -C ⁇ cycloalkyl, C 3 -C 6 cycloalkyl methyl, benzyl, or phenethyl, in which the phenyl group within said benzyl or phenethyl group is optionally substituted with one or more groups selected independently from halogen, Ci-C 6 alkyl, and Ci-C 6 alkoxy, wherein said Ci-C 3 alkyl group, and the Ci -C 3 alkyl moiety of said Ci-C 3 alkoxy group are optionally substituted with one, two, or three chlorine or fluorine atoms;
  • Z 2 H, NH 2 , NHMe, or NMe 2 ; and
  • Z 6 OH or NR 4 R 5 , where R 4 is H, Ci-C 4 alkyl, or cyclopropyl; R 5 is H or NHR 6 ; R 6 is H, C 1 - C 4 alkyl, or SO 2 R 7 ; and R 7 is Ci-C 4 alkyl. All tautomeric forms are included in the embodiment.
  • the invention provides a compound of formula I-
  • the invention provides a compound according to Formula I-B3
  • the invention also provides compounds of Formula I-Bl
  • the invention provides or contemplates compounds of Formula I-Bl, I-B-2, and I-B3, where Ri and R 2 are, independently, H, C 1 -C 5 alkyl, or C 2 -C 5 alkenyl.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B-2, and I-B3, where R] and R 2 are, independently, H, Ci-C 3 alkyl, or C 2 -C 3 alkenyl.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B-2, and I-B3, where R 1 and R 2 are, independently, H or methyl, or where Ri and R 2 are -CH 2 -CH 2 - and, together with the ⁇ carbon, form a cyclopropyl group.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B-2, and I-B3, where R] and R 2 are, independently, H or methyl, or where Ri and R 2 are -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 - and, together with the ⁇ carbon, form a cyclobutyl or cyclopentyl group.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B2, or I-B3, where Ar is phenyl, optionally substituted with alkyl groups or with nitro, halo, or cyano groups.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B2, or I-B3, where Ar is phenyl, />-chlorophenyl o ⁇ p- bromophenyl and R 3 is isopropyl, benzyl, ⁇ -methylbenzyl, or ⁇ -(trifluoromethyl)benzyl.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B2, or I-B3, where R 3 is Ci-C ⁇ alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl methyl.
  • the invention provides or contemplates compounds of Formula I-Bl, I-B2, or I-B3, where R 3 is benzyl or phenethyl, where the phenyl group thereof is optionally substituted as described above.
  • the invention provides or contemplates compounds of formula I-B2 or I-B3, where Z 6 is NR 4 R 5 .
  • the invention provides or contemplates compounds of formula I-B2 or I-B3, where Z 6 is NR 4 Rs, where R 4 is H, Ci-C 2 alkyl, or cyclopropyl; R 5 is H or NHR 6 ; R& is H, Ci-C 2 alkyl, or SO 2 R 7 ; and R 7 is Ci-C 3 alkyl.
  • the invention provides or contemplates compounds of formula I-B2 or I-B3, where Z 6 is -N(cyclopropyl)NH 2 or - N(cyclopropyl)NHSO 2 CH 3 ; and Z 2 is H or NH 2 .
  • the invention provides or contemplates compounds of formula I-B2 or I-B3 , where Z 6 is -NMeNH 2 or -NMeNHSO 2 CH 3 ; and Z 2 is H Or NH 2 .
  • the invention provides or contemplates compounds of formula I-B2, or I-B3, where Z 6 is NH 2 and Z 2 is H or NH 2 .
  • the invention provides or contemplates compounds of formula I-B3 , where Z 6 is NH 2 , Z 2 is H or NH 2 , and Z 7 is F, Cl, Br, or CN.
  • the invention provides or contemplates compounds of formula I-B3, where Z 6 is NH 2 , Z 2 is H or NH 2 , and Z 7 is H or F.
  • the general procedure involves reaction of an amino acid ester hydrochloride with an aryl dichlorophosphate in the presence of at least two equivalents of a suitable base.
  • suitable bases include, but are not limited to, imidazoles, pyridines like lutidine and DMAP, tertiary amines like triethylamine and DABCO, and substituted amidines such as DBN and DBU. Tertiary amines are particularly effective.
  • the product of each step is is preferably used directly in subsequent steps, without recrystallization or chromatography. Specific examples are provided below.
  • 2-Amino-2-methylpropionic acid benzyl ester (5) To a solution of 4 (3 g, 0.01 mol) in anhydrous dichloromethane (15 ml) at 0 0 C was added slowly trifluoroacetic acid (15 ml, 0.19 mol) with stirring at 0 0 C. The mixture was stirred at 0 0 C for 30 minutes and the allowed to gradually warm to room temperature over 4 hours. The reaction mixture was evaporated under reduced pressure and was extracted with ethyl acetate and washed with 3x15 ml water.
  • 2-Amino-2-methylpropionie acid benzyl ester hydrochloride (6) A IM solution of hydrochloric acid in diethyl ether (25 ml, 0.025 mol) was added to 2-amino-2-methylpropionic acid benzyl ester (5) (1.9 g, 0.01 mol) at 0 0 C, and the mixture was stirred for 16 hours.
  • Phenyl [(l-benzyloxycarbonyl-l-methylethyl)amino]phosphorochloridate (7) This was synthesized from the amino acid ester hydrochloride 6 according to the general procedure (1).
  • Phenyl [[(lS)-l-(l-methylethoxycarbonyl)ethyl]amino]phosphorochIoridate (10) This compound was prepared according to the general procedure (1) in the same manner as compound 9.
  • the general procedure involves reaction of a nucleoside or a 7-deazanucleoside with a free 5' OH with an amino acid derivative of a phosphorochloridate, in the presence of a suitable base.
  • suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DABCO, and substituted amidines such as DBN and DBU.
  • the product may be isolated by recrystallization and/or chromatography. Specific examples are provided below.
  • nucleoside phosphoramidates described herein are obtained and tested as mixtures of enantiomers and diastereomers.
  • the present invention also encompasses the individual pure stereoisomers, which may be obtained by high-performance liquid chromatography of the final products, or by the use of enantiomerically or diastereomerically pure phosphorochloridates, as is known in the art.
  • the mixture was diluted with dichloromethane and washed with 2 x 1 ml IN HCl, 2 x 1 ml sat. NaHCO 3 , and 2 x 5 ml brine, then back-extracted with dichloromethane.
  • reaction mixture was stirred at -10°C/-20°C for 2 hours then gradually stirred at room temperature for 8 hours.
  • the mixture was evaporated under reduced pressure, and the crude was purified by silica gel chromatography in a gradient of 8% methanol in chloroform to afford the product as a yellow paste (28mg, 0.05mmol, 19%)
  • the anti-HCV activities of the exemplary compounds were tested in two biological assays: a cell-based HCV replicon assay and a cytotoxicity assay.
  • a human hepatoma cell line (Huh-7) containing replicating HCV Conl subgenomic replicon with a luciferase reporter gene (luc-ubi-neo) was used to evaluate anti-HCV activity of the compounds. In this assay, the level of luciferase signal correlates directly with the viral RNA replication.
  • the HCV replicon-reporter cell line (NK/luc-ubi-neo) was cultured in DMEM medium supplemented with 10 % fetal bovine serum and 0.5 mg/ml Geneticin (G418). Cells were maintained in a subconfluent state to ensure high levels of HCV replicon RNA synthesis.
  • a Huh-7 cell line carrying a luciferase reporter gene (driven by a HIV LTR promoter) stably integrated into the chromosome was used to analyze the cytotoxic effect of the selected compounds.
  • This cell line (LTR-luc) was maintained in DMEM medium with 10 % FBS.
  • Design of the cytotoxicity assay was similar to that of the HCV replicon assay. Reduction of luciferase activity in the treated cells correlated with the cytotoxic effect of the test compound and was used to calculate the CC 50 value (concentration that inhibited cell growth by 50%).
  • CC 50 A (>300 ⁇ M), B (50 to 300 ⁇ M) and C ( ⁇ 50 ⁇ M) TABLE 1 -ACTIVITY OF COMPOUNDS OF FORMULA I-B2

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Abstract

L'invention concerne des phosphoramidates de 2'-méthyl ribonucléotide qui sont des promédicaments neutres transformés in vivo en triphosphates de 2'- methyl ribonucléotide. Ces composés conviennent pour le traitement d'infections virales. Les promédicaments de triphosphate de méthylsulfonylhydrazinyl purine 2'-méthyl nucléotide, à savoir le triphosphate de 2'methyl- N6-alkyl-N6- (N-méthylsulfonamide) adénosine et son dérivé 2-amino présentent un intérêt pariticulier.
PCT/US2006/017314 2005-05-05 2006-05-05 Promedicaments de phosphoramidate pour traitement d'infections virales WO2006121820A1 (fr)

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US67863605P 2005-05-05 2005-05-05
US60/678,636 2005-05-05
US74803405P 2005-12-06 2005-12-06
US60/748,034 2005-12-06

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