Anti-HCV nucleoside derivatives

Details Anti-HCV nucleoside derivatives Anti-HCV nucleoside derivatives

2002-03-26

2003-12-09

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S042000, C514S043000, C514S046000, C514S047000, C514S048000, C514S049000, C514S052000, C536S018700, C536S022100, C536S028100, C536S028600, C536S028700

Reexamination Certificate

active

06660721

ABSTRACT:

BACKGROUND OF THE INVENTION
Hepatitis C virus is the leading cause of chronic liver disease throughout the world. Patients infected with HCV are at risk of developing cirrhosis of the liver and subsequent hepatocellular carcinoma and hence HCV is the major indication for liver transplantation. Only two approved therapies are currently available for the treatment of HCV infection (R. G. Gish, Sem. Liver. Dis., 1999, 19, 35). These are interferon-&agr; monotherapy and, more recently, combination therapy of the nucleoside analogue, ribavirin (Virazole), with interferon-&agr;.
Hepatitis C virus belongs to the family of Flaviviridae. It is an RNA virus, the RNA genome encoding a large polyprotein which after processing produces the necessary replication machinery to ensure synthesis of progeny RNA. It is believed that most of the non-structural proteins encoded by the HCV RNA genome are involved in RNA replication. Lohmann et al. [V. Lohmann et al., Science, 1999, 285, 110-113] have described the construction of a human hepatoma (Huh7) cell line in which subgenomic HCV RNA molecules have been introduced and shown to replicate with high efficiency. It is believed that the mechanism of RNA replication in these cell lines is identical to the replication of the full length HCV RNA genome in infected hepatocytes. The subgenomic HCV cDNA clones used for the isolation of these cell lines have formed the basis for the development of a cell-based assay for identifying nucleoside analogue inhibitors of HCV replication.
2′-Fluoronucleoside analogues are described in WO 99/43691 as being useful in the treatment of hepatitis B infection, hepatitis C infection, HIV and abnormal cellular proliferation, including tumours and cancer. 2′-Deoxy-2′-fluoro ribonucleoside derivatives are not described specifically.
SUMMARY OF THE INVENTION
The present invention comprises the novel use of known 2′-deoxy-2′-fluoro nucleoside derivatives as inhibitors of hepatitis C virus (HCV) RNA replication and pharmaceutical compositions of such compounds. The compounds of this invention are therefore of use as therapeutic agents for the treatment of HCV infections.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes the use of 2′-deoxy-2′-fluoro nucleoside derivatives of formula I
wherein
R
1
is hydrogen or phosphate and
B signifies a 1-pyrimidinyl or 9-purinyl residue of formulae B1, B2 or B3
and of pharmaceutically acceptable salts thereof for the treatment of diseases mediated by the hepatitis C virus (HCV) or for the preparation of medicaments for such treatment.
The term “phosphate” as used herein for R
1
, denotes a monophosphate, diphosphate or triphosphate group of the formula —[P(═O)(OH)O]
n
H, wherein n is an integer selected from 1, 2 and 3. Phosphate in R
1
is preferably a monophosphate group. The term “phosphate” further includes stabilized monophosphate prodrugs or other pharmaceutically acceptable leaving groups which, when administered in vivo, are capable of providing a compound wherein R
1
is monophosphate. These “pronucleotides” can improve the properties such as activity, bioavailability or stability of the parent nucleotide.
Examples of substituent groups which can replace one or more of the hydrogens in the monophosphate moiety are described in C. R. Wagner et al Medicinal Research Reviews, 2000, 20(6), 417 or in R. Jones and N. Bischofberger, Antiviral Research 1995, 27, 1. Such pronucleotides include alkyl and aryl phosphodiesters, steroid phosphodiesters, alkyl and aryl phosphotriesters, cyclic alkyl phosphotriesters, cyclosaligenyl (CycloSal) phosphotriesters, S-acyl-2-thioethyl (SATE) derivatives, dithioethyl (DTE) derivatives, pivaloyloxymethyl phosphoesters, para-acyloxybenzyl (PAOB) phosphoesters, glycerolipid phosphodiesters, glycosyl lipid phosphotriesters, dinucleosidyl phosphodiesters, dinucleoside phosphotriesters, phosphorodiamidatescyclic phosphoramidates, phosphoramidate monoesters and phosphoramidate diesters.
The invention also includes pro-drugs or bioprecursors of the parent nucleoside which are converted in vivo to the compound of formula I wherein R
1
is hydrogen or physiologically acceptable salts thereof. Preferred pro-drug derivatives include carboxylic ester derivatives of the 3′- or 5′-hydroxyl group in which the non-carbonyl moiety of the ester group is selected from straight or branched alkyl (e.g. methyl, n-propyl, n-butyl or tert.-butyl), alkoxyalkyl (e.g. methoxymethyl), araalkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C
1-4
alkyl or C
1-4
alkoxy or amino); sulphonate esters such as alkylsulphonyl or arylsulphonyl (e.g. methanesulphonyl); amino acid esters (e.g. L-valyl or L-isoleucyl) or pharmaceutically acceptable salts thereof. The preparation is carried out according to known methods in the art, for example methods known from textbooks on organic chemistry e.g. from J. March (1992), “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 4
th
ed. John Wiley & Sons).
In the pictorial representation of the compounds given throughout this application, a thickened tapered line (
) indicates a substituent which is above the plane of the ring and a dotted line (
) indicates a substituent which is below the plane of the ring.
Compounds of the present invention exhibit stereoisomerism and therefore include compounds wherein the carbon atoms have the S, R, or R,S-configuration. The compounds of this invention can be any isomer of the compound of formula I or mixtures of these isomers. The compounds and intermediates of the present invention having one or more asymmetric carbon atoms may be obtained as mixtures of stereoisomers which can be resolved, at the appropriate steps in the process of this invention by stereospecific methods known in the art to obtain a given stereoisomer or pure enantiomer having a desired stereoconfiguration. Alternatively, the desired isomers may be directly synthesised by methods known in the art.
In a preferred embodiment of the invention the ribofuranoside is a &agr;-D, &bgr;-D, &agr;-L or &bgr;-L ribofuranosyl ring, more preferred a &bgr;-D or &bgr;-L ribofuranosyl ring, and most preferred a &bgr;-D ribofuranosyl ring.
The preferable relative configuration of compounds of this invention is that of formula I-a,
wherein
R
1
and B are as defined above, and of pharmaceutically acceptable salts thereof.
Compounds of formula I exhibit tautomerism (as known from textbooks on organic chemistry e.g. J. March (1992), “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 4
th
ed. John Wiley & Sons) that means that the compounds of this invention can exist as two or more chemical compounds that are capable of facile interconversion. In many cases it merely means the exchange of a hydrogen atom between two other atoms, to either of which it forms a covalent bond. Tautomeric compounds exist in a mobile equilibrium with each other, so that attempts to prepare the separate substances usually result in the formation of a mixture that shows all the chemical and physical properties to be expected on the basis of the structures of the components.
The most common type of tautomerism is that involving carbonyl, or keto, compounds and unsaturated hydroxyl compounds, or enols. The structural change is the shift of a hydrogen atom between atoms of carbon and oxygen, with the rearrangement of bonds.
For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is the predominant one; in phenols, the enol form is the major component. An intermediate situation is represented for example in ethyl acetoacetate, which at room temperature contains about 92.4% keto and 7.6% enol; at −78° C., the interconversion of the two forms is slow enough for the individual substances to be isolated.
It will be appreciated that within the present invention compounds of formula I exist in various tautomeric forms and that they are encompassed by the present

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