4′-substituted nucleoside derivatives as inhibitors of...

Details 4′-substituted nucleoside derivatives as inhibitors of... 4′-substituted nucleoside derivatives as inhibitors of...

2002-06-11

2004-08-31

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S461000, C514S438000, C514S045000, C514S046000, C514S263400

Reexamination Certificate

active

06784166

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATION
This application claims benefit under Title 35, United States Code, §119 of Great Britain Patent Application No. 00114286.8, filed on Jun. 12, 2001.
BACKGROUND OF THE INVENTION
The invention relates to nucleoside derivatives as inhibitors of HCV replicon RNA replication. In particular, the invention is concerned with the use of purine and pyrimidine nucleoside derivatives as inhibitors of subgenomic Hepatitis C Virus (HCV) RNA replication and pharmaceutical compositions containing such compounds.
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;.
Many of the drugs approved for the treatment of viral infections are nucleosides or nucleoside analogues and most of these nucleoside analogue drugs inhibit viral replication, following conversion to the corresponding triphosphates, through inhibition of the viral polymerase enzymes. This conversion to the triphosphate is commonly mediated by cellular kinases and therefore the direct evaluation of nucleosides as inhibitors of HCV replication is only conveniently carried out using a cell-based assay. For HCV the availability of a true cell-based viral replication assay or animal model of infection is lacking.
Hepatitis C virus belongs to the family of Flaviridae. 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.
SUMMARY OF THE INVENTION
The invention is concerned with the use of compounds of the formula I
wherein
R is hydrogen or —[P(O)(OH)—O]
n
H and n is 1, 2 or 3;
R
1
is alkyl, alkenyl, alkynyl, haloalkyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, alkoxy, cyano, azido, hydroxyiminomethyl, alkoxyiminomethyl, halogen, alkylcarbonylamino, alkylaminocarbonyl, azidoalkyl or aminomethyl, alkylaminomethyl, dialkylaminomethyl or heterocyclyl;
R
2
is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, alkoxy, halogen, cyano, or azido;
R
3
and R
4
are hydrogen, hydroxy, alkoxy, halogen or hydroxyalkyl, provided that at least one of R
3
and R
4
is hydrogen; or
R
3
and R
4
together represent ═CH
2
or ═N—OH, or
R
3
and R
4
both represent fluorine;
X is O, S or CH
2
;
B signifies a 9-purinyl residue B1 of formula
wherein
R
5
is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, NHR
8
, halogen or SH;
R
6
is hydroxy, NHR
8
, NHOR
9
, NHNR
8
, —NHC(O)OR
9′
or SH;
R
7
is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, NHR
8
, halogen, SH or cyano;
R
8
is hydrogen, alkyl, hydroxyalkyl arylcarbonyl or alkylcarbonyl;
R
9
is hydrogen or alkyl;
R
9′
is alkyl; and
B signifies a 1-pyrimidyl residue B2 of formula
wherein
Z is O or S;
R
10
is hydroxy, NHR
8
, NHOR
9
, NHNR
8
, —NHC(O)OR
9′
or SH;
R
11
is hydrogen, alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl or halogen;
R
8
R
9
and R
9′
are as defined above;
and of pharmaceutically acceptable salts thereof;
for the treatment of diseases mediated by the Hepatitis C Virus (HCV), pharmaceutical compositions comprising such compounds or for the preparation of medicaments for such treatment.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I have been shown to be inhibitors of subgenomic Hepatitis C Virus replication in a hepatoma cell line. These compounds have the potential to be efficacious as antiviral drugs for the treatment of HCV infections in human.
In compounds, wherein R is a phosphate group —[P(O)(OH)—O]
n
H, n is preferably 1. The phosphate group may be in the form of a stabilized monophosphate prodrug or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R 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 phosphate 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, phosphorodiamidates, cyclic 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 is hydrogen, or at least one of R
2
, R
3
and R
4
is hydroxy. Preferred pro-drug derivatives include carboxylic esters 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), aralkyl (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).
The term “alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms. Preferably, the term “alkyl” denotes a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Most preferred are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or pentyl. The alkyl may be unsubstituted or substituted. The substituents are selected from one or more of cycloalkyl, nitro, amino, alkyl amino, dialkyl amino, alkyl carbonyl and cycloalkyl carbonyl.
The term “cycloalkyl” as used herein denotes an optionally substituted cycloalkyl group containing 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term “alkoxy” as used herein denotes an optionally substituted straight or branched chain alkyl-oxy group wherein the “alkyl” portion is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, pentyloxy, hexyloxy, heptyloxy including their isomers.
The term “alkoxyalkyl” as used herein denotes an alkoxy group as defined above which is bonded to an alkyl group as defined above. Examples are meth

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