Azapeptides useful in the treatment of Hepatitis C

Details Azapeptides useful in the treatment of Hepatitis C Azapeptides useful in the treatment of Hepatitis C

2001-02-06

2003-09-23

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

C530S329000, C530S331000, C514S016700, C514S017400

Reexamination Certificate

active

06624290

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel azapeptide compounds, compositions comprising such compounds and methods of using them for the treatment of Hepatitis C Viral infections.
BACKGROUND OF THE INVENTION
Infection by hepatitis C virus (“HCV”) is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis. Four million individuals may be infected in the United States alone.
WO 99/07734 assigned to Boehringer Ingelheim discloses azapeptides which inhibit NS3 protease useful in treating Hepatitis C. WO 99/20272 assigned to Merck & Co., discloses azapeptides useful as cell adhesion inhibitors. U.S. Pat. No. 5,837,687 and U.S. Pat. No. 5,965,538 both assigned to Fujirebro, disclose bicyclic ring azapeptides. WO 99/40063 assigned to Yoshitomi, discloses azapeptides having hydroxamic acid derivatives.
The HCV genome encodes a polyprotein of 3010-3033 amino acids [Choo, Q. -L., et al. “Genetic Organization and Diversity of the Hepatitis C Virus,”
Proc. Natl. Acad. Sci. USA,
88, pp. 2451-2455 (1991); Kato, N. et al., “Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis,”
Proc. Natl. Acad. Sci. USA,
87, pp. 9524-9528 (1990); Takamizawa, A. et al., “Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers,”
J. Virol.,
65, pp. 1105-1113 (1991)]. The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The NS proteins are derived by proteolytic cleavage of the polyprotein [Bartenschlager, R. et al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions,”
J. Virol.,
67, pp. 3835-3844 (1993); Grakoui, A. et al. “Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites”,
J. Virol.,
67, pp. 2832-2843 (1993); Grakoui, A. et al., “Expression and Identification of Hepatitis C Virus Polyprotein Cleavage Products,” 1385-1395 (1993); Tomei, L. et al., “NS3 is a Serine Protease Required for Processing of Hepatitis C Virus Polyprotein,”
J. Virol.,
67, pp. 4017-4026 (1993)].
The HCV NS protein 3 (NS3) contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. The first 181 amino acids of NS3 (residues 1027-1207 of the viral prolyprotein) have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics,”
J. Virol.,
68, pp. 8147-8157 (1994)].
The HCV NS3 serine protease and its associated cofactor, NS4A, helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral polyprotein processing. HIV protease inhibitors, which inhibit viral protein processing, are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently the HCV NS3 serine protease is an attractive target for drug discovery.
There is a need for new treatments and therapies for HCV infection. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of one or more symptoms of HCV infection.
It is a further object herein to provide methods of treatment or prevention of HCV.
A still further object of the present invention is to provide methods for modulating the activity of serine proteases, particularly the HCV NS3/NS4a serine protease, using the compounds provided herein.
SUMMARY OF THE INVENTION
The present invention relates to azapeptide compounds represented by the formula:
wherein:
(a) n 3-7;
(b) R
1
=a substituted or unsubstituted amino acid or analog thereof;
(c) R
2
=substituted or unsubstituted alkyl;
substituted or unsubstituted alkenyl;
substituted or unsubstituted heteroalkyl;
substituted or unsubstituted cycloalkyl;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl;
substituted or unsubstituted arylalkyl;
substituted or unsubstituted alkoxycarbonyl, or
substituted or unsubstituted aryloxycarbonyl;
(d) R
3
=—O—CH(R
4
)—R
5
; O—R
5
, or S—R
5
,
wherein R
4
is selected from the group consisting of:
H;
halo;
cyano;
substituted or unsubstituted alkyl, and
substituted or unsubstituted alkenyl;
and wherein R
5
is selected from the group consisting of:
substituted or unsubstituted alkyl;
substituted or unsubstituted haloalkyl;
substituted or unsubstituted haloalkenyl;
substituted or unsubstituted heteroalkyl;
substituted or unsubstituted cycloalkyl;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl, and
substituted or unsubstituted arylalkyl,
or a pharmaceutically acceptable salt thereof.
The present invention further relates to a method of treating Hepatitis C comprising administering an effective amount of a compound having the formula:
wherein:
(a) n=3-7;
(b) R
1
=a substituted or unsubstituted amino acid or analog thereof;
(c) R
2
=substituted or unsubstituted alkyl;
substituted or unsubstituted alkenyl;
substituted or unsubstituted heteroalkyl;
substituted or unsubstituted cycloalkyl;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl;
substituted or unsubstituted arylalkyl;
substituted or unsubstituted alkoxycarbonyl or
substituted or unsubstituted aryloxycarbonyl;
(d) R
3
=—O—CH(R
4
)—R
5
, —O—R
5
, or —S—R
5
,
wherein R
4
is selected from the group consisting of:
H;
halo;
cyano;
substituted or unsubstituted alkyl, and
substituted or unsubstituted alkenyl;
and wherein R
5
is selected from the group consisting of
substituted or unsubstituted alkyl;
substituted or unsubstituted alkenyl;
substituted or unsubstituted haloalkyl;
substituted or unsubstituted haloalkenyl;
substituted or unsubstituted heteroalkyl;
substituted or unsubstituted cycloalkyl;
substituted or unsubstituted aryl;
substituted or unsubstituted heteroaryl, and
substituted or unsubstituted arylalkyl,
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
The following definitions and terms are used herein:
The term “amino acid”, as used herein, refers to organic compounds having the structure:
Amino acids useful in the present invention include, but are not limited to Alanine (Ala), Arginine (Arg), Asparagine (Asn), Aspartic Acid (Asp), Cysteine (Cys), Glutamic Acid (Glu), Glutamine (Gln), Glycine (Gly), Histidine (His), Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Methionine (Met), Phenylalanine (Phe), Proline (Pro), Serine (Ser), Threonine (Thr), Tryptophan (Trp), Tyrosine (Tyr), Valine (Val). Said amino acids can be substituted or unsubstituted. The amino acids can be in the D or L configuration in the present invention.
Amino acid analogs useful in the present invention include, but are not limited to, substituted proline, pipecolic acid, cyclohexylglycine, tert-butylglycine, D-&ggr;-carboxyglutamic acid (D-Gla), and aminoadipic acid.
The term “peptide bond”, as used herein, means the linkage that is formed between individual amino acids that is formed by the elimination of a molecule of water from the amino group of one amino acid and the carboxyl group of the next amino acid.
The term “heteroatom,” as used herein, means a nitrogen, sulfur, or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
The term “alkyl”, as used herein, means an unsubstituted or substituted, straight or branched, saturated hydrocarbon chain. Said hydrocarbon chain having 1 to 8 carbon atoms, and preferably, unless otherwise stated, from 1 to 4 carbon atoms. Preferred alkyl groups include,

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