Macrocyclic peptides active against the hepatitis C virus

Details Macrocyclic peptides active against the hepatitis C virus Macrocyclic peptides active against the hepatitis C virus

2001-01-16

2003-08-19

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S010100, C514S011400, C514S018700, C514S019300, C530S317000, C530S321000, C530S331000, C540S454000, C540S455000, C540S460000, C548S536000, C548S537000

Reexamination Certificate

active

06608027

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds, compositions, the preparation of such compounds and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel peptide analogues, pharmaceutical compositions containing such analogues and methods for using these analogues in the treatment of HCV infection.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 170 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.
The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established. Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulins treatment for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions. Various clinical studies have been conducted with the goal of identifying pharmaceutical agents capable of effectively treating HCV infection in patients afflicted with chronic hepatitis C. These studies have involved the use of interferon-alpha, alone and in combination with other antiviral agents. Such studies have shown that a substantial number of the participants do not respond to these therapies, and of those that do respond favorably, a large proportion were found to relapse after termination of treatment.
Until a few years ago, interferon (IFN) was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C. However the sustained response rate is low, and interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Interferon in combination with ribavirin was originally approved for patients non-responsive to IFN alone. It has now been approved for naive patients and presently constitutes the gold standard in HCV therapy. However, the side effects caused by IFN are not alleviated with this combination therapy.
Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies.
HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one, as yet poorly characterized, cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (henceforth referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
Patent application WO 97/06804 describes the (−) enantiomer of the nucleoside analogue cytosine-1,3-oxathiolane (also known as 3TC) as active against HCV. This compound, although reported as safe in previous clinical trials against HIV and HBV, has yet to be clinically proven active against HCV and its mechanism of action against the virus has yet to be reported.
A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes that are essential for the replication of the virus.
In this vein, intense efforts to discover compounds which inhibit the NS3 protease or RNA helicase of HCV have led to the following disclosures:
U.S. Pat. No. 5,633,388 describes heterocyclic-substituted carboxamides and analogues as being active against HCV. These compounds are directed against the helicase activity of the NS3 protein of the virus but clinical tests have not yet been reported. A phenanthrenequinone has been reported by Chu et al., (Tet. Lett., (1996), 7229-7232) to have activity against the HCV NS3 protease in vitro. No further development on this compound has been reported.
A paper presented at the Ninth International Conference on Antiviral Research, Urabandai, Fukyshima, Japan (1996) (Antiviral Research, (1996), 30, 1, A23 (abstract 19)) reports thiazolidine derivatives to be inhibitory to the HCV protease.
Several studies have reported compounds inhibitory to other serine proteases, such as human leukocyte elastase. One family of these compounds is reported in WO 95/33764 (Hoechst Marion Roussel, 1995). The peptides disclosed in that application are morpholinylcarbonyl-benzoyl-peptide analogues that are structurally different from the peptides of the present invention.
WO 98/17679 from Vertex Pharmaceuticals Inc. discloses inhibitors of serine protease, particularly, Hepatitis C virus NS3 protease Hoffman LaRoche (WO 98/22496; U.S. Pat. Nos. 5,866,684 & 6,018,020) has also reported hexapeptides that are proteinase inhibitors useful as antiviral agents for the treatment of HCV infection.
Steinkühler et al. and Ingallinella et al. have published on NS4A-4B product inhibition (Biochemistry (1998), 37, 8899-8905 and 8906-8914).
WO 97/43310 by Schering Corporation discloses 20 and 21 amino acid peptide sequences active against the HCV NS3 protease.
WO 98/46597 by Emory University discloses peptides and peptidomimetics active in vitro against serine proteases.
WO 98/46630 by Peptide Therapeutics Limited discloses depsipeptide substrate inhibiting the HCV NS3 protease.
Finally, U.S. Pat. No. 5,869,253 discloses enzymatic RNA molecules that inhibit the HCV NS3 protease.
None of the prior patent applications described above disclose suggest cyclic peptides active and selective against the Hepatitis C virus NS3 protease.
WO 99/07733, WO 99/07734, WO 00/09543 and WO00/09558 disclose hexa to tetra-peptides and tripeptide analogs that inhibit the NS3 protease. However, these disclosures do not suggest or lead to the design of macrocyclic analogs of the present invention.
WO 99/38888 published Aug. 5, 1999 by the Institute de Richerche di Biologia Moleculare (IRBM) discloses small peptides inhibitors of the HCV NS3 protease. Nothing in this disclosure suggest or indicates the cyclic nature of the peptides of the present invention. In addition, this PCT application was published after the priority date of the present application.
WO 99/64442 by IRBM, also published after the priority date of this application, discloses oligopeptides with ketoacids at P1.
WO 99/50230 from Vertex Pharmaceuticals (published on Oct. 7, 1999) was also published aft

Affiliated with

Also associated with

Rating

Macrocyclic peptides active against the hepatitis C virus does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Macrocyclic peptides active against the hepatitis C virus, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Macrocyclic peptides active against the hepatitis C virus will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3095543