Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-25
2004-01-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S476000, C514S535000, C514S538000, C514S646000, C514S678000, C514S688000
Reexamination Certificate
active
06673788
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of antiviral agents and specifically relates to compounds, compositions and methods for treating herpesvirus infections.
BACKGROUND OF THE INVENTION
There is a great need for new therapies active in the treatment of viral diseases. Whereas there has been great progress in developing a variety of therapies for the treatment of bacterial infections, there are few viable therapies for the treatment of herpesvirus. ganciclovir, aciclovir and foscarnet are currently utilized for the treatment of herpesvirus infections, however, these therapies can have substantial side effects based on their deleterious effects on host cell DNA replication. They also affect a limited number of viral infections. In addition, viruses are known to develop resistance to therapies, and such resistance causes a progressive decline in efficacy.
Viruses are classified into broad categories based on whether they incorporate RNA or DNA. Important virus families classified of RNA type include orthomyxoviridae, paramyxoviridae, picornaviridae, rhabdoviridae, coronaviridae, togaviridae, bunyaviridae, arenaviridae and retroviridae. Important virus families classified of DNA type include adenoviridae, poxviridae, papovaviridae and herpesviridae.
Herpesviridae is a family of DNA viruses which include herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
It is known that herpesvirus replicate by directing the synthesis of a number of proteins encoded by the herpesvirus DNA in the host cell. One of the important virus-encoded proteins is made as a fusion protein precursor consisting of an amino terminal-located protease and carboxyl terminal-located capsid assembly protein. This precursor is proteolytically processed in an autocatalytic manner at a specific amino acid sequence known as the “release” site, yielding separate protease and capsid assembly protein. The capsid assembly protein is cleaved further by the protease at another specific amino acid sequence known as the “maturation” cleavage site. U.S. Pat. No. 5,478,727, to Roizman and Liu, describes a virus-specific serine protease which has a role in HSV replication. Liu and Roizman [
J. Virol,
65, 5149 (1991)] describe the sequence and activity of a protease and the associated assembly protein encoded by U
L
26 of HSV-1. Recently, U.S. Pat. No. 5,434,074, to W. Gibson and A. Welch, describes a simian CMV protease. A. Welch et al. [
Proc. Natl. Acad. Sci. USA,
88, 10792 (1991)] describe the related protease (also known as assemblin) and assembly protein encoded by U
L
80 of a human CMV. An approach currently being investigated for potential use in the treatment of herpesvirus infections is the development of inhibitors of herpesvirus proteases.
Arylketones containing a tetrazolylcarbonylamino substituent have been described. European publication EP 337,701, published Apr. 11, 1988, describes the use of 3-acetyl-5-fluoro-2-hydroxytetrazole-5-carboxanilide for treating autoimmune disorders or arthritis.
Substituted arylureas have been described in European publication EP 355,819, published Feb. 28, 1990, as high intensity sweeteners.
Aryltrihalomethylketones combined with hydrogen peroxide have been described in European patent publication EP 298,020, published Jan. 4, 1989, as reagents for epoxidation of steroids. German patent document DE 4,201,435, describes a method of preparing trifluoromethylketones from the alcohols.
U.S. Pat. No. 4,855,460, to M. Tordeux et al., describes the formation of simple pseudoacids via perfluoroalkylation of acid anhydrides. Specifically, trifluoroacetophenone is described.
WO 92/18475, published Oct. 29, 1992, describes phenylsubstituted pyrrolidines as dopamine receptor agonist/antagonists. Aryltrifluoromethylcarbinols have been described in U.S. Pat. No. 4,285,943, issued to M. Vincent et al., as analgesic, antipyretic, and anti-inflammatory agents.
Inhibition of serine proteases by electrophilic carbonyl derivatives, in particular peptidyl derivatives possessing an electrophilic carbonyl or boron group, is a well documented process. Early work describes where the P
1
cleavage site is mimicked by an electrophilic aldehyde, alpha-ketoester, trifluoromethylketone, alphaketoamide, or boronic ester. [See J. Powers and J. Wade Harper, “
Inhibitors of Serine Proteases
”, in Proteinase Inhibitors, 55-152 (1986); R. Wiley and D. Rich,
Medicinal Research Reviews,
13, 327-384 (1993).]
For example, the compounds in European patent publication EP 276,101, published Jul. 27, 1988, are described as inhibiting human leukocyte elastase (HLE). Generally, the inhibitors consist of a proline-based peptidyl sequence which is terminated by a trifluoromethylketone. European publication EP 249,349, published Dec. 16, 1987, describes a proline-derived peptide sequence terminated by a 2,2-difluoro-3-phenyl-1,3-dicarbonyl group. European publication EP 204,571, published Dec. 12, 1986, describes a proline-derived peptide sequence consisting of one-three amino acids and terminated by a 2,2-difluoro-3-phenyl-1,3-dicarbonyl group.
Several references have described aryltrifluoromethylketones as inhibitors of acetylcholinesterase, a serine esterase. European publication EP 403,713, published Dec. 27, 1990, describes m-(silyl)phenylfluoroketones in treatment of Alzheimers disease and senile dementia. U.S. Pat. No. 5,166,181 describes [m-(alkylaminoalkyl)aryl]-haloketone compounds as acetylcholinesterase inhibitors. Specifically, 1-[3-[1-(N,N-dimethylamino)ethyl]phenyl]-2,2,2-trifluoroethanone is described.
Halosubstituted acetophenones have not previously been described as selective herpesvirus protease inhibitors or for the treatment and/or prophylaxis of herpesvirus infection.
DESCRIPTION OF THE INVENTION
The present invention relates to a class of halo-substituted acetophenones, useful in the therapeutic and prophylactic treatment of viral infections, as defined by Formula I:
wherein each of R
1
, R
2
, R
3
, and R
4
is independently selected from hydrido, alkyl, aralkyl, halo, alkoxy, cyano, nitro, amino, alkylamino, N-acylamino, alkylsulfonyloxy, aminosulfonyl, N-(haloalkylcarbonyl)amino, peptidyl, amino acid residue,
wherein R
5
is selected from alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio, alkylamino, arylamino, aralkylamino, alkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl, wherein R
5
is optionally substituted at a substitutable position with one or more substituents selected from alkyl, alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, N-acylamino, amino, alkylamino, alkoxycarbonyl, amino acid residue and peptidyl;
wherein R
6
is selected from alkyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl, wherein R
6
is optionally substituted at a substitutable position with a radical selected from alkoxy, aryloxy, alkylthio, arylthio, halo, nitro, N-acylamino, amino, alkylamino and alkoxycarbonyl;
wherein Y is selected from fluoroalkyl and
wherein Q is selected from alkoxy, aryloxy, aralkyloxy, amino acid residue, peptidyl, and —NHR
7
; and
wherein R
7
is a radical selected from alkyl, aralkyl, and heterocyclylalkyl, wherein R
7
is optionally substituted at a substitutable position with a radical selected from amino, nitrogen-containing heterocyclyl and alkylamino;
or a pharmaceutically-acceptable salt or tautomer thereof.
The compounds of this invention have been shown to be particularly effective against herpetoviridae. Thus they are particularly useful for the treatment of herpes simplex viruses (HSV-1, HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr (EBV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
The invention further involves a method of treating a s
Flynn Daniel L.
Hockerman Susan L.
Williams Kenneth
Zablocki Jeffery
Bulock Joseph W.
G. D. Searle & Co.
Patel Sudhaker B.
Polster Rachel A.
Shah Mukund J.
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