Therapeutic method to treat herpes virus infection

Details Therapeutic method to treat herpes virus infection Therapeutic method to treat herpes virus infection

1999-02-26

2002-04-09

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S461000, C514S462000, C514S449000, C549S429000, C549S456000

Reexamination Certificate

active

06369101

ABSTRACT:

BACKGROUND OF THE INVENTION
The herpes simplex viruses (HSV) are a group of about 100 different double-stranded DNA animal viruses. At least seven are known to be pathogenic to humans and are known as human herpes viruses or HHV. HHV include herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), varicella zoster virus (VSV or HHV3, which causes chickenpox), cytomegalovirus (HCMV), human herpesvirus type 6 and type 7 (HHV-6 and HHV-7) and Epstein-Barr virus (EBV or HHV4 which causes infectious mononucleosis). Infections by these viruses are among the most common and easily transmitted viral infections, afflicting greater than one million individuals each year in the United States. The hallmark of herpes virus infections is latency. The site of latency is the dorsal root ganglia or the sacral ganglia. Here the virus remains latent and can be reactivated under various conditions of stress. See, for example, B. Roizman et al.,
Am. Rev. Microbiol
., 41, 543 (1987); B. Roizman et al., “Herpes Simplex and Their Replication”, B. Fields, ed.,
Virology
, Raven Press, NY (2d ed., 1990) at pp. 1795-1841; A. H. Haase et al.,
Viral Pathogenesis
, N. Nathanson, ed., Lippincott-Raven (1996) at pp. 465-506.
HSV-1 mainly affects areas above the waist and is most common in children between the ages of one and five. HSV-2 is primarily a sexually transmitted virus affecting the genital areas, sacrum and buttocks. These two types can infect any mucutaneous surface or visceral site and produce clinically indistinguishable lesions. The degree of infection greatly varies from patient to patient, however, those with T-cell defects experience more frequent and severe HSV infections (D. M. Arbesfeld et al.,
Am. Family Physician
, 43, 1655 (1991)).
Numerous treatments for HSV infections have been tried and none have been entirely satisfactory. Chemotherapy (topical or systemic) for HSV infection has included the use of idoxuridine, trifluorothymidine, adenine arabinoside (ara-A), acyclovir, bromovinyl deoxyuridine, foscarnet, and other acyclic nucleoside analogues. Among all the anti-HSV agents, acyclovir (ACV) was the first genuinely selective agent. It profoundly affects viral DNA polymerase function through obligatory chain termination and competitive inhibition. See B. Beam,
Postgrad. Med
., 77, 297 (1983). The poor absorption rate and pharmacokinetics of acyclovir have been overcome to some extent by the use of prodrugs like valaciclovir and penciclovir in treating infected individuals. However, many HSV-1 and HSV-2 strains have produced mutants that are resistant to ACV. Also, drugs such as ACV require the virus to be actively multiplying and are not active when the virus is latent. The greatest difficulty in finding antiviral compounds is due to the requirement that the active compound must act on virus within a host cell without causing damage to the host cell (A. Chatos et al.,
Virol
., 180, 793 (1991)).
U.S. Pat. No. 5,750,578, issued May 12, 1998, discloses that betulin and certain specific analogs thereof possess antiviral activity. However, there is a continuing need for additional antiviral and antibacterial agents, useful to treat herpes viruses.
SUMMARY OF THE INVENTION
The present invention provides a therapeutic method for treating a human afflicted with herpesvirus infection comprising administering to said human an effective anti-viral amount of a compound of formula (I):
wherein
one of R
1
and R
2
is —O—Y and the other is hydrogen or (C
1
-C
6
)alkyl optionally substituted by hydroxy, (C
1
-C
6
)alkoxy, halo, halo(C
1
-C
6
)alkoxy or NR
j
R
k
wherein R
j
and R
k
are independently H, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkonyl; or R
1
and R
2
together are oxo (═O);
R
3
is hydrogen, halo, carboxy, mercapto, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, or —O—Y;
R
4
and R
5
are each independently hydrogen, (C
1
-C
6
)alkyl, or hydroxy(C
1
-C
6
)alkyl;
R
6
is hydrogen or is absent when the adjacent—is a bond;
R
7
is hydrogen or (C
1
-C
6
)alkyl;
R
8
is hydrogen, (C
1
-C
6
)alkyl, or hydroxy(C
1
-C
6
)alkyl and R
11
, is hydrogen, (C
1
-C
6
)alkyl, carboxy, or hydroxy(C
1
-C
6
)alkyl; or R
8
and R
11
together are —O—C(═X)—;
R
9
and R
10
, are each independently hydrogen or (C
1
-C
6
)alkyl;
each of the bonds represented by—is independently absent or is present;
X is two hydrogens, oxo (═O) or thioxo (═S);
each Y is independently H, aryl, P(O)(C)
2
, (C
3
-C
8
)cycloalkyl, adamantyl, —SO
2
R
a
O═P(R
b
)
2
, O═P(R
c
)
2
OP(O)(R
d
)—, Si(R
e
)
3
, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and —N(R
f
)—; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(R
g
)(R
h
), (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
R
a
is (C
1
-C
6
)alkyl or aryl;
R
b
, R
c
, and R
d
are each independently hydroxy, (C
1
-C
6
)alkoxy, hydroxy(C
2
-C
6
)alkoxy, adamantyloxy, adamantyl(C
1
-C
6
)alkoxy, norbomyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C
1
-C
6
)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C
3
-C
8
)cycloalkyloxy, NR
x
R
y
, or aryloxy;
R
e
is H, aryl or (C
1
-C
6
)alkyl;
R
f
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl;
R
g
and R
h
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, adamantyl, adamantyl(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, aminosulfonyl, (C
1
-C
6
)alkanoyl, aryl and benzyl; or R
b
and R
c
together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
R
x
and R
y
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, aryl or benzyl;
wherein each aryl of Y, R
a
—R
d
, R
g
—R
h
, R
x
, and R
y
may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NR
i
R
j
, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, trifluoromethoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, or (C
1
-C
6
)alkanoyloxy; wherein R
i
and R
j
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl, or benzyl;
or a pharmaceutically acceptable salt thereof.
The invention also provides novel compounds of formula I, as well as intermediates and processes useful for preparing compounds of formula I. The compound of formula (I): 3&bgr;-hydroxy-19&agr;H-19,28-epoxy-oleanane is known as allobetulin. Additionally, the compounds uvaol, ursolic acid, and hederin hydrate are known compounds of formula I (see FIG. I). Accordingly, compounds of the formula I preferably exclude allobetulin, uvaol, ursolic acid, and hederin hydrate. Compounds of the invention also preferably exclude the corresponding acetates of these alcohols.
J. Schmidt and S. Huneck
Organic Mass Spectrometry
, 1979, 14, 646-655 disclose the mass spectrometry behavior of certain compounds of formula (I). Accordingly, compounds of the invention preferably exclude:
a) a compound of formula (I) wherein: R
1
is OH; when R
2
is hydrogen, R
3
is hydrogen, R
4
is methyl, R
5
is methyl, R
6
is hydrogen, R
7
is hydrogen, R
9
is methyl, R
10
is methyl, the bond at the 1 and 2 positions represented by --- is present or absent, the bond at the 12 and 13 positions represented by --- is absent, and R
8
and R
11
together are —O-CH
2
—.
b) a compound of formula (I) wherein: R
1
is hydroxy or acetoxy;
when R
2
is hydrogen, R
3
is hydrogen, R
4
is methyl, R
5
is methyl, R
6
is hydrogen, R
7
is hydrogen, R
9
is methyl, R
10
is methyl, the bond at the 1 and 2 positions represented by—is present or absent, the

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