Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-16
2004-03-16
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S354000, C514S355000, C546S298000
Reexamination Certificate
active
06706729
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to the field of virology and anti-viral therapeutics. In particular, this invention pertains to the discovery of a novel family of thiolesters and uses thereof.
BACKGROUND OF THE INVENTION
Viruses, especially retroviruses such as HIV, can become rapidly resistant to drugs used to treat the infection. This extreme adaptability of retroviruses is due to the high error rate of the reverse transcriptase enzyme responsible for transcribing its RNA genome. HIV is an example of such a hyper-mutable virus. It has diverged into two major species, HIV-1 and HIV-2, each of which has many clades, subtypes and drug resistant variations.
Strategies for coping with emergence of viral drug-resistant strains include combination drug therapies (Lange (1996)
AIDS
10 Suppl 1:S27-S30). Drugs against different viral proteins and drugs against multiple sites on the same protein are commonly used as a strategy to overcome the adaptability of the virus. Combination therapies for retroviruses, using, e.g., protease inhibitors and nucleoside analogues, such as AZT, ddI, ddC and d4T, can become ineffectual; the virus develops complete resistance in a relatively short period of time (Birch (1998)
AIDS
12:680-681; Roberts (1998)
AIDS
12:453-460; Yang (1997)
Leukemia
11 Suppl 3:89-92; Demeter (1997)
J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.
14(2):136-144; Kuritzkes (1996)
AIDS
10 Suppl 5:S27-S31). Furthermore, no effective anti-retroviral vaccine is currently available (Bolognesi (1998)
Nature
391:638-639; Bangham (1997)
Lancet
350:1617-1621).
The HIV-1 caused AIDS epidemic began about 18 years ago. Since then the number of new cases have increased over time. By the end of 1994, 1,025,073 AIDS cases had been reported to the WHO, with a 20% increase in the number of cases since December, 1993 (Galli (1995)
Q. J. Nucl. Med.
39:147-155). By the year 2000, the WHO predicts that there will be 30 to 40 million cumulative HIV-1 infections in the world (Stoneburner (1994)
Acta Paediatr. Suppl.
400:1-4). Thus, there exists a great need for compounds effective against retroviruses such as HIV-1. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
The invention provides a novel genus of compositions comprising a thiolester having a chemical structure selected from the group consisting of:
a thiolester having a formula selected from the group consisting of Template I and Template II, wherein Template I and Template II have the structures
wherein X is a member selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl groups; R
1
is —Y—Z—,
wherein Y is selected from the group consisting of —(CH
2
)
m
—, wherein m is an integer from 1 to 6,
where Z is selected from the group consisting of dialkyl or aryl or alkylaryl sulfonium (Z1), trialkyl or aryl or alkylaryl ammonium (Z2), trialkyl or aryl or alkylaryl phosphonium (Z3), or pyridinio (Z4) having the structure
wherein R
12
, R
13
, R
14
, R
15
, and R
16
, are members independently selected from the group consisting of H—, —C(═O)NH
2
, and substituted carboxamide groups, or,
R
1
is selected from the group consisting of alkyl, substituted alkyl, -aryl, substituted aryl, -arylalkyl, -Ph—CH
3
, arylalkoxy, -Ph—OCH
3
, nitroaryl, -Ph—NO
2
and —(CH
2
)
n
—X groups, where X is a halogen, and n is an integer from 1 to 6;
R
2
is selected from the group consisting of —H, —CH
3
, —C(═O)NH
2
and —C(═O)OCH
3
groups;
R
3
, R
4
and R
5
are members independently selected from the group consisting of H, a halogen, —NO
2
, —C(═O)ONH
2
, and —C(═O)OCH
3
groups;
R
6
is selected from the group consisting of —H , alkyl, —CH
3
, substituted alkyl, aryl, substituted aryl, and arylalkyl groups;
R
7
, R
8
, R
9
, R
10
, and R
11
are H except either R
7
, R
8
, or R
9
can be (O═S═O)—G′ wherein G′ is selected from the group consisting of —NH
2
, —NH-alkyl, —NH-aryl, —NH-acyl, aryl-NH
2
, nitroaryl, aryl-NH-acyl, and aryl-NH-alkyl groups;
a thiolester having a formula selected from the group consisting of Template III and Template IV, wherein Template III and Template IV have the structures
wherein G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and alkylaryl groups,
R
6
is selected from the group consisting of —H , alkyl, —CH
3
, substituted alkyl, aryl, substituted aryl, and arylalkyl groups;
R
7
, R
8
, R
9
, R
10
and R
11
are H except either R
7
, R
8
, or R
9
can be (O═S═O)—G′ wherein G′ is selected from the group consisting of —NH
2
, —NH-alkyl, —NH-aryl, —NH-acyl, aryl-NH
2
, nitroaryl, aryl-NH-acyl, and aryl-NH-alkyl groups;
a thiolester having a formula selected from the group consisting of Template V and Template VI, wherein Template V and Template VI have the structures
wherein n is any integer, R
2
through R
5
, R
6
, and R
12
through R
16
are defined as above, Y is as defined above, R
17
is —H or —CH
3
, R
18
is —H, —CH
3
, alkyl, aryl, arylalkyl, or an amino acid side chain, wherein the stereochemical configuration about the carbon atom to which R
18
is attached may be R or S, R
19
is —OH, —NH
2
, N-substituted amide nitrogen, or an ester group (—OR);
a thiolester having a formula of Template VII with the structure
wherein R
0
is any substituted or unsubstituted aryl or heteroaryl ring system attached directly to the sulfur atom,
Y and R
12
through R
16
are defined as above; and
a pyridinioalkanoyl thiolester having a formula
wherein m is an integer from 1 to 6, n is 0 or an integer from 1 to 6, and R is selected from the group consisting of alkyl, substituted alkly, aryl, substituted aryl, akylaryl, carboxamide, carboxamido, substituted carboxamide, substituted carboxamido, —NH
2
groups, and substituted —NH
2
groups.
In alternative embodiments, in the thiolester, X is a member selected from the group consisting of —(CH
2
)m-, wherein m is an integer 1 to 6, and —CH
2
(C═O)NH—; R
1
is selected from the group consisting of —CH
3
, —(CH
2
)
n
—CH
3
, —CH(CH
3
)
2
, —C(CH
3
)
3
, —(CH
2
)
n
—Cl, —(CH
2
)
n
—Br, and —(CH
2
)
n
—I groups; G is selected from the group consisting of —CH(CH
3
)
2
, —C(CH
3
)
3
; and 2,6-dimethyl phenyl groups; and, the pyridinioalkanoyl thiolester R group is selected from the group consisting of —NHC(═O)CH
3
, —C
6
H
4
NO
2
, —C
6
H
4
NHSO
2
CH
2
C
6
H
4
NO
2
and —C
6
H
4
NHCOCH
3
groups. The pyridinioalkanoyl thiolester can have a structure wherein m is the integer 4 and n=0 or the integer 1 or 2.
In one embodiment, the thiolester of the invention is capable of dissociating a metal ion from a zinc finger in vitro. In another embodiment the thiolester of the invention has antiviral activity.
The invention provides a method for dissociating a metal ion from a zinc finger-containing protein, the method comprising the step of contacting said zinc finger with a thiolester of the invention. In alternative embodiments, the metal ion is a zinc ion; the zinc finger comprises a viral protein; the viral protein is a nucleocapsid protein, a Gag protein, or a Gag-Pol protein; and, the zinc finger-containing protein is incorporated into an intact virus.
In one embodiment, in the method for dissociating a metal ion from a zinc finger-containing protein, the contacting of said virus with said compound is performed in vitro. The contacting of said virus with said compound can also be performed in vivo. The zinc finger can comprises a retroviral protein derived from a avian sarcoma and leukosis retroviral group, a mammalian B-type retroviral group, a human T cell leukemia and bovine leukemia retroviral group, a D-type retroviral group, a murine leukemia-related group, or a lentivirus group. The retroviral protein can be from an HIV-1, an HIV-2, an SIV, a BIV, an EIAV, a Visna, a CaEV, an HTLV-1, a BLV, an MPMV, an MMTV, an RSV, an MuLV, a FeLV, a BAEV, or an SSV retrovirus. This method can further comprising detecting the dissociation of said metal ion from the zinc finger of s
Appella Ettore
Covell David G.
Huang Mingjun
Inman John K.
Maynard Andrew
Robinson Binta
Rotman Alan L.
The United States of America as represented by the Department of
Townsend and Townsend / and Crew LLP
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