Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1994-01-20
2004-11-09
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000
Reexamination Certificate
active
06815461
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of inhibiting retroviral integrases with dicationic bis-benzimidazoles.
BACKGROUND OF THE INVENTION
The genome of the typical retrovirus encodes three primary enzymes that mediate the virus replication cycle. Reverse transcriptase converts the viral RNA genome into a double stranded DNA. Integrase nonspecifically inserts this DNA copy into the host cell genome, and protease cleaves viral structural and nonstructural proteins into their mature forms.
An essential step of the retroviral life cycle is the integration of its double-stranded DNA copy into the host genome. H. Sakai et al,
J. Virol.
67, 1169-74 (1993). This process requires highly conserved sequence recognition and cleaving steps. For this reason, a therapeutic agent that can interrupt this process should be an effective and specific antiviral agent. A protein at the C-terminus of the viral polymerase, integrase (IN), is the only viral protein required for this process. R. LaFemina et al.,
J. Virol.
66, 7414-7419 (1992).
A. Fesen et al.,
Proc. Natl. Acad. Sci. USA
90, 2399-2403 (1993) discuss investigations using an in vitro integrase assay of a variety of chemicals as potential human immunodeficiency virus type I (HIV-1) integrase inhibitors. The article reports several topoisomerase inhibitors, such as doxorubicin, mitoxantrose, ellipticines and quercetin as potent inhibitors. While some topoisomerase inhibitors were excellent anti-integrase agents, no correlation was observed with antiviral effects. This is believed to be at least partially due to the fact that a number of topoisomerase inhibitors have severe cytotoxic effects, depending upon their mechansim of inhibition.
R. LaFemina et al.,
J. Virology
56, 7414-7419 (1992) reports studies assessing the usefulness of the integrase enzyme as a target for specific HIV-1 anti-viral therapeutic agents by determining its absolute requirement for productive HIV-1 infection. The article reports the results of the introduction of specific amino acid substitution into recombinant integrase and assesses the ability of the mutant proteins to properly mediate specific and non-specific cleavage as well as integration.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of inhibiting retroviral integrase (e.g. in vitro, or in a subject in need of such treatment). The method comprises administering to the subject or contacting to the retroviral integrase an effective retroviral integrase-inhibiting amount of a compound according to Formula (I):
wherein:
R
1
and R
2
are each independently selected from the group consisting of H or lower alkyl, or R
1
and R
2
together represent —(CH
2
)
m
— wherein m is from two to four;
R
3
is H or lower alkyl; and
X is C1 to C2 saturated or unsaturated alkyl containing up to one double bond (e.g., —(CH
2
)
n
wherein n is from 1-2, which is unsubstituted or substituted from 1 to 2 times with lower alkyl, and which is saturated or unsaturated and contains up to one double bond);
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, R
1
and R
3
are each H; R
2
is H or lower alkyl; and x is selected from the group consisting of —CH
2
—CH
2
— and —CH═CH— and any of the foregoing substituted from 1 to 2 times with lower alkyl; and the pharmaceutically acceptable salts thereof. Currently preferred compounds are bis[5-amidino-2-benzimidazolyl]methane; 1,2-bis[5-amidino-2-benzimidazolyl]ethane; 1,2-bis[5-amidino-2-benzimidazolyl]ethene; 1,2-bis[5-isopropylamidino-2-benzimidazolyl]ethene, or pharmaceutically acceptable salts thereof.
A second aspect of the present invention is a method of combatting a retroviral infection (e.g. in vitro, or in a subject in need of such treatment). The method comprises administering to the subject or contacting to the retrovirus an effective retroviral infection combatting amount of a compound according to Formula (I) as given above or a pharmaceutically acceptable salt thereof. Currently preferred compounds are bis[5-amidino-2-benzimidazolyl]methane; 1,2-bis[5-amidino-2-benzimidazolyl]ethane; 1,2-bis[5-amidino-2-benzimidazolyl]ethene; 1,2-bis[5-isopropylamidino-2-benzimidazolyl]ethene, or pharmaceutically acceptable salts thereof.
Compounds of formula I, or there pharmaceutically acceptable salts, may be included in a therapeutically effective amount in a pharmaceutically acceptable carrier to provide pharmaceutical formulations, with the therapeutically effective amount being effective to carry out the methods set forth above.
Further aspects of the present invention include the use of compounds of Formula (I) above and their pharmaceutically acceptable salts for the preparation of a medicament for inhibiting retroviral integrase, or for combatting a retroviral infection.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth hereinbelow.
REFERENCES:
patent: 4933347 (1990-06-01), Tidwell et al.
patent: 4963589 (1990-10-01), Tidwell et al.
patent: WO95/08540 (1995-03-01), None
S.L. Vonderfecht et al;Protease Inhibitors Suppress the in Vitro and in Vivo Replication of Rotavirus; J. Clin. Invest.82: 2011-2016 (1988).
T.A. Fairley et al;Structure, DNA Minor Groove Binding, and Base Pair Specificity of Alkyl-and Aryl-Linked Bis(amidinobenzimidazoles)and Bis(amidinoindoles);J. Med. Chem.36; 1746-1753 (1993).
Robert L. LaFemina et al.;Requirement of Active Human Immunodeficiency Virus Type 1 Integrase Enzyme for Productive Infection of Human T-Lymphoid Cells; Journal of Virology66; Dec. 1992; pp. 7414-7419.
Mark R. Fesen et al.;Inhibitors of Human Immunodeficiency Virus Integrase; Proc. Natl. Acad. Sci. USA90; Mar. 1993; pp. 2399-2403.
Dykstra Christine C.
Swanstrom Ronald I.
Tidwell Richard R.
Jenkins & Wilson & Taylor, P.A.
Peoples Mary
The University of North Carolina at Chapel Hill
Travers Russell
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