Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-06
2004-04-06
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S139000, C548S181000, C548S304700
Reexamination Certificate
active
06716866
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compounds having an aryl-benzimidazole structural element, in particular ones binding to nucleic acids and having anti-bacterial properties, and methods for their use.
2. Description of Related Art
A number of naturally occurring or synthetic compounds bind to double stranded nucleic acid, especially double stranded DNA (“dsDNA”). Some bind to the major groove, while others bind to the minor groove. Still others intercalate between adjacent base pairs. Combination binding modes are known, in which a compound has binding interactions with more than one nucleic acid site.
It has been proposed to use dsDNA binding compounds to regulate the expression of genes for medical purposes. If a disease is characterized by the overexpression or undesired expression of a gene (e.g., an oncogene), in principle the disease can be treated by suppressing wholly or partially the gene's expression via the binding of a compound to the gene or a promoter site thereof and interfering with transcription. Infections by pathogens such as fungi, bacteria, and viruses can be treated with compounds that affect the expression of genes essential for the pathogen's proliferation. Or, in a disease characterized by non- or under-expression of a beneficial gene, the expression of the beneficial gene can be up-regulated with a compound that binds to the binding site of a repressor.
The natural products distamycin and netropsin represent a class of DNA-binding compounds that has been studied over the years:
Structurally, distamycin and netropsin may be viewed as heteroaromatic polyamides, having as their core structural motif N-methylpyrrole carboxamide residues. They bind to the minor groove, their crescent molecular shapes providing a conformational fit within the groove. The binding occurs with a preference for A,T rich dsDNA tracts.
A number of analogs of distamycin or netropsin have been synthesized, with the objective of enhancing or varying biological properties, increasing binding affinity to dsDNA, and/or improving specificity in base pair sequence recognition. Examples include Matsunaga et al., U.S. Pat. Nos. 5,808,087 (1998), 5,821,258 (1998), 5,852,011 (1998); JP 11-171886; and JP 11-89594.
BRIEF SUMMARY OF THE INVENTION
This invention provides aryl-benzimidazole compound having the formula
and pharmaceutically acceptable salts thereof.
Ar
1
is a substituted or unsubstituted phenyl, naphthyl, 5-member heteroaromatic, 6-member heteroaromatic, or fused ring heteroaromatic group.
Subscript m is 0 or 1, while subscript n is an integer from 1 to 25, inclusive, with the proviso that if m is 0, then at least one moiety Y is a moiety M
4
and n is at least 2.
Each moiety Y is independently selected from the group consisting of
(a) moieties M
1
having the formula
wherein
one of X
1
, X
2
, and X
3
is a ring vertex selected from the group consisting of —O—, —S—, and —NR
2
—, and the other two of X
1
, X
2
, and X
3
are ring vertices selected from the group consisting of ═N— and ═CR
1
—;
(b) moieties M
2
having the formula
wherein
x is 0 or 1 and
each R
15
is independently H, OH, NH
2
, or F;
(c) moieties M
3
having the formula
wherein each L is independently a divalent moiety separating —NH— and —(C═O)— by 3 or 4 atoms; and
(d) moieties M
4
having the formula
wherein each Ar
2
is independently selected from the group consisting of
W is N(R
2
)
2
or OR
2
.
In the preceding formulae each R
1
is independently H, F, Cl, Br, I, CN, OH, NO
2
, NH
2
, a substituted or unsubstituted (C
1
-C
12
)alkyl group, or a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group; and each R
2
is independently H, a substituted or unsubstituted (C
1
-C
12
)alkyl group, or a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group.
Preferably, R
1
is H, halogen (F, Cl, Br, or I), a (C
1
-C
5
)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like, a (C
1
-C
5
)alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like, hydroxy, or cyano. Preferably, each R
2
is H or a (C
1
-C
5
)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like.
REFERENCES:
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patent: 5808087 (1998-09-01), Matsunaga et al.
patent: 5821258 (1998-10-01), Matsunaga
patent: 5852011 (1998-12-01), Matsunaga
patent: 5998140 (1999-12-01), Dervan et al.
patent: 6090947 (2000-07-01), Dervan et al.
patent: 6153642 (2000-11-01), Cozzi et al.
patent: 19920936 (2000-11-01), None
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patent: 11171886 (1999-06-01), None
patent: 11189594 (1999-07-01), None
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patent: WO 98/37066 (1998-08-01), None
patent: WO 98/37067 (1998-08-01), None
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patent: WO 98/45284 (1998-10-01), None
patent: WO 98/49142 (1998-11-01), None
patent: WO 98/50582 (1998-11-01), None
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patent: WO 99/50266 (1999-10-01), None
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patent: WO 01/19792 (2001-03-01), None
Baird et al., “Solid Phase Synthesis of Polyamides Containing Imidazole and Pyrrole Amino Acids,”J. Am. Chem. Soc.,118:6141-6146 (1996).
Baraldi et al., “Synthesis and Antitumor Activity of New Benzoheterocyclic Derivatives of Distamycin A,”J. Med. Chem.43:2675-2684 (2000).
Boger et al., “Total Synthesis of Distamycin A and 2640 Analogues: A Solution-Phase Combinatorial Approach to the Discovery of New Bioactive DNA Binding Agents and Development of a Rapid High-Throughput Screen for Determining Relative DNA Binding Affinity of DNA Binding Sequence Selectivity,”J. Am. Chem. Soc.122:6382-6394 (2000).
Floreancig et al., “Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing &agr;-Susbstituted-&bgr;-Amino Acids,”J. Am. Chem. Soc.122:6342-6350 (2000).
Khalaf et al., “The Synthesis of Some Head to Head Linked DNA Minor Groove Binders,”Tetrahedron 56(2000) 5225-5239.
Matsuba et al., “A Novel Synthetic DNA Minor Groove Binder, MS-247:AntiTumor Activity and Cytotoxic Mechanism,”Cancer Chemo. Pharm.46: 1-9 (2000).
Trauger et al., “Recognition of DNA By Designed Ligands At Subnanomolar Concentrations,”Nature,382: 559-561 (1996).
Baird Eldon E.
Bürli Roland W.
Kaizerman Jacob
McMinn Dustin L.
Taylor Matthew J.
GeneSoft Pharmaceuticals, Inc.
Gerstl Robert
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