Benzothiophene compounds having antiinfective activity

Details Benzothiophene compounds having antiinfective activity Benzothiophene compounds having antiinfective activity

2002-06-06

2004-11-30

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S444000, C514S235800, C514S232800, C544S141000, C548S527000, C549S059000

Reexamination Certificate

active

06825228

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compounds having benzothiophene groups, in particular those 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.
The natural products distamycin and netropsin represent a class of DNA-binding compounds that has been studied over the years:
Structurally, distamycin and netropsin are 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 heteroaromatic polyamides have been synthesized elaborating on the distamycin
etropsin motif, with the objective of enhancing or varying biological properties, increasing binding affinity to dsDNA, and/or improving specificity in base pair sequence recognition. The use of synthetic heteroaromatic polyamides in therapeutics has been proposed, for example, in Dervan et al., U.S. Pat. No. 5,998,140 (1999); Dervan et al., WO 00/15209 (2000); Dervan, WO 00/15773 (2000); and Gottesfeld et al., WO 98/35702 (1998).
The effect of structural variations in the heteroaromatic ring has been a focus of extensive research. See, e.g., reviews by Bailly et al.,
Bioconjugate Chemistry
, Vol. 9, No. 5, pp. 513-538 (1998) and Neidle,
Nat. Prod. Rep
. 2001, 18, 291-309. Alternative heteroaromatic rings reported in the art include furan, imidazole (especially N-methylimidazole), isoxazole, oxazole, pyrazole, pyridine, thiophene, triazole rings, and others. Art that may be relevant to the use of benzothiophene groups in DNA binding compounds includes Boger et al.,
J. Am. Chem. Soc
., 2000, 122, 6382; Kutyavin et al., U.S. Pat. No. 5,801,155 (1998); Tidwell et al., U.S. Pat. No. 6,172,104 (2001); Cozzi et al., WO 98/21202 (1998); Cozzi et al., WO 99/50266 (1999); and Turin et al., WO 01/19792 (2001).
BRIEF SUMMARY OF THE INVENTION
The present invention provides benzothiophene compounds of the formula
including the pharmaceutically acceptable salts thereof.
Each R
5
is independently H, F, Cl, Br, I, CN, OH, NH
2
, a substituted or unsubstituted (C
1
-C
12
)alkyl group, a substituted or unsubstituted (C
1
-C
12
)alkoxy group, or a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group. 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. Subscript m is an integer from 1 to 25, inclusive. Z is either O or N, with n being 1 if Z is O and 2 if Z is N. Each Y is independently a branched or unbranched, substituted or unsubstituted (C
1
-C
5
)alkylene group or a substituted or unsubstituted, aromatic or heteroaromatic ring system, wherein the ring system can comprise a 5- or 6-member aromatic or heteroaromatic ring or fused 6,6 or 6,5 aromatic or heteroaromatic rings, with the proviso that at least one Y is a substituted or unsubstituted aromatic or heteroaromatic ring system. Preferably, at least one Y is a 5- or 6-member heteroaromatic ring. More preferably, Y in the moiety —(NH—Y—CO)— immediately adjacent to the moiety
is a 5- or 6-member heteroaromatic ring.
Preferably, each moiety —(NH—Y—CO)— is independently selected from the group consisting of
(a) moieties M
1
of 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
of the formula
 wherein x is 0 or 1 and each R
15
is independently H, OH, NH
2
, or F;
(c) moieties M
3
of 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
of the formula
 with the proviso that at least one moiety —(NH—Y—CO)— is M
1
or M
4
;
and the compound contains a basic group having a pK
b
of 12 or less or a quaternized nitrogen group.
Preferably, at least one moiety —(NH—Y—CO)— is a moiety M
1
. More preferably, the moiety —(NH—Y—CO)— immediately adjacent to the residue
is a moiety M
1
.
In the preceding formulae R
1
and R
2
are as previously defined.
Preferably, R
1
is hydrogen, halogen (F, Cl, Br, or I, especially F or Cl), 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.


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Bremer et al., “Recognition of the DNA Minor Groove by Pyrrole-Imidazole Polyamides: Comparison of Desmethyl-and N-Methylpyroole.”Bioorganic&Medicinal Chemistry,8:1947-1955 (2000).
Bailey et al., “Sequence-Specific DNA Minor Groove Binders. Design and Synthesis of Netropsin and Distamycin Analogues,”Bioconjugate Chemistry,9:513-538 (1998).
White et al., “On the pairing rules for recognition in the minor groove of DNA by pyrrole-imidazole polyamides,”Chemistry&Biology,4:569-578 (1997).
Mrksich et al., “Hairpin Peptide Motif, A New Class of Oligopeptides for Sequence-Specific Recognition in the Minor Groove of Double-Helical DNA,”J. Am. Chem. Soc.,116:7983-7988 (1994).
Floreancig et al., “Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing &agr;-Substituted-&bgr;-Amino Acids,”J. Am. Chem. Soc.,122:6342-6350 (2000).
Trauger et al., “Recognition of DNA by designed ligands at subanomolar concentrations,”Nature,382:559-561 (1996).
White et al., “Recognition of the four Watson-Crick base pairs in the DNA minor groove by synthetic ligands,”Nature,391:468-471 (1998).
Neidle, Stephen, “DNA minor-groove recognition by small molecules,”Nat. Prod. Rep.,18:291-309 (2001).
Fenwick et al., “Solid-Phase Synthesis of Cyclic Alkoxyketones, Inhibitors of the Cysteine Protease Cathepsin K,”Bioorg. Med. Chem. Lett.,11:195-198 (2001).
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 or DNA Binding Sequence Selectivity,” 122:6382-6394 (2000).

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