Isoquinoline compounds having antiinfective activity

Details Isoquinoline compounds having antiinfective activity Isoquinoline compounds having antiinfective activity

2002-06-06

2004-08-17

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S146000

Reexamination Certificate

active

06777425

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to isoquinoline compounds, 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 interfere with 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, displacing the 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 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.
Many heteroaromatic polyamides have been synthesized elaborating on the distamycin
etropsin motif, with the objective of enhancing or varying biological activity, increasing binding affinity to dsDNA, and/or improving specificity in base pair sequence recognition. See Bailly et al.,
Bioconjugate Chemistry
1998, 9 (5), 513-538, and Neidle,
Nat. Prod. Rep.
2001, 18, 291-309. 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).
BRIEF SUMMARY OF THE INVENTION
This invention provides isoquinoline compounds having the formula
including the pharmaceutically acceptable salts thereof.
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, a substituted or unsubstituted (C
1
-C
12
)alkoxy group, or a substituted or unsubstituted (C
1
-C
12
)heteroalkyl group.
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 has 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
is a 5- or 6-member heteroaromatic ring.
Subscript m is an integer from 1 to 25, inclusive, preferably from 1 to 6, more preferably from 2 to 4.
Z is either O or N, with n being 1 if Z is O and 2 if Z is N.
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.
Compound (I) has a basic group having a pK
b
of 12 or less or a quaternized nitrogen group.
Preferably, each moiety —(NH—Y—CO)— 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
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), 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:
patent: 5395849 (1995-03-01), Wittman et al.
patent: 5545640 (1996-08-01), Beaulieu et al.
patent: 5698674 (1997-12-01), Bruice et al.
patent: 5844110 (1998-12-01), Gold
patent: 5852011 (1998-12-01), Matsunaga et al.
patent: 5998140 (1999-12-01), Dervan et al.
patent: 6090947 (2000-07-01), Dervan et al.
patent: 6143901 (2000-11-01), Dervan
patent: WO 96/26950 (1996-09-01), None
patent: WO 97/25351 (1997-07-01), None
patent: WO 98/35702 (1998-08-01), None
patent: WO 98/37066 (1998-08-01), None
patent: WO 98/37067 (1998-08-01), None
patent: WO 98/37087 (1998-08-01), None
patent: WO 98/43663 (1998-10-01), None
patent: WO 98/45284 (1998-10-01), None
patent: WO 98/49142 (1998-11-01), None
patent: WO 98/50582 (1998-11-01), None
patent: WO 98/52614 (1998-11-01), None
patent: WO 99/00364 (1999-01-01), None
patent: WO 00/15209 (2000-03-01), None
patent: WO 00/15773 (2000-03-01), None
patent: WO 0121615 (2000-09-01), None
patent: WO 01/19792 (2001-03-01), None
patent: WO 01/21615 (2001-03-01), None
patent: WO 01/74898 (2001-10-01), None
Sen, Chemical Abstracts, vol. 71, No. 1, col. 1, Abstract 12986e, Jul. 7, 1969.*
Bremer, et al., Recognition of the DNA Minor Groove by Pyrrole-Imidazole polyamides: Comparison of Desmethyl- and N-Methylpyrrole, Bioorganic & Medicinal Chemistry 8 (2000), pp 1947-1955.
Bailly, et al., Sequence-Specific DNA Minor Groove Binders. Design and Synthesis of Netropsin and Distamycin Analogues, Bioconjugate Chemistry, vol. 9, No. 5 (Sep./Oct. 1998).
White, et al., On the Pairing Rules for Recognition in the Minor Groove of DNA by Pyrrole-Imidazole Polyamides, Chemistry & Biology 1997, vol. 4, No. 8.
Wade, et al., Design of Peptides that Bind in the Minor Groove of DNA at 5′-(A,T)G(A,T)C(A,T)-3′ Sequences by a Dimeric Side-by-Side Motif, Journal of the American Chemical Society, 1992, 114.
Mrksich et al., Hairpin Peptide Motif. A New Class of Oligopeptides for Sequence-Specific Recognition in the Minor Groove of Double-Helical DNA, Journal of the American Chemical Society, 1994, 116.
Baird et al., Solid Phase Synthesis of Polyamides Containing Imidazole and Pyrrole Amino Acids, J. Am. Chem. Soc. 1996, 118, 6141-6146.
Floreancig et al., Recognition of the Minor Groove of DNA by Hairpin Polyamides Containing &agr;-Substituted-&bgr;-Amino Acids, J. Am. Chem. Soc. 2000, 122, 6342-6350.
Trauger et al., Recognition of DNA by Designed Ligands at Subnanomolar Concentrations, Nature, vol. 382, (Aug. 1996).
White et al., Recognition of the Four Watson-Crick Base Pairs in the DNA Minor Groove by Synthetic Ligands, Nature, vol. 391, (Jan. 1998).
Stephen Neidle, DNA Minor-Groove Recognition by Small Molecules, Nat. Prod. Rep., 2001, 18, 291-309.
Kelly et al., Binding Site Size Limit of the 2:1 Pyrrole-Imidazole Polyamide-DNA Motif, Proc. Natl. Acad. Sci. USA, vol. 93, pp. 6981-6985 (Jul.

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