Substituted aurone derivatives

Details Substituted aurone derivatives Substituted aurone derivatives

1998-07-24

2001-10-23

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S052000

Reexamination Certificate

active

06307070

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to substituted aurone derivatives and to methods of inhibiting microbial infections with substituted aurone derivatives.
Microbial infections, such as fungal infections and bacterial infections, can contribute to and complicate many diseases, including meningitis, pulmonary diseases, and respiratory tract diseases. Opportunistic infections have proliferated, particularly in immunocompromised patients, such as those with AIDS, those undergoing chemotherapy for cancer, and those undergoing therapy to prevent graft rejection following organ transplant surgery.
Fungal infections (mycoses) may be cutaneous, subcutaneous, or systemic. Superficial mycoses include tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, and other candidoses such as vaginal, respiratory tract, biliary, eosophageal, and urinary tract candidoses. Systemic mycoses include systemic and mucocutaneous candidosis, cryptococcosis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, and sporotrichosis.
Pathogenic organisms include dermatophytes (e.g., Microsporum canis and other M. spp.; and Trichophyton spp. such as
T. rubrum
, and
T. mentagrophytes
), yeasts (e.g.,
Candida albicans
or
C. tropicalis
),
Torulopsis glabrata, Epidermophyton floccosum, Malassezia furfur
(
Pityropsporoti orbictilare
, or
P. ovale
),
Cryptococcus neoformans, Aspergillus fumigatus
and other Aspergillus spp., Zygomycetes (e.g., Rhizopus, Mucor),
Paracoccidiodes brasiliensis, Blastomyces dermatitidis, Histoplasma captuslatum, Coccidioides immitis
, and
Sporothrix schenckii.
SUMMARY OF THE INVENTION
In one aspect, the invention features a method for treating a microbial infection. The method includes administering to a patient a pharmaceutical composition containing a compound of formula (IA):
where
each R is independently H, OH, Br, Cl, I, amino, thoil, nitro, C
1-4
alkoxy, C
1-4
alkenyloxy, C
2-6
alkoxyalkyleneoxv, C
1-4
alkylthio, C
3-18
alkyl, or C
3-18
alkenyl; or two adjacent Rs, taken together, are a C
2-18
bivalent moiety containing at least one oxgen atom, substituted or disubstituted with A or B, or both, A being H, OH, Br, Cl, I, amino, or thiol, and B being H, C
1-10
alkyl, C
2-18
alkenyl, or C
6-18
aryl; provided at least two Rs are not H;
X is C
4-10
alkyl, C
4-20
alkenyl, or a C
4-20
single, C
6-20
bridged, or C
6-20
fused ring moiety containing cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl, where X is substituted with H, OH, Cl, Br, I, amino, cyano, nitro, alkyl, alkoxy, alkenyl, or alkenyloxy; provided that if X is a heteroaryl or heterocyclic moiety where two of R are each OH and meta to each other, the remaining R is H and ortho to each of the two hydroxyls, Y and Z are each O, and a ring atom of X is linked directly to the sp
2
carbon atom adjacent to X, then substituted with H, OH, Cl, Br, I, amino, cyano, alkyl, alkoxy, alkenyl, or alkenyloxy; and
each of Y and Z is independently selected from O, S, and NH; or a pharmaceutically acceptable salt or ester thereof.
In another aspect, the invention provides a compound selected from formulae (I)-(IV) below:
where
V is a bivalent C
2-18
moiety containing at least one oxygen atom and substituted with A, B, or both;
each of W and W′ is independently selected from the values for A, cyano, nitro, C
1-4
alkoxy, C
1-4
alkenyloxy, C
2-6
alkyloxyalkyleneoxy, C
2-7
carboxyalkyloxy, C
7-15
arylalkoxy, and C
1-4
alkylthio;
R
a
is H, C
3-18
alkyl, C
3-18
alkenyl, C
5-18
cyclohexenyl, C
6-18
aryl;
each of R
b
and R
a
is independently selected from H and C
1-4
alkyl;
X is substituted or unsubstituted C
3-15
alkyl C
3-18
alkenyl, C
3-15
cycloalkyl, C
4-15
cycloalkenyl, C
4-20
bicyclo[a.b.c]alkyl, C
5-20
bicyclo[a.b.c] alkenyl, C
8-20
tricyclo[a.b.c.d]alkyl, C
8-20
tricycloalkenyl, C
2-20
heterobicyclo[a.b.c]alkyl, or a combination thereof, where each of a, b, c, and d is independently 0 to 10 (e.g., 0 to 4, 0 to 6, or 1 to 7); and
each of Y and Z is independently selected from O and S.
In another aspect, the invention features compounds of the formulae below:
The invention also features synthetic methods suitable for combinatorial synthetic strategies for the production of diverse libraries of structurally related compounds. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
DETAILED DESCRIPTION
In one aspect, the invention features a method of inhibiting a microbial infection, where the compound of formula (IA) is selected from formulae (I)-(IV):
In one aspect, V is a bivalent C
2-18
moiety containing at least one oxygen atom and substituted with A, B, or both. V can contain between 1 and 3 rings, e.g., 1 ring, 2 rings, or three rings. For example, V can be selected from the following five formulae:
Each of W and W′ is independently selected from the values for A, cyano, nitro, C
1-4
alkoxy, C
1-4
alkenyloxy. C
2-6
alkyloxyalkyleneoxy, C
2-7
carboxyalkyloxy, C
7-15
arylalkoxy, and C
1-4
alkylthio.
R
a
is H, C
3-18
alkyl, C
3-18
alkenyl, C
5-18
cycohexenyl, or C
6-18
aryl. For example, R
a
is H, prop-2-enyl, cinnamyl, 2-methylprop-2-enyl, but-2-enyl, 3-methylbut-2-enyl, 3,7-dimethylocta-2,6-dienyl, (cyclohexenyl)methyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, or benzyl. In some cases, R
a
is not prenyl or isoprenyl.
Each of R
b
and R
c
is independently selected from H and C
1-4
alkyl. In one method, the compound can be of the formula Q=(CHX) where Q is derived from the benzofuranone analogs or derivatives in from Schemes Q-1 through Q-11, and the geometry of the double bond is E or Z. In Schemes Q-1 through Q-11, the compounds are of the formula Q-H
2
, where the two hydrogens are methylene hydrogens.
In another aspect, the compound has an IC
50
of less than 50 micrograms per milliliter against at least one pathogenic strain of Candida or Aspergillus.
In another aspect, a compound is of formula (III), where each of Y and Z is independently selected from 0 and S, for example, formulae S01-S06 and S08-S19 of Scheme P-1. Other embodiments include a compound where: W and W′ are independently selected from H, OH, methoxy, methoxymethyleneoxy, and carboxymethoxy; where Y and Z are O, and at least one of W and W′ is OH; where X is a heterocyclic radical, e.g., a heteroaryl; where X is C
4-10
alkyl, C
4-20
alkenyl, or a C
4-20
single, C
6-20
bridged, or C
6-20
fused ring moiety containing cycloalkyl, cycloalkenyl, or aryl; where X is a nonaromatic moiety containing cycloalkyl, cycloalkenyl, alkyl, or alkenyl; or where the compound is selected from S12 and S02.
Examples of X include benzyl, 2,5-dimethoxyphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-benzyloxyphenyl, 3-phenoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 4-[3-propenoic acid]-phenyl, 2-ethoxy-1-naphthyl, 1-(methylthio)ethyl, DL-1-phenylethyl, 4-n-pentyloxyphenyl, 1-(phenylsulfonyl)-2-pyrrolyl, 4-(3-dimethylaminopropoxy)phenyl, 3-phenylpropyl, 2,4-diethoxy-m-tolulyl, 2,6,6-trimethylcyclohexene-1-methyl, 2,5-dimethoxy-3-tetrahydrofuranyl, 4-methyl-5-imidazolyl, 4-n-pentylphenyl, 2-benzyloxy-4,5-dimethoxyphenyl, 1-pyrenyl, 3,5-dibenzyloxy-3-methoxyphenyl, 3-methyl-4-methoxyphenyl, 4-n-decyloxyphenyl, 2,4-dimethoxy-3-methylphenyl, t-butyl, 3-(4-t-butylphenoxy)phenyl, 2-n-hexyloxyphenyl, 2-(4-chlorophenylthio)phenyl, cyclopropyl, 2,6-dimethoxy-4-hydroxyphenyl, 4-benzyloxyphenyl, 2-benzyloxyphenyl, 8-hydroxy-1,1,7,7-tetramethyljulolidin-9-yl, 2,3,6,7-tetrahydro-8-hydroxyjulolidin-9-yl, 2-methoxymethyl-1-pyrrolidinyl, 5-(2-nitrophenyl)furanyl, 1,1-dimethyl-2-hydroxyethyl, 5-methylfuranyl, 5-(3-chlorophenyl)furanyl, 2,4-hexadienyl, 5-[3(trifluoromethyl)-phenylfuranyl], 4,5-dimethyl-4-pentenyl, imidazolyl, ferrocenyl, 2,6-dimethylhept-5-enyl, 5-[2-(trifluoromethyl)-phenyl] furanyl, 5-(hydroxy-2-nitromethyl)furanyl, 2,4

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