Di-nitrogen heterocycle compositions

Details Di-nitrogen heterocycle compositions Di-nitrogen heterocycle compositions

1998-08-03

2003-12-09

Baker, Maurie Garcia (Department: 1639)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C435S007100, C435S007200, C435S091500, C435S091500, C436S501000, C436S518000, C530S333000, C530S334000, C530S317000, C544S098000, C544S358000

Reexamination Certificate

active

06660466

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to combinations of di-nitrogen heterocycles and their uses, inter alia in pharmaceuticals.
BACKGROUND OF THE INVENTION
From the discovery of penicillin by Fleming in 1940's there has been a constant search for new antibiotics, which search continues to this day. Although many antibiotics have been discovered, there is an on-going need for the discovery of new antibiotic compounds because of the emergence of drug resistant strains of bacteria. Thus, research on bacterial infection is a perpetual cycle of development of new antibiotics. When penicillin was first discovered, its broad-spectrum antibiotic activity was hailed as the “magic bullet” in fighting many bacterial infections. However, over the years, many strains of bacteria have developed a resistance to penicillin and other currently available antibiotic drugs. No antibiotic drug is effective against all bacterial infections. Many antibiotic drugs available today have narrow-spectrum of activity, that is, they are effective against only few specific types of bacterial infections. Thus, for example, the majority of current antibiotic drugs are ineffective against syphilis and tuberculosis. In addition, some strains of syphilis, tuberculosis and other bacteria have developed resistance to currently available antibiotic drugs, which were effective drugs in the past.
Most bacteria which are resistant to a given drug also exhibit similar resistance to chemically similar drugs. Currently, many antibiotics are based on the &bgr;-lactam chemical core structure of penicillin. Although other chemically diverse antibiotics, such as vancomycin, are currently available, it is only a matter of time before the emergence of bacterial strains which will be resistant to all currently available antibiotic drugs. Thus, to prevent a future world-wide epidemic of drug resistant bacterial infections, there is a never ending need for a development of antibiotic drugs with novel chemical structures. This invention addresses this goal among others.
It is, accordingly, an object of this invention to provide novel di-nitrogen heterocycle compounds and combinations of such compounds for use in the preparation of antibiotics and other pharmaceuticals.
A further object of the invention is to provide combinations of such compounds in a form such that resulting compositions have structurally and chemically diverse properties for use as research reagents and otherwise.
Yet another object is to provide products produced by processes herein disclosed for the preparation of pharmaceuticals and other useful chemical species.
A further object is to provide methods for the identification of useful drugs and reagents.
These and other objects will become apparent to persons of ordinary skill in the art from a review of the present specification and appended claims.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to compounds having a di-nitrogen-containing heterocyclic portion to which pluralities of substituents are appended. In accordance with preferred embodiments, compositions are prepared comprising a plurality of such compounds, preferably more than three and even more preferably, more than six, such that such compositions can be seen to be mixtures of species having a di-nitrogen heterocyclic framework. It is preferred that the substituents appended to the framework, preferably the di-nitrogen heterocyclic frameworks as discussed hereinafter, be varied in terms of size, hydrophobicity, charge, chemistry, orientation, and subsequent reactivity. The resulting compositions are useful per se, as, for example, antibiotics, reagents for use in scientific research, and otherwise. Certain preferred compositions, comprising mixtures of such compounds, have been shown to have antibiotic activity and otherwise to be useful.
This invention is also directed to constituent portions of novel compounds, which components can be combined to form compositions having utility per se as well as in the preparation and identification of more complex pharmaceutical and other compositions.
In accordance with preferred embodiments of the present invention, compositions are provided comprising the reaction products of di-nitrogen heterocycles with chemically diverse substituents. Compounds of one such type have Formula I:
wherein
each of n, x and y is 1, 2 or 3;
R
1
is halogen, cyano, C
1
-C
6
alkyl, perhalo C
1
-C
3
alkyl, nitro, nitroso or carboxylate, and
R
2
is hydrogen, C
1
-C
6
alkyl, C
6
-C
15
aryl, C
7
-C
20
alkaryl, C
4
-C
15
heterocycle or a moiety of the formula —(CH
2
)
m
—R
3
—R
4
where
m is 0 or 1;
R
3
is —CH
2
—, —C(═O)— or —C(═S)—; and
R
4
is —O—R
5
, —N(R
5
)(R
6
), —N(R
5
)—O—R
6
, C
1
-C
6
alkyl, C
6
-C
15
aryl or
C
4
-C
15
heterocycle where R
5
and R
6
are independently hydrogen, C
1
-C
6
alkyl, C
6
-C
15
aryl, C
3
-C
12
cycloalkyl, C
4
-C
15
heterocycle or C
7
-C
20
alkaryl.
It is preferred that such compositions comprise a plurality of compounds having Formula I (or other formulas set forth herein). Such compositions have been shown to have antibiotic activity and, hence, to be useful in the formulation of pharmaceuticals and otherwise.
In a preferred embodiment of the present invention, the compounds in accordance with Formula I are such that n is 1 or 2, and each of x and y is 2 or 3. More preferably n is 1, and x and y are 2.
In another preferred embodiment of the invention, R
1
is halogen, cyano, C
1
-C
6
alkyl, perhalo C
1
-C
3
alkyl, nitro, or carboxylate. Exemplary C
1
-C
6
alkyls include, methyl, ethyl, propyl, butyl, 1-butyl, pentyl and hexyl. Exemplary perhalo C
1
-C
3
alkyls include, trifluoromethyl, trichloromethyl, truiodomethyl, pentafluoroethyl, pentachloroethyl, and heptafluoropropyl. Exemplary carboxylates include methyl carboxylate, ethyl carboxylate, t-butyl carboxylate, and sodium carboxylate. More preferably, R
1
is fluorine, cyano, methyl, trifluoromethyl or methyl carboxylate.
In yet another preferred embodiment of the invention, R
2
is hydrogen, C
6
-C
15
aryl, C
7
-C
20
alkaryl, C
4
-C
15
heterocycle or a moiety of the formula —(CH
2
)
m
—R
3
—R
4
. Heterocycles are ring systems which contain one or more of heteroatoms, such as O, N or S, A heterocycle may be aromatic or contain one or more non-aromatic unsaturated bonds, i.e., &pgr;E-bonds. Exemplary C
4
-C
15
heterocycles include pyran, pyrrolidone, benzothiazole, pyridine, benzoxazole, piperidine, piperazine, furan, thiofuran, pyrimidine and carbazole. Exemplary C
6
-C
15
aryls include phenyl, aminophenyl, halophenyl, methoxyphenyl, hydroxyphenyl, toluyl, trifluoromethylphenyl, xylyl, ethylphenyl, propylphenyl, naphthyl, bromonaphthyl, chloronaphthyl, methylnaphthyl, hydroxynaphtyl, anthracyl, bromoanthracyl, and chloroanthracyl. Halophenyls are phenyl groups with one or more halogens substituted on the phenyl ring. Exemplary halophenyls include chlorophenyl, bromophenyl, chlorophenyl, fluorophenyl, dichlorophenyl, chlorofluorophenyl and dibromophenyl. A preferred halophenyl is o-chlorophenyl. Exemplary C
7
-C
20
alkaryl include benzyl, methoxybenzyl, bromobenzyl, fluorobenzyl, naphthylmethyl, methoxyphenylmethyl, acetoxyphenylmethyl, 2-phenylethyl, 2-naphthylethyl, 3-phenylpropyl and 2-phenylpropyl.
More preferably, R
2
is hydrogen, phenyl, halophenyl, -trifluoromethylphenyl, benzyl, m-methylbenzyl, m-nitrobenzyl, m-fluorobenzyl, -cyanobenzyl, m-trifluoromethylbenzyl, m-methylcarboxylbenzyl, 6-trifluoromethyl-2-pyridyl or a moiety of the formula —(CH
2
)
m
—R
3
—R
4
.
R
3
is —CH
2
—, —C(═O)— or —C(═S)—. Preferably, R
3
is —CH
2
— or —C(═O)—, and m is 0 or 1.
R
4
is —O—R
5
, —N(R
5
)(R
6
), —N(R
5
)—O—R
6
, C
1
-C
6
alkyl, C
6
-C
15
aryl or C
4
-C
15
heterocycle. Preferably, R
4
is —O—R
5
, —N(R
5
)(R
6
), —N(R
5
)—O—R
6
, C
6
-C
15
aryl or C
4
-C
15
heterocycle. Preferred C
6
-C
15
aryl groups for R
4
are phenyl, m-methylphenyl, -nitrophenyl, m-fluorophenyl, m-cyanophenyl, m-trifluoromethylphenyl or m-methylcarboxylphenyl. A preferred

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