Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-09
2002-11-05
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06476013
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to metallo-organic cobalt compounds and their use in the prophylactic treatment of subjects to prevent chlamydia infections.
It has been discovered that certain conditions and diseases, e.g., inflammation, burns, wounds, and diseases caused by bacteria, fungi and viruses in mammalian species can be treated with certain complexes of cobalt having the structure:
wherein
each A may be the same or different and is an alkyl group, a phenyl group or a substituted derivative of a phenyl group;
wherein each Y may be the same or different and is hydrogen, an unbranched alkyl group, a halide or a group having the structure
wherein R is hydrogen, an alkoxide group, and alkyl group, or OH;
wherein each B may be the same or different and each is hydrogen or an alkyl group;
wherein each X may be the same or different and each is a water soluble group having weak to intermediate ligand filed strength; and
Z
−
is a soluble, pharmaceutically acceptable negative ion.
Today, chlamydia infections are known to be significant causes of morbidity in human and veterinary medicine. Many of these infections present no noticable symptoms, yet can lead to sterility. New prophylactic treatments would decrease the incidence of these infections and improve overall health.
SUMMARY OF THE INVENTION
We have discovered a prophylactic use for the series of compounds having the structure:
wherein
each A may be the same or different and is an alkyl group, a phenyl group or a substituted derivative of a phenyl group;
each Y may be the same or different and is hydrogen, an unbranched alkyl group, a halide or a group having the structure
wherein R is hydrogen, an alkoxide group, an alkyl group, or OH;
each B may be the same or different and each is hydrogen or an alkyl group;
Z
−
is a soluble, pharmaceutically acceptable negative ion; and
each X may be the same or different and is an axial ligand selected from the group consisting of moieties having the formula:
wherein R
1
, R
2
, R
3
, and R
4
may be the same or different and maybe hydrogen or lower alkyl having from 1 to 4 carbon atoms; and
wherein R
5
, R
6
, R
7
, R
8
and R
9
may be the same or different and may be selected from the group consisting of electron donating groups and electron withdrawing groups;
with the proviso that R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are of a sufficiently small size so as not to prohibit the attachment of the axial ligand to the Co atom due to steric hindrance.
As used herein, the term “axial” when used in conjunction with the term “ligand” refers to the fact that the ligand is oriented outside the plane of the molecule and has the same meaning as described in connection with FIG. 1 of U.S. Pat. No. 5,049,557. As used herein, and unless otherwise indicated, an alkyl group means a linear, branched or cyclic alkyl group containing from one to six carbon atoms.
The compounds having the structure of Formula II exhibit prophylactic efficacy when applied as a topical composition to the contact site prior to contact with chlamydia and/or by inactivating chlamydia exposed to the composition. The compositions of the invention may further be used for antisepsis or disinfection of surfaces, such as, surgical tools or preparations such as, media or blood-derived products, which are contaminated with chlamydia.
DETAILED DESCRIPTION OF THE INVENTION
The compounds used in the present invention may be crystallized with numerous counter-anions. Counter-anions which are pharmaceutically acceptable and are water soluble, such as, halide ions, PF
6
−
and BF
4
−
, are preferred. The bromide and chloride salts of the present compounds are the most preferred because they are more water soluble than other salts of the compounds.
As discussed above, A may be an alkyl group, a phenyl group or a substituted derivative of a phenyl group. Preferably, the alkyl group is a C
1
-C
5
group with methyl, ethyl, and butyl groups being particularly preferred. Suitable substituted derivatives of the phenyl group are derivatives wherein each substituent is a halide, an alkyl group or a group having the structure
wherein R is hydrogen, an alkoxide group, an alkyl group or an OH group. To date, the most useful derivatives have proven to be those in which the substituents are halides, or alkyl groups.
Y may be hydrogen, an unbranched alkyl group, a halide or a group having the structure
wherein R is hydrogen, an alkoxide group, an alkyl group or an OH group. In certain embodiments, it is preferred that Y is chlorine, a hydrogen atom or a C
1
-C
3
alkyl group. In embodiments where Y has a structure
is preferred that R is hydrogen, a methyl group or an OH group.
B may be hydrogen or an alkyl group, and preferably is a C
1
-C
3
alkyl group.
X may be imidazole or pyridinyl groups linked to the cobalt atom through a nitrogen of the ring. The imidazole or pyridinyl nuclei may have hydrogen atoms, or electron donating or withdrawing groups substituted thereon.
The electron withdrawing or donating groups which may constitute appendant groups R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are those known in the art to exert the specified electron withdrawing or donating effects on aromatic nuclei. Typical of electron donating groups are NO
2
−
, Cl
−
, Br
−
, and the like. The identity of the particular group is not crucial so long as it does not impart properties to the molecules which are detrimental to the desired properties of the compound, e.g., decreased antiviral activity, increased toxicity, and the like. Additionally, the group must not be so large as to prevent the axial ligand to attach to the cobalt atom due to steric effects, e.g., steric hindrance.
Preferably, the groups attached to the imidazole nucleus are alkyl having from one to three carbon atoms. Of these, methyl and ethyl are most preferred. Preferred are the unsubstituted, 2-methyl, 4-methyl, and 2-ethyl imidazoles and the unsubstituted pyridinyl.
The following Table provides the structures of preferred compounds in accordance with the present invention. Compound 23, which is disclosed in U.S. Pat. No. 5,142,076 as exhibiting antiviral activity, is included as a comparison in the examples that follow.
In the following diagram, B is, in each case, methyl, and A, Y, X and Z
−
refer to those symbols as used in structure II.
COMPOUND
Y
X
Z
A
23
H
—NH
3
Cl
—CH
3
76
H
Br
—CH
3
82
H
Cl
CH
3
93
Cl
Br
—CH
3
96
H
Br
—CH
3
97
H
Br
—CH
3
98
H
Br
C
6
H
5
100
Cl
Br
—CH
3
101
Cl
Br
—CH
3
102
H
Cl
C
6
H
5
109
H
Cl
—CH
3
“Chlamydia” is used herein to mean any one or more of the bacteria in the genus chlamydia. The genus chlamydia includes the species
C. pneumoniae, C. psittaci
and
C. trachomatis.
The compositions used in the instant invention include a pharmaceutically acceptable carrier and a compound as defined above in a chlamydia prophylactic effective amount. As used herein, the expressions chlamydia prophylactic effective amount, dosage or regimen mean that amount, dosage or regimen which results in a sufficient concentration of the particular compound at an appropriate site to reduce the risk of infection by chlamydia. By appropriate site, it is meant a site which potentially contains chlamydia or is an area of a subject of potential exposure to chlamydia or is an area of a subject that has been exposed to chlamydia but as a result of such exposure, the subject has not yet acquired chlamydia disease. As used herein, the expression acquired chlamydia disease means that the subject, in fact, has the disease and can no longer be treated prophylactically to reduce the risk of infection by chlamydia, but, rather, must be treated therapeutically to cure, ameliorate or reduce the effects of the disease.
For topical administration, the inventive composition may be placed in a pharmaceutically acceptable aqueous solution, ointment, salve, cream or the like. The compounds used in the present invention are water soluble, although the degree of solubility may
Bourne Nigel
Stanberry Lawrence R.
Children's Hospital Medical Center
Reed Smith LLP
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