Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-07-29
2004-09-07
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C514S690000, C424S049000, C424S401000
Reexamination Certificate
active
06787675
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related generally to tropolone compounds, more particularly to substituted tropolone compounds and compositions containing the same, and methods of using the same for oral care.
BACKGROUND OF THE INVENTION
Oral malodor, plaque, gingivitis, periodontal disease, and discoloration of the teeth, are all undesirable conditions that affect many people. First malodor of the oral cavity also known as halitosis or oral malodor has been broadly estimated to afflict 20 to 90 million individuals in the US. It is generally believed that the presence of anaerobic bacteria, especially gram-negative anaerobic bacteria, in the mouth contributes to this condition. Other oral conditions caused by microorganisms include periodontal disease, tooth decay, inflammation and the like.
Periodontal disease is a major cause of tooth loss in adults, and can manifest itself in people as young as age 12. Periodontal disease affects the periodontum, which is the investing and supporting tissues surrounding a tooth (i.e., the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontatitis are disorders of the gingiva and the deeper periodontal tissues, respectively. Periodontal disease is generally associated with the accumulation of plaque on the teeth. The teeth are coated with a salivary proteinaceous material (pellicle) and thereafter streptococci adhere to this coating. Gingivitis occurs from the dental plaque, and periodontatitis is caused by the infection spreading to the periodontal pocket or space between the gingival and the tooth root.
Many of the current oral care compositions including toothpastes, mouthwashes, rinses and tooth gels are formulated to clean the oral cavity and kill pathogenic microbes. Such oral care compositions are typically formulated with one or more antimicrobial agents to suppress microorganisms that contribute both to the initiation and progression of oral malodor, periodontal disease and other undesirable oral conditions. One such antimicrobial agent is hinokitiol, or beta-thujaplicin. Hinokitiol has been used as an antiseptic that exhibits low stimulative or irritative effects on the skin of the human body. However, hinokitiol is not very water-soluble, and is not sufficiently stable under all conditions in which its use is desirable. Compositions containing hinokitiol lose antimicrobial efficacy when exposed to air and light, and form hinokitiol precipitates on the walls of the container, thus further reducing the efficacy and usefulness of such compositions.
There is a need for developing efficacious oral care compositions such as mouthwashes or rinses, containing antimicrobial agents having favorable antimicrobial kinetics while exhibiting suitable chemical stability and solubility for effective delivery of the agents to the oral cavity. There is a need for compositions with enhanced antimicrobial kinetics to provide effective prevention or treatment of diseases and conditions of the oral cavity by killing pathogenic oral microorganisms responsible for plaque, gingivitis and other undesirable oral conditions.
SUMMARY OF THE INVENTION
There are provided novel compounds having antimicrobial properties that are especially effective for use in oral care products. In accordance with the present invention, tropolone compounds exhibiting such properties are disclosed. In one aspect of the present invention, there are provided compounds of Formula (I), isomers and pharmaceutically acceptable salts thereof,
wherein R
1
, R
2
, and R
3
are each independently selected from the group consisting of hydrogen, an alkyl group, a hydroxyalkyl group, and an alkoxyalkyl group, with the proviso that when R
2
and R
3
are each hydrogen, then R
1
is not isopropyl.
In a preferred embodiment, R
1
, R
2
, and R
3
are each independently selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, and an alkoxyalkyl group wherein the “alkoxy” portion and the “alkyl” portion each have from 1 to 6 carbon atoms.
In another aspect of the present invention, there is provided an oral care composition for preventing or treating diseases and conditions of the oral cavity, comprising an oral care effective amount of at least one of the compounds of Formula (I), and isomers and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable oral carrier.
In a further aspect of the present invention, there is provided a method for preventing or treating diseases and conditions of the oral cavity in warm-blooded animals including humans, comprising applying an oral care effective amount of the present oral care composition to the oral cavity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel tropolone compounds exhibiting effective antimicrobial properties suitable for use in oral care products. The present invention is further directed to oral care compositions including dentifrice, mouthwash or rinse, oral gel, lozenge, mouth spray, and the like, that comprise the novel tropolone compounds effective for cleaning the oral cavity and/or preventing or treating diseases or conditions of the oral cavity in warm-blooded animals including humans, including, but not limited to, gingivitis, periodontatitis, oral malodor, tooth decay and the like. The oral care compositions of the present invention provide a high degree of antiseptic efficacy against microorganisms, and particularly oral microorganisms, including, but not limited to,
Fusobacterium nucleatum, Prevotella intermedia, Actinomyces viscosus, Campylobacter rectus, Porphyromonas gingivalis, Streptococcus sanguis, Streptococcus mutans
, Actinobacillus, Bacteroides, Capnocytophaga, Eikenella, Propionibacterium, and
Candida albicans
responsible for oral malodor and build-up of plaque and calculus and the resulting tooth and gum diseases that may follow.
The present invention is also directed to methods of cleaning the oral cavity, and/or preventing or treating diseases or conditions of the oral cavity in warm-blooded animals including humans, by applying to the oral cavity, an oral care effective amount of the oral care composition containing the tropolone compounds of the present invention.
In one embodiment of the present invention, there are provided compounds of Formula (I), and isomers and pharmaceutically acceptable salts thereof,
wherein R
1
, R
2
, and R
3
are each independently selected from the group consisting of hydrogen, an alkyl group, a hydroxyalkyl group, and an alkoxyalkyl group, with the proviso that when R
2
and R
3
are each hydrogen, then R
1
is not isopropyl.
The term “alkyl”, “hydroxyalkyl”, and “alkoxyalkyl” cover all such groups exhibiting the desired oral activity. Preferably each of said groups has from about 1 to 6 atoms (i.e., the alkyl portion of the group has 1 to 6 carbon atoms and the alkoxy portion of the group has 1 to 6 carbon atoms).
The term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts which are derived from a variety of organic and inorganic cations well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and anions, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
Isomers of the compounds of Formula (I) having the desired antimicrobial activity mixtures thereof are included in the scope of the present invention.
In addition, hydrates and solvates with pharmaceutically acceptable organic solvents, as well as prodrugs of the compounds of the present invention are also encompassed by the present invention.
In addition, compounds of Formula (I) or pharmaceutically acceptable salts thereof may be present in the form of addition products with water or various solvents, and these addition products are also included in the scope of the present invention.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable n
Arvanitis Georgia
Berardini Michael
Finnegan Marybeth
Pan Pauline
Soshinsky Andre
Frederman Evan
Little Darryl
Richter Johann
Singleton Wilson Erika
Warner-Lambert & Company
LandOfFree
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