Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-21
2002-10-22
Jones, Dway C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S350000
Reexamination Certificate
active
06469033
ABSTRACT:
Infections of the skin are caused to a vast extent by skin-pathogenic bacteria or fungi. Their treatment—depending on the particular pathogen—is carried out either using antibacterial or using antimycotic agents.
Staphylococci and streptococci are a cause of bacterial infections of the skin in about 70% of all cases. Further important pathogens of bacterial skin infections which may be mentioned are Proteus sp. Other bacteria which grow under aerobic and anaerobic conditions, such as enterococci,
Escherichia coli, Pseudomonas aeruginosa
and Klebsiella come into question far less frequently as pathogens of skin infections.
Yeasts, on the other hand, have recently markedly gained in importance as pathogens of skin infections, in particular in immunosuppressed patients, in which the mucocutaneous and systemic spread of the yeasts can be a therapeutic problem.
Since bacteria as a rule have no noticeable keratinase activity, which is necessary for the start of an infection, fungal infections are frequently a starting point for the emergence of bacterial secondary infections.
The present invention therefore relates to substances which are suitable for the topical treatment both of fungal infections and of bacterial infections of the skin. Topical wide-spectrum antiinfectives according to the present invention were until now not available as monopreparations for the treatment of skin infections.
In the choice of agents for antibacterial therapy, inter alia, development of resistance must in particular be taken into consideration. Especially in the case of longer treatment, the pathogen spectrum should be determined by wound smears and its behavior checked with respect to the compositions used. Furthermore, note must be made of contact sensitivities and intolerability reactions. Especially in the case of neomycin and gentamycin, which have been used for many years in the treatment of skin infections, the danger of sensitization is high.
For staphylococcal infections of the skin, which are frequent everywhere, erythromycin and clindamycin are frequently also employed in addition to gentamycin. They are used both locally, mainly in acne therapy, and also systemically.
However, owing to systemic administration, which has been carried out for many years, therapy-resistant bacterial strains have developed both against gentamycin and against erythromycin and clindamycin to a great extent—even against modern gyrase inhibitors, such as, for example, ofloxacin. In a retrospective study, Th. Forssmann et al. (H+G Volume 69, Part 12, 1994, pp. 828-832) analyzed the antibiotic resistance of
Propionibacterium acnes
and
Staphylococcus epidermidis
in acne patients who were pretreated with antibiotics.
The investigations show that, with respect to Propionibacteria, resistances were found to erythromycin in 36% and to clindamycin in 11% of the cases. With
Staphylococcus epidermidis
, resistances were found to erythromycin in 90% and to clindamycin in 40% of the cases.
The increasing number of resistances of enterococci to gentamycin (up to 50% in isolates from various centers) gives reason to think particularly the same strains also are resistant to many other substances, including vancomycin (Martindale 30th Edition, 1993, pp. 171,2).
The same problem exists with gentamycin-resistant
Staphylococcus aureus
strains, which as a rule are also insensitive to methicillin and ofloxacin (Martindale 30th Edition, 1993, pp. 171,2 own investigations).
It is furthermore known from the literature that among the conventional antibiotics cross-resistances are developing to an increasing extent. Thus, inter alia, in the case of patients who were only pretreated with erythromycin, in 20% of the cases a resistance to clindamycin was also observed.
For the reasons outlined, it no longer applies as a therapeutic standard today also to employ topically antibiotics which are used systemically.
In the search for a new therapeutic standard for antibiotically active substances to be used topically, it has now surprisingly been found that substances from the 1-hydroxy-2-pyridone class, which until now have found their way into therapy exclusively as antimycotics, are also excellently suited for the topical treatment of bacterial skin infections.
In more recent experiments, it was possible, in particular, to show that 1-hydroxy-2-pyridones have an uninterrupted spectrum of action against the bacterial species occurring in skin infections, in particular also against antibiotic-resistant strains. In combination with the already-known antimycotic properties of the 1-hydroxy-2-pyridones, this is an extremely important finding for the successful treatment of skin infections, as the hitherto obligatory bacterial identification with subsequent resistance testing on treatment with the substances according to the invention is no longer necessary, which in the end also leads, inter alia, to a substantial reduction in the treatment costs.
The invention therefore relates to the use of 1-hydroxy-2-pyridones of the formula I
in which
R
1
, R
2
and R
3
, which are identical or different, are a hydrogen atom or alkyl having 1-4 carbon atoms, and
R
4
is a saturated hydrocarbon radical having 6 to 9 carbon atoms or a radical of the formula II
where
X is S or O,
Y is a hydrogen atom or up to 2 halogen atoms such as chlorine and/or bromine,
Z is a single bond or the divalent radicals O, S, —CR
2
(R=H or (C
1
-C
4
)-alkyl) or other divalent radicals having 2-10 carbon and optionally O and/or S atoms linked in the form of a chain, where—if the radicals contain 2 or more O and/or S atoms—the latter must be separated from one another by at least 2 carbon atoms and where 2 adjacent carbon atoms can also be linked to one another by a double bond and the free valencies of the carbon atoms are saturated by H and/or (C
1
-C
4
)-alkyl groups,
Ar is an aromatic ring system having up to two rings which can be substituted by up to three radicals from the group consisting of fluorine, chlorine, bromine, methoxy, (C
1
-C
4
)-alkyl, trifluoromethyl and trifluoromethoxy in free or in salt form,
for the production of a pharmaceutical for the topical treatment of skin infections which are caused by fungi and bacteria.
In the radicals “Z”, the carbon chain members are preferably CH
2
groups. If the CH
2
groups are substituted by C
1
-C
4
alkyl groups, CH
3
and C
2
H
5
are preferred substituents. Exemplary radicals “Z” are:
—O—, —S—, —CH
2
—, —(CH
2
)
m
— (m=2-10), —C(CH
3
)
2
—, —CH
2
O—, —OCH
2
—, —CH
2
S—, —SCH
2
—, —SCH(C
2
H
5
)—, —CH═CH—CH
2
O—, —O—CH
2
—CH═CH—CH
2
O—, —OCH
2
—CH
2
O—, —OCH
2
—CH
2
CH
2
O—, —SCH
2
CH
2
CH
2
S—, —SCH
2
CH
2
CH
2
CH
2
O—, —SCH
2
CH
2
OCH
2
CH
2
O—, —SCH
2
CH
2
OCH
2
CH
2
O—CH
2
CH
2
S— or —S—CH
2
—C(CH
3
)
2
—CH
2
—S—.
The radical “S” denotes a sulfur atom, the radical “O” denotes an oxygen atom. The term “Ar” denotes phenyl or condensed systems such as naphthyl, tetrahydronaphthyl and indenyl, and also isolated systems such as those which are derived from biphenyl, diphenylalkanes, diphenyl ethers and diphenyl thioethers.
In the formula I, the hydrocarbon radical R
4
is an alkyl or cyclohexyl radical which can also be bonded to the pyridone ring via a methylene or ethylene group or can contain an endomethyl group. R
4
can also be an aromatic radical which, however, is preferably bonded to the pyridone radical via at least one aliphatic carbon atom.
Important representatives of the class of compound characterized by the formula I are:
6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-[4-(2,4-dichlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-(biphenylyl-4-oxymethyl)-1-hydroxy-4-methyl-2-pyridone, 6-(4-benzyl-phenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, 6-[4-(2,4-dichlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, 6-[4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, 6-[4-(cinnamyloxy
Bohn Manfred
Kraemer Karl Theodor
Markus Astrid
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Jones Dway C.
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