WO2004054509A2 - Tetracyclines as anti-fungal agents for treatment of ringworm - Google Patents

Abstract

The invention provides a method of inhibiting growth of a fungus that causes ringworm on a mammal in need thereof. In another embodiment, the invention provides a method of treating ringworm on a mammal in need thereof. The methods comprise contacting the ringworm on the mammal with an effective amount of a tetracycline compound.

Description

TETRACYCLINES AS ANTI-FUNGAL AGENTS FOR TREATMENT OF

RINGWORM

This application asserts the priority of U.S. Provisional Application No. 60/433,326 filed on December 13, 2002. The specification of U.S. Provisional Application No. 60/433,326 is hereby incorporated by reference.

BACKGROUND OF INVENTION

The invention relates to methods of inhibiting the growth of fungus, specifically fungi that causes ringworm. The method relates to the use of non- antibacterial tetracycline compounds for the inhibition of growth of a fungus that causes ringworm.

Certain tetracycline compounds, including tetracycline itself, as well as sporocycline, etc., are broad spectrum antibiotics, having utility against a wide variety of bacteria. The parent compound, tetracycline, has the following general structure:

Structure A

The numbering system for the multiple ring nucleus is as follows:

Structure B Tetracycline, as well as the 5-OH (terramycin) and 7-C1 (aureomycin) derivatives, exist in nature, and are all well known antibiotics. Semisynthetic derivatives such as 7-dimethylaminotetracycline (minocycline) and 6α-deoxy-5- hydroxytetracycline (doxycycline) are also known antibiotics. Natural tetracyclines may be modified without losing their antibiotic properties, although certain elements of the structure must be retained to do so.

A class of compounds has been defined wherein the compounds are structurally related to the antibiotic tetracyclines, but which have had their antibiotic activity substantially or completely expunged by chemical modification.

Modifications to the basic tetracycline structure have been reviewed by Mitscher (1978). According to Mitscher, modification at positions 5-9 of the tetracycline ring system can be made without causing the complete loss of antibiotic properties.

However, changes to the basic structure of the ring system, or replacement of substituents at positions 1 -4 or 10- 12, generally lead to synthetic tetracyclines with substantially less, or essentially no, antibacterial activity. For example, 4- de(dimethylamino)tetracycline is commonly considered to be a non-antibacterial tetracycline. These compounds, known as chemically-modified tetracyclines (CMTs), have been found to possess a number of interesting properties, such as the inhibition of excessive mammalian collagenolytic activity both in vitro and in vivo. See, for example, Golub et al. (1991).

It has been established that tetracyclines, which are rapidly absorbed and have a prolonged plasma half-life, exert biological effects independent of their antibacterial activity (Golub et al. 1991, Golub et al. 1992, Uitto et al. 1994). Such effects include inhibition of some, but not all, animal and human derived matrix metalloproteinases.

Studies have suggested that, in some systems, certain tetracyclines and inhibitors of metalloproteinases can inhibit tumor progression (DeClerck et al. 1994) or angiogenesis (WIPO publication WO 92/12717; Maragoudakis et al. 1994). Zucker et al. (1985) showed that minocycline can inhibit melanoma cell activity in vitro. Some tetracyclines may exhibit cytostatic effects against some tumors (Rroon et al. 1984; van den Bogert et al. 1986). Pro-gelatinase A (MMP-2) has been reported to be associated with tumor spread (Yu et al. 1997). 6-demethyl-6-deoxy-4- de(dimethylamino)tetracycline (CMT-3) has been shown to suppress prostate and melanoma tumor growth and metastasis in vivo (Lokeshwar et al. 1998; Seftor et al. 1998).

Ringworm is a contagious disease which is caused by a fungus. The infection is generally a topical infection which is typically characterized by ring-shaped discolored patches on the skin. Parts of the body which can be infected with ringworm include the head, feet, nails, skin, and hair. Depending on the part of the body that is infected, the infection can be referred to as Tinea capitϊs, Tinea corporis, Tinea pedis, or Tinea unguium.

Fungal growth is an important clinical problem, especially in patients whose immune system has been depressed. Liu et al. (Antimicro. Agents Chemo. 2002, 46: 1447) reported that chemically modified tetracycline (CMT)-3 is potent, in vitro, against filamentous fungi, including Microsporum canis, Trichophyton rubrum, Trichophyton mentagrophytes, and Trichophyton tonsurans. However there is no disclosure that CMT-3 is effective in vivo.

International application PCT/US01/17750 discloses the use of non- antibacterial tetracyclines to inhibit growth of fungus. However, there is no disclosure to treat fungi that cause ringworm.

There are relatively few anti-fungal drags presently available for clinical use. Additionally, fungi are developing resistance to the few anti-fungal agents approved for clinical use. Furthermore, most anti-fungal drugs presently available in clinics are much more toxic to mammals, such as humans, than antibacterial drugs. For example, amphotericin B may not only cause disorders of the digestion system, but also cause damage to the nervous system. Currently available anti-fungal agents are generally quite toxic and can cause side effects such as renal impairment, phlebitis, and gastrointestinal disturbance. Some anti-fungal agents, such as Nystatin™ are poorly absorbed by the gastrointestinal tract. Thus, there is a need for new and improved anti-ringworm agents.

SUMMARY OF THE INVENTION

The invention provides a method of inhibiting growth of a fungus that causes ringworm on a mammal in need thereof. The method comprises contacting the ringworm on the mammal with an effective amount of a tetracycline compound.

In another embodiment, the invention provides a method for treating ringworm on a mammal in need thereof. The method comprises contacting the ringworm on the mammal with an effective amount of a tetracycline compound.

DETAILED DESCRIPTION OF INVENTION

The present invention provides a method of inhibiting the growth of a fungus that causes ringworm. The method includes the administration of a tetracycline compound that is effective in inhibiting the growth of a fungus that causes ringworm, but has substantially no antibacterial activity.

The fungus can be any fungus which causes ringworm. Fungi which can cause ringworm include Microsporum spp., such as for example, Microsporum canis, and Trichophyton spp. , such as for example, Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.

Tetracycline compounds utilized in the method of the invention can inhibit the growth of more than one type of fungus. In addition, some tetracycline compounds inhibit the growth of some species of fungi more effectively than others. Accordingly, a single tetracycline compound or combination of tetracycline compounds can be administered to inhibit the growth of a plurality of fungi that causes ringworm. The tetracycline compound administered can be an antibacterial or non- antibacterial compound or a combination thereof. The tetracycline compound has the general structure indicated above.

Some examples of antibacterial tetracycline compounds include doxycycline, minocycline, tetracycline, oxytetracycline, chlortetracycline, demeclocycline, lymecycline and their pharmaceutically acceptable salts. Doxyclycline is preferably administered as its hyclate salt or as a hydrate, preferably monohydrate.

The antibacterial tetracycline compound is administered in an amount that is effective in reducing the growth of a fungus that causes ringworm, but does not significantly reduce the growth of bacteria.

For example, tetracycline compounds that have significant antibacterial activity may be administered in a sub-antibacterial amount, e.g., approximately 10- 80% of the antibacterial amount. In one preferred embodiment, the antibacterial tetracycline compound is administered in an amount which is approximately 10-50% of the antibacterial amount. In another preferred embodiment, the antibacterial tetracycline compound is administered in an amount which is approximately 40-70%ι of the antibacterial amount.

Some examples of antibacterial amounts of members of the tetracycline family include lOOmg/day of doxycycline, lOOmg/day of minocycline, 250mg of tetracycline four times a day, lOOOmg/day of oxytetracycline, 600mg/day of demeclocycline and 600mg/day of lymecycline.

In a preferred embodiment, a non-antibacterial tetracycline is administered. Non-antibacterial tetracycline compounds are structurally related to the antibacterial tetracyclines, but have had their antibiotic activity substantially or completely eliminated by chemical modification. Chemically modified tetracyclines are referred to herein as CMTs.

In one embodiment, for example, non-antibacterial tetracycline compounds are capable of achieving antibacterial activity comparable to that of tetracycline at concentrations at least about ten times, preferably at least about twenty five times, greater than that of tetracycline. In another embodiment, for example, non- antibacterial tetracycline compounds are capable of achieving antibacterial activity comparable to that of tetracycline at concentrations at least about ten times, preferably at least about twenty five times, greater than that of doxycycline.

Examples of chemically modified non-antibacterial tetracyclines (CMTs) include those that lack the dimethylamino group at position 4 of the tetracycline ring structure, e.g.,:

4-dedimethylaminotetracycline (CMT- 1 ),

6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3), 7-chloro-4-de(dimethylamino)tetracycline (CMT-4),

4-hydroxy-4-de(dimethylamino)tetracycline (CMT-6),

4-de(dimethylamino)- 12α-deoxytetracycline (CMT-7),

6-deoxy-5α-hydroxy-4-de(dimethylamino)tetracycline (CMT-8),

4-dedimethylamino- 12α-deoxyanhydrotetracycline (CMT-9), 7-dimethylamino-6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-

10),

4-dedimethylamino-5-oxytetracycline,

5α,6-anhydro-4-hydroxy-4-de(dimethylamino)tetracycline,

4-de(dimethylamino)- 11 -hydroxy- 12α-deoxytetracy cline, 12α-deoxy-4-deoxy-4-de(dimethylamino)tetracycline, and

12α,4α-anhydro-4-de(dimethylamino)tetr acycline .

Further examples of tetracyclines modified for reduced antibacterial activity include 6-α-benzylthiomethylenetetracycline, tl e mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracy cline, 1 lα-chlorotetracycline, tetracyclinonitrile (CMT-2), and tetracycline pyrazole (CMT-5).

The preferred chemically-modified tetracyclines include CMT-3, CMT-4, CMT-7 and CMT-8. CMT-3, CMT-7, and CMT-8 are most preferred.

Derivatives of CMTs as mentioned above can also be used. Derivatives of CMTs include any compound derived from a CMT. Combinations of tetracycline compounds, such as CMTs and/or their derivatives, can be used in the method of the invention. CMTs in combinbation with other tetracyclines and/or pharmaceutical compounds can also be employed.

For example, derivatives of CMT-3 include:

CMT-301 7-bromo-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-302 7-nitro-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-303 9-nitro-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-304 7-acetamido-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-305 9-acetamido-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-306 9-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-307 7-amino-6-de ethyl-6-deoxy-4-dedimethylaminotetracycline CMT-308 9-amino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-309 9-dimethylaminoacetamido-6-demethyl-6-deoxy-4-dedimet-hylaminotetracycline CMT-310 7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-311 9-palmitamide-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-312 2-CO-N]ΗCH₂-pyrrolidin-l-yl-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-313 2-CONHCH₂-ρiρeridin-l-yl-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-314 2-CONHCH₂-morpholin-l-yl-6-demethyl-6-deoxy-4-dedimethylaminotetracycline CMT-315 2-CONHCH₂-piperazin-l-yl-6-demethyl-6-deoxy-4-dedimethylaminotetracycline

Derivatives of CMT-8 include:

CMT-801 9-acetamido-4-dedimethylaminodoxycycline CMT-802 9-dimethylaminoacetamido-4-dedimethylaminodoxycycline CMT-803 9-palmitamide-4-dedimethylaminodoxycycline CMT-804 9-nitro-4-dedimethylaminodoxycycline CMT-805 9-anιino-4-dedimethylaminodoxycycline CMT-806 9-dimethylamino-4-dedi ethylaminodoxycycline CMT-807 2-CONHCH₂-pyrrolidin- 1 -yl-4-dedimethylaminodoxycycline CMT-808 2-CONHCH₂-ρiperidin- 1 -yl-4-dedimethylaminodoxycycline CMT-809 2-CONHCH₂-piperazin- 1 -yl-4-dedimethylaminodoxycycline

Derivatives of CMT- 10 include:

CMT- 1001 7-trimethylammonium-4-dedimethylaminosancycline CMT- 1002 9-nitro-4-dedimethylaminominocycline

Preferred derivatives are CMT-302, CMT-306, CMT-308 and CMT-315.

CMT-308 and CMT-315 are most preferred. Further examples of such CMT derivatives include the structures described in U.S. Appl. Serial No. 09/573,654 assigned to CollaGenex Pharmaceuticals, Inc. of Newtown, PA. The application, including all the compounds described therein ,are incorporated herein by reference in its entirety.

The tetracycline compounds administered can be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to non-toxic salts prepared from tetracycline compounds and pharmaceutically acceptable acids or bases. Such salts are formed by well known procedures.

Some examples of suitable salts include acid addition salts of basic tetracycline compounds or basic addition salts of acidic tetracycline compounds. Suitable acids may be inorganic acids, such as mineral acids, or organic acids. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, metaphosphoric, nitric and phosphoric acids. Suitable inorganic bases include sodium hydroxide and potassium hydroxide.

The radical of the organic acids may be aliphatic or aromatic. Some examples of organic acids include formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic, stearic, sulfanilic, alginic, tartaric, citric, gluconic, gulonic, arylsulfonic, and galacturonic acids. Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

The compounds described above are used to treat ringworm by inhibiting the growth of fungi that cause ringworm. The inhibition of fungal growth occurs over a wide range of concentrations.

The effective amount of tetracycline used according to the invention is an amount that effectively inhibits the growth of fungi that cause ringworm. An amount of tetracycline is effectively inhibitory to fungal growth if the amount significantly reduces fungal growth activity or fungal growth. Inhibition of fungal growth can also include the inhibition of the invasiveness of the fungus, for example, in mammalian tissue.

The minimal amount of tetracycline administered is the lowest amount capable of inhibiting or eliminating the growth of fungi that cause ringworm. CMTs exhibit their anti-fungal inhibitory properties at concentrations that lead to relatively few side effects, and in some cases are substantially free of side effects. In general, CMTs can be used at higher levels than antibacterial tetracyclines, while avoiding the disadvantages associated with antibacterial activity, such as the indiscriminate killing of beneficial bacteria, and the emergence of resistant bacteria which often accompanies the use of antibacterial compounds over prolonged periods of time.

The maximal amount of tetracycline administered is the highest dosage that does not cause undesirable or intolerable side effects. Such doses can be readily determined by those skilled in the art. For example, CMTs can be systemically administered in a mammal in an amount of from about 0. lmg/kg/day to about 60mg/kg/day, and preferably from about lmg/kg/day to about 18mg/kg/day. The practitioner is guided by skill and knowledge in the field, and the present invention includes, without limitation, dosages that are effective to achieve the desired anti- fungal activity.

Preferably, the CMT has a low phototoxicity, or is administered in an amount that results in a serum level at which the phototoxicity is acceptable. Phototoxicity is a chemically-induced photosensitivity. Such photosensitivity renders skin susceptible to damage, e.g. sunburn, blisters, accelerated aging, erythemas and eczematoid lesions, upon exposure to light, in particular ultraviolet light.

Phototoxicity can be evaluated in terms of a photoirritancy factor (PIF), as described in the examples. A PIF value of about 1.0 indicates that a compound is considered to have no measurable phototoxicity.

The low phototoxic derivatives preferably have PIF values no greater than about 5, preferably no greater than about 2, more preferably no greater than about 1.5, most preferably no greater than about 1.2, and optimally about 1. An example of a CMT having a low phototoxicity is CMT-8. The CMTs useful according to the invention possess a desirable but unusual combination of physicochemical properties, including activity, bioavailability, solubility, and reduction of side effects. These properties render the compounds particularly desirable for the inhibition of fungal growth activity in mammals. In addition, it is believed that the properties of hydrophilicity and hydrophobicity are well balanced in these compounds, enhancing their utility both in vitro and especially in vivo, while other compounds lacking such balance are of substantially less utility.

Specifically, the compounds have an appropriate degree of solubility in aqueous media to permit absorption and bioavailability in the body, while also having a degree of solubility in lipids to permit traversal of the cell membrane to a putative site of action. CMT-3, which is highly lipophilic, may be readily absorbed by tissues during topical administration. The compounds are maximally effective if they can be delivered to the site or region of the fungal growth activity.

In the treatment of certain localized conditions, the degree of hydrophilicity of the CMT can be of lesser importance. Such compounds as tetracyclinonitrile (CMT- 2) and 4-hydroxy-4-de(dimethylamino)tetracycline (CMT-6), which have low solubility in aqueous systems, can be used in direct or topical treatment of fungal growth. Animal experiments, in which adult rats are orally gavaged with these two CMTs, have shown no detectable blood levels of these compounds, indicating a lack of systemic absorption and/or extraordinarily rapid excretion.

Accordingly, a method of treating fungal growth in ringworm infection (i.e., treating ringworm) in a mammal in need thereof is specifically provided. The method includes administering to the living organism a tetracycline compound in an amount that is effective in inhibiting the growth of a fungus that causes ringworm. Preferably, the amount of tetracycline administered has substantially no antibacterial activity.

In a preferred embodiment, the tetracycline is a CMT. Preferred CMTs include CMT-3, CMT-4, CMT-7, CMT-8, CMT-302, CMT-306, CMT-308, and CMT-315. CMT-3, CMT-7, CMT-8, CMT-308, and CMT-315 are most preferred. Administration can be topical or systemic. Effective amounts can be readily determined by those skilled in the art. Mammals include, for example, humans, baboons and other primates, as well as pet animals such as dogs and cats, laboratory animals such as rats and mice, and farm animals such as horses, sheep, and cows. Humans are preferred.

The invention can also be practiced by including with the tetracycline compound one or more other therapeutic agents, such as any conventional anti-fungal agent. The combination of the tetracycline compound with such other agents can potentiate the therapeutic protocol. Numerous therapeutic protocols will present themselves in the mind of the skilled practitioner as being capable of incorporation into the method of the invention.

The preferred pharmaceutical composition for use in the method of the invention includes a combination of the tetracycline compound in a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art. Examples of carriers and excipients include starch, sugar, certain types of clay, gelatin, stearic acid or salts thereof, talc, vegetable fats or oils, and other oil-based vehicles such as petroleum jelly, gums and glycols.

The tetracycline compound may be administered to mammals by sustained release, as is known in the art. Sustained release administration is a method of drug delivery to achieve a certain level of the drug over a particular period of time. The level typically is measured by serum concentration. Further description of methods of delivering tetracycline compounds by sustained release can be found in U.S.

Application Serial No. 60/281,854 and assigned to CollaGenex Pharmaceuticals, Inc. of Newtown, Pennsylvania, which application is incorporated herein by reference in its entirety.

Systemic administration can be enteral or parenteral. Enteral administration is a preferred route of delivery of the tetracycline, and compositions including the tetracycline compound with appropriate diluents, carriers, and the like are readily formulated. Liquid or solid (e.g., tablets, gelatin capsules) formulations can be employed. Parenteral use (e.g., intravenous, intramuscular, subcutaneous injection) is also contemplated, and formulations using conventional diluents, carriers, etc., such as are known in the art can be employed to deliver the compound.

Alternatively, delivery of the tetracycline compound can include topical application. Compositions deemed to be suited for such topical use include as gels, salves, lotions, ointments and the like. In a preferred embodiment, the tetracycline compound is administered topically directly to the fungal infection on the mammal. Particular CMTs have only limited biodistribution, e.g. CMT-5. In such cases, topical administration is the preferred route of administration of the compound.

The appropriate dose of the tetracycline compound for topical administration can also be readily determined by those skilled in the art. For example, topical administration of CMTs in amounts of up to about 25% (w/w) in a vehicle can be administered without any toxicity in a human. Amounts from about 0.1 % to about 10% are preferred.

References

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Claims

What is claimed is:

1. A method of inhibiting growth of a fungus that causes ringworm on a mammal in need thereof comprising contacting the ringworm on the mammal with an effective amount of a tetracycline compound.

2. A method according to claim 1, wherein said fungus is selected from the group consisting of Microsporum species, Trichophyton species, and combinations thereof.

3. A method according to claim 1, wherein said tetracycline is an antibacterial tetracycline in a sub-antibacterial amount.

4. A method according to claim 1, wherein said tetracycline is a non- antibacterial tetracycline.

5. A method according to claim 4, wherein said non-antibacterial tetracycline is CMT-3.

6. A method according to claim 4, wherein said non-antibacterial tetracycline is CMT-308.

7. A method according to claim 1 , wherein said mammal is a human.

8. A method according to claim 1, wherein said administration is systemic.

9. A method according to claim 8, wherein said non-antibacterial tetracycline is administered in an amount from about 0.1 mg/kg/day to about 60 mg/kg/day.

10. A method according to claim 8, wherein said non-antibacterial tetracycline is administered in an amount from about 1 mg/kg/day to about 18 mg/kg/day.

11. A method according to claim 1, wherein the tetracycline is administered topically directly to the fungal infection on the mammal.

12. A method for treating ringworm on a mammal in need thereof comprising contacting the ringworm on the mammal with an effective amount of a tetracycline compound.

13. A method according to claim 12, wherein said fungus is selected from the group consisting of Microsporum species, Trichophyton species, and combinations thereof.

14. A method according to claim 12, wherein said tetracycline is an antibacterial tetracycline in a sub-antibacterial amount.

15. A method according to claim 12, wherein said tetracycline is a non- antibacterial tetracycline.

16. A method according to claim 15, wherein said non-antibacterial tetracycline is CMT-3.

17. A method according to claim 15, wherein said non-antibacterial tetracycline is CMT-308.

18. A method according to claim 12, wherein said mammal is a human.

19. A method according to claim 12, wherein said administration is systemic.

20. A method according to claim 19 wherein said non-antibacterial tetracycline is administered in an amount from about 0.1 mg/kg/day to about 60 mg/kg/day.

21. A method according to claim 19, wherein said non-antibacterial tetracycline is administered in an amount from about 1 mg/kg/day to about 18 mg/kg/day.

22. A method according to claim 12, wherein the tetracycline is administered topically directly to the fungal infection on the mammal.