AU1663401A - New use - Google Patents

Description

Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

*4 4 4 4*4*.4 4 4 *44* 4.

*4 4 4* Name of Applicant: Actual Inventors: Address for Service: Invention Title: Fujisawa Pharmaceutical Co., Ltd.

MATSUMOTO, Satoru; WAKAI, Yoshimi; OTOMO, Kazumi; TERATANI, Noriko; IKEDA, Fumiaki; NAKAI, Toru; HATANO, Kazuo; SHIOKAWA, Akiko; MORINAGA, Chizu; and NAKAOKA, Kyoko DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, Victoria 3000.

New Use Details of Associated Provisional Application: Nos: PQ5480/00 filed 7 February 2000 PQ8506/00 filed 30 June 2000 The following statement is a full description of this invention, including the best method of performing it known to us: -1- NEW USE TECHNICAL FIELD The present invention relates to a use of antifungal agents.

BACKGROUND ART In U.S. Pat. No. 5,376,634, U.S. Pat. No. 5,502,033, W096/11210, W099/40108, etc, there are disclosed the polypeptide compound and a pharmaceutically acceptable salt thereof, which have antimicrobial activities [especially, antifungal activities, in which the fungi may include Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, Fusarium and the like.] DISCLOSURE OF THE INVENTION The present invention relates to a use of lipopeptide compound for the prophylactic and/or therapeutic treatment of dermatophytosis trichophytosis), in a human being or an animal, and to a method for the prophylactic and/or therapeutic treatment of dermatophytosis trichophytosis), in a human being or an animal by using the lipopeptide compound SThe lipopeptide compound in the present invention can be described in the following.

oo* 2 R

OH

HO O H3C NH N \N NH-RI N 0 HO -O HN

OH

2 NH O CH 3 H2N 0 N- 3

O

R NH

OH

II OH O

HO-S-O

HO

[I]

Wherein R' is acyl group,

R

2 is hydrogen or hydroxy and

R

3 is hydrogen or hydroxy, 5 or a salt thereof.

Suitable salt of the lipopeptide compound is a pharmaceutically acceptable and conventional non-toxic salt, and may include a salt with a base or an acid addition salt 10 such as a salt with an inorganic base, for example, an alkali metal salt sodium salt, potassium salt, etc.), S* an alkaline earth metal salt calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine S 15 salt triethylamine salt, diisopropylethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt hydrochloride hydrobromide, sulfate, phosphate, etc.); an organic carboxylic sulfonic acid addition salt formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid arginine, aspartic acid, glutamic acid, etc.).

It is to be noted that the lipopeptide compound [I] may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all such isomer(s) and the mixture thereof are included within the scope of the present invention.

The lipopeptide compound or a salt thereof includes solvated compound enclosure compound hydrate, etc.)].

The lipopeptide compound or a salt thereof includes both its crystal form and non-crystal form.

It should be understood that the lipopeptide compound 20 in the present invention may include the prodrug form.

Suitable example of "acyl group" may include aliphatic Sacyl, aromatic acyl, arylaliphatic acyl and heterocyclicaliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like.

Suitable example of said "acyl group" may be illustrated as follows.

Aliphatic acyl such as lower or higher alkanoyl S 30 formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, t-butoxycarboflyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl methoxysulfonyl, ethoxysulfonyl, etc.); or the like; Aromatic acyl such as aroyl benzoyl, toluoyl, naphthoyl, etc.); aroyl which has one or more suitable substituent(s); ar(lower)alkanoyl phenyl(Cl-C 6 )alkanoyl phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(Cl-C 6 )alkaloyl naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(l6wer)alkenoyl phenyl(C 3

-C

6 )alkenoyl phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl, phenyihexenoyl, etc.), naphthyl (C 3

-C

6 )alkenoyl naphthylpropenoyl, 20 naphthylbutenoyl, etc.), etc.]; ar(lower)alkoxycarboflyl phenyl(Cl-C 6 )alkoxycarbonyl benzyloxycarbonyl, etc.), fluorenyl(Cl-C 6 )alkoxycarbonyl fluorenylmethyloxycarbolyl, etc.), etc.]; aryloxycarbonyl phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower)alkanoyl phenoxyacetyl, phenoxypropionyl, etc.); arylcarbamoyl phenylcarbamoyl, etc.); arylthiocarbamoyl phenylthiocarbamoyl, etc.); aryiglyoxyloyl phenylglyoxyloyl, naphthylglyoxyloyl, etc.) arylsulfonyl which may have 1 to 4 lower alkyl phenylsulfonyl, p-tolylsulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic(lower)alkenoyl heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like.

Among them, more preferred "acyl group" is aroyl which has one or more suitable substituent(s).

Suitable example of "suitable substituent(s)" in the term of "aroyl which has one or more suitable substituent(s)" may be heterocyclic group substituted with aryl having lower alkoxy, heterocyclic group substituted with aryl having lower alkoxy(lower)alkoxy, heterocyclic group substituted with aryl having lower alkoxy(higher)alkoxy, heterocyclic group substituted with aryl having cyclo(lower)alkyloxy, heterocyclic group 20 substituted with aryl having heterocyclic group, heterocyclic group substituted with cyclo(lower)alkyl having cyclo(lower)alkyl, heterocyclic group substituted with aryl having aryl substituted with lower alkoxy(lower)alkoxy, heterocyclic group substituted with aryl having heterocyclic group substituted with S* cyclo(lower)alkyl; in which the preferred one may be unsaturated 3 to 8membered heteromonocyclic group containing 1 to 2 oxygen oo atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having (C 4

-C

6 )alkoxy, unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having (C 4

-C

6 )alkoxy, unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having (C 1

-C

4 )alkoxy-

(C

4

-C

6 )alkoxy, unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having (C 1

-C

4 )alkoxy(C 7

C

14 )alkoxy, saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with phenyl having (C 1

-C

4 )alkoxy(C 7

-C

14 )alkoxy, unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having cyclo(C 4

-C

6 )alkyloxy, unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with cyclo(C 4

-C

6 )alkyl having cyclo(C 4

-C

6 )alkyl, unsaturated 3 to 8-membered :i heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having phenyl substituted with (C 1

-C

4 )alkoxy(C 1

-C

4 )alkoxy, unsaturated 3 to 8-membered heteromonocyclic group Scontaining 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having saturated 3 to 8membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with cyclo(C 4

-C

6 )alkyl, unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl having saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having cyclo(C 4

-C

6 )alkyl, etc.

Among them, the most preferred one may be isoxazolyl substituted with phenyl having pentyloxy, imidazothiadiazolyl substituted with phenyl having pentyloxy, thiadiazolyl substituted with phenyl having methoxyhexyloxy, thiadiazolyl substituted with phenyl having methoxyoctyloxy, thiadiazolyl substituted with phenyl having methoxyheptyloxy, imidazothiadiazolyl substituted with phenyl having cyclohexyloxy, imidazothiadiazolyl substituted with phenyl having dimethylmorpholino, piperazinyl substituted with phenyl having methoxyheptyloxy, piperazinyl substituted with phenyl having methoxyoctyloxy, piperazinyl substituted with cyclohexyl having cyclohexyl, thiadiazolyl substituted with phenyl having phenyl substituted with methoxyethoxy, thiadiazolyl substituted with phenyl having phenyl substituted with methoxybutoxy, thiadiazolyl substituted with phenyl having phenyl substituted with ethoxypropoxy, imidazothiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl, imidazothiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl.

The more suitable example of "acyl group" of R' may be S: benzoyl which has isoxazolyl substituted with phenyl having pentyloxy, benzoyl which has imidazolthiadiazolyl 20 substituted with phenyl having pentyloxy, benzoyl which has thiadiazolyl substituted with phenyl having methoxyhexyloxy, benzoyl which has thiadiazolyl substituted with phenyl having methoxyoctyloxy, benzoyl which has thiadiazolyl substituted with phenyl having methoxyheptyloxy, benzoyl which has imidazothiadiazolyl substituted with phenyl having cyclohexyloxy, benzoyl which has imidazothiadiazolyl substituted with phenyl having dimethylmorpholino, benzoyl which has piperazinyl substituted with phenyl having S methoxyheptyloxy, benzoyl which has piperazinyl substituted with phenyl having methoxyoctyloxy, benzoyl which has piperazinyl substituted with cyclohexyl having cyclohexyl, benzoyl which has thiadiazolyl substituted with phenyl having phenyl substituted with methoxyethoxy, benzoyl which has thiadiazolyl substituted with phenyl having phenyl substituted with methoxybutoxy, benzoyl which has thiadiazolyl substituted with phenyl having phenyl substituted with ethoxypropoxy, benzoyl which has imidazothiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl, benzoyl which has imidazothiadiazolyl substituted with phenyl having piperazinyl substituted with cyclohexyl.

The lipopeptide compound its preparation, its dosage, etc. are disclosed in U.S. Patent Nos. 5,376,634, 5,569,946, W096/11210 and W099/40108, the disclosures of which are incorporated herein by reference.

The lipopeptide compound has a strong antifungal activity against Trichophyton and Microsporum, and therefore are useful for the prevention or treatment of the various infectious diseases caused by Trichophyton and/or Microsporum, such as trichophytosis trichophytosis :barbae, trichophytosis capitis, trichophytosis, corporis, trichophytosis cruris, trichophytosis unguim, athlete's 20 foot and so on).

The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid 25 form, which contains the lipopeptide compound or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular; external (topical); oral administration; parenteral (including subcutaneous, intravenous and intramuscular) administrations; insufflation (including aerosols from metered dose inhalator); nebulizer; or dry powder inhalator.

The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsules, or suppositories; creams; ointments; aerosols; powders for insufflation; in a liquid form such as solutions, emulsions, or suspensions for injection; ingestion; syrup; eye drops; and any other form suitable for use. And, if necessary, there may be included in the above preparation auxiliary substance such as stabilizing, thickening, wetting, emulsifying and coloring agents; perfumes or buffer; or any other commonly may be used as additives.

The lipopeptide compound or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial effect upon the process S or condition of diseases.

For applying the composition to human, it is preferable to apply it by intravenous, intramuscular, pulmonary, oral administration, eye drop or insufflation.

While the dosage of therapeutically effective amount of the lipopeptide compound varies form and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily 25 dose of 0.01-20 mg of the lipopeptide compound per kg weight of human being in the case of intramuscular administration, a daily dose of 0.1-20 mg of the lipopeptide compound per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the lipopeptide compound per kg weight of human being is generally given for treating or preventing dermatophytosis caused by Trichophyton and/or Microsporum.

The invention is further described in connection with the following non-limiting examples.

EXAMPLE 1 In vitro antifungal activity of the lipopeptide compound was evaluated.

Test Compound (1) HO OH HO 0 o H3C

NH

N 0 -(CH2)4CH3 110 0O HN

OH

NH o cn 3 H2N 0 HO NH OH

O

OH 0 and/or Microsporum. Test compound was evaluated by the NaO-S-O

HO

Test Method 15 The broth microdilution method using RPMI medium ~(pH7.0) was used for each clinical isolate of Trichophvton and/or Microsporum. Test compound was evaluated by the broth microdilution method.

All tubes were examined macroscopically for growth and compared to a control (no drug). MIC was visually determined as the lowest concentration resulting in prominent decrease in turbidity compared to controls.

Test Result organism MIC (Ig/ml) Trichophyton rubrum FP1477 1 0.0078 Trichophyton mentagrophytes TIMM1189 0.0078 Microsporum gypseum ATCC14683 0.0078 Microsporum canis 7009 5 0.0078 From the result of example 1, antifungal activity of the lipopeptide compound against the Trichophyton and Microsiporum was confirmed. Therefore, the lipopeptide compound are useful for the prevention or treatment of the various infectious diseases caused by Tricholphyton and/or Microsporum, such as trichophytosis.

Additionally, the lipopeptide compounds was also confirmed to have the antifungal activity, particularly against the following fungi.

Acremonium; Absidia Absidia corymbifera, etc); Aspergillus Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus. Asrergillus nidulans, Aspergillus niger, Asperpillus terreus, Aspergillus versicolor, etc); Blastomyces Blastomyces dermatitidis, etc); Candida Candida albicans. Candida glabrata. Candida puilliermondii,Candida kefyr, Candida krusei,Candida parapsilosis, Candida stellatoidea, Candida tropicalis, Candida utilis.- etc.); Cladosporium Cladosporium trichoides, etc); Coccidioides Coccidioides immitis, etc); Cryptococcus Cryptococcus neoformans, etc); Cunninghamella Cunninghamella elegans, etc); Dermatophyte; Exophiala Exophiala dermatitidis, Exophiala spinifera, etc); Epidermophyton Epidermophyton floccosum, etc); Fonsecaea Fonsecaea pedrosoi, etc); Fusarium Fusarium solani, etc); Geotrichum Geotrichum candidlum, etc); Histoplasma Histoplasma capsulatum var. capsulatum, etc); Malassezia Malassezia furfur, etc); Mucor; Paracoccidioides Paracoccidioides brasiliensis,etc); Penicillium Penicillium marneffei, etc); Phialophora; Pneumocvstis Pneumocvstis carinii, etc); Pseudallescheria Pseudallescheria boydii, etc); Rhizopus Rhizolpus microsporus var. rhizopodiformis, Rhizopus oryzae, etc) 20 Saccharomyces Saccharornvces cerevisiae, etc); Scopulariopsis; Sporothrix Sporothrix schenckii, etc); Trichosporon Trichosporon asahii, Trichosporon cutaneun, etc).

The above fungi are well known to cause various infectious diseases in skin, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal protion, oral cavity, ophthalmus, systemic, kidney, bronchus, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, and so on.

13 Therefore, the lipopeptide compound is useful for preventing or treating various infectious diseases caused by various fungi described above, such as dermatophytosis, pityriasis versicolor, candidiasis, cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratitis, otomycosis, pneumocystosis, and so on.

Example 2 In vitro antifungal activities of the lipopeptide compound against various fungi were evaluated according to a similar manner to that of Example 1 by using Test Compound and were shown in the following.

Organism MIC (Pg/ml) Candida glabrata ATCC90030 0.02 Aspergillus fumiqatus TIMM0063 0.02 Asperqillus niaer ATCC6275 0.02 Aspergillus nidulans IFM5369 0.02 Aspergillus flavus ATCC9643 0.02 Aspergillus terreus IFM40852 0.02 Aspergillus versicolor IFM41406 0.02 Coccidioides immitis IFM4935 0.02 Example 3 In vivo antifungal activity of the lipopeptide 20 compound was evaluated.

Test Method Congenitally immunodeficient NIH-III mice (bg/bg-nu/nu) were induced oropharyngeal and esophageal Candidiasis by oral inoculation of 10' Candida albicans cells per day for 4 days. The mice were intravenously administered Test Compound or saline alone from day 13 after the initial

S

S

S

.5S* 5* S S

S

SS

inoculation through day 23 twice daily. The rapeutic effect was evaluated as reduction of colony counts. The mice were sacrificed on day 13 (saline group only) and 24 after the initial inoculation, and tongue, esophagus, stomach, and cecum were removed aseptically. The tissues were then homogenized in saline, and cultured in serial dilutions.

Test Results TABLE. Tissue colony counts in alimentary tract of C.

albicans orally infected mice Group mean Log CFU S. D.

Day 13 Day 24 Tongue Saline 4.90±0.42 5.01±0.25 Test Compound <1.00** mg/kg Esophagus Saline 3.40-±1.01 4.50±1.17 Test Compound <1.00** 5 mg/kg Stomach Saline 3.95±1.00 4.69-0.49 Test Compound <1.19±0.26** 5 mg/kg Cecum Saline 6.12±-0.45 6.12±0.20 Test Compound <2.14:0.31** 5 mg/kg Significantly different from saline control groups (p<0.05).

Significantly different from saline control groups (p<0.01).

From the results of the above Examples, it is confirmed that the lipopeptide compound is useful for the prevention or treatment of the various infectious diseases P:\OPER\MJC\fuji spec.doc-25/01/01 caused by those fungi, such as oropharyngeal Candidiasis and esophageal Candidiasis.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

It is intended that the above examples should be construed as illustrative and that the invention disclosed herein should be limited only by the following claims.

o

Claims (4)

1. A method for treatment or inhibition of the dermatophytosis caused by Trichophyton and/or Microsporum, which comprises administering an effective amount of a lipopeptide compound of the following formula: H3C NH-R 1 OH a a a a OH 0 a 10 *1 a. Wherein R' is acyl group, R 3 is hydrogen or hydroxy and R' is hydrogen or hydroxy, or a salt thereof. The method of Claim 1, wherein the dermatophytosis is trichophytosis. The method of Claim 1, wherein the lipopeptide compound is HO OH HO 0 O H3C NH 3C NH NI O-(CH2)4C-H3 O--N N 0 HO HN OH NH O= CH 3 H2N o- N OOH 0 OH 0 HO-S-O HO or a salt thereof. A pharmaceutical composition for the prophylactic and/or therapeutic treatment of the dermatophytosis caused by Trichophyton and/or Microsporum, which comprises the lipopeptide compound in claim 1 as an active ingredient. Use of the lipopeptide compound in claim 1 for the manufacture of medicament for preventing and/or treating the dermatophytosis caused by Trichophyton and/or Microsporum. a o ao a.o. a a a a a a. a a. P:\OPER\MJCfuji spc.doc-25/01/01 -18-

6. A commercial package comprising the pharmaceutical composition of claim 4 and a written matter associated therewith, wherein the written matter states that the pharmaceutical composition can or should be used for preventing or treating infectious disease.

7. A method according to claim 1 wherein the compound of formula is substantially is hereinbefore described with reference to any one of the examples.

8. A pharmaceutical composition of claim 4 wherein the compound of formula is substantially as hereinbefore described with reference to any one of the examples. 00* S