GB2306474A - Antifungal agent - Google Patents
Antifungal agent Download PDFInfo
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- GB2306474A GB2306474A GB9621972A GB9621972A GB2306474A GB 2306474 A GB2306474 A GB 2306474A GB 9621972 A GB9621972 A GB 9621972A GB 9621972 A GB9621972 A GB 9621972A GB 2306474 A GB2306474 A GB 2306474A
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- compound
- antifungal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Disclosed is a novel compound having the formula (I), the compound exhibits antifungal activity.
Description
TITLE OF THE INVENTION
ANTIFUNGAL AGENT
BACKGROUND OF THE INVENTION
The present invention relates to a novel antifungal compound, compositions and methods of use. The compound and compositions exhibit broad spectrum antifungal activity against both human and plant fungal pathogens. Clinical treatment of human fungal infections has relied mainly on two types of antifungal agents. These agents are amphotericin B, which is fungicidal and capable of curing fungal infections at the cost of severe side effects to the patient, and ketoconazole and other azole agents, which exhibit fewer side effects but are only fungi static.
Thus, there is a need for new human antifungal agents.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of the formula (I)
The compound has antimicrobial and fungicidal properties and may be useful for controlling systemic and superficial fungal infections in humans with fewer side effects than standard antifungal agents such as amphotericin B or ketoconazole.
The compounds are obtained by cultivation of an unidentified sterile fungus MF 6189 in the culture collection of Merck & Co., Inc., Rahway, N.J.
DETAILED DESCRIPTION OF THE INVENTION
The compound is colorless and characterized by the following spectral properties:
ULTRAVIOLET SPECTRAL DATA xmax(MeOH): 204 (e 15,036), 232(sh) ( 9,980), 299 (e 8,982) u INFRARED SPECTRAL DATA
Recorded as a thin film on ZnSe: 3265, 2934, 1769, 1703, 1645, 1290, 1134, 922 cm-l MASS SPECTRAL DATA
Mass spectra were recorded on a JEOL SX-102A (electron impact, EI, 90eV) mass spectrometer. Exact mass measurements were performed at high resolution (HR-EI) using perfluorokerosene (PFK) as the internal standard.
HR EI-MS Found: 665.3252
Calculated for C37H470 i gN 665.3200
NMR SPECTRAL DATA
NMR spectra were recorded in acetone-d6 at 500
MHz (lH) or 125 MHz (13C). Chemical shifts are reported downfield from TMS (tetramethylsilane) and spectra were referenced to the solvent peak (2.05 ppm for 1H spectra and 29.9 ppm for 13C spectra).
13C NMR SPECTRA 613C: 199.9(s), 178.6(s), 176.5(s), 171.3(s), 166.5(s), 165.9(s), 165.1(s), 148.7(d), 146.5(d), 140.0(s), 138.9(d), 137.0(s), 125.1(d), 118.6(t), 118.2(d), 108.5(s), 87.1(s), 53.8(s), 53.4(d), 52.0(d), 51.7(d), 44.43(d), 44.39(t), 43.45(d), 39.0(t), 36.9(d), 34.7(t), 32.6(t), 30.9(t), 30.8(t), 28.2(t), 27.8(t), 23.3(t), 20.5(q), 18.4(q), 14.3(q), 12.9(q) ppm 1H NMR SPECTRA 6 1H: 10.50 (br s; 1H), 9.71(br s; 1H), 8.49(br s; 1H), 7.24(dt; 15.8, 6.6; 1H), 6.95(dq; 15.2, 7.0; 1H), 6.49(dq; 15.2, 1.8; 1H), 6.41(dt; 15.8, 3.2; lH), 5.97(ddd; 17.1, 10.2, 10.2; lH), 5.17(dd; 10.2, 2.1; 1H), 5.12(dd; 17.1, 2.1; 1H), 4.84(br s; 1H), 4.69(d; 11.7; 1H), 3.23(d; 15.0; 1H), 2.77(d; 15.0; 1H), 2.69(br dd; 10.2, 10.2; 1H), 2.50(tt; 12.1, 3.3; 1H), 2.41(dd; 13.9, 7.7; 1H), 2.29(qdd; 7.3, 6.6, 3.2; 2H), 2.17(br d; 11.9; 1H), 1.99(br d; 14.4; 1H), 1.86(dud; 7.0, 1.8; 3H), 1.75(m; 2H), 1.60(m; 1H), 1.48(dd; 13.9, 10.8; 1H), 1.33(m; 1H), 1.32(m; 1H), 1.25(m; 1H), 1.22(m; 2H), 1.17(m; 1H), 1.16(m; 2H), 1.08(t; 7.3; 3H), 1.07(m; 1H), 1.02(d; 6.6; 3H), 0.97(m; 1H), 0.83(t; 7.1; 3H) ppm
The compound of this invention has antimicrobial properties and is especially useful as an antifungal agent against both filamentous fungi and yeasts.It is useful against organisms causing systemic human pathogenic mycotic infections such as Candida albicans,
Candida tropicalis, Candida guillermondii, Candida glabrata,
Cryptococcus neofromans, A spergillus fumigatus, Candida pseudotropicalis, Saccharomyces cerevisiae, Aspergillusflavus et al. It is also useful against organisms causing superficial fungal infections such as Trichoderma sp. and Candida sp. These properties may be effectively utilized by administering compositions containing an antifungal amount of the compound to an area, object or subject, on or in which fungi are to be controlled. Thus, compositions containing an antifungally effective amount of the compound and their use for the control of fungi are aspects of the present invention.An especially preferred aspect of the present invention are compositions in a pharmaceutically acceptable carrier and their use for the control of mycotic infections by administering a therapeutically effective amount of the compound.
The compound of the present invention is a natural product produced from a liquid fermentation of an unidentified sterile fungus
MF 6189 in the culture collection of Merck & Co., Inc., Rahway, NJ, which has been deposited under the Budapest Treaty in the culture collection of the American Type Culture Collection on November 29, 1995 at 12301 Parklawn Drive, Rockville, Md. 20852 and assigned accession number ATCC 74355.
The producing organism is an unidentified sterile fungus that was isolated from decaying leaves of Alnus sinuata (Betulaceae) collected near the Columbia Glacier, south central Alaska. The fungus was grown on a variety of mycological media, under different light regimes, and on sterilized leaves and filter paper but in all cases, it has failed to produce reproductive structures and thus cannot be identified.
In agar culture, colonies of the fungus exhibit the following morphology:
Colonies on oatmeal agar (Difco) at 25 C, 12 hr photoperiod, growing very slowly, attaining 9-10 mm in 14 days, with advancing zone submerged to appresed, undulating, with aerial mycelium scant to velvety or floccose, dull, azonate, at first translucent but soon white to pale gray, with surface and submerged hyphae becoming brown to brownish black, Pallid Mouse Gray, Mouse Gray,
Deep Mouse Gray, Hair Brown (capitalized color names from Ridgway,
R. 1912), with reverse dull gray, brown to blackish brown, exudates and odors absent.
Colonies on PDA agar (Difco) at 25 C, 12 hr photoperiod, growing slowly attaining i4-15 mm in 14 days, submerged to appressed at the margin, raised towards the center, with floccose aerial mycelium, azonate, translucent to white to gray, finally blackish brown, color as on oatmeal agar.
Colonies on YM agar (Difco) at 25 C, 12 hr photoperiod attaining 11-12 mm in 14 days, with margin submerged, fimbriate to irregularly undulating, velvety to floccose, azonate, white to pale gray, color essentially the same as on oatmeal agar. No growth at 37 C.
Hyphal cells are multinucleate when viewed by fluorescent staining with 4', 6'-diamidino-2-phenyindole (Sneh, Burpee & Ogoshi, 1991). The mycelium is composed of highly branched, simple septate, hyaline to dematiaceous hyphae characteristic of many ascomycetous fungi.
Sneh, B., Burpee, L. & Ogoshi, A. (1991). Identification of Rhizoctonia species. American Phytopathological Society: St. Paul.
Although the invention is discussed principally with respect to the specific strain, it is well known in the art that the properties of microorganisms can be varied naturally and artificially. Thus, all strains of the sterile fungus MF 61ras9, ATCC 74355 including varieties and mutants, whether obtained by natural selection, produced by the action of mutating agents such as ionizing radiation or ultraviolet irradiation, or by the action of chemical mutagens such as nitrosoguanidine, are contemplated to be within the scope of this invention.
The production of the compound may be carried out by cultivating the sterile fungus MF 6189, ATCC 74355 in a suitable nutrient medium under conditions described herein until a substantial amount of antifungal activity is detected in the fermentation broth, harvesting by extracting the active components from the mycelial growth with a suitable solvent, concentrating the solution containing the desired component, then subjecting the concentrated material to chromatographic separation to isolate the compound from other metabolites also present in the cultivation medium.
Broadly, the sources of carbon include glucose, fructose, mannose, maltose, galactose, mannitol and glycerol, other sugars and sugar alcohols, starches and other carbohydrates, or carbohydrate derivatives such as dextran, cerelose, as well as complex nutrients such as oat flour, corn meal, millet, corn and the like. The exact quantity of the carbon source which is utilized in the medium will depend, in part, upon the other ingredients in the medium, but it is usually found that an amount of carbohydrate between 0.5 and 15 percent by weight of the medium is satisfactory. These carbon sources can be used individually or several such carbon sources may be combined in the same medium.
Certain carbon sources are preferred as hereinafter set forth.
The sources of nitrogen include amino acids such as glycine, arginine, threonine, methionine and the like, ammonium salt, as well as complex sources such as yeast hydrolysates, yeast autolysates, yeast cells, tomato paste, soybean meal, casein hydrolysates, yeast extract, corn steep liquors, distillers solubles, cottonseed meal, meat extract, and the like. The various sources of nitrogen can be used alone or in combination in amounts ranging from 0.05 to 5 percent by weight of the medium.
Among the nutrient inorganic salts, which can be incorporated in the culture media are the customary salts capable of yielding sodium, potassium, magnesium, calcium, phosphate, sulfate, chloride, carbonate, and like ions. Also included are trace metals such as cobalt, manganese, iron, molybdenum, zinc, cadmium, and the like.
Representative suitable solid and liquid production media may be seen in the tables which follow. Also included is a representative seed medium. These, however, are merely illustrative of the wide variety of media which may be employed and are not intended to be limiting.
TABLE 1
KF SEED MEDIUM Trace Element Mix
per liter per liter
Corn Steep Liquor 5 g FeS047-H20 1 g
Tomato Paste 40 g MnSO44H2O 1 g
Oat flour 10 g CuCl22H2O 25 mg
Glucose 10 g CaC12 100 mg Trace Element Mix 10 ml H3BO3 56 mg (NH4)6Mo7024-4H20 19 mg pH=6.8 ZnSO47H2O 200 mg
TABLE 2 PRODUCTION MEDIUM CYS80
Component per liter
Sucrose 80 g
Corn Meal 50 g
(yellow)
Yeast Extract 1 g
No pH adjustment
TABLE 3
PRODUCTION MEDIUM MV8
Base Liquid per liter
Maltose 75.0 g V8 Juice 200 ml
Soy Flour 1.0 g
L-proline 3.0 g
MES* 16.2 g (*) - [2-(N-morpholino)ethanesulfonic acid] monohydrate
pH adjusted to 6.5 with NaOH
Of the foregoing media, the MV8 medium, was found to give the best yield of the compound. In the production of the compound, generally, the culture is first grown in a seed medium and the culture growth then used to inoculate a production medium. The production medium may be a solid medium or a liquid medium.
The culture was maintained in sterile soil and stored at 40C until ready for use. The seed culture was inoculated by aseptically transferring a small amount of the preserved soil into a 250 ml
Erlenmeyer flask containing 50 mls of seed medium of the following composition (in g/liter); corn steep liquor, 5.0; tomato paste, 40.0; oat flour, 10.0; glucose, 10.0; and trace elements solution, 10 mls/liter (consisting of, in g/liter: FeSO4 7H2O, 1.0; MnSO4.4H2O, 1.0; CuCl22H2O, 0.025; CaCl22H2O, 0.1; H3BO3, 0.056; (NH4)oMoO244H20, 0.019; ZnSO47H20, 0.2; dissolved in 0.6 adjusted N HCl).
Seed medium was prepared with distilled water, the pH was adjusted to 6.8 by adding NaOH and the medium dispensed into 250 ml Erlenmeyer flasks and capped with cotton plugs before being autoclaved at 121 C for 20 minutes. The seed culture was incubated at 250C on a gyrotory shaker (220 rpm, 5.1 cm throw) for 66 hours prior to the inoculation of fermentation flasks.
The MOVES production medium was prepared using distilled water; 50 mls medium was dispensed into 250 ml Erlenmeyer flasks that were capped with cotton plugs before being autoclaved at 1210C for 20 minutes. Production flasks were inoculated with 2.0 mls vegetative seed growth and were incubated at 250C, on a gyrotory shaker (220 rpm, 5.1 cm throw) for 14 to 17 days. After the incubation period, each production flask was extracted with 50.0 mls of methanol, shaken for 60 minutes, pooled and delivered for the isolation of active compounds.
The usefulness of the compound as an antifungal agent, especially as antimycotic agents, may be demonstrated with the compound in a broth microdilution assay for the determination of minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) against fungi. In such assay against a panel of fungi selected for their resistance/susceptibility to known compounds, animal virulence, source and clinical importance, the compound is found to be effective at concentrations comparable to an established antifungal agent, amphotericin B.
In the microbroth dilution assay, microorganisms were selected by streaking a yeast culture on Sabouraud dextrose agar (SDA) incubating for 24-48 hours at 35-37"C, thereafter selected 3 to 5 characteristic colonies and transferring to a fresh plate and incubating under similar conditions. From the regrowth, 3 to 5 colonies were selected and suspended in 10 milliliters of YM broth (Difco) and incubated for 4 hours at 35-370C shaking at 225 rpm. The 4 hour broth cultures were adjusted optically to 86% transmission resulting in a concentration of 1-5 X 106 cfu/ml which was further diluted 1:100 in
YNBD (yeast nitrogen base with 1 % dextrose) to obtain a concentration of 1-5 X 104 cfu/ml for use as inocula.
The test compound was dissolved at 512 ,ug/ml in 10%
DMSO and diluted 2X into the first well to achieve a concentration of 256 pg/ml at 5% DMSO in the first well. Compounds are subsequently serially diluted 2X and cell suspension is added to each well resulting in an additional 2X dilution of compound. 75 Ill of said solution is delivered to each well in column I of a 96-well, U-bottomed microtiter plate. The compounds in column 1 were then serially diluted two-fold to yield concentrations from 122is ,ug/ml to 0.06 Rg/ml.
Amphotericin B, the control compound, was prepared as a stock solution of 512 pg/ml in 10% DMSO and 75 pI of said solution delivered to column I of a 96-well, U-bottomed microtiter plate. The compounds in column 1 were then serially diluted two-fold to yield concentrations from 128 llg/ml to 0.06 ug/ml.
The plates containing the diluted compounds were then inoculated with 75 ,ul/well of the appropriate microorganism and incubated for 48 hours at 35-37"C with MIC (minimum inhibitory concentration) determinations carried out after 24 hours of incubation (except Cryptococcus strains which are read at 48 hours). Growth and sterility controls for each organism and sterility checks for the compounds also were carried out.
After recording MICs at 24 hours, the microtiter plates were shaken gently to resuspend the cells. A 1.5 ltl sample was transferred from each well of the 96-well microtiter plate to a single reservoir inoculum plate containing SDA. The inoculated SDA and corresponding microtiter plates were incubated for 24 hours at 3537 C. For Cryptococcus neoformans, SDA plates were inoculated at 48 hours after recording MICs and incubated 48 hours before reading the
MFC. MFC is the lowest concentration of compound at which either no growth or growth of < 4 colonies occur.
Minimum Fungicidal Concentration (MFC)
Minimum Inhibitorv Concentration (MIC) g/ml
Strain MIC MFC Candida albicans (MY 1055) 0.25 0.25 Candida iabrata(MY1381 4 4 Candida ara silosis (MY 1010) 0.25 Candida pseudorropicalis (MY2099) > 128 8 Candida tropicalis (MY1124) 1 4 Candida albicans (CLY539) 1 1 Candida albicans (CA2) 0.5 0.125 Candida tropicalis (MY1012) 0.5 0 25 Candida uillermondii (MY1019) 2 1 Cryptococcus neoformans 1 (MY2061) Cryptococcus neoformans 0.5 0.125 (MY2062) Saccharomyces cerevisiae (MY2 140) 8 Saccharoni cues evisiae (MY2141) As er illus umi atus (MY4839) 0.5 Aspergillus fumigatus (MY5668) 2 The compound is also useful for inhibiting the growth of filamentous fungi. Such use may be illustrated in the following tests with Aspergillus flavus, Fusarium oxysporum, Ustilago zeae and the like.
Inocula for filamentous fungi are prepared by scraping the surface of stock plates maintained on potato dextrose agar with a moistened sterile dacron swab. The spores and mycelia are then suspended in 10 milliliters of sterile potato dextrose broth and adjusted to 70 percent transmission at 660 nm.
The samples to be tested for production of antifungal agent are applied directly to the agar plates as methanol solutions. When the sample to be tested is crude broth, it may be centrifuged prior to application. The assay plates are then incubated at either 28"C or 37"C for 24 hours. Following incubation, the inhibition zones are measured.
Growths are also noted as to appearance. The compounds is seen to effectively inhibit growth of the fungal organisms.
In view of the broad spectrum of activity, the products of the present invention either singly or as a mixture are adaptable to being utilized in various applications of antifungal compositions. In such case, compounds may be admixed with a biologically inert carrier, generally with the aid of a surface active dispersing agent, the nature of which would vary depending on whether the use is for the control of pathogens infecting man or animals, or for control of fungi in agriculture such as in soil or plant parts, or for the control of fungi in inanimate objects.
In compositions for medical applications, the compounds may be admixed with a pharmaceutically acceptable carrier, the nature of which will depend on whether the composition is to be topical, parenteral or oral.
If said application is to be topical, the drug may be formulated in conventional creams and ointments such as white petrolatum, anhydrous lanolin, cetyl alcohol, cold cream, glyceryl monostearate, rose water and the like.
For parenteral applications, the compounds may be formulated in conventional parenteral solutions such as 0.85 percent sodium chloride or 5 percent dextrose in water, or other pharmaceutically acceptable compositions.
Compositions for oral administration may be prepared by mixing the component drugs with any of the usual pharmaceutical media, including for liquid preparations, liquid carriers such as water, glycols, oils, alcohols, and the like; and for solid preparations such as capsules and tablets, solid carriers such as starches, sugars, kaolin, ethyl cellulose, surface active dispersing agents, generally with lubricants such as calcium stearate, together with binders, disintegrating agents and the like.
These compositions are then administered in amounts sufficient to obtain the desired antifungal effect. For medical applications, the method comprises administering to a subject in need of treatment a therapeutically effective antifungal amount of the compounds. The appropriate dose will vary depending on age, severity, body weight and other conditions. For topical application, the compositions are applied directly to the area where control is desired.
For internal administration, the composition may be applied by injection or may be administered orally.
For non-medical application, the product of the present invention, either alone or as a mixture, may be employed in compositions in an inert carrier which included finely divided dry or liquid diluents, extenders, fillers, conditioners and excipients, including various clays, diatomaceous earth, talc, and the like or water and various organic liquids such as lower alkanols, such as ethanol and isopropanol, or kerosene, benzene, toluene and other petroleum distillate fractions or mixtures thereof.
The following example illustrates the invention but is not to be construed as limiting the invention disclosed herein.
EXAMPLE I
ISOLATION
The compound derived from an unclassified fungus, was received as a MEK-extracted whole broth sample (2000 ml wbe). The
MEK layer (2.1 g total solids; 40 mg/L of the compound by HPLC assay) was separated from the aqueous layer and concentrated in vacuo.
This material was then partitioned between equal volumes of EtOAc and 0.1 % aqueous TFA. The EtOAc layer (0.97 g), which contained all of the CAFKA activity, was subjected to reversed phase open column chromatography [75%v MeOH/25% H20, containing 0.1 % TFA (v/v);
Amicon Matrex Silica C-8, 100 , 20 Rm] followed by reversed phase
HPLC [Zorbax-RXC8 column; 9.4 X 250 mm; ambient temperature, 2 ml/min] employing 65% ACN/35% H2O, containing 0.1% TFA (v/v) as the mobile phase. The two reversed phase chromatography steps resulted in the production of 38.5 mg of pure compound for a 48% overall recovery (25X purification).
Compound I had the spectral properties previously described.
The following examples illustrate representative compositions containing Compound 1.
EXAMPLE A
1000 compressed tablets each containing 500 milligrams of
Compound I are prepared from the following formulation:
Grams
Compound 1 500
Starch 750
Dibasic calcium phosphate hydrous 5000
Calcium stearate 2.5
The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets.
EXAMPLE B
1000 hard gelatin capsules, each containing 500 milligrams of Compound I are prepared from the following formulation:
Compound 1 500
Starch 250
Lactose 750
Talc 250
Calcium stearate 10
A uniform mixture of the ingredients is prepared by blending and used to fill two-piece hard gelatin capsules.
EXAMPLE C
250 milliliters of an injectible solution are prepared by conventional procedures from the following formulation:
Dextrose 12.5 grams
Water 250 milliliters
Compound I 400 milligrams
The ingredients are blended and thereafter sterilized for use.
EXAMPLE D
An ointment suitable for topical application may be prepared by intimately dispersing 13 mg of Compound I in 1 g of commercially available polyethylenelhydrocarbon gel.
EXAMPLE E
An aerosol composition may be prepared having the
following formulation (per canister):
Compound I 24 mg
Lecithin NF, liquid concentrate 1.2 mg
Trichlorofluoromethane 4.025 g
Dichlorodefluoromethane 12.15 g
Claims (7)
1. A substantially pure compound having the structure:
2. An antifungal composition comprising an antifungal amount of the compound of Claim 1 in admixture with a biologically inert carrier or diluent.
3. A composition according to Claim 2 wherein the carrier is a pharmaceutically acceptable carrier.
4. A method for controlling fungal growth which comprises administering to the site where growth is to be controlled, an effective amount of the compound of Claim 1.
5. A method for combatting fungal infections in
mammals which comprises administering to a region of the animal
afflicted with said fungi a therapeutically effective amount of the
compound of Claim 1.
6. A process for producing the compound of Claim 1
which comprises aerobically cultivating a culture of ATCC 74355 in a nutrient medium containing assimilable sources of carbon and nitrogen and isolating said compound therefrom.
7. A biologically pure culture of fungus (ATCC 74355) capable of producing the compound of Claim 1 in recoverable amounts.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US808295P | 1995-10-30 | 1995-10-30 | |
US895495P | 1995-12-20 | 1995-12-20 | |
GBGB9603722.1A GB9603722D0 (en) | 1996-02-22 | 1996-02-22 | Antifungal |
Publications (2)
Publication Number | Publication Date |
---|---|
GB9621972D0 GB9621972D0 (en) | 1996-12-18 |
GB2306474A true GB2306474A (en) | 1997-05-07 |
Family
ID=27268140
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9621972A Withdrawn GB2306474A (en) | 1995-10-30 | 1996-10-22 | Antifungal agent |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2306474A (en) |
-
1996
- 1996-10-22 GB GB9621972A patent/GB2306474A/en not_active Withdrawn
Also Published As
Publication number | Publication date |
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GB9621972D0 (en) | 1996-12-18 |
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WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |