Compounds having antifungal activity

Details Compounds having antifungal activity Compounds having antifungal activity

2002-03-01

2004-11-16

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C435S071300, C530S317000

Reexamination Certificate

active

06818614

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds having antifungal activity; to a process for preparation of said compounds, comprising isolation of said compounds from the fermentation product of a microorganism producing said compounds; to medicaments containing said compounds as an active ingredient; to pharmaceutical compositions containing said compounds as an active ingredient; to therapeutic or prophylactic agents for fungal infectious diseases containing said compounds as an active ingredient; to a microorganism producing said compounds; to uses of said compounds; and to methods for treating or preventing fungal infectious diseases, comprising administering a pharmaceutically effective amount of said compounds to an animal.
2. Background Information
At the present time, amphotericin B, flucytosine and azole derivatives are clinically used as antifungal agents. Some of these compounds have begun become to exhibit some problems, such as the emergence of cytotoxicity, and of fungi resistant to these compounds.
It has been disclosed that some microorganisms produce antifungal compounds. For example, Zalerion genus produces pneumocandins (Schmatz, D. M., et al., J. Antibiotics 45, 1886(1992)),
Aspergillus
genus produces echinocandins (Nyfeler, R. and Keller-Schierlein, W., Helv. Chim. Acta 57, 2459(1974)) and
Aureobasidium
genus produces
aureobasidins
(Ikai, K., et al., J. Antibiotics, 44, 925(1991)). However, these have not been clinically used yet.
SUMMARY OF THE INVENTION
The inventors have found novel compounds having antifungal activity in fermentation products of a microorganism,
Phoma
sp. SANK 13899 strain, that was obtained from a soil sample collected in Chichi-island, Ogasawara-mura, Tokyo.
The present invention provides novel compounds having antifungal activity; a process for preparation of said compounds; medicaments containing said compounds as an active ingredient; pharmaceutical compositions containing said compounds as an active ingredient; therapeutic or prophylactic agents for fungal infectious diseases containing said compounds as an active ingredient; a microorganism producing said compounds; uses of said compounds; and methods for treating or preventing fungal infectious diseases comprising administering an effective amount of said compounds to an animal.
(1) The present invention includes a new antifungal compound of the following chemical structure (I), or a salt thereof.
(2) The present invention includes a compound having the following physicochemical properties, or a salt thereof:
1) Property: Basic liposoluble powder
2) Molecular formula: C
55
H
98
N
8
O
14
3) Molecular weight: 1094 (FAB-MS method)
4) High resolution FAB-MS [M+H]
+
calculated for C
55
H
99
N
8
O
14
1095.7281
found 1095.7365
5) Ultra violet absorption spectrum: End absorption
6) Infra red absorption spectrum (KBr pellet, cm
−1
): 3434, 3335, 2962, 2937, 2875, 2806, 1750, 1684, 1641, 1509, 1469, 1412, 1371, 1314, 1294, 1271, 1204, 1156, 1128, 1074, 1020
7) Optical rotation: [&agr;]
D
25
−120° (c 1.0, methanol)
8)
1
H NMR spectrum (in CDCl
3
, 500 MHz, &dgr; (ppm), internal standard: tetramethylsilane) 0.78(3H), 0.79(3H), 0.80(3H), 0.82(3H), 0.87(3H), 0.88(1H), 0.92(3H), 0.94(3H), 0.96(3H), 0.97(3H), 0.98(3H), 1.01(3H), 1.02(3H), 1.03(3H), 1.06(3H), 1.21(1H), 1.41(3H), 1.41(1H), 1.48(1H), 1.48(1H), 1.49(1H), 1.52(3H), 1.55(1H), 1.65(1H), 1.66(1H), 1.70(2H), 1.73(1H), 1.81(1H), 1.87(1H), 2.28(1H), 2.31(1H), 2.37(1H), 2.48(3H), 2.89(3H), 2.94(3H), 2.96(1H), 3.29(3H), 3.56(1H), 4.06(1H), 4.14(1H), 4.77(1H), 4.78(1H), 4.84(1H), 4.91(1H), 4.96(1H), 5.21(1H), 5.25(1H), 5.53(1H), 6.39(1H), 7.83(1H), 7.94(1H), 8.28(1H)
9)
13
C NMR spectrum (in CDCl
3
, 500 MHz, &dgr; (ppm), internal standard: tetramethylsilane): 10.9(q), 11.9(q), 15.0(q), 15.1(q), 16.0(q), 16.6(q), 17.4(q), 18.3(q), 18.6(q), 18.7(q), 19.1(q), 21.0(q), 21.4(q), 22.1(q), 23.1(q), 23.51(q), 23.54(q), 24.2(t), 24.6(d), 24.8(d), 25.4(d), 25.5(t), 27.7(d), 29.5(q), 29.8(d), 30.2(q), 36.1(q), 36.5(t), 37.7(t), 38.8(d), 38.4(d), 39.7(t), 40.9(q), 46.2(d), 51.8(d), 53.1(d), 54.7(d), 55.1(d), 63.9(d), 64.7(d), 68.1(d), 70.1(d), 73.4(d), 74.3(d), 77.1(d), 169.03(s), 169.04(s), 169.6(s), 169.8(s), 169.9(s), 170.3(s), 172.0(s), 173.4(s), 173.8(s), 174.0(s)
10) High performance liquid chromatography:
Column: SHODEX ASAHIPAK C8P 50 4E (4.6 mm (diameter)×250 mm (length); product of Showa Denko K.K.)
Mobile phase: acetonitrile: 10 mM aqueous ammonium
hydrogencarbonate solution=13:7
Flow rate: 0.7 ml/minute
Wavelength of detection: &lgr;210 nm
Retention time: 10.20 minutes
11) Solubility: Soluble in dimethylsulfoxide, methanol, and chloroform
12) Amino acid analysis: Threonine, alanine and isoleucine were detected from the hydrolysate.
(3) The present invention includes a new antifungal compound of the following chemical structure (II).
(4) The present invention includes a compound having the following physicochemical properties:
1) Property: Neutral liposoluble powder
2) Molecular formula: C
57
H
100
N
8
O
15
3) Molecular weight: 1136 (FAB-MS method)
4) High resolution FAB-MS [M+H]
+
calculated for C
57
H
101
N
8
O
15
1137.7387
found 1137.7410
5) Ultra violet absorption spectrum: End absorption
6) Infra red absorption spectrum (KBr pellet, cm
−1
): 3433, 3333, 2963, 2937, 2875, 1751, 1686, 1642, 1516, 1469, 1409, 1388, 1372, 1311, 1292, 1272, 1201, 1156, 1128, 1074, 1017
7) Optical rotation: [&agr;]
D
25
−131° (c 1.0, methanol)
8)
1
H NMR spectrum (in CDCl
3
, 500 MHz, &dgr; (ppm), internal standard: tetramethylsilane): 0.78(3H), 0.79(3H), 0.80(3H), 0.83(3H), 0.87(1H), 0.87(3H), 0.90(3H), 0.92(3H), 0.93(3H), 0.95(3H), 0.95(3H), 0.98(3H), 0.98(3H), 1.01(3H), 1.01(3H), 1.03(1H), 1.05(3H), 1.28(3H), 1.37(1H), 1.40(1H), 1.46(1H), 1.47(1H), 1.49(1H), 1.51(3H), 1.64(1H), 1.65(1H), 1.66(1H), 1.86(1H), 1.72(1H), 1.78(1H), 2.12(3H), 2.13(1H), 2.26(1H), 2.31(1H), 2.37(1H), 2.88(3H), 2.93(3H), 2.97(3H), 3.28(3H), 3.56(1H), 4.03(1H), 4.15(3H), 4.73(1H), 4.78(3H), 4.82(1H), 4.83(1H), 4.91(1H), 4.97(1H), 5.15(1H), 5.28(1H), 5.50(1H), 6.37(1H), 6.87(1H), 7.86(1H), 8.29(1H)
9)
13
C NMR spectrum (in CDCl
3
, 500 MHz, &dgr; (ppm), internal: tetramethylsilane): 10.5(q), 10.9(q), 14.9(q), 15.1(q), 15.6(q), 16.6(q), 16.7(q), 18.3(q), 18.7(q), 19.0(q), 20.8(q), 21.4(q), 22.0(q), 22.1(q), 23.1(q), 23.6(q), 23.6(q), 24.1(t), 24.6(t), 24.7(d) 24.8(d), 25.4(d), 27.7(d), 29.5(q), 29.8(d), 30.2(q), 31.6(d), 31.8(q), 36.1(t), 37.6(t), 38.4(d) 39.6(t), 40.9(q), 46.1(d), 51.8(d), 53.1(d), 54.7(d), 54.7(d), 61.2(d), 63.9(d), 64.6(d), 68.1(d) 73.1(d), 74.3(d), 77.0(d), 168.9(s), 168.9(s), 169.1(s), 169.9(s), 169.9(s), 170.3(s), 170.6(s), 171.7(s) 172.0(s), 173.3(s), 173.8(s)
10) High performance liquid chromatography:
Column: SHODEX ASAHIPAK C8P 50 4E (4.6 mm (diameter)×250 mm (length); product of Showa Denko K.K.)
Mobile phase: acetonitrile: 10 mM aqueous ammonium
hydrogencarbonate solution=13:7
Flow rate: 0.7 ml/minute
Wave length of detection: A 210 nm
Retention time: 9.05 minutes
(5) The present invention includes a process for preparing a compound according to any of (1) to (4), comprising fermentating a microorganism that belongs to
Phoma
genus and produces a compound according to any of (1) to (4), and isolating a compound according to any of (1) to (4) from the fermentation product of said microorganism.
(6) The present invention includes a process according to (5) wherein the microorganism that belongs to
Phoma
genus and produces a compound according to any of (1) to (4) is
Phoma
sp. SANK 13899 (FERM BP-6851) strain.
(7) The present invention includes a medicament containing a compound according to any of (1) to (4) or a salt thereof as an active ingredient.
(8) The present invention includes a therapeutic or prophylactic agent for fungal infectious diseases containing a compound according to any of (1) to (4) or a salt thereof as an active ingredient.
(9) The present inventio

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