Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-07-28
2004-12-28
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S313000, C514S473000
Reexamination Certificate
active
06835747
ABSTRACT:
BACKGROUND OF THE INVENTION
(1) Field of the Invention
This invention relates to novel FT-0554A substance useful for treatment for infection of parasite, especially helminth, and its production.
(2) Description of the Related Art
Parasitosis is reducing as a result of improvement in sanitary conditions and progress of anthelmintics. Recently, however, the import parasitosis, zoonotic parasitosis, opportunistic parasitosis and parasitosis originated from perishable foods are prevailing and become crucial problems. Further the parasitosis produces large economical burdens in the stock-farming and agriculture. For infection of helminth in the parasite, at present, avermectins, mebendazole, praziquantel, and others are used for treatment of helminth.
SUMMARY OF THE INVENTION
Anthelmintics used at present, such as avermectins, mebendazole and praziquantel, are not always sufficient for satisfactory in efficacy and toxicity, in addition, helminth which acquired resistance to the conventional anthelmintics is increasing, consequently novel drugs are strongly required.
We have studied NADH-fumarate reductase, which was one of the promising targets against anthelmintics, in the electron transport system of the helminth, and explored for the inhibitor of the NADH-fumarate reductase from the microbial culture. As a result, we have found that FT-0554 substance produced by a strain belonging, to genus
Aspergillus, Aspergillus niger
had NADH-fumarate reductase inhibitory activity, and had made international patent application (international publication no. WO99/24439).
The above described
Aspergillus niger
is described in Boris Schilling et al., “Amine oxidases from
Aspergillus niger
:identification of a novel flavin-dependent enzyme”, Biochimica et Biophysica Acta Vol. 1243 (1995) p. 529-537, and Yoshiharu Inoue et al., “Metabolism of 2-oxoaldehyde in mold. Purification and characterization of two methylglyoxal reductases from
Aspergillus niger
”, Eur. J. Biochem Vol. 171 (1988) p. 213-218.
As a result of our continued studies, we have found that novel FT-0554A substance derived from FT-0554 substance had also equivalent level of inhibitory activity of NADH-fumarate reductase, and completed the present invention.
Namely, the present invention relates to FT-0554A substance represented by the formula [I]:
or its tautomer of the formula [II]:
Further, the present invention relates to FT-0554A substance having the following physicochemical properties.
(1) Nature: white powder or amorphous
(2) Molecular weight: 383.2201 (M+Na, high resolution fast atom bombardment mass spectrometry)
(3) Molecular formula: C
22
H
32
O
4
(4) Melting point: 101-103° C.
(5) Specific rotation: [&agr;]
D
26
=+4.6° (c=1, chloroform)
(6) IR absorption maximum (KBr Tab): As shown in
FIG. 1
, maximum absorption at 3375, 2960, 2926, 1755, 1738, 1660, 1456, 1261, 1074, 1024, and 800 cm
−1
(7) Solubility in solvent: soluble in chloroform and ethyl acetate; insoluble in water and n-hexane,
(8) Color reaction: positive for phosphomolybdic acid reagent.
Further, the present invention relates to a process for production of FT-0554A substance of the formula [I]
or its tautomer of the formula [II]
wherein FT-0554 substance represented by the formula [III]
is treated by alkali.
The present invention further relates to NADH-fumarate reductase inhibitor comprising FT-0554A substance as an active ingredient.
Furthermore, the present invention relates to antihelminthic agent comprising FT-0554A substance as an active ingredient.
Detailes physicochemical properties of FT-0554A substance of the present invention are as follows.
(1) Nature: white powder or amorphous
(2) Molecular weight: 383.2201 (M÷Na, high resolution fast atom bombardment mass spectrometry)
(3) Molecular formula: C
22
H
32
O
4
(4) Melting point: 101-103° C.
(5) Specific rotation: [&agr;]
D
26
=+4.60° (c=1, chloroform)
(6) IR absorption maximum (KBr Tab): As shown in
FIG. 1
, maximum absorption at 3375, 2960, 2926, 1755, 1738, 1660, 1456, 1261, 1074, 1024, and 800 cm
−1
(7)
1
H-proton Nuclear Magnetic Resonance spectrum: chemical shift of FT-0554A substance [I] in deuteroacetone (ppm) is as follows.
s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, H: number of proton, J: coupling constant (Hz)
6.17 s (1H, H-3), 6.25 dd (1H, J=10.5, 15.1, H-7), 6.18 dd (1H, J=10.7, 15.1, H-14), 6.02 dd (1H, J=10.5, 15.4, H-8), 5.74 d (1H, J=10.7, H-13), 5.61 dd (1H, J=7.2, 15.4, H-9), 5.58 dd (1H, J=7.2, 15.1, H-6), 5.39 dd (1H, J=8.0, 15.1, H-15), 4.32 br.d (1H, J=4.0, 5-OH), 4.08 m (1H, H-5), 2.40 m (1H, H-10), 2.05 m (1H, Ha-11), 2.01 m (1H, H-16), 1.93 m (1H, Hb-11), 1.67 s (3H, 12-CH
3
), 1.32 s (3H, 4-CH
3
), 1.25 m (2H, H
2
-17), 0.93 d (3H, J=6.6, 16-CH
3
), 0.91 d (3H, J=6.9, 10-CH
3
), 0.80 t (3H, J=7.4, H
3
-18)
(8)
1
H-proton Nuclear Magnetic Resonance Spectrum: chemical shift of FT-0554A substance [II] in deuteroacetone (ppm) is as follows.
s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, H: number of proton, J: coupling constant (Hz)
6.34 dd (1H, J=10.5, 15.1, H-7), 6.18 dd (1H, J=10.7, 15.1, H-14), 6.05 dd (1H, J=10.5, 15.4, H-8), 5.74 d (1H, J=10.7, H-13), 5.67 dd (1H, J=7.2, 15.4, H-9), 5.61 dd (1H, J=7.2, 15.1, H-6), 5.39 dd (1H, J=8.0, 15.1, H-15), 5.11 br.d (1H, J=3.6, 5-OH), 4.22 m (1H, H-5), 2.88 d (1H, J=18.7, Ha-3), 2.55 d (1H, J=18.7, Hb-3), 2.40 m (1H, H-10), 2.05 m (1H, Ha-11), 2.01 m (1H, H-16), 1.93 m (1H, Hb-11) 1.67 s (3H, 12-CH
3
), 1.48 s (3H, 4-CH
3
), 1.25 m (2H, H
2
-17), 0.93 d (3H, J=6.6, 16-CH
3
), 0.91 d (3H, J=6.9, 10-CH
3
), 0.80 t (3H, J=7.4, H
3
-18)
(9)
13
C-Nuclear Magnetic Resonance spectrum: chemical shift of FT-0554A substance [I] in deuteroacetone (ppm) is as follows.
s: singlet, d; doublet, t: triplet, q: quartet
169.0 s (C-1), 141.4 d (C-9), 138.8 d (C-15), 134.74 s (C-12), 133.8 d (C-7), 130.0 d (C-6), 128.6 d (C-8), 127.7 d (C-13), 125.9 d (C-14), 121.5 d (C-3), 86.2 s (C-4), 76.6 d (C-5), 48.1 t (C-11), 39.3 d (C-16), 35.6 d (C-10), 30.4 t (C-17), 21.3 q (4-CH
3
), 20.5 q (16-CH
3
), 20.1 q (10-CH
3
), 16.5 q (12-CH
3
), 12.0 q (C-18), C2 cannot be identified.
(10)
13
C-Nuclear Magnetic Resonance spectrum: chemical shift of FT-0554A substance [II] in deuteroacetone (ppm) is as follows.
s: singlet, d: doublet, t: triplet, q: quartet
193.7 s (C-2), 161.5 s (C-1), 142.4 d (C-9), 138.9 d (C-15), 135.0 d (C-7), 134.66 s (C-12), 128.7 d (C-6), 128.3 d (C-8), 127.6 d (C-13) 125.9 d (C-14), 84.9 s (C-4), 77.0 d (C-5), 48.2 t (C-11), 40.6 d (C-3), 39.3 d (C-16), 35.5 d (C-10), 30.4 t (C-17), 23.3 q (4-CH
3
), 20.5 q (16-CH
3
), 20.0 q (10-CH
3
), 16.5 q (12-CH
3
), 12.0 q (C-18)
(11) Solubility in solvent: soluble in chloroform and ethyl acetate; hardly soluble in water and n hexane
(12) Color reaction: positive for phosphomolybdic acid reagent.
As a result of detailed examination of physico-chemical properties and spectra data of FT-0554A substance, FT-0554A substance is determined as the following chemical structure [I]:
or its tautomer of the formula [II]:
As shown in the above, physico-chemical properties of FT-0554A substance are described in detail, however no compound having identical properties has been reported. Consequently, FT-0554A substance is defined as novel substance.
Next, the production of FT-0554A substance of the present invention from FT-0554 substance is explained concretely.
A microorganism having FT-0554 substance producing activity belonging to
Aspergillus, Aspergillus niger
FT-0554 FERM BP-6443, disclosed in the international publication no. WO99/24439 is cultured in the medium, to accumulate FT-0554 substance in the cultured medium and to isolate FT-0554 substance r
Iwai Yuzuru
Nagamitsu Tohru
Omura Satoshi
Shiomi Kazuro
Sunazuka Toshiaki
Coppins Janet L
McKane Joseph K.
The Kitasato Institute
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