Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-21
2001-01-23
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S399000
Reexamination Certificate
active
06177458
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel isochroman compound or a pharmaceutical acceptable salt thereof, which is useful as an amyloid aggregation inhibitor and for treating Alzheimer's disease. Particularly, this invention relates to the new isochroman compound produced by fermentation of an fungus
Penicillium simplicissimum
, which has been deposited as FERM BP-6357. This invention also relates to processes for producing the isochroman compound, and to a pharmaceutical composition thereof.
BACKGROUND ART
Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by the accumulation of intracellular neurofibrillary tangles and extracellular deposition of amyloid fibrils. The principal component of the amyloid fibrils is the beta-amyloid (A&bgr;) peptide, which is derived from the amyloid precursor protein (APP). Drugs that prevent or retard assembly of the A&bgr; peptide into amyloid fibrils without non-specific disruption of protein—protein interactions are thought to arrest or slow the neurodegeneration and progressive cognitive decline in patients with AD by blocking amyloid plaque deposition.
This invention is directed to a novel isochroman compound and a salt thereof which is useful as an A&bgr; protein aggregation inhibitor and for treating Alzheimer's disease, and pharmaceutical compositions of the compound. Another object of the present invention is to provide processes for producing the isochroman compound.
C. J. Pike et al. suggest that the A&bgr; protein aggregation inhibitor is useful for treating Alzheimer's disease (European Journal of Pharmacology—Molecular Pharmacology Section, Vol. 207, pp. 367-368, 1991).
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides the isochroman compound of formula (I):
or a pharmaceutically acceptable salt thereof.
Another aspect of this invention is to provide a culture of
Penicillium simplicissimum
FERM BP-6357 which is capable of producing said isochroman compound.
Another aspect of this invention is to provide a process for producing above isochroman compound, which comprises cultivating a microorganism having the identifying characteristics of
Penicillium simplicissimum
FERM BP-6357, or a mutant or recombinant form thereof. The process may further comprises the subsequent step of isolating isochroman compound from the fermentation broth.
Another aspect of this invention is directed to a pharmaceutical composition for inhibiting A&bgr; protein aggregation and treating or preventing Alzheimer's disease, which comprises the isochroman compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Another aspect of this invention is directed to a method for inhibiting A&bgr; protein aggregation and for treating or preventing Alzheimer's disease, which comprises administering to a mammal including human in need of such treatment or prevention an amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The microorganism used in this invention is a strain of
Penicillium simplicissimum
which was isolated from a soil collected in Philippines. It was deposited on May 14, 1998 under the accession number FERM BP-6357 to National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology (located at 1-3 Higashi 1-chome, Tsukuba, Ibaraki 305, Japan) under the Budapest Treaty.
Culture Description/Characterization
The strain CL39461 was isolated from a soil sample collected in Philippines. It was three-spot inoculated from 3-weeks-old culture plates of potato dextrose agar onto plates of identification media and the plates were incubated at 5, 25, and 37° C. for one to two weeks. The results were read at one week for cultural characteristics unless indicated otherwise and at 14 days for temperature studies. The colors were determined by comparisons with color chips from
Color Standards and Color Nomenclature
by Robert Ridgway, 1912.
Identification media used for the characterization of the strain and references for their composition are as follows:
1. Cornmeal Agar: Carmichael, J. W. 1957. Mycologia 49: 820-830.
2. Czapek-Sucrose Agar: Raper, K. B. and D. I. Fennell. 1965. The Genus Aspergillus, the Williams & Wilkins, Baltimore, p. 36.
3. Malt Extract Agar: Ibid, p. 38.
4. Czapek Yeast Autolysate Agar: Pitt, J. I. 1979. Penicillium and Its Teleomorphic States Eupenicillium and Talaromyces, the Academic Press, New York, p. 18.
5. 25% Glycerol Nitrate Agar: Ibid.
6. Potato Dextrose Agar: ATCC medium #336, ATCC Media Handbook, 1984, p. 17.
7. V-8 Juice Agar: ATCC medium #343, Ibid.
8. Temperature Studies: malt extract agar.
Cultural Characteristics
25° C. Czapek Yeast Autolysate Agar—Colonies attaining 5.6 cm diam., white but pale olive-gray (LI) in some areas; raised, radiately wrinkled, velvety to lowly floccose, sporulation none to poor; reverse light buff to warm buff (XV); no soluble pigment.
25° C. Czapek Sucrose Agar—Colonies attaining 4.4 cm diam., white to off-white, becoming light olive-gray (LI) in 12 days, with radiating white strips; slightly raised, smooth, velvety to lowly floccose, no sporulation; reverse white to cream color (XVI); no soluble pigment.
25° C. Malt Extract Agar—Colonies attaining 4.5 cm diam., white to light celandine green to celandine green (XLVII), becoming pea green to artemisia green (XLVII) in 12 days; raised, smooth, floccose, sporulation poor to moderate; reverse pinard yellow (IV) to amber yellow (XVI) but colorless toward edge; no soluble pigment. 25° C., 25% Glycerol Nitrate Agar—Colonies attaining 2.3 cm diam., white; raised, radiately wrinkled, velvety to slightly lowly floccose, no sporulation; reverse warm buff, antimony yellow to yellow ocher (XV); no soluble pigment.
5° C. Czapek Yeast Autolysate Agar—Germination into microcolony.
37° C. Czapek Yeast Autolysate Agar—Colonies attaining 6.7 cm diam., white but pale olive-gray (LI) in some areas; raised, radiately wrinkled, velvety to lowly floccose, sporulation none to poor; reverse warm buff to ochraceous buff (XV); no soluble pigment.
25° C. Cornmeal Agar—Colonies attaining 4.5 cm diam., tea green to sage green (XLVII) at center but colorless toward edge, becoming vetiver green (XLVII) in 12 days; thin, submerged to velvety, smooth; sporulation good at the inoculation center, poor toward edge; reverse sage green (XLVII) to olive-gray (LI) at center but colorless toward edge; no soluble pigment.
25° C. Potato Dextrose Agar—Colonies attaining 4.3 cm diam., gnaphalium green to pea green (XLVII) but white toward edge, becoming slate-olive to andover green (XVII) in 12 days; raised, smooth, floccose, sporulation moderate to good; reverse razel (XIV) straw yellow to amber yellow (XVI) but colorless at edge; soluble pigment none to cream color (XVI).
25° C. V-8 Juice Agar—Colonies attaining 3.9 cm diam., tea green, pea green to sage green (XLVII), becoming light grayish olive (XLVI) in 12 days; moderately raised, radiately wrinkled, velvety to floccose, sporulation good to excellent; reverse garnet brown (I) to madder brown (XIII); no soluble pigment.
Morphological Properties
Morphological properties were observed on malt extract agar and Czapek yeast autolysate agar after 7 days of incubation. On malt extract agar conidiophores with walls roughened, varying in dimensions, ranging from 100 to 700 &mgr;m or longer by 1.5 to 3.0 &mgr;m wide in the larger structures to the very short 40-80×1.5-2.0 &mgr;m; penicilli characterized by long, divergent to loosely tangled chains of conidia, monoverticillate or biverticillate-divaricate, consisting of 2 to 4 divergent metulae bearing verticils of phialides; metulae with walls smooth or roughened, measuring 12-20×2-3 &mgr;m; phialides mostly in clusters of 4 to 8, measuring 8-11×2.0-2.5 &mgr;m; conidia globose to subglobose, sometimes oval to elliptical, measuring 2.5-3.2 (−3.5) &mgr;m diam. or 3.0-3.5 (−4.0)×(2.0−) 2.5-3.0 &mg
Hirai Hideo
Ichiba Toshio
Tonai Hiroko
Ginsburg Paul G.
Koller Alan L.
Owens Amelia
Pfizer Inc
Richardson Peter C.
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