2-n-substituted or...

Details 2-n-substituted or... 2-n-substituted or...

2001-08-01

2003-08-26

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S323000, C514S328000, C546S200000, C546S242000, C546S244000

Reexamination Certificate

active

06610709

ABSTRACT:

This application is a 371 application of PCT/JP00/00572 filed Feb. 2, 2000.
TECHNICAL FIELD
This invention relates to a 2-N-substituted or unsubstituted-2-amino-5-methylpiperidine-3,4-diol which is a novel compound having an inhibitory activity against glycosidases, or pharmaceutically acceptable salts thereof. This invention also relates to a process for the preparation of such a novel compound. Furthermore, this invention relates to a novel glycosidase inhibitor consisting of such a novel compound. Moreover, this invention relates to a pharma-ceutical composition comprising as an active ingredient said 2-N-substituted or unsubstituted-2-amino-5-methylpiperidine-3,4-diol having an inhibitory activity against glycosidases. Besides, this invention includes an intermediate compound to be used for the synthesis of said novel compound.
BACKGROUND ART
Various glycosidases which are a glycoside hydrolase are an enzyme which is distributed widely in animal cells, microorganisms, viruses, and so on. In mammalian animals, it has been considered that glycosidases control a great variety of physiological mechanisms, including oncogenesis, metastasis of cancer cells, viral or bacterial infection, inflammation, immunological functions, fertilization of an ovum, and others, in which carbohydrate chains of glycoproteins and glycolipids can participate through the carbohydrate metabolism. Moreover, certain glycosidases participate in the digestive mechanism of food through the degradation of polysaccharides such as starch and sucrose, and oligosaccharides. Furthermore, it has been found that such a substance, which is inhibitory to glycosidases capable of liberating the carbohydrate chains bound to the surface of a cell membrane, is possible to have an immunomodulating action, an action of controlling inflammation and an action of controlling the metastasis of cancer cells, as well as an action of controlling infection of an AIDS virus or an influenza virus. Moreover, such substances that are inhibitory to glycosidases having catabolism which can participate in the digestive mechanism of food are found to be important, since they are useful as an antidiabetic agent or an agent for obesity.
Thus, in view that glycosidases are an enzyme which is important in the living body, it is also important to study physiological properties of glycosidases. In the study of the properties of glycosidases, use can be made of a substance having an action which inhibits the enzymatic activities of glycosidases. Moreover, it can be expected that certain glycosidase-inhibitory substances can be utilized as an inhibitor to the metastasis of cancer cells, and chronic articular rheumatism.
Therefore, it has been keenly demanded to provide such a novel compound which is of low toxicity, which is water-soluble and which has a potent inhibitory activity against glycosidases.
DISCLOURE OR INVENTION
It is an object of this invention to provide a novel compound having a potent inhibitory activity against glycosidases, and also to provide a novel glycosidase inhibitor. Moreover, it is another object of this invention to provide a process for the preparation of such a novel compound.
In order to achieve the above-mentioned objects of this invention, we, the present inventors, have paid attention to 1-N-iminosugars which are active as a glycosidase inhibitor, and we eagerly have made research about these 1-N-iminosugars. As a result, the present inventors have now succeeded in synthesizing several novel piperidine derivatives which have a potent inhibitory activity against glycosidases and which are represented by the general formula (I) given hereinafter. Moreover, the present inventors have now found a new preparation process which is able to synthesize efficiently the novel piperidine derivatives of the general formula (I). Based on these findings, the present inventors have completed this invention.
According to the first aspect of this invention, therefore, there is provided (2R,3S,4R,5R)-2-amino-5-methypiperidine-3,4-diol or a (2S,3S,4R,5R)-2-N-substituted-2-amino-5-methylpiperidine-3,4-diol represented by the general formula (I):
wherein R
1
and R
2
each are a hydrogen atom, or R
1
is a hydrogen atom and R
2
is a lower alkanoyl group or a lower &ohgr;-trihaloalkanoyl group, or R
1
and R
2
together denote a phthaloyl group, or a pharmaceutically acceptable salt thereof.
The salt of the compound of the general formula (I), which is provided according to the first aspect of this invention, includes acid addition salts at the imino group of the compound of the general formula (I). Such acid addition salts include, in particular, such pharmaceutically acceptable acid addition salts of said compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid and sulfuric acid or a pharmaceutically acceptable organic acid such as acetic acid, propionic acid, and the like.
In the compound of the general formula (I), the lower alkanoyl group or lower &ohgr;-trihaloalkanoyl group mentioned for the definition of R
2
is preferably acetyl group, trifluoroacetyl group or trichloroacetyl group, but generally may be the known lower alkanoyl groups or lower &ohgr;-trihaloalkanoyl groups which are conventionally used in chemistry of an amino sugar.
Examples of the compound of the general formula (I), which is provided according to the first aspect of this invention, include such compounds given in the following (1) to (5):
(1) (2S,3S,4R,5R)-2-acetamido-5-methylpiperidine-3,4-diol represented by the formula (Ia):
(2) (2S,3S,4R,5R)-2-trifluoroacetamido-5-methyl-piperidine-3,4-diol represented by the formula (Ib):
(3) (2S,3S,4R,5R)-2-trichloroacetamido-5-methyl-piperidine-3,4-diol represented by the formula (Ic):
(4) (2S,3S,4R,5R)-2-phthalimido-5-methylpiperidine-3,4-diol represented by the formula (Id):
and
(5) (2R,3S,4R,5R)-2-amino-5-methylpiperidine-3,4-diol represented by the formula (Ie):
Next, there are described the physicochemical properties of (2S,3S,4R,5R)-2-acetamido-5-methylpiperidine-3,4-diol of the formula (Ia), (2S,3S,4R,5R)-2-trifluoro-acetamido-5-methylpiperidine-3,4-diol of the formula (Ib), (2S,3S,4R,5R)-2-trichloroacetamido-5-methylpiperidine-3,4-diol of the formula (Ic), (2S,3S,4R,5R)-2-phthalimido-5-methylpiperidine-3,4-diol of the formula (Id) and (2R,3S,4R,5R)-2-amino-5-methylpiperidine-3,4-diol of the formula (Ie), among the compound of the general formula (I) which are provided according to the first aspect of this invention.
1. Hydrochloride of (2S,3S,4R,5R)-2-Acetamido-5-methylpiperidine-3,4-diol [the Compound of the Formula (Ia)]
Color and Appearance: Colorless amorphous solid; Molecular formula: C
8
H
16
N
2
O
3
.HCl; Specific rotation: [&agr;]
27
D
−32.3° (c 0.41, methanol);
1
H-NMR spectrum (CD
3
OD, &dgr; ppm): 1.05 (3H, d, J=6.8 Hz, —CH
3
), 1.95-2.06 (1H, m, H-5), 2.05 (3H, s, —NHCO
CH
3
), 2.92 (1H, dd, J=12.2 and 3.9 Hz, H-6eq), 3.05 (1H, br t, J=12.5 Hz, H-6ax), 3.72 (1H, dd, J=10.3 and 2.4 Hz, H-3), 3.84-3.87 (1H, m, H-4), 4.91 (1H, d, J=10.3 Hz, H-2); IR spectrum (KBr): 3325, 1660, 1460, 1400, 1140, 1060, 910 cm
−1
; Mass spectrum (FAB-MS): m/z 189.2 (M+H)
+
, 176.1, 154.1, 137.1, 120.1, 107, 89, 77.
2. Hydrochloride of (2S,3S,4R,5R)-2-Trifluoroacetamido-5-methylpiperidine-3,4-diol [the Compound of the Formula (Ib)]
Color and Appearance: Colorless amorphous solid; Molecular formula: C
8
H
13
N
2
O
3
F
3
.HCl; Specific rotation: [&agr;]
28
D
−42.3° (c 0.46, methanol);
1
H-NMR spectrum (CD
3
OD, &dgr; ppm): 1.06 (3H, d, J=6.8 Hz, —CH
3
), 1.95-2.06 (1H, m, H-5), 2.97 (1H, dd, J=12.2 and 4.4 Hz, H-6eq), 3.09 (1H, br t, J=12 Hz, H-6ax), 3.84 (1H, dd, J=10.3 and 2.4 Hz, H-3), 3.87-3.90 (1H, m, H-4), 4.99 (1H, d, J=10.3 Hz, H-2) IR spectrum (KBr): 3440, 3250, 2950, 2780, 1730, 1555, 1400, 1260, 1220, 1180, 1100, 990, 900 cm
−1
; Mass spectrum (FAB-MS): m/z 243.2 (M+H)
+
, 154.1, 137.1, 120.1, 107.1, 89, 77.
3. Hydrochlori

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