1
DESCRIPTION
Oglycoside Derivatives and Salts Thereof
FIELD OF THE INVENTION
The present invention relates to C-glycoside derivatives and
salts thereof. More particularly, the present invention relates to
C-glycoside derivatives and salts thereof useful as a Na+-glucose
cotransporter inhibitor. Oglycoside derivatives and salts thereof
of the present invention are useful for treatment of various
diabetes-related diseases inclusive of insulin-dependent diabetes
(type 1 diabetes), insulin-independent diabetes (type 2 diabetes),
insulin-resistant diseases and obesity, and the prevention of these
diseases.
BACKGROUND OF THE INVENTION
In recent years, a medicine to inhibit glucose-reabsorption
by Na+-glucose cotransporters (SGLT) in the intestinal tract and
kidney (a Na+-glucose cotransporter inhibitor) has been demanded
as an antidiabetic agent to rapidly normalize hyperglycemia and
improve the energy balance in the body. Such a Na+-glucose
cotransporter inhibitor has been expected as an excellent agent for
treating or preventing various diabetes-related diseases such as
insulin-dependent diabetes (type 1 diabetes) and insulin-
independent diabetes (type 2 diabetes), as well as insulin-resistant
diseases and obesity.
As compounds used for the Na+-glucose cotransporter

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inhibitor, phloridzin described in Welch, C.A. et al. (J. Natr., 1989,
119(11) 1698) and synthetic Oglycoside derivatives described in
Hongu, M. et al. (Chem. Pharm. Bull., 1998, 46(1) 22) and
JP-A-11-21243 are known, for example. These compounds are
reported to discharge excess blood glucose into urine and reduce
blood glucose level by inhibiting glucose-reabsorption by
Na+-glucose cotransporters in the intestinal tract or in the kidney.
However, because any of these compounds is an O-glycoside
derivative comprising an O-glucoside bond formed between glucose
and an aglycon moiety, it has a problem that the inhibition effect is
reduced due to hydrolysis of Oglucoside bond by glucosidase or the
like in the small intestine when orally absorbed.
In addition, in the case of phloridin, phloretin, which is an
aglycon moiety of phloridin, is known as a strong inhibitor for a
facilitated diffusion-type glucose transporter. For example, it is
reported that the cerebral glucose concentration decreases when
phloretin is administered to the vein of a rat (e.g. Stroke, 1983, 14,
388). Phloretin is also known as an inhibitor of a vitamin C
transporter (Wang, Y. et al., Biochem. Biophys. Res. Commun., 2000,
267, 488-494).
Therefore, an attempt has been made to use a C-glycoside
prepared by converting oxygen in the glucoside bond of the
O-glycoside to carbon as the Na+-glucose cotransporter inhibitor.
For example, JP-A-2001-288178 (Patent Document l)
describes that compounds of the following formula are effective in
inhibiting Na+-glucose cotransporters and are useful as a treating
agent or preventing agent for diabetes and a hypoglycemic agent.

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(Chemical Formula)

wherein R1 represents H, OH, lower alkyl group, -Olower alkyl
group, or the like; R2 represents H, -COO-lower alkyl group, or the
like; R5 represents -CH2OH, -CH2OCOO-lower alkyl group, or the
like! Ai represents pyridine, furan, thiophene, quinoline, indole, or
the like; n is 0, 1, 2, or 3, and m is 0 or 1 (See Patent Document 1 for
further details on the symbols of the above formula).
In addition, the pamphlet of WO 01/27128 (Patent Document
2) describes that a compound of the following formula can be used
as the Na+-glucose cotransporter inhibitor to treat obesity or type 2
diabetes.
(Chemical Formula)

wherein R1, R2, and R2a individually represent a hydrogen atom,
OH, OR5, alkyl, CF3> OCHF2, OCF3, or the like; R3 and R4
individually represent a hydrogen atom, OH, OR5a, -O-aryl,

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-O-CBVaryl, alkyl, cycloalkyl, CF3, or the like; A represents O, S,
NH, or (CH2)n, and n is 0, 1, 2, or 3 (See Patent Document 2 for
further details on the symbols of the above formula).
As explained above, the C-glycoside derivatives are useful to
a certain extent for treating diabetes due to the effect of inhibiting
a Na+-glucose cotransporter. However, due to the recent rise in
incidence of diabetes which is a lifestyle-related disease and could
even be called one of the most popular diseases in Japan,
compounds having a chemical structure different from that of
known compounds and showing the effect of inhibiting Na+-glucose
cotransporters more rapidly and more significantly have been
increasingly desired for the clinical practice of diabetes treatment
or the like.
DISCLOSURE OF THE INVENTION
The present inventors have found that C-glycoside
derivatives, which have B ring ((l) a saturated or an unsaturated
eight to ten-membered bicyclic hetero ring having 1 to 4 hetero
atom(s) selected from N, S, and O, (2) a saturated or an
unsaturated five or six-membered monocyclic hetero ring having 1
to 4 hetero atom(s) selected from N, S, and O, (3) a saturated or an
unsaturated eight to ten-membered bicyclic hydrocarbon ring, or
(4) a benzene ring) bonded to A ring ((l) a benzene ring, (2) a five or
six-membered monocyclic heteroaryl ring having 1 to 4 hetero
atom(s) selected from N, S, and O, or (3) a saturated or an
unsaturated eight to ten-membered bicyclic hetero ring having 1 to
4 hetero atom(s) selected from N, S, and 0) via -X- (a bond or lower

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alkylene), with the A ring being directly bonded to a glucose residue
(wherein A ring, B ring, and X have a correlation that (l) when A
ring is a benzene ring, B ring is a ring other than a benzene ring or
that (2) when A ring is a benzene ring, and B ring is a saturated or
an unsaturated eight to ten-membered bicyclic hetero ring having 1
to 4 hetero atom(s) selected from N, S, and 0 including a benzene
ring, or a saturated or an unsaturated eight to ten-membered
bicyclic hydrocarbon ring including a benzene ring, X is bonded to
the B ring in a part other than the benzene ring included in the B
ring), shown by the following formula (I), has a significant effect of
inhibiting a Na+-glucose cotransporter, thereby the present
invention has been achieved. That is, the present invention
relates to compounds shown by the following formula (I) or salts
thereof (hereinafter both sometimes referred to as "compound of the
present invention"). The compound of the present invention can
be suitably used as a Na+-glucose cotransporter inhibitor using the
compound as an active ingredient, particularly as a therapeutic
agent or preventive agent for diabetes.
The chemical structure of the compound of the present
invention differs from those of Patent Documents 1 and 2 in that
the A ring and the B ring of the compound of the present invention
cannot be benzene rings at the same time. That is, the present
invention provides a Na+-glucose cotransporter inhibitor having a
new structure.
Specifically, the present invention provides C-glycoside
derivatives described bellow, pharmaceutically acceptable salts
thereof, pharmaceutical compositions containing these compounds,

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use of these compounds for producing a Na+-glucose cotransporter
inhibitor or an antidiabetic agent, and methods for treating
diabetes.
[l] C-glycoside derivatives of the following formula (I) and salts
thereof

wherein A ring represents (l) a benzene ring, (2) a five or
six-membered monocyclic heteroaryl ring having 1 to 4 hetero
atom(s) selected from N, S, and 0, or (3) a saturated or an
unsaturated eight to ten-memhered bicyclic hetero ring having 1 to
4 hetero atom(s) selected from N, S, and O;
B ring represents (l) a saturated or an unsaturated eight to
ten-membered bicyclic hetero ring having 1 to 4 hetero atom(s)
selected from N, S, and 0, (2) a saturated or an unsaturated five or
six-membered monocyclic hetero ring having 1 to 4 hetero atom(s)
selected from N, S, and O, (3) a saturated or an unsaturated eight
to ten-membered bicyclic hydrocarbon ring, or (4) a benzene ring;
X represents a bond or lower alkylene;
(wherein A ring, B ring, and X have a correlation that (l)
when A ring is a benzene ring, B ring is a ring other than a benzene
ring or that (2) when A ring is a benzene ring, and B ring is a
saturated or an unsaturated eight to ten-membered bicyclic hetero

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ring having 1 to 4 hetero atom(s) selected from N, S, and 0
including a benzene ring, or a saturated or an unsaturated eight to
ten-membered bicyclic hydrocarbon ring including a benzene ring,
X is bonded to the B ring in a part other than the benzene ring
included in the B ring: Incidentally, this correlation specifically
means that the A ring and the B ring cannot be benzene rings
simultaneously and that when the A ring is a benzene ring and the
B ring is benzofuran or indane, X is not a benzene ring constituting
a part of the B ring but bonds with a furan ring or a cyclopentane
ring.)
R1 to R4 individually represent a hydrogen atom, a lower
alkyl, -C(=O)-lower alkyl, or -lower alkylene-aryl; and
R5 to Ru individually represent a hydrogen atom, a lower
alkyl, a cycloalkyl, a halogen, a halogen-substituted lower alkyl, -OH,
=0, -NH2, lower alkyl sulfonyl-, halogen-substituted lower alkyl
sulfonyl-, aryl sulfonyl-, an aryl, a saturated or an unsaturated five
or six-membered monocyclic hetero ring having 1 to 4 hetero
atom(s) selected from N, S, and O, -lower alkylene-OH, -lower
alkylene-O-lower alkyl, -lower alkylene-O-C(:=O)-lower alkyl, -lower
alkylene-O-lower alkylene-COOH, -lower alkylene-O-lower
alkylene-C(=0)-01ower alkyl, -lower alkylene-NH2, -lower
alkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)2, -lower
alkylene-NH-C(=O)-lower alkyl, -COOH, -CN, -C(=0)-Olower alkyl,
-C(=O)-NH2) -C(=O)-NH-lower alkyl, -C(=0)-N(lower alkyl)2,
-0-lower alkyl, -O-cycloalkyl, -Olower alkylene-OH, -O-lower
alkylene-O-lower alkyl, -0-lower alkylene-COOH, -O-lower
alkylene-C(=O)-O-lower alkyl, -0-lower alkylene-C(=O)-NH2,

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-Olower alkylene-C(=O)-NH-lower alkyl, -O-lower
alkylene-C(=O)-N(lower alkyl)2,
-O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH2j
'O-lower alkylene-NH-lower alkyl, -O-lower alkylene-NQower
alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl,
-N(lower alkyl)2, -NH-SO2"lower alkyl,
-NH-S02-halogen-substituted lower alkyl, -NH-lower alkylene-OH,
-NH-C(=O)-lower alkyl, -NH-C(=O)-NH2, -NH-C(=O)-NH-lower
alkyl, -NH-C(=O)-N(lower alkyl)2, or , -NH-C(=O)-O-lower alkyl;
wherein -N(lower alkyl)2 in R5 to Ru includes the case of
being constituted by different lower alkyls besides the case of being
constituted by the same lower alkyl. -N(lower alkyl)2 includes, for
example, a methylethylamino group.
[2] C-Glycoside derivatives and the salts thereof according to the
above [l], wherein the A ring in the formula (I) is (l) a benzene ring
or (2) a five or six-membered monocyclic heteroaryl ring having 1 to
4 hetero atom(s) selected from N, S, and 0.
[3] OGlycoside derivatives and the salts thereof according to the
above [2], wherein the B ring in the formula (I) is (l) a saturated or
an unsaturated eight to ten-membered bicyclic hetero ring having 1
to 4 hetero atom(s) selected from N, S, and 0 or (2) a saturated or
an unsaturated five or six-membered monocyclic hetero ring having
1 to 4 hetero atom(s) selected from N, S, and O.
[4] OGlycoside derivatives and the salts thereof according to the
above [3], wherein the A ring in the formula (I) is a benzene ring
and the B ring is a saturated or an unsaturated eight to
ten-membered bicyclic hetero ring having 1 to 4 hetero atom(s)

9
selected from N, S, and 0.
[5] OGlycoside derivatives and the salts thereof according to the
above [4], wherein the X in the formula (I) is methylene.
[6] OGlycoside derivatives and the salts thereof according to the
above [5], wherein the R1 to R4 in the formula (I) are hydrogen
atoms.
[7] OGlycoside derivatives and the salts thereof according to the
above [l], wherein the Oglycoside derivative of the formula (I) is at
least one compound selected from the group consisting of
(IS)-1,5-anhydro-1-[3-(l-benzothiene-2-ylmethyl)phenyl-D-glucitol,
(lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-hydroxyphenyl
]-D-glucitol, (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-
methoxyphenyl]-D-glucitol, (lS)-1,5-anhydro-l-[5-(l-benzothiene-
2-ylmethyl)-2-(2-hydroxyethoxy)phenyl]-D-glucitol, (lS)-1,5-
anhydro- l-[5-(l -benzothiene-2-ylmethyl)-2-(methylamino)phenyl]-
D-glucitol, (lS)-l,5-anhydro-l-{5-(l-benzothiene-2-ylmethyl)-2-
[(2-hydroxyethoxy)amino]phenyl}-D-glucitol, (IS)- 1,5-anhydro
-l-[5-(l-benzothiene-2-ylmethyl)-4-methoxyphenyl]-D-glucitol,
(lS)-l,5-anhydro-l"[5-(l-benzothiene-2-ylmethyl) -4-chlorophenyl]
-D-glucitol, (IS)-1,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)
-4-fluorophenyl]-D-glucitol, (IS)- 1,5-anhydro-1-
[5-(l-benzothiene-2-ylmethyl)-2,4- dimethoxy phenyl]-D-glucitol,
(IS)-1,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-4-chloro
-2-methoxyphenyl]-D-glucitol, (lS)- 1,5-anhydro-1-[5-(l-benzo
thiene-2-ylmethyl)-4-chloro-2-hydroxyphenyl]-D-glucitol,
(IS)-1,5-anhydro-1-[5-(l-benzothiene-2-ylmethyl)-4-fluor 0-2-
hydroxyphenyl]-D-glucitol, and (lS)-l,5-anhydro-l-[5-

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(l-benzothiene-2-ylmethyl)-4-fluoro-2-methoxyphenyl]-D-glucitol.
[8] A pharmaceutical composition containing a Oglycoside
derivative or a salt thereof according to any one of the above [l] to
[7].
[9] A pharmaceutical composition according to the above [8],
wherein the composition is a Na+-glucose cotransporter inhibitor.
[10] A pharmaceutical composition according to the above [8],
wherein the composition is an antidiabetic agent,
[ll] Use of the C-glycoside derivatives and the salts thereof
according to any one of the above [l] to [7] for producing a
Na+-glucose cotransporter inhibitor or an antidiabetic agent.
[12] A method for treating diabetes comprising administering an
effective amount of the C-glycoside derivatives and the salts
thereof according to any one of the above [l] to [7] to a patient.
BEST MODE FOR CARRYING OUT THE INVENTION
The best mode for carrying out the present invention will
hereinbelow be described in detail.
Examples of "a five or six-membered monocyclic heteroaryl
ring having 1 to 4 hetero atom(s) selected from N, S, and 0" include
pyridine, pyrimidine, pyrazine, thiophene, pyrrole, furan, thiazole,
oxazole, imidazole, triazole, and tetrazole. Of these, pyridine,
thiophene, furan, and tetrazole are preferable.
Examples of "a saturated or an unsaturated eight to
ten-membered bicyclic hetero ring having 1 to 4 hetero atom(s)
selected from N, S, and 0" include benzofuran, benzothiophene,

11
indole, benzoxazole, benzothiazole, benzimidazole, quinoline,
isoquinoline, quinazoline, quinoxaline, and tetrahydroisoquinoline.
Of these, benzofuran, benzothiophene, benzoxazole, and
benzothiazole are preferable.
Examples of "a saturated or an unsaturated five or
six-membered monocyclic hetero ring having 1 to 4 hetero atom(s)
selected from N, S, and 0" include pyridine, pyrimidine, pyrazine,
thiophene, pyrrole, furan, thiazole, oxazole, imidazole, triazole,
tetrazole, morpholine, piperidine, pyrrolidine, and piperazine. Of
these, pyridine, thiophene, furan, tetrazole, morpholine, piperidine,
and pyrrolidine are preferable.
Examples of "a saturated or an unsaturated eight to
ten-membered bicyclic hydrocarbon ring" include indane, indene,
and tetrahydronaphthalene. Of these, indene is preferable.
In the definition of the formulas in this specification, "lower"
refers to a linear or branched carbon chain having 1-6 carbon atoms,
unless otherwise specified. Accordingly, examples of "a lower
alkyl" include linear or branched alkyls having 1-6 carbon atoms
such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, hexyl, and isohexyl. Of these, alkyls
having 1-3 carbon atoms are preferable, and a methyl and ethyl are
particularly preferable.
As "a lower alkylene", in addition to a methylene, ethylene,
propylene, and butylene, a branched lower alkylene may be used.
Of these, a methylene and ethylene are preferable.
Examples of "a cycloalkyl" include three to eight-membered
cycloalkyls. Of these, cyclopropyl, cyclobutyl, cyclopentyl, and

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cyclohexyl are preferable.
Examples of "a halogen atom" include fluorine atom, chlorine
atom, bromine atom, or iodine atom. Of these, fluorine atom,
chlorine atom, and bromine atom are preferable.
Examples of "a halogen-substituted lower alkyl" and "a
halogen-substituted lower alkylene" include a lower alkyl
substituted with the above halogen atom and a lower alkylene
substituted with the above halogen atom, respectively. Of these, a
lower alkyl and a lower alkylene substituted with one or more
fluorine atoms are particularly preferable.
"An aryl" refers to a monocyclic to tricyclic aromatic
hydrocarbon group having 6-14 carbon atoms. Examples of the
aryl include phenyl, naphthyl, anthranyl, and phenanthryl. Of
these, phenyl and naphthyl are preferable.
Examples of "a lower alkylene-aryl" include benzyl and
phenethyl.
Examples of "an acyl" include formyl, acetyl, propionyl,
butyryl, valeryl, and pivaloyl. Of these, acetyl is preferable.
In R5 to R11, "=O" means an oxo group. However, when A
ring or B ring is, for example, a pyridine ring, "=O" sometimes
means an oxopyridine ring, which is an N-oxide of a pyridine ring.
In addition, the compounds of the present invention includes
a mixture or isolated product of various stereoisomers such as a
tautomer and an optical isomer.
The compounds of the present invention may form an
acid-addition salt or, depending on the type of substituent, a salt
with a base. Specific examples of such a salt include an

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acid-addition salt with a mineral acid such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and
phosphoric acid; with an organic acid such as formic acid, acetic
acid, propionic acid, oxalic acid, malonic acid, succinic acid,
fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,
citric acid, methanesulfonic acid, and ethanesulfonic acid; or with
an acidic amino acid such as aspartic acid and glutamic acid; a salt
with an inorganic base such as sodium, potassium, magnesium,
calcium, and aluminum; with an organic base such as methylamine,
ethylamine, and ethanolamine; or with a basic amino acid such as
lysine and ornithine; and ammonium salts.
The compounds of the present invention further include
hydrates and various pharmaceutically acceptable solvates and
polymorphs.
Incidentally, as a matter of course, the compounds of the
present invention should not be limited to the compounds later
described in Examples, but include all the compounds of the above
formula (I) (Oglycoside derivatives) and the pharmaceutically
acceptable salts thereof.
Moreover, the compounds of the present invention include
what is called a prodrug, which are compounds being convertible to
compounds of the above formula (I) or salts thereof as a result of
the metabolism in the body. As a group for forming a prodrug of a
compound of the present invention, a group described in Prog. Med.
5- 2157-2161 (1985) or a group described in "Development of
Pharmaceuticals," vol. 7, Molecular Design, 163-198 (Hirokawa
Shoten, 1990) can be given.

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The compounds of the present invention (compounds shown
by the above formula (I) or pharmaceutically acceptable salts
thereof) can be produced by various known synthetic methods
utilizing characteristics based on the type of its basic structure or
substituent. In this case, from the viewpoint of production
technique, it may be effective to substitute the functional group
with a suitable protective group, that is, a group which can readily
be converted to the functional group, at the stage of a starting
material or intermediate, depending on the type of functional group.
Following this, the protective group is optionally removed to obtain
the target compound. Examples of such a functional group include
a hydroxyl group and a carboxyl group, and examples of a
protective group for these functional groups include protective
groups described in Greene and Wuts, "Protective Groups in
Organic Synthesis," Third Edition. These groups may be suitably
used according to the reaction conditions.
( Preparation Examples )
Examples of typical production processes of a compound of
the present invention will be hereinbelow described-
( Preparation Process 1 )
In Preparation Process 1 are carried out an addition reaction
with a halide (l) and an aldehyde derivative (2), followed by
reduction, an addition reaction with a lactone derivative (4),
followed by reduction to obtain a compound (I), and deprotecting
the compound (i) to obtain a compound (IJ), as shown in the
following formula.
( Reaction formula )

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wherein A ring, B ring, X, and R1 to Ru in the formula mean the
same things as the ones mentioned above .
The addition reaction with a halide (l) and an aldehyde
derivative (2) is carried out in the presence of an alkyl lithium
reagent such as n-butyl lithium, sec-butyl lithium, or t-butyl
lithium in a suitable solvent. Specific examples of the solvent
include ethers such as diethyl ether, tetrahydrofuran, and diglyme,
and the solvent is appropriately selected according to the type of
reaction substrate or the reaction conditions. The reaction
temperature is generally from about -100°C to about 180°C, and
preferably from about -80°C to about 30°C though it varies,
depending upon the type of starting material compounds, the
reaction conditions, or the like.
The subsequent reduction reaction is carried out in the
presence of an appropriate reducing agent and acid catalyst in a

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suitable solvent. Specific examples of the reducing agent include
triethylsilane, triisopropylsilane, and t-butyldimethylsilane.
Specific examples of the acid catalyst include boron
trifluoride-diethyl ether complex, trifluoroacetic acid, and
trimethylsilyl trifluoromethanesulfonate. Specific examples of
the solvent include haloalkyls such as chloroform, dichloromethane,
and 1,2-dichloroethane; ethers such as diethyl ether,
tetrahydrofuran, and diglyme,' acetonitrile; and a mixture of these
solvents; and the solvent is appropriately selected according to the
type of reaction substrate or the reaction conditions. The reaction
temperature is generally from about -100°C to about 180°C, and
preferably from about -40°C to about 20°C though it varies,
depending upon the type of starting material compounds, the
reaction conditions, or the like.
The subsequent addition reaction of a lactone derivative (4)
is carried out in the presence of an alkyl lithium reagent such as
n-butyl lithium, sec-butyl lithium, or t-butyl lithium in a suitable
solvent. Specific examples of the solvent include ethers such as
diethyl ether, tetrahydrofuran, and diglyme, and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is generally
from about -100°C to about 180°C, and preferably from about -80°C
to about 30°C though it varies, depending upon the type of starting
material compounds, the reaction conditions, or the like.
The subsequent reduction reaction is carried out in the same
manner as the above reduction reaction.
The deprotection is carried out in the presence of a metal

17
catalyst such as palladium/carbon, palladium hydroxide, or
platinum/carbon in a suitable solvent in a hydrogen atmosphere, or
in the presence of a Lewis acid in a suitable solvent. Specific
examples of the Lewis acid include boron trichloride, boron
tribromide, and aluminum trichloride. Specific examples of the
solvent include ethers such as tetrahydrofuran and dioxane; esters
such as ethyl acetate; alcohols such as methanol and ethanol;
acetonitrile; and a mixture of these solvents, and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is from about
-100°C to about 180°C, and preferably from about -40°C to about
20°C though it varies, depending upon the type of starting material
compounds, the reaction conditions, or the like.
( Preparation Process 2 )
In Preparation Process 2 are carried out an addition reaction
with an aldehyde derivative (5) and a halide (6), followed by
reduction, an addition reaction with a lactone derivative (4),
followed by reduction to obtain a compound (I), and deprotecting
the compound (I) to prepare a compound (I'), as shown in the
following formula.
( Reaction formula )

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wherein A ring, B ring, X, and R1 to R11 in the formula mean the
same things as the ones mentioned above .
The addition reaction with an aldehyde derivative (5) and a
halide (6) is carried out in a manner similar to that of the addition
reaction with a halide (l) and an aldehyde derivative (2).
The addition reaction may be carried alternatively by
reacting the compound (6) with the compound (5) in an appropriate
solvent, using a Grignard reagent prepared using a metal reagent
such as magnesium. Specific examples of the solvent include
ethers such as diethyl ether, tetrahydrofuran, and diglyme; and the
solvent is appropriately selected according to the type of reaction
substrate or the reaction conditions. The reaction temperature is
generally from about 0°C to about 180°C, and preferably from about
20°C to about 80°C though it varies, depending upon the type of
starting material compounds, the reaction conditions, or the like.
The subsequent reduction reaction is carried out in the same
manner as the reduction reaction in Preparation Process 1.

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The subsequent addition reaction of a lactone derivative (4)
is carried out in the same manner as the addition reaction of a
lactone derivative (4) in Preparation Process 1.
The subsequent reduction reaction is carried out in the same
manner as the reduction reaction in Preparation Process 1.
The deprotection is carried out in the same manner as the
deprotection in Preparation Process 1.
( Preparation Process 3 )
In Preparation Process 3 are carried out a substitution
reaction in an appropriate solvent with a compound (8) and a
compound (9), followed by alkylation by halide (ll) to obtain a
compound (I), and deprotecting the compound (I) to obtain a
compound (I').
( Reaction Formula )

wherein A ring, B ring, X, and R1 to Ru in the formula mean the

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same things as the ones mentioned above , and Y is a group to be
eliminated. Examples of the group to be eliminated are halide,
acetoxy, trifluoroacetoxy, and trifluoromethanesulfoxy.
The substitution reaction is carried out in an appropriate
solvent in the presence of an appropriate Grignard reagent.
Specific examples of the Grignard reagent include
methylmagnesium chloride, ethylmagnesium bromide, and
isopropylmagnesium chloride. Specific examples of the solvent
include ethers such as diethyl ether, tetrahydrofuran, and diglyme!
benzene; and a mixture of these solvents! and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is generally
from about 0°C to about 180°C, and preferably from about 20°C to
about 80°C though it varies, depending upon the type of starting
material compounds, the reaction conditions, or the like.
The alkylation is carried out in the presence of an
appropriate base. Specific examples of the base include potassium
hydroxide; sodium hydroxide; and Grignard reagents include ethers
such as methylmagnesium chloride, ethylmagnesium bromide, and
isopropylmagnesium chloride. Specific examples of the solvent
include ethers such as diethyl ether, tetrahydrofuran, and diglyme;
benzene; and a mixture of these solvents; and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is generally
from about 0°C to about 180°C, and preferably from about 20°C to
about 80°C though it varies, depending upon the type of starting
material compounds, the reaction conditions, or the like.

21
The deprotection is carried out in the same manner as the
deprotection in Preparation Process 1.
( Preparation Process 4 )
In Preparation Process 4 are carried out protection of an
alcohol (12), followed by an addition reaction with a lactone
derivative (4), reduction, followed by deprotection to obtain a
compound (13), which is then subjected to oxidation and an addition
reaction with a compound (15), followed by reduction to obtain a
compound (I), and deprotecting the compound (I) to prepare a
compound (IJ).
( Reaction formula )

wherein A ring, B ring, X, and R1 to R11 in the formula mean the

22
same things as the ones mentioned above , and Y and Z are halogen
or hydrogen.
The alcohol (12) is protected according to a general manner
with, for example, an appropriate protecting group such as
tert-butyldimethylsilyl group, tert-butyldiphenylsilil group, and
tetrahydropyranyl group. Then, the addition reaction with a
lactone derivative (4) is carried out in an appropriate solvent in the
present of an alkyllithium reagent such as n-butyllithium,
sec-butyllithium, and tert-butyllithium. Specific examples of the
solvent include ethers such as diethyl ether, tetrahydrofuran, and
diglyme; and the solvent is appropriately selected according to the
type of reaction substrate or the reaction conditions. The reaction
temperature is generally from about -1OO°C to about 180°C, and
preferably from about -80°C to about 30°C though it varies,
depending upon the type of starting material compounds, the
reaction conditions, or the like.
The subsequent reduction reaction is carried out in the same
manner as the reduction reaction shown in Preparation Process 1.
The subsequent deprotection is carried out in an appropriate
solvent in the presence of an appropriate catalyst. Examples of
the catalyst include tetrabutylammoniumfluoride, boron trifluoride
ethylether complex, hydrogen fluoride, acetic acid, and
p-toluenesulfonic acid. Examples of the solvent include ethers
such as tetrahydrofuran and dioxaneJ alcohols such as methanol
and ethanol; water; and a mixture of these solvents; and the solvent
is appropriately selected according to the type of reaction substrate
or the reaction conditions. The reaction temperature is generally

23
from about -100°C to about 180°C, and preferably from about 20°C
to about 80°C though it varies, depending upon the type of starting
material compounds, the reaction conditions, or the like.
The subsequent oxidation is carried out in a solvent in the
presence of an appropriate oxidizing agent. Specific examples of
the oxidizing agent include manganese dioxide, hydrogen peroxide,
and pyridinium chlorochromate. Specific examples of the solvent
include ethers such as tetrahydrofuran and dioxaneJ haloalkyls
such as chloroform, dichloromethane, and 1,2-dichloroethaneJ and a
mixture of these solvents; and the solvent is appropriately selected
according to the type of reaction substrate or the reaction
conditions. The reaction temperature is generally from about
■100°C to about 180°C, and preferably from about 20°C to about
80°C though it varies, depending upon the type of starting material
compounds, the reaction conditions, or the like.
The subsequent addition reaction is carried out in the same
manner as the addition reaction of a halide (l) and an aldehyde
derivative (2) shown in Preparation Process (l).
The subsequent reduction reaction is carried out in the same
manner as the reduction reaction shown in Preparation Process 1.
The deprotection is carried out in the same manner as the
deprotection in Preparation Process 1.
( Preparation Process 5 )
In Preparation Process 5, a compound (16) alone or a
compound (16) and a metal are reacted to prepare a metal reagent,
which is reacted with a compound (17) in the present of a palladium
catalyst and, as necessary, an appropriate phosphine to obtain a

24
compound (I), and the compound (I) is deprotected to obtain a
compound (I').
( Reaction Formula )

wherein A ring, B ring, X, and R1 to R11 in the formula mean the
same things as the ones mentioned above , and Y is a group to be
eliminated. Examples of the group to be eliminated are halogen,
acetoxy, trifluoroacetoxy, and trifluoromethanesulfoxy. Z
represents a hydrogen atom, MeS-, Ra3Sn-, and (RaO)sB-. Rfl
represents a lower alkyl.
Specific examples of the metal used in the reaction of the
compound (16) and the compound (17) include copper, zinc, iron,
and magnesium. Specific examples of the palladium catalyst
include tetrakistriphenylphosphine palladium (0), palladium
acetate (II), bistriphenylphosphine palladium dichloride (II), and
trisdibenzyliden acetone dipalladium (0). Specific examples of the
phosphine include triphenylphosphine, trifurylphosphine,
diphenylphosphino ferrocene, diphenylphosphino ethane,
dicyclohexylphosphino biphenyl, and tritert-butylphosphine.

25
Specific examples of the solvent include ethers such as diethyl
ether, tetrahydrofuran, and diglyme; and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is generally
from about 20°C to about 180°C, and preferably from about 40°C to
about 100°C though it varies, depending upon the type of starting
material compounds, the reaction conditions, or the like.
The deprotection is carried out in the same manner as the
deprotection in Preparation Process 1.
( Preparation Process 6 )
In Preparation Process 6, a nitrile compound is subjected to
a cyclization reaction to obtain an alkylated compound (I), followed
by deprotection to obtain a compound (I)'.
( Reaction Formula )

wherein A ring, B ring, X, and R1 to R11 in the formula mean the
same things as the ones mentioned above , and Y is a group to be

26
eliminated. Examples of the group to be eliminated are halogen,
acetoxy, trifluoroacetoxy, and trifluoromethanesulfoxy.
The cyclization reaction is carried out in an appropriate
solvent in the presence of an appropriate azide derivative and a
hydrochloride of an amine. Specific examples of the azide
derivative include sodium azide and trimethylsilyl azide. Specific
examples of the amine include triethyl amine, triisopropyl amine,
and diisopropylethyl amine. Specific examples of the solvent
include dimethylformamide! dimethylsulfoxide;
N-methylpyrrolidone; l,3-Dimethyl-2-imidazolidinone; and a
mixture of these solvents; and the solvent is appropriately selected
according to the type of reaction substrate or the reaction
conditions. The reaction temperature is generally from about
-100°C to about 180°C, and preferably from about 20°C to about
80°C though it varies, depending upon the type of starting material
compounds, the reaction conditions, or the like.
The alkylation is carried out in an appropriate solvent in the
presence of a halide (13) and an appropriate amine. Specific
examples of the amine include triethyl amine, diisopropylethyl
amine, andpyridine. Examples of the solvent include ethers such
as tetrahydrofuran and dioxane; dimethyl formaldehyde;
acetonitrile! and a mixture of these solvents! and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is generally
from about -100°C to about 180°C, and preferably from about 20°C
to about 80°C though it varies, depending upon the type of starting
material compounds, the reaction conditions, or the like.

27
The deprotection is carried out in the presence of an
appropriate base. Specific examples of the base include sodium
hydroxide; potassium hydroxide; sodium carbonate; potassium
carbonate; sodium methoxide; and sodium ethoxide. Specific
examples of the solvent include alcohols such as methanol and
ethanol; water; and a mixture of these solvents, and the solvent is
appropriately selected according to the type of reaction substrate or
the reaction conditions. The reaction temperature is from about
-100°C to about 180°C, and preferably from about 20°C to about
80°C though it varies, depending upon the type of starting
materials, the reaction conditions, or the like.
EXAMPLES
The compound of the present invention will now be described
in more detail by way of examples. Since starting materials of the
compounds of the present invention include novel compounds, the
methods for preparing these compounds will also be described in
Reference Examples.
( Reference Example 1 )
Potassium carbonatede (2.08 g) was added to a solution of
5-bromo-2,4-dihydroxybenzaldehyde (l.09g) in acetone (20 ml), and
the mixture was stirred for 30 minutes at room temperature. Then,
chloromethyl methyl ether (l.Olg) was added to the reaction
mixture, and the mixture was stirred over night at room
temperature. To the reaction mixture were added water and
toluene, and the toluene layer was separated, and then washed
with saturated sodium bicarbonate solution and saturated saline

28
solution, followed by drying and filtration, and the solvent was
evaporated from the filtrate under reduced pressure to give the
residue to obtain a solid. The solid was washed with
diisopropylether and dried to obtain 5-bromo-2,4-bis
(methoxymethoxy)benzaldehyde (0.91 g).
( Reference Example 2 )
N-Bromosuccinimide (7.35 g) and benzoyl peroxide (196 mg)
were added to a solution of 4-bromo-2-methylbiphenyl (5.0g) in
carbon tetrachloride (150 ml), and the mixture was stirred over
night under reflux condition. After cooling to room temperature,
the reaction mixture was poured into water and extracted with
chloroform. The organic layer was washed with saturated saline
solution and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated therefrom under reduced
pressure to give the residue. The residue was purified by silica gel
column chromatography (n-hexane-ethyl acetate) to obtain
4-bromo-2-(dibromomethyl)biphenyl (7.9 g). Sodium acetate (9.6
g) was added to a solution of 4-bromo-2-(dibromomethyl)biphenyl in
acetic acid (240 ml) and stirred for two days under reflux condition.
After cooling to room temperature, 4M hydrochloric acid (50 ml)
was added to the reaction mixture, and the resulting mixture was
stirred for two hours under reflux condition. After cooling to room
temperature, the solvent was evaporated therefrom under reduced
pressure to give the residue, ethyl acetate was added to the
resulting residue, and the resultant was washed with 1M
hydrochloric acid and saturated saline solution in order and dried
over anhydrous magnesium sulfate. After filtration, the solvent

29
was evaporated from the filtrate under reduced pressure to give the
residue, and the resulting residue was dried to obtain 4-bromo
biphenyl-3-carboaldehyde (5.05 g).
( Reference Example 3 )
Imidazole (3.3 g) and tert-butyl-diphenylchlorosilane (10.0
g) were added to a solution of (3-bromo-5-fluorophenyl)methanol
(5.0g) in dimethylformamide (50 ml), and the mixture was stirred
over night at room temperature. The reaction mixture was poured
into water and extracted with ethyl acetate. The organic layer
was washed with saturated saline solution and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
[(3-bromo'5-fluorobenzyl)oxy] (tert-butyl)diphenylsilane (9.5 g).
The compounds in Reference Examples 4, 5, 6 were obtained
in a manner similar to that of Reference Example 3.
( Reference Example 7 )
Ten percents of palladium/carbon (500 mg) was added to a
solution of (lS)-l,5-anhydro-2,3,4,6-tetra-O-benzyl-l-
(3-([[tert-butyl (diphenyl)silyl]oxy]methyl)phenyl)-D-glucitol (5.93
g) in tetrahydrofuran (45 ml), and the mixture was stirred for 20
hours at room temperature in a hydrogen atmosphere. After
filtration through celite of the reaction mixture, the solvent was
evaporated from the filtrate under reduced pressure to give the
residue, and the residue (3.47 g) was dissolved in pyridine (40 ml).
To the resulting solution were added acetic anhydride (2.68 ml) and

30
4-dimethylaminopyridine (catalyst amount), and the resulting
mixture was stirred for 16 hours at room temperature. Then,
methanol (50ml) was added dropwise to the reaction mixture, the
solvent was evaporated therefrom under reduced pressure to give
the residue, and the resulting residue was subjected to
co-evaporation with toluene. The resulting residue was dissolved
in ethyl acetate-toluene (3^2), washed, and then dried over
magnesium sulfate. Then, the solvent was evaporated therefrom
under reduced pressure to give the residue, and the residue (4.48 g)
was dissolved in tetrahydrofuran (100 ml), and 1M tetrahydrofuran
solution (8.12 ml) of tetrabutylammoniumfluoride was dropped, and
the solution was stirred for two hours at room temperature. Then,
the reaction mixture was concentrated and purified by silica gel
column chromatography to obtain (lS)*2,3J4J6-tetra-0-acetyl
-lf5-anhydro-l-[3-(hydroxymethyl)phenyl]-D-glucitol (1.30 g).
( Reference Example 8 )
Triphenylphosphine (926 m) and carbon tetrabromide (1.17
g) were added to a solution of (lS)-2,3,4,6-tetra-0-acetyl-l,5-
anhydro-l-[3-(hydroxymethyl)phenyl]-D-glucitol (1.29 g) in
dichloromethane (40 ml) under cooling with ice, and the mixture
was stirred for 20 minutes at room temperature. Saturated
aqueous solution of sodium bicarbonate (60 ml) was added to the
reaction mixture to separate the organic layer. Then, the mixture
was dried over magnesium sulfate, and the solvent was evaporated
therefrom under reduced pressure to give the residue. The residue
was purified by silica gel column chromatography to obtain
(lS)-2,3,4,6-tetra-0-acetyl'l,5-anhydro'l-[3-(bromomethyl)phenyl]-

31
D-glucitol (1.04 g).
( Reference Example 9 )
1.56 Moles of n-hexane solution of n-butyllithium (50 ml)
were added dropwise to a solution of l-(benzyloxy)-2-bromo
■4-methylbenzene (20 g) in tetrahydrofuran (250 ml) at -78°C in an
argon atmosphere, and the mixture was stirred for one hour at the
same temperature. To the reaction mixture was added dropwise a
solution of 2,3,4,6-tetra-0-benzyl-D-(+)-glucono-l,5-lactone (35.0 g)
in tetrahydrofuran (200 ml) at -78°C, and the resulting mixture was
stirred for one hour at the same temperature. Aqueous solution of
1M hydrochloric acid (10 ml) was added to the mixture, and the
temperature was raised to room temperature. Then, anhydrous
magnesium sulfate (50 g) was added to the mixture, and the
mixture was stirred for one hour at room temperature. After
filtration, the filtrate was concentrated, and the resulting residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain 2>3,4,6"tetra-0-benzy-l-C-[2-(benzyloxy)
■5-methylphenyl]-D-glucopyranose (37 g). Triisopropylsilane (31
ml) and borontrifluoride diethylether complex (12.6 ml) were added
to a solution of 2,3,4,6-tetra-0-benzy-l-C-[2-(benzyloxy)
■5-methylphenyl]-D-glucopyranose in dicyclomethane-acetonitrile
(1*3) (400 ml) under cooling with ice in an argon atmosphere, and
the mixture was stirred for one hour at the same temperature.
The reaction mixture was poured into saturated aqueous solution of
sodium bicarbonate and extracted with chloroform. The organic
layer was dried over anhydrous magnesium sulfate and filtrated,
and then the solvent was evaporated from the filtrate under

32
reduced pressure to give the residue. The residue was purified by
silica gel column chromatography (rrhexane-ethyl acetate) to
obtain (lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-[2-(benzyloxy)
-5-methylphenyl]-D-glucitol (16.9 g).
( Reference Example 10 )
1.56 Moles of n-hexane solution of n-butyllithium (14.5 ml)
were added dropwise to a solution of [(3-bromo-5-fluorobenzyl)oxy]
(tert-butyl)diphenylsilane (10 g) in tetrahydrofuran (100 ml) at
-78°C in an argon atmosphere, and the mixture was stirred for half
an hour at the same temperature. To the reaction mixture was
added dropwise a solution of 2,3,4,6'tetra-0-benzyl-D-(+)-glucono
-1,5-lactone (12.2 g) in tetrahydrofuran (100 ml) at -78°C, and the
mixture was stirred for two hours at the same temperature.
Aqueous solution of 1M hydrochloric acid (10 ml) was added to the
mixture, and the temperature was raised to room temperature.
Then, anhydrous magnesium sulfate (50 g) was added to the
mixture, and the mixture was stirred for one hour at room
temperature. After filtration, the filtrate was concentrated, and
the residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain 2,3,4,6-tetra-0-benzy-l-C-[3-
({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-fluorophenyl]-D-
glucopyranose (6 g). Triethylsilane (1.3 ml) and borontrifluoride
diethylether complex (0.9 ml) were added to a solution of
2,3,4,6-tetra-0-benzyl-C-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl
)-5-£Luorophenyl]-D-glucopyranose in dicyclomethane-acetonitrile
(l^l) (120 ml) under cooling with ice in an argon atmosphere, and
the mixture was stirred for one hour at the same temperature.

33
The reaction mixture was poured into saturated aqueous solution of
sodium bicarbonate and extracted with chloroform. The organic
layer was dried over anhydrous magnesium sulfate and filtrated,
and then the solvent was evaporated from the filtrate under
reduced pressure to give the residue. The residue was purified by
silica gel column chromatography (n-hexane-ethyl acetate) to
obtain (lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyM-[3-({[tert-butyl
(diphenyl)silyl]oxy}methyl)-5'fluorophenyl]-D-glucitol (4.2 g). 1 M
tetrahydrofuran solution of tetrabutylammoniumfluoride (9.5 ml)
was added dropwise to a solution of (lS)-l,5-anhydro-2,3,4,6-tetra
-0-benzyl-l-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-fluorophe
nyl]-D-glucitol in tetrahydrofuran (90 ml), and the mixture was
stirred for one hour at room temperature. The reaction mixture
was concentrated, and the resulting residue was purified by silica
gel column chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-[3-fluoro-5-(hydroxymeth
yl)phenyl]-D-glucitol (0.5 g).
The compounds in Reference Examples 11, 12, 13 were
obtained in a manner similar to that of Reference Example 10.
( Reference Example 14 )
Methanol (75 ml), Pd(OH)2 (168 mg) was added to a solution
of (lS)-l,5-anhydro-2,3J4,6-tetra-0-benzyl-l-[2-(benzyloxy)-5-
methylphenyl]-D-glucitol (16.8 g) in ethyl acetate (150 ml), and the
mixture was stirred over night in a hydrogen atmosphere. After
filtration through celite, the filtrate was concentrated. The
obtained solid was recrystallized from ethyl acetate. Acetic
anhydride (15 ml) was added to a solution of the obtained white

34
crystals (6.6 g) in pyridine (30 ml) and the mixture was stirred over
night at room temperature. Methanol was added to the reaction
mixture, the solvent was evaporated therefrom under reduced
pressure to give the residue, and the resulting residue was
subjected to co-evaporation with toluene. The obtained solid was
recrystallized from ethanol to obtain (lS)-l-[2-(acetoxy)-5-
methylphenyl]-2,3,4,6-tetra-0-acetyl-l,5-anhydro-D-glucitol (9.1 g).
( Reference Example 15)
N-bromosuccinimide and (a, a3-azoisobutylo)nitrile was
added to (lS)-l-[2-(acetoxy)-5-methylphenyl]-2,3,4,6-
tetra-0-acetyl-l,5-anhydro-D-glucitol (9.1 g) in carbon tetrachloride
(180 ml), and the mixture was stirred for two hours under reflux
condition. After cooling to room temperature, the reaction
mixture was poured into water and extracted with chloroform.
The organic layer was washed with water and saturated saline
solution and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue. The resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-l-[2-(acetoxy)-5'(bromomethyl)phenyl]
-2,3,4,6-tetra-0-acetyl-l,5-anhydro-D-glucitol (7.8 g).
The compound in Reference Example 16 was obtained in a
manner similar to that of Reference Example 9.
( Reference Example 17 )
3-(2,3,4,6-Tetra-0-benzyl-/?-D-glucopyranosyl)-4-
fluorobenzonitrile (1.20 g) was dissolved in morpholine (10 ml), and
the mixture was stirred for 24 hours at 110°C. The mixture was

35
cooled to room temperature, and the solvent was evaporated from
the filtrate under reduced pressure to give the residue. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain 3-(2,3,4,6-tetra-0-benzyl- /3
-D-glucopyranosyl) -4-morpholinobenzonitrile (0.93 g).
( Reference Example 18 )
A solution of 1.01 M toluene (2.1 ml) of diisobutyl aluminum
hydride was added dropwise to a solution of
3-(2,3,4,6-tetra-0-benzyl-/3 -D-glucopyranosyl)-4-morpholino
benzonitrile (700 mg) in toluene (10 ml) cooled at -78°C under an
argon atmosphere, and the mixture was stirred for 1.5 hours.
Aqueous solution of saturated ammonium chloride was added to the
mixture, and extracted with chloroform. The organic layer was
washed with saturated saline solution and dried over anhydrous
sodium sulfate. After filtration, the solvent was evaporated from
the filtrate under reduced pressure to give the residue. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain 3-(2,3,4,6-tetra-0-benzyl-/5
-D-glucopyranosyl)-4-morpholinobenzaldehyde (517 g).
( Reference Example 19 )
Manganese dioxide (740 mg) was added to a solution of
(lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-[3-fluoro-5-(hydroxyl
methyl)phenyl]-D-glucitol (0.5 g) in chloroform (10 ml), and the
mixture was stirred for 24 hours. After filtration through celite,
washing with chloroform was carried out, and the filtrate was
concentrated. The resulting residue was dried to obtain
3-(-2>3,4,6-tetra-0-benzyl'/3 -D-glucopyranosyl)-5-fluoro

36
benzaldehyde (0.4 g).
The compounds in Reference Examples 20 to 22 were
obtained in a manner similar to that of Reference Example 19.
( Reference Example 23 )
1.6 Moles of n-hexane solution of n-butyllithium (4.6 ml)
were added dropwise to a solution of l-bromo-3-(dimethoxymethyl)
benzene (1.7 g) in tetrahydrofuran (20 ml) at -78°C, and the mixture
was stirred for half an hour. To the reaction mixture was added
dropwise a solution of 2,3,4J6-tetra-0-benzyl-D-(+)-glucono-l,5-
lactone (4.0 g) in tetrahydrofuran (20 ml), and the mixture was
stirred for one hour. Aqueous solution of saturated ammonium
chloride was added to the mixture, and extracted with ethyl acetate.
The organic layer was washed with saturated saline solution and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated from the filtrate under reduced pressure to give the
residue. The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
2)3)4,6-tetra-0-benzyl-l-C-[3-dimethoxymethyl]phenyl]-D
-glucopyranose (1.83 g). To a solution of 2,3,4,6-tetra-0-benzyl
-l-C-3-dimethoxymethyl]phenyl]-D-glucopyranose in acetone-water
(2^1) (30 ml) were added sulfamic acid (0.51 g) and sodium chlorite
(0.6 g), and the mixture was stirred for eight hours at room
temperature. Ten percents of hydrochloric acid was added to the
reaction mixture to adjust the pH to 2, and extracted with
chloroform. The organic layer was washed with saturated saline
solution and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated from the filtrate under reduced

37
pressure to give the residue. The resulting residue was purified
by silica gel column chromatography (n-hexane-ethyl acetate) to
obtain 3-(2,3,4,6-tetra-0-benzyl-D-glucopyranose-l-C)-yl-benzoic
acid (1.3 g). Triethylsilane (0.63 ml) and trifluoroacetic acid (0.15
ml) were added to a solution of 3-(2,3,4,6-tetra-0-benzyl-D-
glucopyranose-l-C)-yl-benzoic acid in dichloromethane (15 ml), and
the mixture was stirred for 15 hours at room temperature.
Aqueous solution of 10% sodium hydroxide was added to the
reaction mixture, and extracted with dichloromethane. The
organic layer was washed with saturated saline solution and dried
over anhydrous sodium sulfate. After filtration, the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
3-(2,3,4,6-tetra-0-benzyl-/? -D-glucopyranosyl)benzoic acid (0.85 g).
N,0-dimethylhydroxylamine hydrochloride (0.14 g), triethyl arnine
(0.2 ml), and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.28
g) were added to a solution of 3-(2,3,4,6'tetra-0-benzyl- /? -
D-glucopyranosyl) benzoic acid in dichloromethane (10 ml), and the
mixture was stirred for four hours at room temperature. Then, the
reaction mixture was poured into ice-cooled water and extracted
with ethyl acetate. The organic layer was washed with saturated
saline solution and dried over anhydrous sodium sulfate. After
filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue, and the resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain 3-(2,3,4,6-tetra-0-benzyl-/5 -D-glucopyranosyl)-

38
N-methyl-N-methoxybenzamide (0.42 g).
The compound in Reference Example 24 was obtained in a
manner similar to that of Example 47.
( Reference Example 25 )
Diisopropyl amine (2.34 g) was dissolved in tetrahydrofuran
(60 ml). 1.58 M n-hexane solution (13.3 ml) of n-butyllithium was
added dropwise to the mixture at -78°C, and the mixture was
stirred for half an hour at 0°C. Then, 2,6-dichloropyrazine (2.98 g)
was added to the reaction mixture at -78°C, and the mixture was
stirred for ten minutes. Then, a solution of
2,3,4,6-tetra-0-benzyl-D-(+)-glucono-l,5-lactone (10.8 g) in
tetrahydrofuran (100 ml) was added to the mixture, and the
mixture was stirred for three hours at -78°C. The reaction mixture
was washed with saturated ammonium chloride, and the water
layer was extracted with diethyl ether. The organic layer was
dried over sodium sulfate, the solvent was evaporated therefrom
under reduced pressure to give the residue, and the resulting
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain 2,3,4,6-tetra-O-benzyl-l-C-
(3,5-dichloropyrazine-2-yl)-D-glucopyranose (9.07 g). The
obtained 2,3,4,6'tetra-O-benzyl-l-C-(3,5-dichloropyrazine
-2-yl)-D-glucopyranose (7.93 g) was dissolved in dichloromethane
(90 ml), and triethyl silane (36.8 ml) and trifluoloacetic acid (17.7
ml) were added to the mixture, and the mixture was stirred for 19
days at room temperature. The reaction mixture was washed with
saturated sodium bicarbonate solution, and the water layer was
extracted with chloroform. The organic layer was dried over

39
sodium sulfate, the solvent was evaporated therefrom under
reduced pressure to give the residue, and the resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-lJ5-anhydro-2,3,4!6-tetra-
0-benzyl-l-(3,5-dichloropyrazine-2-yl)-D-glucitol (2.15 g).
( Reference Example 26 )
1,3-Dibromobenzene (25 g) and a solution of a Grignard
reagent prepared using metal magnesium in ether (50 ml) were
added to a solution of 5-ethylthiophene-2-carboxyaldehyde (5.0 g)
in tetrahydrofuran (50 ml) at 0°C, and the mixture was stirred for
one hour. The reaction mixture was poured into ice-cooled water
and extracted with ethyl acetate. The organic layer was washed
with saturated saline solution and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated from the
filtrate under reduced pressure to give the residue, and the
resulting residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain (3-bromophenyl)
(5-ethyl-2-thienyl) methanol (5.57 g). Borontrifluoride diethyl
ether complex (1.57 ml) and triethylsilane (3.83 ml) were added to a
solution of (3-bromophenyl) (5-ethyl-2-thienyl) methanol in
acetonitrile (20 ml) at -40°C, and the mixture was stirred for two
hours. Aqueous solution of saturated potassium carbonate was
added to the reaction mixture, and extracted with ethyl acetate.
The organic layer was washed with saturated saline solution and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated from the filtrate under reduced pressure to give the
residue, and the residue was purified by silica gel column

40
chromatography (n-hexane-ethyl acetate) to obtain
2-(3-bromobenzyl)-5'methylthiophene (3.77 g).
The compounds in Reference Examples 27 and 28 were
obtained in a manner similar to that of Reference Example 26.
( Reference Example 29 )
A solution of 1.56 M hexane (23.7 ml) of n-butyl lithium was
added dropwise to a solution of 3-methyl-l-benzothiophene (5.0 g)
in tetrahydrofuran (50 ml) at -78°C under an argon atmosphere,
and the mixture was stirred for half an hour at the same
temperature. Then, a solution of 3-bromobenzaldehyde (6.05 g) in
tetrahydrofuran (6 ml) was added dropwise to the mixture, and the
mixture was stirred for half an hour. Water was added to the
reaction mixture, and extracted with ethyl acetate. The organic
layer was washed with aqueous solution of saturated ammonium
chloride and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue, and the residue was purified
by silica gel column chromatography (n-hexane-ethyl acetate) to
obtain (3-bromophenyl)(3-methyl-l"benzothiene-2-yl) methanol
(10.0 g) as achromatic oily matter. Borontrifluoride diethyl ether
complex (4.42 ml) and triethylsilane (9.58 ml) were added to a
solution of (3-bromophenyl)(3-methyl-l-benzothiene-2-yl) methanol
in dichloromethane (100 ml) at -30°C, and the mixture was stirred
for half an hours. After the reaction mixture was heated to -10°C
and stirred for 10 minutes, aqueous solution of saturated sodium
carbonate was added to the reaction mixture, and extracted with
ethyl acetate. The organic layer was washed with saturated saline

41
solution and dried over anhydrous magnesium sulfate. After
filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue, and the residue was purified
by silica gel column chromatography (n-hexane-ethyl acetate) to
obtain 2-(3-bromobenzyl)-3-methyl'l-benzothiophene (6.68 g).
The compounds in Reference Examples 30 to 36 were
obtained in a manner similar to that of Reference Example 29.
( Reference Example 37 )
Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran
(50 ml). This solution was cooled to -78°C, and a solution of 1.58
M hexane (10.5 ml) of n-butyllithium was added dropwise to the
solution, and the mixture was stirred for 15 minutes at -78°C.
Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in
tetrahydrofuran (50 ml) was added dropwise to the reaction
mixture, and the mixture was stirred for two hours at room
temperature. Aqueous solution of saturated ammonium chloride
was added to the reaction mixture, and then the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. Ethyl acetate and water were added to the residue
obtained, and extracted with ethyl acetate. The organic layer was
dried over magnesium sulfate, the solvent was evaporated from the
filtrate under reduced pressure to give the residue, and the residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain l-benzothiene-2-yl(5-bromo-2-chlorophenyl)
methanol (4.75 g). Imidazole (1.08 g) and tert-butyl
dimethylchlorosilane (2.99 g) were added to a solution of
l-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol in

42
dimethylformamide (100 ml), and the mixture was stirred for three
hours at 70°C. Water was added to the reaction mixture, and
extracted with diethyl ether. The organic layer was dried over
magnesium sulfate, the solvent was evaporated therefrom under
reduced pressure to give the residue, and the resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain [l-benzothiene-2-yl(5-bromo-2-chloro
phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g).
The compounds in Reference Examples 38, 39 and 40 were
obtained in a manner similar to that of Reference Example 37.
( Reference Example 41 )
Aluminum chloride (8.9 g) and 4-ethylbenzoylchloride (5.96
g) were added to a solution of 2-bromothiophene (3.2 ml) in
dichloromethane (50 ml) at 0°C, and the mixture was stirred for
four hours at room temperature. 10% hydrochloric acid was added
to the reaction mixture, and extracted with ethyl acetate. The
organic layer was washed with water and saturated saline solution
in order and dried over anhydrous sodium sulfate. After filtration,
the solvent was evaporated from the filtrate under reduced
pressure to give the residue. The residue was purified by silica gel
column chromatography (n-hexane-ethyl acetate) to obtain
(5-bromo-2-thienyl)(4-ethylphenyl) methanone (8.97 g).
Borontrifluoride diethyl ether complex (1.57 ml) and triethylsilane
(3.83 ml) were added to a solution of (5"bromo-2-thienyl)
(4-ethylphenyl) methanone in acetonitrile (20 ml) at -40°C, and the
mixture was stirred for two hours. Aqueous solution of saturated
potassium carbonate was added to the reaction mixture, and

43
extracted with ethyl acetate. The organic layer was washed with
saturated saline solution and dried over anhydrous sodium sulfate.
After filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue, and the residue was purified
by silica gel column chromatography (n-hexane-ethyl acetate) to
obtain 2-bromo-(4-ethylbenzyl)thiophene (6.78 g).
( Reference Example 42 )
A solution of 1M tetrahydrofuran (2.98 ml) of
ethylmagnesium bromide was added dropwise to pyrrole (0.2 g),
and the mixture was stirred for half an hour. The solvent was
evaporated from the filtrate under reduced pressure to give the
residue, and 4-ethylbenzyl bromide (663 mg) was added to a
solution of the obtained residue in benzene (5.0 ml), and the
mixture was stirred for five hours at 60°C. Aqueous solution of
saturated ammonium chloride was added to the reaction mixture,
and extracted with ethyl acetate. The organic layer was washed
with saturated saline solution and dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated from the
filtrate under reduced pressure to give the residue, and the residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain 2-(4-ethylbenzyl)-lH-pyrrole (0.12 g).
( Reference Example 43 )
A solution of 1.5 M hexane (21 ml) of n-butyllithium was
added dropwise to a solution of 6,7-dimethyl-benzofuran (4.1 g) in
tetrahydrofuran (100 ml) at -78°C under an argon atmosphere, and
the mixture was stirred for half an hour. Then, chloro
tri-n-butyltin (8.4 ml) was added to the mixture, and the mixture

44
was stirred for one hour. Aqueous solution of saturated
ammonium chloride was added to the reaction mixture, and
extracted with ethyl acetate. The organic layer was washed with
saturated saline solution and dried over anhydrous sodium sulfate.
After filtration, the filtrate was concentrated, and the residue was
purified by silica gel column chromatography (n-hexane) to obtain
tri-n-butyl(6,7-dimethyl-benzofuran-2-yl) tin (10.8 g).
The compounds in Reference Examples 44 to 49 were
obtained in a manner similar to that of Reference Example 43.
( Reference Example 50 )
Sodium borohydride (1.3 g) was added to a solution of
6-methyl-indane-l-one (5.0 g) in methanol (50 ml) at 0°C, and the
mixture was stirred for one hour. The reaction mixture was
poured into ice-cooled water, and extracted with ethyl acetate.
The organic layer was washed with saturated saline solution and
dried over anhydrous sodium sulfate. After filtration, the filtrate
was concentrated to obtain 6-methylindane-l-ol (5.5 g). To a
solution of 6-methylindane-l-ol in toluene (50 ml) was added
p-toluene sulfonic acid monohydrate (0.2 g), and the mixture was
stirred for 20 minutes. The temperature of the reaction mixture
was returned to room temperature, and the reaction mixture was
washed with water, 5% sodium hydrogencarbonate aqueous solution,
and saturated saline solution in order and dried over anhydrous
sodium sulfate. After filtration, the filtrate was concentrated to
obtain 5-methyl-lH-indene (5.5 g).
The compound in Reference Example 51 was obtained in a
manner similar to that of Reference Example 50.

45
( Reference Example 52 )
Water (0.6 ml) and N-bromosuccinimide (6.1 g) was added to
a solution of 5-methyl-lH-indene (4.4 g) in dimethylsulfoxide (50
ml), and the mixture was stirred for 40 minutes at room
temperature. The reaction mixture was poured into ice-cooled
water, and extracted with ether. The organic layer was washed
with water, 5% sodium hydrogencarbonate aqueous solution, and
saturated saline solution in order and dried over anhydrous sodium
sulfate. After filtration, the filtrate was concentrated, and the
resulting crystals were washed with hexane to obtain, by filtration,
2-bromo-6-methylindane-l-ol (4.4 g). To a solution of
2-bromo-6-methylindane-l-ol in toluene (50 ml) was added
p-toluene sulfonic acid monohydrate (0.1 g), and the mixture was
stirred for 20 minutes. The temperature of the reaction mixture
was returned to room temperature, and the reaction mixture was
washed with water, 5% sodium hydrogencarbonate aqueous solution,
and saturated saline solution in order and dried over anhydrous
sodium sulfate. After filtration, the filtrate was concentrated, and
the residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain 2-bromo-5-methyl-lH-indene
(1.7 g).
The compound in Reference Example 53 was obtained in a
manner similar to that of Reference Example 52.
( Reference Example 54 )
2-Bromo-lH-indene (3.0 g) and a solution of a Grignard
reagent prepared using metal magnesium in tetrahydrofuran (20
ml) were added to a solution of 3-(2,3,4,6-tetra-0"benzyl-/?

46
-D-glucopyranosyl)-N-methyl-N-methoxybenzamide (6.99 g) in
tetrahydrofuran (20 ml) at 0°C, and the mixture was stirred for two
hours. The reaction mixture was poured into ice-cooled water and
extracted with ethyl acetate. The organic layer was washed with
saturated saline solution and dried over anhydrous sodium sulfate.
After filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue, and the residue was purified
by silica gel column chromatography (n-hexane-ethyl acetate) to
obtain (lH-indene-2-yl)[3-(2,3,4,6-tetra-0-benzyl-/?
-D-glucopyranosyl)phenyl] methanone (0.84 g).
( Reference Example 55 )
Pentamethylbenzene (3.62 g) was dissolved in a solution of
methyl-4-(l-benzothiene-2-ylmethyl)-2-(2)3,4,6-tetra-0-benzyl-/?-
D-glucopyranosyl) benzoate (1.31 g) in dichloromethane (150 ml),
and 1 M n-heptane solution (6.83 ml) of boron trichloride was added
dropwise to the mixture at -78°C, and the mixture was stirred for
two hours at the same temperature. Then, methanol (40 ml) was
added dropwise to the reaction mixture at -78°C. After the
temperature was raised to room temperature, the solvent was
evaporated therefrom under reduced pressure to give the residue,
and the resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(2R>3S,4S,4aR,10bS)-7-(l-benzothiene-2-ylmethyl)-3,4-dihydroxy2
-(hydroxymethyl)-3,4,4a,10b-tetrahydropyrano[3,2-c]isocumene
-6(2H)-one (420 mg).
( Example 1 )
1.58 Moles of n-hexane solution of n-butyllithium (2.4 ml)

47
were added dropwise to a solution of benzo[b]thiophene (504 mg) in
tetrahydrofuran (10 ml) at -78°C in an argon atmosphere, and the
mixture was stirred for two hours at the same temperature. To the
reaction mixture was added dropwise a solution of 3-(2,3,4,6"tetra
■0-benzyl-/? -D-gluglucopyranosyl) benzaldehyde (1.57 g) in
tetrahydrofuran (45 ml), and the mixture was stirred for five hours
at the same temperature. Water (60 ml) was added to the reaction
mixture, and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated from the filtrate under reduced pressure to give the
residue. The residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate). Triethylsilane (0.67
ml) and a solution of boron trifluoride diethylether complex (447
ml) in dichloromethane (15 ml) were added dropwise to a solution of
the residue (1.6 g) in dichloromethane (25 ml) under cooling with
ice, and the mixture was stirred for two hours at the same
temperature. Saturated sodium bicarbonate was added to the
reaction mixture, and the organic layer was separated and dried
over anhydrous magnesium sulfate. After filtration, the solvent
was evaporated from the filtrate under reduced pressure to give the
residue. The residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain (IS)"
l,5-anhydro-2,3)4,6-tetra-0-benzyl-l-t3-[(l-benzothiene-2-yl)
methyl]phenyl]-D-glucitol (1.56 g).
The compounds in Examples 2 to 16 were obtained in a
manner similar to that of Example 1.
( Example 17 )

48
1.58 Moles of n-hexane solution of n-butyllithium (1.18 ml)
were added dropwise to a solution of 3-(4-methoxybenzyl) thiophene
(0.38 g) in tetrahydrofuran (10 ml) at -78°C, and the mixture was
stirred for one hour. To the reaction mixture was added dropwise
a solution of 2,3J4,6-tetra-0"benzyl-D-(+)-glucono-l,5-lactone (l.O g)
in tetrahydrofuran (10 ml), and the mixture was stirred for one
hour. 1.0 M hydrochloric acid was added to the reaction mixture,
and extracted with ethyl acetate. After washing with saturated
saline solution, the resultant was dried over anhydrous sodium
sulfate. After filtration, the solvent was evaporated from the
filtrate under reduced pressure to give the residue. The resulting
residue was purified by silica gel column chromatography
(n-hexane-chloroform-acetone). Triisopropylsilane (0.78 ml) and
boron trifluoride diethylether complex (0.32 ml) were added to a
solution of the residue (0.94 g) in chloroform (l.O ml) and
acetonitrile (5.0 ml) under cooling with ice, and the mixture was
stirred for half an hour. Triethyl amine (l.O ml) was added to the
reaction mixture, and the solvent was evaporated therefrom under
reduced pressure to give the residue. The resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain l,4:5,9-dianhydro-6,7,8,10-tetra-0-benzyl
-2,3-dideoxy-2(4-methoxybenzyl)-l-thio-D-glycero-D-glo-deca-l,3-d
ienitol (0.72 g).
The compounds in Examples 18 to 24 were obtained in a
manner similar to that of Example 17.
( Example 25 )
2-[3-Bromo-4-(methoxymethoxy)benzyl]-l-benzothiophene

49
(17.4 g) was dissolved in tetrahydrofuran (200 ml). 1.58 Moles of
n-hexane solution of n-butyl lithium (30.4 ml) were added dropwise
to the mixture at -78°C, and the mixture was stirred for one hour at
-78°C. Then, to the reaction mixture was added a solution of
2J3)4,6-tetra-0-benzyl-D-(+)-glucono-l)5-lactone (21.6 g) in
tetrahydrofuran (150 ml), and the mixture was stirred for three
hours at -78°C. The reaction mixture was washed with saturated
ammonium chloride solution, and a water layer was extracted with
ethyl acetate. The whole organic layer combined was dried over
anhydrous sodium sulfate, and the solvent was evaporated
therefrom under reduced pressure to give the residue. The
obtained solid was recrystallized (hexane-ethyl acetate) to obtain
l-C-[5-(l-benzothiene-2-ylmethyl)-2-(methoxymethoxy)phenyl]-
2,3,4,6-tetra-O-benzyl-D-glucopyranose (25.3 g). This was
dissolved in dichloromethane (500 ml). Triethylsilane (14.7 ml)
and boron trifluoride diethylether complex (4.1 ml) were added to
the solution at -40°C, and the mixture was stirred for four hours at
-20°C. The reaction mixture was washed with saturated sodium
bicarbonate, and a water layer was extracted with chloroform.
The whole organic layer combined was dried with sodium sulfate,
and the solvent was evaporated therefrom under reduced pressure
to give the residue. The resulting residue was purified by silica
gel column chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-(methoxy
methoxy)phenyl]-2,3,4,6-tetra-0-benzyl-D-glucitol (21.8 g).
The compounds in Examples 26 to 29 were obtained in a
manner similar to that of Example 25.

50
(Example 30 )
(lS)-l,5-Anhydro-l-t5-(l-benzothiene-2-ylmethyl)-2-
(methoxymethoxy)phenyl]'2,3,4)6'tetra-0-benzyl-D-glucitol (21.7 g)
was dissolved in ethyl acetate (135 ml). To the mixture was added
4M hydrochloric acid-ethyl acetate solution (135 ml), and the
mixture was stirred for 14 hours at room temperature. The
reaction mixture was concentrated, and the resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)
-2-hydroxyphenyl]-2,3,4,6-tetra-0-benzyl-D-glucitol (18.6 g).
The compounds in Examples 31 and 32 were obtained in a
manner similar to that of Example 30.
(Example 33 )
(lS)-l,5-Anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-
hydroxyphenyl]-2,3,4,6-tetra-0-benzyl-D-glucitol (763 rag) was
dissolved in dimethylformamide (10 ml). To the mixture was
added potassium carbonate (207 mg) and methyl iodide (0.095 ml),
and the mixture was stirred for 16 hours at room temperature.
The reaction mixture was diluted with sodium sulfate washed with
water and saturated saline solution. The organic layer was dried
with sodium sulfate, and the solvent was evaporated therefrom
under reduced pressure to give the residue. The resulting residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-yl
methyl)-2-methoxyphenyl]-2J3(4)6-tetra-0-benzyl-D-glucitol (736
mg).
The compounds in Examples 34 to 40 were obtained in a

51
manner similar to that of Example 33.
( Example 41 )
Tert-butyl[2-(4-(l-benzothiene-2-ylmethyl)-2-(2,3)4)6-tetra-0
-benzyl-/?-D-glucopyranosyl)phenoxy)ethyl]carbamate (910 mg)
was dissolved in tetrahydrofuran (20 ml), and lithium aluminum
hydride (76 mg) was added to the mixture, and the mixture was
stirred for seven hours under reflux condition. Aqueous solution
of sodium hydroxide was added to the reaction mixture, and the
precipitate was separated by filtration through celite. The filtrate
was concentrate, and the resulting residue was diluted with
chloroform and dried over sodium sulfate. The solvent was
evaporated therefrom under reduced pressure to give the residue,
and the obtained residue was purified by silica gel column
chromatography (chloroform-methanol) to obtain (lS)-l,5-anhydro
-l-[5-(l-benzothiene-2-ylmethyl)-2-[2-methylamino]ethoxy]phenyl]
-2,3,4,6-tetra-O-benzyl-D-glucitol (612 mg).
( Example 42 )
Tert-butyl[2-(4-(l-benzothiene-2-ylmethyl)-2-(2,3,4,6-tetra-0
-benzyl-/?-D-glucopyranosyl)phenoxy)ethyl]carbamate (906 mg)
was dissolved in acetonitrile (10 ml), and methanol (0.08 ml),
sodium iodide (300 mg), and acetyl chloride (0.28 ml), and the
mixture was stirred for one hour at room temperature. To the
mixture was added diisopropylethylamine (0.70 ml), and the
mixture was stirred for 1.5 hours at room temperature. Further,
acetyl chloride (0.14 ml) and diisopropylethylamine (0.35 ml) were
added to the mixture, and the mixture was stirred for 14 hours at
room temperature. The reaction mixture was diluted with 1M

52
hydrochloric acid and extracted with diethyl ether. The organic
layer was dried over sodium sulfate, and the solvent was
evaporated therefrom under reduced pressure to give the residue.
The residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain N-[2-(4-(l-benzothiene-2-yl
methyl)-2-(2,3,4,6-tetra-0-benzyl-/3 -D-glucopyranosyl)phenoxy)
ethyl]acetamide (387 mg).
( Example 43 )
(lS)-l,5'Anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-hydroxy
phenyl]-D-glucitol (1.33 g) was dissolved in acetic anhydride
•pyridine (l-2) (30 ml), and the mixture was stirred for 25 hours at
room temperature. The reaction mixture was concentrated, and
the obtained solid was washed with ethanol to obtain
(lS)-2,3)4J6-tetra-0-acetyl-l,5-anhydro-l-[2-acetoxyphenyl-
5-(l-benzothiene-2-ylmethyl)-D-glucitol (1.93 g).
The compound in Example 44 was obtained in a manner
similar to that of Example 43.
( Example 45 )
(lS)-2,3,4,6-Tetra-0-acetyl-l,5'anhydro-l-[2-acetoxyphenyl-
5-(l-benzothiene-2-ylmethyl)-D-glucitol (1.93 g) was dissolved in
acetonitrile (30 ml). 1,1,3,3-Tetramethylguanidine (l.6 ml) was
added to the mixture, and the mixture was stirred for 2.5 hours at
50°C. The reaction mixture was concentrated, and the resulting
residue was diluted with saturated ammonium chloride solution
and extracted with ethyl acetate. The organic layer was dried over
sodium sulfate. The solvent was evaporated therefrom under
reduced pressure to give the residue. The resulting residue was

53
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-2,3,4,6-tetra-0-acetyl-l,5-anhydro-l-
[5-(l-benzothiene-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol (1.85
g).
The compound in Example 46 was obtained in a manner
similar to that of Example 45.
( Example 47 )
(lS)-2)3J4,6-Tetra-0-acetyl-l,5-anhydro-l-[5-(l-benzothiene-
2-ylmethyl)-2-hydroxyphenyl]-D-glucitol (570 mg) was dissolved in
dimethylformamide (10 ml), and potassium carbonate (0.69 g),
cyclopentyl bromide (0.54 ml), and potassium iodide (83 mg) were
added to the mixture, and the mixture was stirred for two days at
50°C. The reaction mixture was diluted with ethyl acetate and
washed with water. The organic layer was dried with sodium
sulfate, and the solvent was evaporated therefrom under reduced
pressure to give the residue. The resulting residue was purified
by silica gel column chromatography (n-hexane-ethyl acetate) to
obtain (lS)-2,3,4,6-tetra-0-acetyl-l,5-anhydro-l-[5-(l-benzo
thiene-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucitol (393 mg).
The compound in Example 48 was obtained in a manner
similar to that of Example 47.
( Example 49 )
(lS)-2,3)4)6-Tetra-0-acetyl-l,5-anhydro-l-[5-(l-benzothiene
-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol (570 mg) was dissolved in
tetrahydrofuran (10 ml). 2-propanol (0.38 ml), diethyl
azodicarboxylato (0.63 ml), and triphenylphosphine (1.05 g) were
added to the mixture, and the mixture was stirred for two days at

54
room temperature. Further, 2-propanol (0.23 ml), diethyl
azodicarboxylato (0.31 ml), and triphenylphosphine (0.52 g) were
added to the mixture, and the mixture was stirred for four hours at
room temperature. The reaction mixture was concentrated, and
the residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain (lS)-2,3,4,6-tetra-0-acetyl
-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-(isopropyloxy)
phenyl]-D-glucitol (544 mg).
( Example 50 )
Sodium hydride (60 %) is suspended in dimethylsulfoxide (3
ml), and the mixture was stirred for half an hour at 60°C. To the
mixture was added a solution of (lS)-2,3,4,6-tetra-0-acetyl
-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-hydroxyphenyl]-D-
glucitol (571 mg) in dimethylsulfoxide (2 ml), and the mixture was
stirred for one hour at room temperature. Then, (S)-(-)-4-chloro
methyl-2,2-dimethyl-l,3-dioxolane (0.21 ml), and the mixture was
stirred for seven hours at 80°C. The reaction mixture was diluted
with water and extracted with dichloromethane. The organic
layer was dried over sodium sulfate, and the solvent was
evaporated therefrom under reduced pressure to give the residue.
The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-2,3,4,6-tetra-0-acetyl-l,5-anhydro-l-[5-(l-benzothiene-2-yl
methyl)-2-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methoxy}phenyl)-
D-glucitol (77 mg).
( Example 51 )
2,6-Lutidine (3.98 ml) and trifluoromethanesulfonic

55
anhydride (3.45 ml) were added to a solution of (lS)-l,5-anhydro-
l-[5-(benzothiene-2-ylmethyl)-2-hydroxyphenyl]-2,3,4,6-tetra-0-
benzyl-D-glucitol (13.1 g) in dichloromethane (150 ml) cooled at
■20°C under an argon atmosphere, and the mixture was stirred for
three hours. To the mixture were further added 2,6-lutidine (2.00
ml) and trifluoromethanesulfonic anhydride (1.73 ml), and the
mixture was stirred for one hour. Aqueous solution of saturated
sodium bicarbonate was added to the mixture, and extracted three
times with chloroform. The organic layer was washed with water
and saturated saline solution and dried over anhydrous magnesium
sulfate. The solid was removed by filtration, and the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. The residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l,5-anhydro-l-[5-(benzothiene-2-ylmethyl)-2-trifluoromethane
sulfonylphenyl]-2,3,4,6-tetra-0-benzyl-D-glucitol (13.9 g).
( Example 52 )
(lS)-l,5-Anhydro-l-[5-(benzothiene-2-ylmethyl)-2-trifluorom
ethanesulfonylphenyl]-2,3f4,6-tetra-0-benzyl-D-glucitol (5.67 g)
was dissolved in a mixed solvent of dimethylsulfoxide (30 ml) and
methanol (25 ml). Palladium acetate (II) (285 mg),
l,3-bis(diphenylphosphino)propane (524 mg), and triethyl amine
(1.94 ml) was added to the mixture, and the mixture was stirred for
two days at 55°C in a carbon monoxide atmosphere. The mixture
was cooled to room temperature and then extracted three times
with ethyl acetate. The organic layer was washed with water two
times and saturated saline solution and dried over anhydrous

56
magnesium sulfate. The solid was removed by filtration, and the
solvent was evaporated the filtrate under reduced pressure to give
the residue. The residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain methyl
4-(l-benzothiene-2-ylmethyl)-2-(2,3>4,6-tetra-0-benzyl-/?
-D-glucopyranosyl)benzoate (2.74 g).
( Example 53 )
Methyl 4-(l"benzothiene-2-ylmethyl)-2-(2,3,4,6-tetra-0-
benzyl-/?-D-glucopyranosyl)benzoate (5.26 g) is dissolved in
tetrahydrofuran (5 ml). Methanol (10 ml) and aqueous solution of
10M sodium hydroxide (10 ml) was added to the mixture, and the
mixture was stirred for 21 hours at 60°C. The reaction mixture
was cooled to room temperature, and acidified by addition of 6M
hydrochloric acid, and thereafter extracted three times with
chloroform. The organic layer was washed with saturated saline
solution and dried over anhydrous magnesium sulfate. The solid
was removed by filtration, and the solvent was evaporated from the
filtrate under reduced pressure to give the residue. The residue
was subjected to vacuum drying to obtain 4-(l-benzothiene-2-yl
methyl)-2-(2,3,4,6-tetra-0-benzyl-/5 -D-glucopyranosyl)benzoic acid
(5.13 g).
The compound in Example 54 was obtained in a manner
similar to that of Example 53.
( Example 55 )
Oxarylchloride (0.16 ml) and a drop of dimethylformamide
was added to a solution of [4-(l-benzothiene-2-ylmethyl)-2-(2,3,4,6-
tetra-0-benzyl- /3 -D-glucopyranosyl)phenoxy]acetic acid (770 mg) in

57
dichloromethane (10 ml) under cooling with ice, and the mixture
was stirred for two hours at room temperature. The reaction
mixture was subjected to evaporation under reduced pressure, and
the residue obtained was dissolved in dichloromethane (15 ml).
28% aqueous ammonia (10 ml) was added to the solution, and the
mixture was stirred for one hour at room temperature. The
organic layer was separated and dried over magnesium sulfate.
The solvent was evaporated therefrom under reduced pressure to
give the residue to obtain [4-(l-benzothiene-2-ylmethyl)
-2-(2,3,4,6-tetra-0-benzyl-/? -D-glucopyranosyl) phenoxy]acetamide
(740 mg).
The compound in Example 56 was obtained in a manner
similar to that of Example 55.
( Example 57 )
4-(l-Benzothiene-2-ylmethyl)-2-(2)3,4,6-tetra-0-benzyl-/?
-D-glucopyranosyl)benzoic acid (2.23 g) was dissolved in toluene (20
ml), and triethylamine (0.590 ml) was added to the solution, and
the mixture was cooled to 0°C. Diphenylphosphorylazide (0.67 ml)
was added dropwise gradually to the mixture, and the mixture was
stirred for 2.5 hours at room temperature. The reaction mixture
was diluted with toluene, and then was washed with aqueous
solution of 1% sodium hydrogencarbonate and saturated saline
solution and dried over anhydrous magnesium sulfate. The solid
was removed by filtration, and the solvent was evaporated the
filtrate under reduced pressure to give the residue. The residue
was dissolved in toluene (20 ml), and the mixture was stirred for
three hours at 130°C. 2-Propanol (30 ml) was further added to the

58
mixture, and the mixture was stirred for 16 hours at 110°C. The
mixture was cooled to room temperature, and water was added to
the mixture, and extracted three times with chloroform. The
organic layer was washed with saturated saline solution and dried
over anhydrous magnesium sulfate. The solid was removed by
filtration, and the solvent was evaporated from the filtrate under
reduced pressure to give the residue. The residue was purified by
silica gel column chromatography (n-hexane-ethyl acetate) to
obtain tert-butyl 4-(l-benzothiene'2-ylmethyl)-2-(2,3,4,6-tetra
-0-benzyl-/?-D-glucopyranosyl)phenylcarbamate (1.50 g).
(Example 58 )
Tert-butyl 4-(l-benzothiene-2-ylmethyl)-2-(2,3,4,6-tetra
-0-benzyl-/?-D-glucopyranosyl)phenylcarbamate (l.ll g) was
dissolved in ethyl acetate (3 ml). 4M Ethyl acetate hydrochloride
(3 ml) was added to the mixture under cooling with ice, and the
temperature of the mixture was raised to room temperature. Then,
the mixture was stirred for three hours. Aqueous solution of 1M
sodium hydroxide was added to the mixture, and extracted three
times with chloroform. The organic layer was washed with
aqueous solution of 1M sodium hydroxide and saturated saline
solution and dried over anhydrous magnesium sulfate. The solid
was removed by filtration, and the solvent was evaporated the
filtrate under reduced pressure to give the residue. The residue
was purified by silica gel column chromatography
(n-chloroform-methanol-aqueous ammonia) to obtain
(lS)-l,5-anhydro-l-[2-amino-5-(l-benzothiene-2-ylmethyl)phenyl]-
2-(2,3,4,6-tetra-0-benzyl-D-glucitol (576 mg).

59
( Example 59 )
Lithium aluminum hydride (68 mg) was added to anhydrous
tetrahydrofuran (15 ml) under an argon atmosphere, and a solution
of tert-butyl 4-(l-benzothiene-2-ylmethyl)-2-(2)3)4,6-tetra
-0-benzyl-/? -D-glucopyranosyl)phenylcarbamate (1.27 g) in
anhydrous tetrahydrofuran (15 ml) was gradually added dropwise
to the mixture. The reaction mixture was stirred for two hours at
75°C. After the reaction was completed, the mixture was cooled to
room temperature. Water (l.O ml), aqueous solution of 15%
sodium hydroxide (10 ml), and water (3.0 ml) were added in order,
and the mixture was stirred at room temperature. The solid was
removed by filtration through celite, and the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. Chloroform was added to the mixture, and the mixture
was washed with saturated saline solution and dried over
anhydrous magnesium sulfate. The solid was removed by
filtration, and the solvent was evaporated the filtrate under
reduced pressure to give the residue. The residue was purified by
silica gel column chromatography (n-hexane-ethyl acetate) to
obtain (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-
2-(methylamino)phenyl]-2-(2,3,4,6-tetra-0-benzyl-D-glucitol (737
mg) as achromatic viscous matter.
The compounds in Example 60 to 62 were obtained in a
manner similar to that of Example 59.
( Example 63 )
Phthalimide (294 mg), triphenylphosphine (525 mg), and
diethlazodicarboxylate (0.32 ml) were added to a solution of

60
(lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-(hydroxyl
ethoxy) phenyl]-2-(2,3,4,6-tetra-0-benzyl-D-glucitol (1.35 g) in
tetrahydrofuran (20 ml), and the mixture was stirred for six hours
at room temperature. Silica gel (3 g) was added to the reaction
mixture, and the mixture was dry solidified under reduced pressure
and purified by column chromatography. The residue was
dissolved in tetrahydrofuran (15 ml) and ethanol (15 ml).
Hydrazine hydrate (0.54 ml) was added dropwise to the mixture,
and the mixture was stirred for 24 hours at room temperature.
After insoluble matter was separated by filtration, the filtrate was
concentrated to obtain the residue. Chloroform was added to the
residue, and insoluble matter was further separated by filtration.
The filtrate was washed with water, dried over magnesium sulfate,
and concentrated. The residue obtained was purified by silica gel
column chromatography to obtain (lS)-l,5-anhydro-l-
[2-(aminoethoxy)-5-(l-benzothiene-2-ylmethyl)phenyl]-2,3,4,6-
tetra-O-benzyl-D-glucitol (960 mg).
( Example 64)
(lS)-l,5-Anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-(methyl
amino)phenyl]-2,3,4,6-tetra-0-benzyl-D-glucitol (179 mg) was
dissolved in dichloromethane (3 ml). 35% Formalin (0.008 ml) and
acetic acid (0.02 ml) were added to the mixture, and the mixture
was stirred at room temperature. Sodium triacetoxy boronhydride
(74 mg) was added to the mixture, and the mixture was stirred for
11 hours. Aqueous solution of saturated sodium
hydrogencarbonate was added to the reaction mixture, and
extracted three times with chloroform after decomposition of the

61
excessive reagent. The organic layer was washed with saturated
saline solution and dried over anhydrous magnesium sulfate. The
solid was removed by filtration, and the solvent was evaporated
from the filtrate under reduced pressure to give the residue. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain (lS)-l,5-anhydro-l-[5-(l-benzo
thiene-2-ylmethyl)-2-(dimethylamino)phenyl]-2,3,4)6-tetra-0-benzy
1-D-glucitol (124 mg).
( Example 65 )
A solution of 1.58 M n-hexane (2.2 ml) of n-butyl lithium was
added dropwise to a solution of [l-benzothiene-2-yl(5-bromo-2-
fluorophenyl)methoxy](tert-butyl)dimethylsilane (1.50 g) in
anhydrous tetrahydrofuran (15 ml) cooled at -78°C under an argon
atmosphere, and the mixture was stirred for half an hour. Then, a
solution of 2,3,4,6-tetra-0-benzylgluconolactone (1.90 g) in
anhydrous tetrahydrofuran (20 ml) was added to the reaction
mixture, and the mixture was stirred for 1.5 with gradually raising
the temperature from -78°C to 0°C. Aqueous solution of saturated
ammonium chloride was added to the mixture, and extracted three
times with ethyl acetate. The organic layer was washed with
aqueous solution of saturated ammonium chloride and saturated
saline solution and dried over anhydrous magnesium sulfate. The
solid was removed by filtration, and the solvent was evaporated
from the filtrate under reduced pressure to give the residue. The
residue was purified by silica gel column chromatography
(chloroform-n-hexane-acetone). The residue (1.52 g) obtained was
dissolved in dehydrated tetrahydrofuran (15 ml). A solution of

62
tetra-n-butyl ammonium fluoride in 1.0 M tetrahydrofuran (2.0 ml)
was added to the mixture, and the mixture was stirred for 65
minutes at room temperature. After the solvent was evaporated
therefrom under reduced pressure to give the residue, the residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate). Triethylsilane (0.239 ml) and borontrifluoride diethyl
ether complex (0.175 ml) were added to a solution of the residue
(500 mg) obtained in acetonitrile (5 ml), and the mixture was
stirred for five hours. To the mixture was added aqueous solution
of saturated sodium hydrogencarbonate, and then extracted three
times with chloroform after decomposition of excessive reagent.
The organic layer was washed with aqueous solution of saturated
sodium hydrogencarbonate and saturated saline solution, and dried
over anhydrous sodium sulfate. The solid was removed by
filtration, and the solvent was evaporated from the filtrate under
reduced pressure to give the residue to give the residue. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate) to obtain 1,5-anhydro-l-
[3-(l-benzothiene-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-0-benz
yl-D-glucitol (150 mg) as light-yellow viscous matter.
The compounds in Examples 66 to 68 were obtained in a
manner similar to that of Example 65.
(Example 69 )
Magnesium (granules; 131 mg), and 1,2-dibromoethane (a
drop) were added to tetrahydrofuran (10 ml) under an argon
atmosphere. A solution of 2-(l-benzothiene-2-ylmethyl)
-4-bromophenyl methyl ether (1.5 g) in tetrahydrofuran (15 ml) was

63
gradually added dropwise to the mixture, and the temperature was
raised from room temperature to 60°C to prepare a Grignard
reagent. After cooling to room temperature, a solution of
2,3,4,6-tetra-0-benzyl-D-(+)- glucono-l,5"lactone (2.91 g) in
tetrahydrofuran (20 ml) was added to the reagent, and the mixture
was stirred for three hours. Aqueous solution of saturated
ammonium chloride was added to the mixture, and extracted three
times with ethyl acetate. The organic layer was washed with
aqueous solution of saturated ammonium chloride and saturated
saline solution and dried over anhydrous magnesium sulfate. The
solid was removed by filtration, and the solvent was evaporated
from the filtrate under reduced pressure to give the residue. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate). Triethylsilane (0.146 ml) and boron
trifluoride-diethyl ether complex (0.105 ml) was added to a solution
of the residue (600 mg) obtained in acetonitrile (6 ml) at -20°C, and
the mixture was stirred for three hours. Triethylsilane (0.073 ml)
and boron trifluoride-diethyl ether complex (0.048 ml) was further
added to the mixture. The temperature was raised to -10°C, and
the mixture was stirred for two hours. Aqueous solution of
saturated sodium hydrogencarbonate was added to the mixture to
decompose superfluous reagent, and extracted three times with
chloroform. The organic layer was washed with saturated saline
solution and dried over anhydrous magnesium sulfate. The solid
was removed by filtration, and the solvent was evaporated from the
filtrate under reduced pressure to give the residue. The residue
was purified by silica gel column chromatography (n-hexane-ethyl

64
acetate) to obtain (lS)-l,5-anhydro-l-[3-(l-benzothiene
-2-ylmethyl)-4-methoxyphenyl]-2,3,4,6-tetra-0-benzyl-D-glucitol
(394 mg).
The compound in Example 70 was obtained in a manner
similar to that of Example 69.
( Example 71 )
A solution of 2-bromopyridine (342 mg) in tetrahydrofuran
(13 ml) was added dropwise to a solution of 1.59 M hexane (1.36 ml)
of n-butyl lithium at -78°C under an argon atmosphere, and the
mixture was stirred for one hour at the same temperature. Then,
a solution of 3-(2,3,4,6-tetra-0-benzyl-/? -D-gluglucopyranosyl)
benzaldehyde (1.13 g) in tetrahydrofuran (35 ml) was added
dropwise to the mixture, and the mixture was stirred for 2.5 hours.
Water (40 ml) was added to the reaction mixture, and extracted
with ethyl acetate, and the organic layer was dried over anhydrous
magnesium sulfate. After filtration, the solvent was evaporated
from the filtrate under reduced pressure to give the residue, and
the resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain (lS)-
1,5-anhydro -2,3,4,6-tetra-0-benzyl-l-[3-[hydroxy(pyridine-2-yl)
methyllphenyl] -D-glucitol (0.99 g). Sodium hydride (60%) (202
mg) was added to a solution of (lS)-l,5-anhydro-2,3,4,6-tetra-0-
benzyl -l-[3- [hydroxy(pyridine-2- yl)methyl]phenyl]-D-glucitol
(1.78 g) in tetrahydrofuran (12 ml) at room temperature, and the
mixture was stirred for half an hour. Carbon disulfide (1.15 ml)
was added dropwise to the mixture under cooling with ice, and the
mixture was stirred for two hours at the same temperature and

65
further two hours at room temperature. Methyl iodide (0.28 ml)
was added dropwise to the reaction mixture under cooling with ice,
and the mixture was stirred for 2.5 hours at the same temperature.
Water was added to the reaction mixture, and extracted with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate. After filtration, the solvent was evaporated from the
filtrate under reduced pressure to give the residue, and the residue
was dissolved in toluene (20 ml). Tributyltin hydride (3.28 ml)
and agoisQbutyronitriJre (82 mg) were added to the mixture, and the
mixture was stirred for 64 hours under reflux condition. The
solvent was evaporated from the filtrate under reduced pressure to
give the residue, and the residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l)5-anhydro-2,3(4>6-tetra-0-benzyl-l-[3-[(pyridine-2-yl)methyl
]phenyl]-D-glucitol (1.51 g).
The compound in Example 72 was obtained in a manner
similar to that of Example 71.
( Example 73 )
(lS)-l,5-Anhydro-2,3,4,6-tetra-0-benzyl-l-[3-[(hydroxyl
methyl)phenyl]-D-glucitol (631 mg) and phthalimide (154 mg) were
dissolved in tetrahydrofuran (10 ml). Diethylazodicarboxylate
(0.18 ml) and triphenylphosphine (303 mg) were added to the
mixture under cooling with ice, and the mixture was stirred for 20
hours at room temperature. The reaction mixture was
concentrated, and the residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain (IS)-
l^-anhydro^^^^-tetra-O-benzyl-l-C^S-Id.S-dioxo-l^-dihydro-

66
2H-isoindole-2-yl)methyl]phenyl}-D-glucitol (784 mg).
( Example 74 )
1,2-Dibromoethane (one drop) was added to a solution of zinc
dust (86 mg) in tetrahydrofuran (2.0 ml) in an argon atmosphere,
and the solution was refluxed for five minutes. Chloro-
trimethylsilane (a drop) was added to the mixture at room
temperature, and the mixture was stirred for 15 minutes. Then,
(lS)-2,3,4,6-tetra-0-acetyl-l,5-anhydro-l-(3-bromomethyl
-6-methoxy)phenyl-D-glucitol (700 mg) was added to the mixture,
and the mixture was refluxed for one hour. 2-bromo- lH-indene
(128 mg) and totrakiotriphonylphosphine palladium (76 mg) were
added to the mixture, and the mixture was heaWefluxed for five
hours. The temperature of the mixture was cooled to room
temperature, and aqueous solution of saturated ammonium
chloride was added. The insoluble matter was separated by
filtration, and the filtrate was extracted with ethyl acetate. The
organic layer was washed with saturated saline solution and dried
with anhydrous sodium sulfate. After filtration, the solvent was
evaporated from the filtrate under reduced pressure to give the
residue, and the residue was purified by silica gel column
chromatography (chloroform-ethyl acetate) to obtain
(lS)-2,3,4,6-tetra-0-acetyl-l,5-anhydro-l-[3-[(lH-indene
-2-yl)methyl-6-methoxy]phenyl]-D-glucitol (190 mg).
The compounds in Examples 75 to 79 were obtained in a
manner similar to that of Example 74.
( Example 80 )
Active zinc (131 mg) was suspended in tetrahydrofuran (2

67
ml). 1,2-dibromoethane (0.07 ml) was added to the suspension,
and the suspension was stirred for five minutes at 60°C. Then,
trimethylsilyl chloride (0.10 ml) was added to the mixture, and the
mixture was stirred for 10 minutes at room temperature.
Subsequently, a solution of (lSVl^-anhydro^S^e-tetra-O-
benzyMS-OsromoniethyDphenyll-D-glucitol (694 mg) in
tetrahydrofuran (3 ml) was added to the mixture, and the mixture
was stirred for one hour at 60°C. Then, 2-(methylthio)
benzothiazole (181 mg) and tetrakisphosphine palladium^(231 mg)
were added to the mixture, and the mixture was stirred for 15 hours
at 60°C. After the precipitate was separated by filtration, the
filtrate was concentrated. The residue obtained was diluted with
ethyl acetate and washed with saturated aqueous sodium
bicarbonate and saturated saline solution. The organic layer was
dried over sodium sulfate, and the solvent was evaporated
therefrom under reduced pressure to give the residue. The residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl
-l-[3-(l,3-benzothiazole-2-ylmethyl)phenyl]-D-glucitol (355 mg).
(Example 81 )
1,4-Dioxane (10 ml) suspension of (lS)-2,3,4,6-tetra-0-
acetyl-l,5-anhydro-l-[3-(bromomethyl)phenyl]-D-glucitol (501 mg),
l-methyl-2-(tributylstanyl)-lH-indole (546 mg), tris(dibenzylidene-
acetone)dipalladium (92 mg), 2-(dicyclohexylphosphino)biphenyl
(88 mg), potassium fluoride (174 mg), and cesium carbonate (652
mg) was stirred for 18 hours at 60°C. The insoluble matter was
removed by filtration, and the solvent was evaporated from the

68
filtrate to give the residue. The residue obtained was subjected to
silica gel column chromatography to obtain (lS)-2,3,4,6-tetra
-0-acetyl-l,5-anhydro-l-{3-[(l-methyl-lHundole-2-yl)methyl]pheny
l}-D-glucitol (280 mg).
The compounds in Examples 82 to 91 were obtained in a
manner similar to that of Example 81.
(Example 92 )
Tetrakistriphenylphosphinepalladium(O) (43 mg) and
dimethyl-l-benzothiene-3-ylboronate (132 mg) to a solution of
l-(2,3,4,6-1etra-0-benzyl-/? -D-glucopyranosyl)-3-(trifluoro
methanesulfonyDbenzene (280 mg) in toluene (10 ml) at room
temperature. Aqueous solution of saturated sodium bicarbonate
(4 ml) was further added to the mixture, and the mixture was
stirred for four hours at 90°C. Ethyl acetate and saturated saline
solution were added to the reaction mixture, the insoluble matter
was subjected to filtration through celite, and the organic layer was
extracted. The organic layer was washed with water and
saturated saline solution, dried over anhydrous magnesium sulfate,
and concentrated to give the residue. The resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate) to obtain (lS)-l,5-anhydro-l-[3-(l-benzothiene-3-yl)
phenyl]- 2,3,4,6-tetra-O-benzyl-D-glucitol (170 mg).
(Example 93 )
Twenty percents of palladium hydroxide/carbon (800 mg)
were added to a suspension of l^S^-dianhydro-GJ^lO-tetra
-0-benzyl-2,3-dideoxy-2-(4-methoxybenzyl)-l-thio-D-glycero-
D-deca-l,3-dienitol (0.72 g) in tetrahydrofurane (5.0 ml) and

69
hydrochloric acid in 2% methanol solution (10 ml), and the mixture
was stirred for 18 hours at hydrogen atmosphere (l atm). The
reaction mixture was filtrated through celite, and the filtrate was
concentrated. Then, pyridine (3.0 ml) and acetic anhydride (1.5
ml) were added to the residue, and the mixture was stirred over
night at room temperature. The solvent was evaporated therefrom
under reduced pressure, and the resultant was co-evaporated with
toluene. The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain 6,7,8,10-tetra*
0-acetyl-1,4:5,9-dianhydro-2,3-dideoxy-2-(4-methoxybenzyl)-l-thio-
D-glycero-D-deca-l,3-dienitol (0.13 g).
( Example 94 )
0.76 Mole of tetrahydrofuran solution of
isopropylmagnesium bromide (27.6 ml) was added dropwise to a
solution of 2-(4-ethylbenzyl)-lH-pyrrole (4.14 g) in tetrahydrofuran
(10 ml), and the mixture was stirred for two hours. To the mixture
was added dropwise 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl
fluoride (3.80 g), and the mixture was stirred for five hours.
Aqueous solution of saturated ammonium chloride was added to the
reaction mixture, and extracted with ethyl acetate. The organic
layer was washed with saturated saline solution and dried over
anhydrous sodium sulfate. After filtration, the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. The residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-[5-(4-ethyl
benzyl)-lH-pyrrole-2-yl]-D-glucitol (1.89 g).

70
( Example 95 )
Fifteen mg of sodium hydride (60%) were added to a solution
of (lS)-l,5-anhydro-2)3,4,6-tetra-0-benzyl-l-[5-(4-ethylbenzyl)-lH-
pyrrole-2-yl]-D-glucitol (210 mg) in dimethylformamide (3.0 ml),
and the mixture was stirred for 15 minutes at room temperature.
Then, methyl iodide (0.185 ml) was added to the mixture, and the
mixture was stirred for half an hour. Water was added to the
reaction mixture, and extracted with diethyl ether. The organic
layer was washed with water and saturated saline solution and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated from the filtrate under reduced pressure to give the
residue. The residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-[5-(4-ethylbenzyl)
-l-methyl-lH-pyrrole-2-yl]-D-glucitol (143 g).
( Example 96 )
(lS)-l)5-Anhydro-2,3,4,6-tetra-0-benzyl-l-(lH-pyrrole-2-yl)-
D-glucitol (773 mg) was added to a suspension of tetrabutyl
ammonium bromide (42.2 mg) and potassium hydroxide (150 mg) in
benzene (5.0 ml), and 4-ethylbenzyl bromide (331 mg) was added to
the mixture. The mixture was stirred for two hours at room
temperature. Water was added to the reaction mixture, and
extracted with ethyl acetate. The organic layer was washed with
saturated saline solution and dried over anhydrous sodium sulfate.
After filtration, the solvent was evaporated from the filtrate under
reduced pressure to give the residue. The resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl

71
acetate) to obtain (lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-
[l-(4-ethylbenzyl)-!H-pyrrole-2-yl]-D-glucitol (695 mg).
( Example 97 )
Triethylamine (0.6 ml) was added to a solution of (lS)-
2,3,4,6-tetra-0-acetyl-l,5-anhydro-l-(lH-tetrazole-5-yl)"D"glucitol
(0.85 g) in tetrahydrofuran (10.0 ml), and 4-ethylbenzyl bromide
(0.50 g) was added to the mixture. The mixture was stirred for 17
hours at room temperature. Water was added to the reaction
mixture, and extracted with ethyl acetate. The organic layer was
washed with water and saturated saline solution and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
evaporated from the filtrate under reduced pressure to give the
residue. The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-2,3;4,6-tetra-0-acetyl-l,5-anhydro-l-[2-(4-ethylbenzyl)-lH-tet
razole-5-yl]-D-glucitol (0.22 g).
( Example 98 )
2,3,4,6-Tetra-0-benzyl-l-C-(3,5-dichloropyrazine-2-yD-D-
glucopyranose (7.93 g) was dissolved in dichloromethane (90 ml),
and triethylsilane (36.8 ml) and trifluoroacetic acid (17.7 ml) were
added to the mixture, and the mixture was stirred for 19 days at
room temperature. The reaction mixture was washed with
saturated sodium bicarbonate, and the water layer was extracted
with chloroform. The whole organic layer combined was dried over
sodium sulfate, and the solvent was evaporated from the filtrate
under reduced pressure to give the residue. The resulting residue
was purified by silica gel column chromatography (n-hexane-ethyl

72
acetate) to obtain (lS)-l,5-anhydro-2,3,4,6-tetra'0-benzyl
-l-(3,5-dichloropyrazine-2-yl)-D-glucitol (2.15 g).
(Example 99 )
1.58 Moles of n-hexane solution (2.15 ml) of n-butyllithium
were diluted with tetrahydrofuran (20 ml), and 2,2,6,6-tetramethyl
piperidine (0.64 ml) was added dropwise to the solution at -78°C,
and the mixture was stirred for one hour at 0°C. Subsequently, a
solution of (lS)-l,5-anhydro-2J3,4)6-tetra-0-benzyl
-l-(3,5-dichloropyrazine-2-yl)-D-glucitol (2.09 g) in
tetrahydrofuran (20 ml) was added to the mixture at -78°C, and the
mixture was stirred for one hour at -78°C. Then,
4-ehylbenzaldehyde (1.28 ml) was added to the mixture, and the
mixture was stirred for 1.5 hours at -78°C. The reaction mixture
was washed with saturated aqueous ammonium chloride, and the
water layer was extracted with diethyl ether. The whole organic
layer combined was dried over sodium sulfate, and the solvent was
evaporated therefrom under reduced pressure to give the residue.
The resulting residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate) to obtain
(lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl-l-(3,5-dichloro
-6-[(4-ethylphenyl)(hydroxy)methyl]pyrazine-2-yl)-D-glucitol (842
mg).
( Example 100 )
Pentamethylbenzene (1.57 g) and 1.0 M n-heptane solution
(2.97 ml) of boron trichloride were added to a solution of
(lS)-l>5-anhydro-l-[3-[(5-methyl-l-benzothiene-2-yl)methyl]phenyl
]-2,3,4,6'tetra-0-benzyl-D-glucitol (538 mg) in dichloromethane (25

73
ml), and the mixture was stirred for one hour. After the reaction
was completed, methanol (5 ml) was added to decompose excessive
reagent, and the resultant was subjected to evaporation under
reduced pressure to remove solvent and give the residue. The
residue was purified by silica gel column chromatography
(chloroform-methanol) to obtain (lS)-l,5-anhydro-l-[3-[(5-methyl
-l-benzothiene-2-yl)methyl]phenyl]-D-glucitol (274 mg).
The compounds in Examples 101 to 153 were obtained in a
manner similar to that of Example 100.
( Example 154 )
IMole of n-heptane solution of borontribromide (4.54 ml) was
added dropwise to a solution of (lS)-l,5-anhydro'2,3,4,6-tetra-0-
benzyl-l-[3-[(benzothiophene-2-yl)methyl]phenyl]-D-glucitol (0.77
g) and pentamethylbenzene (2.3 g) in dichloromethane (20 ml) at
•78°C in an argon atmosphere, and the mixture was stirred for 90
minutes. Methanol was added dropwise to the reaction mixture at
-78°C, and the mixture was stirred till the temperature became
room temperature. The solvent was evaporated therefrom under
reduced pressure to give the residue, and methanol (20 ml) was
further added thereto, and concentrated to give the residue. Then,
toluene was added for further thereto, and concentrated to give the
residue. The resulting residue was purified by silica gel column
chromatography (chloroform-methanol) to obtain yellow amorphous
(390 mg). This was further purified by a reversed-phase column
chromatography to obtain (lS)-l,5-anhydro-l-[3-[(l-benzo
thiophene-2-yl)methyl]phenyl] -D-glucitol (270 mg).
The compound in Example 155 was obtained in a manner

74
similar to that of Example 154.
( Example 156 )
(lS)-2>3,4,6-Tetra-0-acetyM,5-anhydro-l-[5-(l-benzo
thiophene-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucitol (381
mg) was dissolved in methanol (10 ml). Sodium methoxide (32 mg)
was added to the solution, and the mixture was stirred for three
hours at room temperature. The reaction mixture was neutralized
with acid ion-exchange resin, and the resin was separated by
filtration. The filtrate was concentrated, and the resulting
residue was purified by silica gel column chromatography
(chloroform-methanol) to obtain (lS)-l,5-anhydro-l-[5-(l-benzo
thiene-2-yl)methyl]-2-(cyclopentyloxy)phenyl]-D-glucitol (215 mg).
The compounds in Examples 157 to 178 were obtained in a
manner similar to that of Example 156.
(Example 179 )
(lS)-l,5-Anhydro-l-{5-[l-benzothiene-2-ylmethyl]-2-[(2-
dimethylamino)ethoxy]phenyl}-2,3,4,6-tetra-0-benzyl-D-glucitol
(520 mg) was dissolved in dichloromethane (25 ml). After
pentamethylbenzene (1.39 g) was added to the solution, the
resultant was cooled to -78°C. 1.0 Mole of n-heptane solution (3.4
ml) of boron trichloride was added thereto, and the resultant
mixture was stirred for four hours at -78°C. Methanol was added
to the reaction mixture, and the solvent was evaporated therefrom
under reduced pressure to give the residue. A mixed solution of
toluene-diethyl ether (i:i) was added thereto, and extracted with
aqueous solution of saturated sodium hydrogencarbonate. Water
was evaporated under reduced pressure, and the residue was

75
purified by a reversed-phase column chromatography
(methanol-water). Finally, the solid obtained was washed with
diethyl ether to obtain (lS)-l,5-anhydro-l-{5-[l-benzothiene-2-yl
methyl]-2-[(2-dimethyl amino)ethoxy]phenyl}-D-glucitol (104 mg).
( Example 180 )
1 Mole of aqueous solution of sodium hydroxide (1.5 ml) was
added to (2R,3S,4S,4aR,10bS)-7-(l-benzothinene-2-ylmethyl)
-3,4-dihydroxy-hydroxymethyl)-3,4,4a,10b-tetrahydropyrano[3,2-c]
isocumene-6(2H)-one (80 mg), and the mixture was stirred for two
hours. Then, the reaction mixture was neutralized by adding 1 M
aqueous solution of hydrochloric acid (1,5 ml) The reaction
mixture was concentrated, and the residue was purified by a
reversed-phase column chromatography (water-methanol) to obtain
4-(l-benzothiene-2-ylmethyl)-2-(/5 -D-glucopyranosyl)benzoic acid
(67 mg).
(Example 181 )
N-Methylmorpholine (412 mg) and chlorotrimethylsilane
(295 mg) were added to a solution of (2R,3S,4S,4aR,10bS)-7-
(l-benzothinene-2-ylmethyl)-3,4-dihydroxy-2-hydroxymethyl)-3,4t4
at10b-tetrahydropyrano[3,2-c]isocumene-6(2H)-one (280 mg) in
tetrahydrofuran (14 ml) at -5°C, and the mixture was stirred for 12
hours at 40°C. Toluene and water were added to the reaction
mixture, and the organic layer was extracted. The organic layer
was washed with water and saturated saline solution and dried
over anhydrous sodium sulfate. The resulting residue (384 mg)
was dissolved in tetrahydrofuran (15 ml), and lithium aluminum
hydride (56 mg) was added to the solution at -10°C. After the

76
mixture was stirred for three hours under cooling with ice, sodium
sulfate decahydrate was added thereto. After the resultant was
filtrated through celite, the filtrate was concentrated to give the
residue. The residue was purified by a reversed-phase column
chromatography (water-methanol) to obtain (lS)-l,5-anhydro
•l-[5-(l-benzothiene-2-ylmethyl)-2-(hydroxymethyl)phenyl]
-D-glucitol (90 mg).
(Example 182 )
Twenty percents of hydrochloric acid-methanol (three drops)
and 5% palladium-carbon (0.1 g) were added to a solution of
(lH'indene-2-yl)[3-(2,3,4)6-tetra-0-benzyl-/?-D-glucopyranosyl)
phenyllmethanone (0.84 g) in methanol (10 ml), and the resultant
was stirred for 18 hours in a hydrogen atmosphere. The reaction
mixture was filtrated, and the solvent was evaporated from the
filtrate under reduced pressure to give the residue, and the
resulting residue was purified by silica gel column chromatography
(chloroform-methanol) to obtain (lS)-l,5-anhydro-l-[3-
[(2,3-dihydro-lH-indene-2-yl)methyl]phenyl]-D-glucitol (16 mg).
The compounds in Examples 183 and 184 were obtained in a
manner similar to that of Example 182.
( Example 185 )
Sodium hydride (42 mg) was added to a solution of pyrrole
(64 mg) in dimethylformamide (10 ml) under cooling with ice, and
the mixture was stirred for half an hour at room temperature.
After the mixture was cooled to -30°C, a solution of
(lS)-2>3,4,6-tetra-0-acetyM,5-anhydro-l-[3-(bromomethyl)phenyl]-
D-glucitol (80 mg) in tetrahydrofuran (2 ml) was added dropwise

77
thereto, and the resultant was stirred for one hour at room
temperature. Methanol (10 ml) and sodium methoxide (44 mg)
was added thereto, and the resultant was stirred for one hour at the
same temperature. After the completion of the reaction, the
reaction mixture was concentrated to give the residue. The
resulting residue was purified by a reversed-phase column
chromatography (water-methanol) to obtain (lS)-l,5-anhydro-l-
[3-(lH-pyrrole -l-ylmethyl)-phenyl]-D-glucitol (18 mg).
(Example 186 )
Twenty percents of palladium hydroxide/carbon (130 mg)
were added to a suspension of (lS)-l,5-anhydro-2,3,4,6'tetra
-0-benzyl-l-[5-(4-ethyl benzyl)-lH-pyrrole-2-yl]-D-glucitol (400 mg)
in ethyl acetate-acetic acid (lO^l) (ll ml), and the resultant was
stirred for one hour in a hydrogen atmosphere (l atm). The
reaction mixture was filtrated through celite, and the filtrate was
concentrated to give the residue. The resulting residue was
purified by silica gel column chromatography
(chloroform-methanol) to obtain (lS)-l,5-anhydro-l-[5-(4-ethyl
benzyl)-lH-pyrrole-2-yl]-D-glucitol (25 mg).
The compound in Example 187 was obtained in a manner
similar to that of Example 186.
( Example 188 )
Ten percents of palladium/carbon (450 mg) was added to a
solution of (lS)-l,5-anhydro-2,3,4,6-tetra-0-benzyl
-l-[l-(4-ethylbenzyl)-lH -pyrrole-2-yl]-D-glucitol (587 mg) in ethyl
acetate-methanol-acetic acid (10^2:1) (39 ml), and the resultant was
stirred for 22 hours in a hydrogen atmosphere. The reaction

78
mixture was filtrated through celite, and the filtrate was
concentrated to give the residue. The resulting residue was
purified by silica gel column chromatography
(chloroform-methanol) to obtain (lS)-l,5-anhydro-l-[l-(4-ethyl
benzyl)-lH-pyrrole-2-yl] -D-glucitol (59 nig).
The structural formulas and physicochemical properties of
the compounds of Reference Examples are shown by the following
Tables 1 - 6. The structural formulas and physicochemical
properties of the compounds of Examples are shown by the
following Tables 7 - 36.
Incidentally, the symbols in the tables have the following
meanings1
Rf.: number of Reference Example, Ex: number of
Example, Structure1 structural formula, Me: methyl group,
Et: ethyl group, Bn: benzyl group, Bu: butyl group,
TBDMS: tert-butyldimethylsilyl group, TBDPS:
tert-butyldiphenylsilyl group, Ac: Acetyl group, Tf:
trifluoromethanesulfonyl group, Data: property data, NMR:
nuclear magnetic resonance spectrum (TMS internal standard),
MS: mass analysis value
Compounds listed in Tables 37 to 39 can be easily prepared
in a manner similar to that of Examples and Preparation Examples
or by a method with minor modifications which are obvious for
persons of ordinary skill in the art. Tables 37 to 39 are given after
Tables 1 to 36.
INDUSTRIAL APPLICABILITY

79
Since Oglycoside derivatives and the salts thereof (the
compounds of the present invention) have the effects of inhibiting a
Na+-glucose cotransporter and reducing the level of blood glucose,
these compounds are useful for treating or preventing diabetes
such as insulin-dependent diabetes (type 1 diabetes) and
insulin-independent diabetes (type 2 diabetes), insulin-resistant
diseases, and obesity, for example, as a medicine, particularly as a
Na+-glucose cotransporter inhibitor.
The significant effects of inhibiting a Na+-glucose
cotransporter and reducing the blood glucose of the compound of
the present invention have been confirmed by the following
pharmacological tests (Test Examples 1 and 2).
Test Example 1
[Inhibition of human Na+-glucose cotransporter (human SGLT2)
activity]
(l) Preparation of human SGLT 2 expression vector
First, single-strand cDNA was reversely transcripted from
total RNA originating from the human kidney (manufactured by BD
Biosciences Clontech) using a Superscript II (manufactured by
Invitrogen Corporation) and a random hexamer. Second, using the
cDNA as a template, a DNA fragment encoding a human SGLT2
(Wells, R.G. et al., Am. J. Physiol., 1992, 263(3) F459) was
amplified by the PCR reaction using Pyrobest DNA polymerase
(manufactured by Takara Bio Inc.). That is, a Hind III site and an
EcoRIsite were inserted into the 5' side and the 3' side of the DNA
fragment, respectively by using primers.
The amplified fragment was cloned into a pCR2.1-Topo

80
vector using a Topo TA Cloning Kit (manufactured by Invitrogen
Corporation) and the cloned vector was transfected into a
competent cell of Escherichia coli JM109. Ampicillin-resistant
clones were cultured in a LB medium containing ampicillin (100
mg/1). Aplasmid was purified from the cultured Escherichia coli
using the method of Hanahan (see Maniatis et al., "Molecular
Cloning"). A DNA fragment for encoding a human SGLT2 was
obtained by the HindIIIIEcoRIdigestion of the plasmid and ligated
and cloned to the same site of the expression vector pcDNA 3.1
(manufactured by Invitrogen Corporation) using a DNA ligase
(manufactured by Roche Diagnostics). The ligated clone was
transfected into a competent cell of Escherichia coli JM109 in the
same manner as described above and cultured in a LB medium
containing ampicillin, and a human SGLT2 expression vector was
obtained using the method of Hanahan.
(2) Preparation of human SGLT2 expressed cells
The human SGLT2 expression vector was transfected into a
CHO-Kl cell using Lipofectamine2000 (manufactured by Invitrogen
Corporation). The cell was cultured in a Ham's F12 medium
(manufactured by Nissui Pharmaceutical Co., Ltd.) containing
penicillin (50 IU/ml, manufactured by Dainippon Pharmaceutical
Co., Ltd.), streptomycin (50 pg/ml, manufactured by Dainippon
Pharmaceutical Co., Ltd.), Geneticin (40 pg/ml, manufactured by
Invitrogen Corporation), and 10% fetal bovine serum in the
presence of 5% CO2 at 37°C for two weeks, and Geneticin-resistant
clones were obtained. A cell which stably expresses the human
SGLT2, which exhibits sodium-dependent intake of methyl-a

81
-D-glucopyranoside, was obtained (See the following paragraphs for
the method for measuring the methyl- a -D-glucopyranoside
intake).
(3) Inhibition of methyl-a-D-glucopyranoside intake
After removing the medium of a CHO cell which stably
expresses the human SGLT2, a pretreatment buffer solution (buffer
solution of pH 7.4 containing choline chloride (140 mM), potassium
chloride (2 mM), calcium chloride (l mM), magnesium chloride (l
mM), 2-[4-(2-hydroxyethyl)l-piperazinyl] ethanesulfonic acid (10
mM), and tris(hydroxymethyl) aminomethane (5 mM)) was added in
the amount of 100 pi per well, and incubated at 37°C for 20
minutes.
11 pi of methyl-a-D-(U'14C)glucopyranoside (manufactured
by Amersham Pharmacia Biotech) was mixed with 1,000 pi of a
buffer solution for intake containing a test compound (buffer
solution of pH 7.4 containing sodium chloride (140 mM), potassium
chloride (2 mM), calcium chloride (l mM), magnesium chloride (l
mM), methyl- a -D-glucopyranoside (50 pM), 2-[4-(2-hydroxy
ethyl)l-piperazinyl]ethanesulfonic acid (10 mM), and
tris(hydroxymethyl)aminomethane (5 mM)) to prepare a buffer
solution for intake. A buffer solution for intake without a test
compound was prepared for a control group. A buffer solution for
basal intake without a test compound containing choline chloride
(140 mM) instead of sodium chloride for measuring the basal intake
was prepared as well.
After removing the pretreatment buffer solution, the buffer
solution for intake was added (25 pi per well) and incubated at 37°C

82
for two hours. After removing the buffer solution for intake, a
buffer solution for washing (buffer solution of pH 7.4 containing
choline chloride (140 mM), potassium chloride (2 mM), calcium
chloride (l mM), magnesium chloride (l mM), methyl- a -D-
glucopyranoside (10 mM), 2-[4-(2-hydroxyethyl) -1-piperazinyl]
ethanesulfonic acid (10 mM), and tris(hydroxymethyl)
aminomethane (5 mM)) was added (200 |jl per one well). The
mixture was immediately removed. This washing operation was
carried out once more. 0.5% Sodium lauryl sulfate was added (25
fjl per well) to solubilize the cells. Seventy five pi of Microscint 40
(manufactured by PerkinElmer, Inc.) was added to the solubilized
cell and the radiation activity was measured using a
microscintillation counter TopCount (manufactured by Perkin
Elmer, Inc.). The value obtained by subtracting the basal intake
amount from the intake amount of the control group was defined as
100%. The concentration for 50% inhibition of the above value
(IC50 value) was calculated from a concentration-inhibition curve
using the least squares method. As a result, the compound of the
present invention exhibited a strong effect of inhibiting a
Na+-glucose cotransporter activity. The IC50 values of typical
compounds of the present invention are shown in Table 40.
Table 40

Compound IC50 (nM) Compound IC50 (nM)
Example 117 13 Example 142 21
Example 134 14 Example 150 6.5
Example 141 3.8 Example 174 6.6

83
Test Example 2
[Hypoglycemic activity confirmation test]
Fed KK-A^ mice (CLEA Japan, Inc., male) were used. The
test compound was suspended in 0.5% methylcellulose solution to a
concentration of 1 mg/10 ml. The weight of each mouse was
measured. The test compound suspension was orally administered
to the mice at a dose of 10 ml/kg. Only 0. 5% methylcellulose
solution was administered to the mice of a control group. Each
group consisted of six mice. Blood was collected from the tail vein
immediately before administering the compound and one, two, four,
and eight hours after administering the compound. The blood
glucose value was measured using a glucose CII Test Wako
(manufactured by Wako Pure Chemical Industries, Ltd.). The
intensity of hypoglycemic activity was determined by calculating
the area under the blood glucose value-time curve (AUC) using a
trapezoidal method from the glucose value of 0'8 hours after
administering the compound and calculating the rate (%) of the
decrease in the AUC of the drug-administered group from that of
the control group.
As a result, the compound of the present invention exhibited
a strong hypoglycemic activity. The hypoglycemic activity of
typical compounds of the present invention are shown in Table 41.
Table 41

Compound Hypoglycemic activity (%)
Example 134 39
Example 141 34

84
As a result of Test Examples 1 and 2, compounds of the present
invention showed a remarkable effect by inhibiting a Na+-glucose
cotransporter activity and a strong hypoglycemic activity.
Therefore, it is expected that compounds of the present invention
can serve as an antidiabetic medicine having the same or higher
effect in comparison with the conventional antidiabetic medicines.
The pharmaceutical composition containing one or more of
the compounds of the present invention and the pharmaceutically
acceptable salts thereof is prepared as a tablet, powder, fine
granule, granule, capsule, pill, liquid, injection, suppository,
ointment, adhesive, or the like using a carrier, vehicle, or other
additives commonly used for preparation and is orally or
parenterally administered.
The amount of the compound of the present invention to be
clinically administered to the human body is appropriately
determined, taking the symptoms, weight, age, sex, and the like of
a patient to which the compound is administered into consideration,
in the range of 0.1-500 mg per day for oral administration or in the
range of 0.01-100 mg per day for parenteral administration, once or
several times a day. Since the amount to be administered varies,
depending upon various conditions, it may be sufficient to
administer the compound at a smaller amount than the
above-described amount.
As a solid composition for oral administration of the
compound of the present invention, a tablet, powder, granule, or the
like is used. In such a solid composition, one or more active
substances are mixed with at least one inert diluent such as lactose,

85
mannitol, glucose, hydroxypropylcellulose, microcrystal cellulose,
starch, polyvinylpyrrolidone, or magnesium aluminometasilicate.
The composition may contain additives other than the inert diluent
such as a lubricant such as magnesium stearate, a disintegrator
such as carboxymethylcellulose calcium, a stabilizer such as
sucrose, a solubilizer such as glutamic acid and aspartic acid, an
adjuvant for solubilization, and the like by a conventional method.
The tablet or pill may be optionally coated with a film of glucose or
a stomach-soluble or intestines-soluble substance such as sucrose,
gelatin, hydroxypropylcellulose, or hydroxypropyl-methylcellulose
phthalate.
The liquid composition for oral administration includes
pharmaceutically acceptable preparations such as an emulsion
preparation, solution preparation, suspension preparation, syrup
preparation, elixir preparation, and the like and contains a
commonly used inert diluent such as purified water and ethyl
alcohol. The composition may contain, in addition to the diluent,
adjuvants such as a solubilizer, humectant, and suspending agent,
sweetener, flavorer, perfume, and preservative.
The injection for parenteral administration includes a
sterilized aqueous or nonaqueous solution, suspension, and
emulsion. Examples of the diluent for the aqueous solution or
suspension include distilled water and a physiological saline
solution for injection. Examples of the diluent for the nonaqueous
solution or suspension include propylene glycol, polyethylene glycol,
and vegetable oils such as olive oil; alcohols such as ethyl alcohol."
and Polysolvate 80 (trade name).

86
Such a composition may further contain additives such as an
isotonizing agent, preservative, humectant, emulsifier, dispersant,
stabilizer (e.g. lactose), solubilizer and adjuvant for solubilization.
These compounds are sterilized by filtering through a
bacteria-retaining filter and adding a disinfectant or irradiating,
for example. These compounds may be used by producing a
sterilized solid composition and dissolving the composition in a
sterilized water or injection solvent before using.

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1. (Amended) A Oglycoside derivative of the following formula (I) and a salt
thereof
R\ R6 /R8
1 ^\/°\^^A4~X—TB^~R9
R2O^^^OR4 R7 R11 R10
OR3 ( I )
wherein A ring represents (l) a benzene ring, (2) a five or six-membered
monocyclic heteroaryl ring having 1 to 4 hetero atom(s) selected from N, S, and
O except for triazoles and tetrazoles, or (3) a saturated or unsaturated eight to
ten-membered bicyclic hetero ring having 1 to 4 hetero atom(s) selected from N,
S, and O;
B ring represents (l) a saturated or unsaturated eight to ten-membered
bicyclic hetero ring having 1 to 4 hetero atom(s) selected from N, S, and O, (2) a
saturated or unsaturated five or six-membered monocyclic hetero ring having 1
to 4 hetero atom(s) selected from N, S, and O, (3) an unsaturated eight or
nine-membered bicyclic hydrocarbon ring, or (4) a benzene ring;
X represents a bond or lower alkylene!
wherein A ring, B ring, and X have a correlation that (l) when A ring is
a benzene ring, B ring is a ring other than a benzene ring or that (2) when A
ring is a benzene ring, and B ring is a saturated or unsaturated eight to
ten-membered bicyclic hetero

ring having 1 to 4 hetero atom(s) selected from N, S, and 0 including a benzene
ring, or a saturated or unsaturated eight to ten-membered bicyclic hydrocarbon
ring including a benzene ring, X is bonded to the B ring in a part other than the
benzene ring included in the B ring;
R1 to R4 individually represent a hydrogen atom, a lower alkyl,
■C(=O)-lower alkyl, or -lower alkylencarylJ and
R5 to R11 individually represent a hydrogen atom, a lower alkyl, a
cycloalkyl, a halogen, a halogen-substituted lower alkyl, -OH, =0, -NH2, lower
alkyl sulfonyl-, halogen-substituted lower alkyl sulfonyl", aryl su]fonyl\ an aryl, a
saturated or unsaturated five or six-membered monocyclic hetero ring having 1
to 4 hetero atom(s) selected from N, S, and O, -lower alkylene-OH, -lower
alkylene-Olower alkyl, -lower alkylene-OC(=0)-lower alkyl, -lower alkyl, -lower
alkylene-Olower alkylene-COOH, -lower alkylene-CHower
alkylene-C(=O)-O-lower alkyl, -lower alkylene-NH2, 'lower alkylene-NH-lower
alkyl, -lower alkylene-NQower alkyl)2, -lower alkylene-NH-C(=O)'lower alkyl,
-COOH, -CN, -C(=O)-O-lower alkyl, -C(=O)-NH2, -C(=O)-NH-lower alkyl,
-C(=O)-N(lower alkyl)2, -Q-lower alkyl, -O-cycloalkyl, -Olower alkylene-OH,
-O-lower alkylene-O-lower alkyl, -Olower alkylene-COOH, -0-lower
alkylene-C(=O)-O-lower alkyl, -0-lower alkylene-C(=O)-NH2, -O-lower
alkylene-C(=O)-NH-lower alkyl, -0-lower alkylene-C(=O)-N(lower alkyl)2,
-0-lower alkylene-CH(OH)-CH2(OH), -O'lower alkylene-NH2, -O-lower
alkylene-NH-lower alkyl, -0-lower alkylene-N(lower alkyl)2, "0-lower
alkylene-NH*C(=O)-lower alkyl, -NH-lower alkyl,

-Ndower alkyl)2, -NH-SCVlower alkyl, -NH-SO2-halogen-substituted lower alkyl,
-NH-lower alkylene-OH, -NH"C(=O)-lower alkyl, -NH-C(=O)-NH2,
-NH-C(=O)-NH-lower alkyl, -NH-C(=O)-N(lower alkyl)2, or ,
-NH-C(=0)-Olower alkyl.
2. (Amended) A Oglycoside derivative and the salt thereof according to Claim
1, wherein the A ring in the formula (I) is (l) a benzene ring or (2) a five or
six-membered monocyclic heteroaryl ring having 1 to 4 hetero atom(s) selected
from N, S, and 0 except for triazoles and tetrazoles.
3. A C-glycoside derivative and the salt thereof according to Claim 2, wherein
the B ring in the formula (I) is (l) a saturated or unsaturated eight to
ten-membered bicyclic hetero ring having 1 to 4 hetero atom(s) selected from N,
S, and O or (2) a saturated or unsaturated five or six-membered monocyclic
hetero ring having 1 to 4 hetero atom(s) selected from N, S, and 0.
4. A C-glycoside derivative and the salt thereof according to Claim 3, wherein
the A ring in the formula (I) is a benzene ring and the B ring is a saturated or
unsaturated eight to ten-membered bicyclic hetero ring having 1 to 4 hetero
atom(s) selected from N, S, and O.
5. A C-glycoside derivative and the salt thereof according to Claim 4, wherein
the X in the formula (I) is methylene.
6. A C-glycoside derivative and the salt thereof according to Claim 5, wherein
the R1 to R4 in the formula (I) are hydrogen atoms.

7. A C-glycoside derivative and the salt thereof according to Claim 1, wherein
the Oglycoside derivative of the formula (I) is at least one compound selected
from the group consisting of
(lS)-l,5-anhydro-l-[3-(l-benzothiene-2-ylmethyl)phenyl-D-glucitol,
(lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol,
(lS)-l,5-anhydro-l-[5-(l-benzothiene'2-ylmethyl)-2-methoxyphenyl]-D-glucitol,
(lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-2-(2-hydroxyethoxy)phenyl]-
D-glucitol, (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)*2-
(methylamino)phenyl]-D-glucitol, (lS)-l,5-anhydro-l-{5-(l-benzothiene-2-
ylmethyl)-2-[(2-hydroxyethoxy)amino]phenyl}-D-glucitol, (lS)"l,5*anhydro-l-
[5-(l"benzothiene'2-ylmethyl)-4-methoxyphenyl]-D-glucitol, (lS)-l,5-anhydro-
l-[5-(l-benzothiene-2-ylmethyl)-4-chlorophenyl]-D-glucitol, (lS)-l,5-anhydro-
l-IS-d-benzothiene^-ylmethyO^-fluorophenyll-D-glucitol, (1S)'1,5-
anhydro-l-[5-(l'benzothiene-2-ylmethyl)-2,4-dimethoxyphenyl]-D-glucitol,
(lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylniethyl)-4-chloro-2-methoxyphenyl]-
D-glucitol, (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-ylmethyl)-4-chloro-2-
hydroxyphenyl]-D-glucitol, (lS)-l,5-anhydro-l-[5-(l-benzothiene-2-
ylmethyl)-4-fluoro-2-hydroxyphenyl]-D-glucitol, and (lS)-l,5-anhydro-l-[5-
(l-benzothiene-2-ylmethyl)-4-fluoro-2-methoxyphenyl]-D-glucitol.
8. A pharmaceutical composition containing a Oglycoside derivative or a salt
thereof according to any one of Claims 1 to 7.

9. A pharmaceutical composition according to Claim 8, wherein the
composition is a Na+-glucose cotransporter inhibitor.
10. A pharmaceutical composition according to Claim 8, wherein the
composition is an antidiabetic agent.
11. Use of the C-glycoside derivative and the salt thereof according to any one
of Claims 1 to 7 for producing a Na+-glucose cotransporter inhibitor or an
antidiabetic agent.
12. A method for treating diabetes comprising administering an effective
amount of the C-glycoside derivative and the salt thereof according to any one
of Claims 1 to 7 to a patient.

The present invention provides C-glycoside derivatives and
salts thereof, wherein B ring is bonded to A ring via -X- and A ring
is directly bonded to the glucose residue, and it is usable as a
and/or preventive agent for diabetes such as insulin-dependent
diabetes), as well as diabetes related diseases such as an
insulin-resistant disease and obesity.