Oligosaccharide derivatives and process for producing the same

Details Oligosaccharide derivatives and process for producing the same Oligosaccharide derivatives and process for producing the same

2000-02-18

2003-02-11

Fonda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S017900

Reexamination Certificate

active

06518249

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an oligosaccharide derivative and a process for producing the same. More specifically, the invention relates to an oligofucose or oligorhamnose derivative, which is effective for prevention and treatment of inflammation and ulceration on the mucosa of gastric organs such as stomach and duodenum.
BACKGROUND OF THE INVENTION
Conventional antiulcer agents include those for controlling gastric juice secretion, such as H
2
-blockers and proton pump inhibitors. For the purpose of active therapeutic treatment of gastritis and gastric mucosal cells, use of prostaglandins or basic fibroblast growth factors have recently been studied. These pharmaceutical agents, on the one hand, exert efficacious therapeutic effects. On the other hand, however, these pharmaceutical agents potentially cause the onset of ulcer, specifically the recurrence of ulcer, for which a specific bacterial species
Helicobacter pylori
is responsible. Therefore, it is remarked that gastric ulcers should essentially be treated, including the disinfection of the bacterial species (Masahiro Asaka, “Helicobacter pylon and disorders of gastric mucosal membrane”, Sentan-Igaku-Sha (Top Medicine Press), Jul. 1, 1995).
It has aaditionally been known that microbial cells of certain species of Bifidobacteria or lactic acid bacteria and polysaccharides or oligosaccharides prepared from these microbial cells,
Phaeophyceae Chordariales nemacystus
or green laver (
Monostroma nitidum
) are effective in not only the prevention of ulceration but also in the promotion of the healing thereof, and thus are useful as antiulcer agents (JP-A-6-247861; JP-A-7-138166) . These polysaccharides and oligosaccharides primarily comprise fucose and/or rhamnose. Specifically, fucoidan, a fucose polymer, exerts effects to prevent ulcer formation and to promote the healing of urceration and additionally exerts an action to inhibit the adhesion of
H. pylori.
Nevertheless, these polysaccharides and oligosaccharides per se are not satisfactory in terms of their antiulcer activity. Furthermore, it is difficult to recover these polysaccharides and oligosaccharides at homogenous states including the homogeneity of their molecular weights.
SUMMARY OF THE INVENTION
It is a primary object of the invention to provide an oligosaccharide derivative having higher homogeneity and greater antiulcer effects than those of the aforementioned conventional polysaccharides, and another object of the present invention is to provide a process for producing the same.
According to an embodiment of the present invention, there is provided an oligosaccharide derivative represented by the following general formula:
Y
1
—OCH(CH
2
NHR)
2
wherein, Y
1
represents an oligofucose at a polymerization number of 2 to 20, where the hydroxyl groups may or may not be partially modified in the form of sulfate ester, and R represents phenyl group, a higher alkylphenyl group, a higher alkyl group or —(CH
2
)
n
—NHX wherein n is an integer of 1 to 10 and X represents a higher alkanoyl group or an alkylamino group with or without substituents.
According to another embodiment of the present invention, there is also provided an oligosaccharide derivative represented by the following general formula:
Y
2
—OCH (CH
2
NHR)
2
wherein, Y
2
represents an oligorhamnose at a polymerization number of 2 to 20, where the hydroxyl groups may or may not be partially modified in the form of sulfate ester, and R represents phenyl group, a higher alkylphenyl group, a higher alkyl group or —(CH
2
)
n
—NHX wherein n is an integer of 1 to 10 and X represents a higher alkanoyl group or an alkylamino group with or without substituents.
These oligosaccharide derivatives have various properties including excellent antiulcer effect.
The present invention also provides a process for producing an oligosaccharide derivative comprising the steps of converting the sugar residue at the reducing end of the oligofucose or oligorhamnose to aldehyde group through oxidative degradation, generating a Schiff base by allowing the aldehyde group to react with at least one of corresponding alkylamines and allylamines, and reducing the Schiff base to obtain an oligosaccharide derivative.
That is, in the process according to the present invention, fucoidan (fucose polysaccharide) or rhamnan (rhamnose polysaccharide) is modified into an oligosaccharide (an oligomer comprising about 3 to 20 molecules of fucose or rhamnose) through acid treatment, and then, the oligosaccharide is subjected to oxidation with periodate, reaction with corresponding amines, and reductive treatment
According to another aspect of the invention, there is provided an inhibitor for
H. pylori
which comprises the oligosaccharide derivative, namely oligofucose derivative and/or oligorhamnose derivative according to the present invention.
According to still another aspect of the present invention, there is provided an agent for preventing and therapeutically treatment of gastric ulcer, said agent comprising the oligosaccharide derivative, namely oligofucose derivative and/or oligorhamnose derivative according to the present invention.
According to one embodiment of the present invention, the process for producing an oligosaccharide derivative comprises the following steps 1 to 8.
Step 1: Using known extraction methods, polysaccharides are extracted from marine algae (such as
Phaeophyceae Chordariales nemacystus,
Hydrilla, Fucus, and
Monostroma nitidum
) containing fucoidan, rhamnan or rhamnan sulfate.
Step 2: The recovered polysaccharides are dissolved in a solution of hydrochloric acid or trifluoroacetate of about 0.075 N to 0.1 N; the mixture is heated at 100° C. for 10 to 20 minutes, to modify the polysaccharides into the form of oligosaccharides. After the treatment, the resulting reaction mixture is neutralized with sodium hydroxide, followed by addition of NaBH
4
to the neutraized mixture for reductive treatment at ambient temperature or 4° C. for 16 hours.
Step 3: The solution of the oligosaccharides in the alditol form as recovered by the procedures of the step 2 is desalted by dialysis (a fractionating molecular weight of 500) or electro-dialysis or by using an ion exchange resin.
Step 4: To the solution recovered at the step 3, sodium metaperiodate is added for reaction in a vessel immersed in an ice bath for about one hour. Herein, an oligosaccharide in a structure such that sugars except the sugars at the reducing ends or the non-reducing ends are never oxidized, for example (1→3) oligosaccharide, may satisfactorily be subjected to the reaction for a longer period of time. Ethylene glycol at a volume excessive to periodic acid is added to the reaction solution, for additional reaction for about one hour. The resulting solution is subjected to desalting in the same manner as in the step 3. By the procedure, an oligosaccharide derivative (in liquid) with an aldehyde group at the end can be recovered.
Step 5: Acetic acid is added to the solution from the step 4 to a final concentration of 0.5 M, which is subjected to reaction at ambient temperature for 20 hours. The reaction solution is dialyzed against a dialysis membrane of a fractionating molecular weight of 500; the inner dialysis residue solution is freeze-dried to recover an objective oligosaccharide. Additionally, the oligosaccharide fraction can be desalted by dialysis. Alternatively, the oligosaccharide fraction can be fractionated and desalted by chromatography on an active-charcoal column and gel filtration to prepare a fraction of an appropriate molecular weight.
Step 6: The oligosaccharide fraction recovered at the step 5 is dissolved in an aqueous solution containing 40% to 50% propanol, followed by addition of allylamines or alkylamines, for reaction at 45° C. for 2 hours, to prepare a Schiff base. In this case, any substance (dimethyl sulfoxide, dimethylformamide, etc.) capable of dissolving oligosaccharides and alkylamines may satisfactorily be used as the solvent. Then, any alkylamine and any allylamine may satisfactorily

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