JPH03218389A - O-substituted glucosamine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> and R<2> are H or CO(CH2)nCH3 ((n) is 10-22); R<3> is H or lower alkyl; (m) is 0-3; R<1> and R<2> are not H at the same time] or its salt. EXAMPLE:6-O-palmitoyl-D-glucosamine methylglycoside. USE:A compounding agent for forming cationic liposome, a cationic surfactant, an adjuvant substance for producing antibody, etc. It has excellent affinity to phospholipid and can impart positive charge to a liposome formed with the compound. PREPARATION:The objective compound can be produced by reacting an amino sugar of formula II with benzyloxycarbonyl chloride to protect the 2-amino group, reacting the product in methanol in the presence of a catalyst such as p-toluenesulfonic acid to obtain a compound of formula III (Z is benzyloxycarbonyl), reacting the compound with a higher fatty acid chloride of formula R<1>Cl, hydrogenating the resultant compound of formula IV and removing the group Z from the product by hydrogenation.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a novel glucosamine derivative or a salt thereof useful as a compounding agent for forming cationic liposomes, a cationic surfactant, or an adjuvant substance for antibody production. .

(Prior art) Novosomes are hollow, closed vesicles consisting of a lipid bilayer membrane produced by suspending a polar lipid thin film formed from phospholipids etc. in an aqueous solution. Since it has basically the same structure as the membrane structure, it is considered a type of biocompatible microcapsule, and various drugs, enzymes, etc. are encapsulated within the capsule and administered to living organisms. Attempts are being made.

Lipids, especially phospholipids such as lecithin, are used as a membrane material to form liposomes, but phospholipids generally have a hydrophilic part consisting of phosphate ester residues and a hydrophobic part consisting of higher fatty acid residues. If the number of carbon atoms in the fatty acid residue is 8 or less, especially 4 or less, molecular aggregates are no longer formed and liposome formation is impossible, so in order to form morphologically clear liposomes, The number of carbon atoms in the fatty acid residue must be 10 or more, preferably 12 to 24. Further, triglyceride, cholesterol, cholesterol ester, α-tocopherol, etc. may be added as an auxiliary agent.

Recently, attempts have been made to adjust the charge on the liposome surface by adding a small amount of a charge-imparting substance such as stearylamine as an auxiliary agent, with the aim of improving the drug encapsulation rate and the cell adhesion of liposomes. There is.

For example, JP-A No. 63-77824 discloses a cation which uses dipalmitoylphosphatidylcholine, cholesterol, and stearylamine as liposome membrane forming materials and encapsulates SOD (superoxide disproportionase) as a drug. [L-SOD] has been described, and [Drasog delivery system J (2(1冫, 41
52 (1987)) also describes a cationic liposome preparation (L-SOD) containing stearinoleamine.

(Problems to be Solved by the Invention) As described above, in the production of conventional cationic liposomes, stearylamine and the like have been used as auxiliary agents to adjust the surface charge.

However, liposomes containing stearylamine have the disadvantage of being highly toxic to living organisms and causing side effects, and have not been able to withstand practical use as liposome preparations.

(Means for Solving the Problems) As a result of intensive studies to overcome the difficulties of these conventional techniques, the present inventors have developed a method for liposome compounding aids, especially charge-imparting agents, cationic surfactants, antibody production agents, etc. We have succeeded in obtaining a new glucosamine derivative useful as an adjuvant substance, etc., and have completed the present invention.

The present invention is based on the following general formula (I) (wherein R1 and R2 are hydrogen atoms or 100(CH2
) nCH3 group (n means an integer of 10 to 22), R3 means a hydrogen atom or a lower alkyl group, m
means an integer from 0 to 3. However, R1 and R2 are never hydrogen atoms at the same time. ) or a salt thereof.

Here, the lower alkyl group is an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a probyl group, an isoprobyl group, a butyl group, etc., and a methyl group is particularly preferable.

Moreover, the compound (I) of the present invention can be used, for example, with hydrochloric acid, sulfuric acid,
Pharmacologically acceptable salts can be produced with inorganic acids such as phosphoric acid, or organic acids such as tartaric acid, maleic acid, and succinic acid.

Furthermore, the compound (I) of the present invention is basically composed of a hydrophobic part consisting of higher fatty acid residues and a hydrophilic part consisting of glucosamine residues, and the higher fatty acid residues constituting the hydrophobic part are The number of carbon atoms in the group is not particularly limited, and the purpose can be sufficiently achieved as long as the group has a carbon chain sufficient to impart hydrophobicity. That is, the higher fatty acid residues at the 3rd and 6th positions are groups for imparting hydrophobicity to the molecule, and like the phospholipids that make up the majority of liposomes, the fatty acid residues of the compound (Il have a carbon number of 10 Above, preferably 12 to 24,
That is, it is desirable that n=10 to 22.

Furthermore, the purpose of the glucosamine moiety is to impart hydrophilicity, and it may be in any form as long as it does not interfere with the ability to form liposomes. However, preference is given to monomers (m=
o), a dimer (m21), a trimer (m=2), or a tetramer (m=3), and particularly preferred are monomers or dimers in which m is 0 or 1. It is the body. Regarding the -OR3 group at the 1st position, this group does not directly participate in the formation of liposomes or imparting a charge, and R3 may be either a lower alkyl group or a hydrogen atom.

An example of the method for producing the compound CI of the present invention is as follows.

However, in the above flow, R, m, and n are the same as above, and 2 is a penzyloxycarbonyl group well known as an amine protecting group. In the above example, the general formula (
R1 in I) is -Co(CH2)nCH3 group, R
The production method when 2 is a hydrogen atom has been shown,
When a compound [I] in which R1 and R2 are simultaneously -C○(CH2)nCH3 groups is desired, in the third step, CICO(CH2)nCH3 is converted to N-penzyloxylponylglucosamine to compound [IV]. It is sufficient to use 2 times the mole or more per residue. Furthermore, if a compound in which R1 and R2 are different acyl groups is desired, another R2C1 may be reacted after the completion of the reaction in the third step. Furthermore, R1 is a hydrogen atom, and R2 is 100(CH2)nCH3
If a compound (r) which is a group is desired, the hydroxyl group at the 6-position may be appropriately protected and then the reaction may be carried out in the same manner as R''CI.

1st step A known amino sugar represented by the general formula (III) or its hydrochloride is reacted with penzyloxycarbonyl chloride (PhCH20COC1) in a solvent such as pyridine to convert the amine group at the 2-position into a penzyloxycarbonyl group (2 groups). ) to obtain the compound (■old).

Second Step Compound [III] obtained in the first step is reacted in methanol using p-toluenesulfonic acid or the like as a catalyst to methoxylate the 1-position to obtain compound [IV]. The monomer compound (IV) in which m is 1 is a known compound or a compound that can be very easily derived by a person skilled in the art according to a conventional method.

In addition, for oligomer compounds where m is 1 to 3, in order to prevent cleavage of the glycosidic bonds between each glucosamine, it is preferable to react as described below without directly methoxylating one part of the compound itself. That is, compound [11] is reacted with acetic anhydride in a solvent such as pyridine to protect all the hydroxyl groups of compound (II) with acetyl groups, and then a small amount of hydrobromic acid l
Add an acetic acid solution to react, then react in methanol solvent in the presence of silver carbonate to selectively replace the acetoxyl group at position 1 with methoxy group, and then react in methanol solvent in the presence of sodium carbonate. By removing the remaining acetyl group to form a hydroxyl group, the compound (I
V) is obtained. This can be shown as a scheme as follows.

Compound C III) Compound (IV) Third step The compound (IVI) obtained in the second step was dissolved in a solvent such as pyridine to an equivalent molar amount of higher fatty acid chloride (CHa(CH2
) ncoCl) to esterify the 6-position hydroxyl group to obtain compound [V]. When esterification at the 3-position is also desired, the above-mentioned higher fatty acid chloride is added to the compound [I
V) may be used in an amount of at least twice the mole per N-pendyloxyluponylglucosamine residue.

Fourth step: The compound [V] obtained in the third step is hydrogenated in the presence of a catalyst such as Pd-C to eliminate two groups and obtain the final target compound [V].

In the above, the case where the 1st position is a lower alkoxy group has been described, but if the final target compound [I] in which the 1st position is a hydroxyl group, that is, R3 is a hydrogen atom, can be obtained as described above. The compound [I] having a lower alkoxy group at the 1-position can be easily produced by hydrolyzing the compound [I] using a known suitable hydrolysis means such as an enzyme to convert the 1-position into a hydroxyl group. Further, depending on the case, the hydroxyl group at the 1-position may be protected with a protecting group, and the protecting group may be finally removed.

The compound (I) of the present invention thus obtained has excellent affinity with phospholipids such as lecithin, and also has an amine group at the 2-position, so when it is blended with lecithin etc. to form liposomes, it has a high affinity with phospholipids such as lecithin. It is extremely useful as a liposome-forming auxiliary agent, especially as a charge-imparting agent. In addition, since the compound [I] of the present invention is composed of a hydrophobic part consisting of a higher fatty acid residue and a hydrophilic part consisting of a glucosamine residue as described above, it can be used as a cationic surfactant or an adjuvant for antibody production. It is also expected to be used as a substance.

The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.

N-penzyloxycarbonyl-D-glucosamine methyl glycoside 1 was obtained from D-glucosamine according to a known method, and the N-penzyloxycarbonyl-D-glucosamine methyl glycoside 1 was dissolved in 50 ml of pyridine.
．． 3 g and 28 ml of palmitoyl chloride were added thereto, and the mixture was stirred at room temperature for 24 hours under a nitrogen gas atmosphere.

After the reaction was completed, the reaction mixture was poured into 10% water-cooled hydrochloric acid,
It was extracted with ethyl acetate. Thereafter, the extract was washed with saturated sodium bicarbonate (NaHCO3) and brine (salt solution), dried over anhydrous sodium sulfate (Na2S04), the solvent was distilled off to obtain a crude product, and further, an ethyl acetate solution Recrystallized from N-penzyloxytriponyl-6-
7.65 g of 0-palmitoyl-D-glucosamine methyl glycoside 3 was obtained. Yield 52%.

m. p. : 96~97°C IR (KBr) : 3330cm, 3030cm
,2920cm',2850cm-1,1735cm
-1.1690cm ,=1 1540cm ,1460cm',1260cm ,M
S(FAB): 566(M+1)+1H-NMR(
DMSO-d5) δ (ppm): 7.36 (s, 5H); 7.12 (d,
J = 8Hz, IH); 5.25 (d, J = 7.4H
z, IH); 5.03 (s, 2H); 4.90 (d,
7=4Hz, IH); 4.58 (d, J=2.4H
z, LH); 4.32 (d, J= 12.4Hz, I
H); 4.07 (dd, J=6.2Hz, J=6.6H
z, LH); 3.4-3.6 (m, 2H); 3.24
(s, 3H); 3.15 (m, LH); 2.31 (
t, J = 7Hz, 2H); 1.51 (m, 2H); 1
．． 24 (b, 24H); 0.86 (t, J=6.2H
z, 3H). 1H-NMR (CDC1a) δ (ppm): 7.36 (s, 5H); 5.18 (d,
J = 8.8Hz, LH); 4.71 (d, J = 3.
6Hz, LH); 4.50 (cld, J = 4Hz
, LH); 4.25 (d, J= 12.4Hz, LH
); 3.6-3.9 (m, 2H); 3.35 (s, 3H
); 2.37 (t, J = 7.4Hz, 2H); 1.
63 (m, 2H); 1.25 (b, 24H); 0.8
8 (t, J=6Hz, 3H). 3135 g of the above N-pendyloxycarbonyl-6-0-palmitoyl-D-glucosamine methyl glycoside
was dissolved in 50 ml of methanol, a catalytic amount of Pd-C was added, catalytic reduction was carried out at room temperature and under normal pressure for 24 hours, and after the reaction was completed, the solution was filtered to remove the solvent, and the residue was subjected to silica gel force column chromatography. Purification yields the target compound 6-0-palmitoyl-D-glucosamine methyl glycoside 4 8
74 mg was obtained. Yield 85%.

m. p. : 70.5-71.5°C Elemental analysis:
CHN Actual value 64.24% 10.84% 3.04% Calculated value * 64.00% 10.51% 3.25% ("C2
Calculated value as 3H4306N) IR (KBr):
3350cm"', 2920cm-", 2850cm-
11730cm, 1460cm' MS (FAB): 432(M+1)+1H-NMR
(DMSO-d6) δ (ppm): 5.15 (m, LH); 5.00 (m,
IH); 4.51 (d, J = 3.4Hz, LH)
; 4.30 (d, J=10.6Hz, LH);
4.04 (dd, J = 6.6Hz, J6.8
Hz, LH); 3.53 (m, IH); 3.2
6 (s, 3H); 3.10 (m, 2H); 2
．． 40 (m, IH); 2.29 (t, J =
7.2Hz, 2H); 1.51 (m, 2H);
1.24 (b, 24H); 0.86 (t, J=
6.0Hz, 3H) Example 2 Method for producing 6-0-lauroyl-D-glucosamine methyl glycoside The title compound was obtained in the same manner as in Example 1, using lauroyl chloride instead of palmitoyl chloride.

Elemental analysis: C H N Actual value 60.34% 9.95% 3.63%
Calculated value* 60.80% 9.87% 3.73
% (*C1gH3706NtL tenometer jtE value) Example 3 Production of Sid The title compound was obtained in the same manner as in Example 1, using myristoyl chloride instead of palmitoyl chloride.

m. p. : 65-70°C Elemental analysis/C HN Actual value 62.18% 10.27% 3.33% Calculated value 62.53% 10.17% 3.47%
(*Calculated value as C21H4106N) Dash +4 6-Q-stearoyl-D-glucosamine methyl glycoside production method The title compound was obtained in the same manner as in Example 1, using stearoyl chloride instead of palmitoyl chloride.

MS: 459.3542 (M+) (Calculated value as C25H4906N: 459.355
9) Example 5 1N-M-dibenzyloxycarbonyl-D-glucoD-
12.5 g of glucosamine-(1-4)-13-D-glucosamine hydrochloride and 2.1 g of sodium bicarbonate were added to 70 g of
After dissolving in ml mixed solvent (water:methanol-3:4 v/v), penzyloxychloride (Ph
2 ml (2.4 g) of CH20COCI) was added thereto, and the mixture was stirred at room temperature for 2 hours. Thereafter, the product was filtered, washed twice each with purified water and dichloromethane, dried under vacuum, and then recrystallized with methanol. ·went. As a result, N,N'-dibenzyloxycarbonyl-D-glucosamin (1-4)-
p-D-glucosamine? 62 mg was obtained. Yield 76.0
2%.

'H-NMR (DMSO-d6) δ (ppm): 3.11 - 3.72 (m, IOH);
4.5 (tetra, J=5.34Hz, Q{); 4,
32 (d, J = 7.04Hz, LH); 4.45 (s
, IH); 4.55 (s, IH); 4.71 (s,
IH); 4.94 -5.13 (m, 8H); 6.
56 (d, J= 4.3, IH); 1.20 (d
, J= 8.36, 2H); 7.36(s, IOH
). IR (KBr): 3325cm, 2940cm'
,1680cm-"1540cm',1280cm,
1245cm-11030cm-1 MS (FAB): 609(M+1)+4-Production method of D-glucosamine
Dissolve in 15 ml of pyridine and add 10 ml (approx.
11 mol) of acetic anhydride was added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After washing the extract with saturated gold brine and drying over anhydrous sodium sulfate, the solvent was removed to obtain the target compound Nfi'.
-dibenzyloxycarbonyl-3. 4, 6. 1
',3',6'-hexer O-acetyl-D-glucosamin (1-4)-13-D-glucosamine 3
1.88g was obtained. Yield 87.04%.

1H-NMR (CDC13) δ (ppm): 1.89 (s, 3H); 1.92 (s,
3H); 1.95 (s, 3H); 1.99 (s, 3H)
;2.07(s,3H);2.08(s,3H);3.
61 - 4.40 (m, 9H); 4,97 - 5.34 (
m, IOH); 6.13 (d, J= 3.66, LH)
;7.33 (s, 10H). The above Nfi' production method of D-glucosamine methyl glycoside
-dibenzyloxycarbonyl-3. 4, 6.1'
, 3', 6'-hexar O-acetyl-D-glucosamino-(1-4)-43-D-glucosamine 1.5
Dissolve g in 30 ml of dry dimethyl chloride and heat at 0°C.
1.5ml of 25% hydrobromic acid! An acetic acid solution was added, and the mixture was stirred for 4 hours under a nitrogen gas atmosphere.

After the reaction was completed, the mixture was placed in ice water to remove hydrobromic acid, extracted with dichloromethane, further dried over anhydrous sodium sulfate, and dichloromethane was distilled off. The obtained crude product was immediately dissolved in dry methanol, further silver carbonate was added thereto, and the mixture was stirred at room temperature for 24 hours, and then filtered to remove the silver carbonate, and then methanol was distilled off. As a result, 1.22 g of crude product was obtained. After column purification, the title N, N'
-dibenzyloxycarbonyl-3. 4, 6. 1
', 3', 6'-hexer O-acetyl-D-glucosaminol (1-4)-13-D-glucosamine methyl glycoside ±0.52 g was obtained. Yield 35.8%.

1H-NMR (CDC13) δ (ppm): 1.91 (s, 3H); 1. 92(s)
, 3H); 1.99 (s, 3H); 2.06 (s, 3H)
); 2.08 (s, 3H); 3.47 (s, 3H); 3
．． 52-3.74 (m, 4H); 3.98-4.37 (
m; 6H); 4.96-5.28 (m, IOH);
7.32 (s, 10H). Manufacturing method N. N'-dibenzyloxycarbonyl-3. 4,
6. 1',3',6'-hexer O-acetyl D-
1.0 g of glucosamino-(1-4)-pD-glucosamine methyl glycoside 4 was added to 30 ml of methanol and stirred to form a suspension. 3m saturated sodium carbonate
After reacting for 24 hours, extraction was performed with ethyl acetate to obtain N,N'-dibenzyloxycarbonyl-D-glucosamine/-(1-4),p-D-glucosamine methyl glycoside 5-0. .45g was obtained. Yield 60%.

1H-NMR (DMSO-d5) δ (ppm): 3.06-3.70 (m, 7H);
4.12-4.16 (m, 2H); 4.99-5.2
8 (m, 6H); 4.52-4.68 (m, LH)
;5.26-5.28(m, 2H);7.36(s,
IOH). (5) Preparation of N-dibenzyloxycarbonyl-66"-diO-mine methyl glycoside N,#'-dibenzyloxycarbonyl-D-glucosamin (1-4)-13-D-glucosamine methyl glycoside 3 g was dissolved in 5 ml of pyridine.While stirring this solution under nitrogen gas atmosphere, 0.2886
Add 0.0 g (approximately 0.3 ml) of palmitoyl chloride.
c ~ Reacted at room temperature for 12 hours. After the reaction was completed, 10% hydrochloric acid solution was added, extracted with ethyl acetate, the extract was further washed with saturated brine, and the solvent was distilled off to obtain 0.58 g of crude product.
This was further purified using a column to obtain 0.1 g of the title compound 6. Yield 19.17%.

'H-NMR (DMSO-d6) δ (ppm): 0.83 ~ 0.88 (m, 6H); 1
．． 23 (s, 54H); 1.51 (m, 4H);
2.27 (m, 5H); 3.35-3.48 (m,
IIH); 3.97-4.61 (m, 6H); 4.
90-5.05 (m, 4H); 7.33 (s, I
OH). (6) Process for producing 66'-diO-palmitoyl-D-glucosamino 1-4D-glucosamine methyl glycoside N,81'-dibenzyloxycarbonyl-6,6'-
G-O-Palmitoy-D-Glucosamino-(1-4
)-13-D-glucosamine methyl glycoside 6 0.
16g to 10ml of tetrahydrofuran/methanol (
After adding the mixture to a 1:1 v/v) mixed solvent and stirring to dissolve it, Pd-C was further added and reacted with hydrogen gas at room temperature for 12 hours. After the reaction is complete, the reaction mixture is filtered to remove Pd.
-C was removed and the solvent was distilled off to obtain 0.11 g of crude product. Further purification by pre-TLC yielded the final product 6,6
'-G-O-Palmitoy-D-Glucosamin (1-
4) -p-D-glucosamine methyl gnocoside 7 0.
02g was obtained. Yield 16.7%.

MS (FAB); 831 (M+1) + IR (KBr)
; 3420cm, 2920cm, 2850cm
'1740cm, 1470cm-1 Example 6 (1) N-henzyloxycarbonyl-36-diO-
Method for producing lauroyl D-glucosamine methyl glycoside 10 g (30.58 mmol) of N-penzyloxycarbonyl D-glucosamine methyl glycoside L obtained from D-glucosamine hydrochloride according to a known method was added to 6
Dissolved in 0 ml of pyridine. 14.71g (6
7.3 mmol) of lauroyl chloride was added and stirred for 24 hours.

After the reaction was completed, 10% hydrochloric acid was added and extracted with ethyl acetate.

The extracted ethyl acetate layer was washed with saturated brine, and the ethyl acetate was distilled off to obtain 19.3 g of a crude product, which was further purified using a column to obtain the title N-penzyloxycarbonyl-3,6-
2.7 g of di-O-lauroyl-D-glucosamine methyl glycoside 2 was obtained. Yield 15.06%.

the N-pendyloxyluponyl-3,6-diO,
Lauroyl D-glucosamine methyl glycoside 22.
7g (3.14mmol) of methanol l ethyl acetate (
Dissolve in a mixed solvent of 1:1 v/v), Pd-C as a catalyst
was added and reacted with hydrogen gas for 10 hours. After the reaction was completed, the catalyst was removed by filtration to obtain 1.85 g of a crude product. By purifying with a column, 0.5 g of the title 3,6-di-O-lauroyl-D-glucosamine methyl glycoside 3 was obtained. Yield 28.57%0 m. p. ; 50-54°C IR (KBr); 3380cm, 2940cm,
2860cm'-1 1730cm, 1580cm-1. 1470cm
,1190cm ,1100cm ,1060cm
,'H-NMR (CDC13) δ (ppm): 0.88 (t, J=6.:14,6H)
; 1.26 (s, 36H); 1.60-1.66 (m,
4H); 2.09 (s, 3H); 2.31-2.4
4(m, 2H); 2.83-2.90(m, IH
); 4.26-4.49 (m, LH); 4.74
-4.99 (m, LH); 3.35-3.45 (m, 4
H); 3.77-3.79 (m, IH). Elemental analysis: CH Actual value 66.40% 10.81% Calculated value 66.78% 10.59% (*C31H
Calculated value as 59NO7) N 2.32% 2.51% The title compound was obtained in the same manner as in Example 6 by using myristoyl chloride in place of laucutyl chloride. Yield 35.54%.

m. p. : 47-50°C IR (KBr): 3380cm"", 2940cm
,2860cm-1.1730cm-1.1580c
m-IJ470cm-1.1190cm', 1100
cm-'', 1060cm,'H-NMR (CDCI
s) δ (ppm): 0.88 (t, J = 6.16.
6H); 1.26 (s, 42H); 1.58-1.7
0 (m, 4H); 1.87-1.93 (m, 2H);
2.34-2.45 (m, 4H); 2.83-2
．． 90 (m, IH); 3.36-3.45 (m, 4H
); 3.77-3.84 (m, IH); 4.26-
4.52 (m, IH); 4.75 (d, J=3.52
, LH); 4.94 (t, J=9.7, IH). Elemental analysis; CHN Actual value 68.43% 11.14% 2.02% Calculated value 68.52% 10.93% 2.28%
(Calculated value as "C35H67NO7") The title compound 3,6-diO-
Stearoyl D-glucosamine methyl glycoside was obtained. Yield 22.27%.

IR (KBr): 3380cm-1.2940cm-
1.2860cm-”, 1730cm, 1580cm
,1470cm"1,1190cm',1100cm
, 1060cm-1"H-NMR (CDCI3) δ (ppm): 0.88 (t, J = 6.21, 6H)
; 1.25 (s, 58H) 1.52 ~ 1.65 (
m, 4H);2. OCl-2.13 (m, 2H); 2.
33-2.45 (m, 4H); 2.82-2.89 (
m, IH); 3.35-3.55 (m, 4H); MS
: 3.77-3.83 (mJH); 4.27 ~ 4.50
(m, LH); 4.75 (d, J=3.28, LH
); 4.94 (t, J=9.52, LH). 725.6155(M”) (043H33NO7 TOL 'C'7) Calculated value 7
25.6167) A lethal toxicity test was conducted on mice of the novel glucosamine derivative represented by the general formula (I) of the present invention.

The following compounds were used as test substances.

■Compounds higher than stearylamine at 0.5% 10MC. Mixed with Na aqueous solution.
The suspension was suspended, and 1.0 ml of the suspension was intraperitoneally administered once to 5-week-old DDY male mice, and their mortality was observed. Note that the solvent control group contained 05% CMC. Administration was performed in the same manner using an aqueous Na solution.

The results are shown in the table below.

Table 1 In the above test, no deaths were observed during the observation period for compounds (1) and (2), and there was no significant change in general condition after administration, and body weight increase was observed as in the control case. For it,
In Compound ■, which is a control example, a decrease in locomotor activity was observed immediately after administration, and body weight decreased sharply, leading to death.

As is clear from the above results, the compound of the present invention has extremely low toxicity and high safety compared to the control compound.

Claims (1)

[Claims] The following general formula▲ includes mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 are hydrogen atoms or -CO(C
H_2)_nCH_3 group (n means an integer of 10 to 22), R^3 means a hydrogen atom or a lower alkyl group, and m means an integer of 0 to 3. However, R^1
, R^2 are never hydrogen atoms at the same time. ) Glucosamine derivatives or salts thereof.