Glycolipid derivative

Details Glycolipid derivative Glycolipid derivative

2001-06-12

2003-10-21

Fonda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S023000, C514S024000, C514S042000, C536S017500, C536S017900, C536S018700, C536S029100

Reexamination Certificate

active

06635622

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel glycolipid derivatives thereof which have effective anti-tumor activity and immunostimulating activity thereof and the production method thereof, further relates to a medicine composition containing the glycolipid derivatives thereof.
2. Description of the Prior Art
A glycolipid play important biological roles to cell deffarantation, proliferation, and navus cell growth. (Hakomori et al, Annu. Rev. Biochem. 1981, 50, 733-764.; Morita et al, Glycosphingolipids. 1985, 59-82, Elsevier Science Publishing Co., New York.). And, Morita et al (J. Med. Chem. 1991, 38, 2176.) and Kawano et al (Proc. Natl. Acad. Sci. USA. 1998, 95, 5690.) have been reported that alpha-galactosylceramides have effective anti-tumor activity and immunostimulating activity. Futhermore, Kawano et al (Science. 1997, 278, 1626-1629.) and Sakai et al (J. Med. Chem. 1999, 42, 1836-1841.) have been reported that alpha-galactosylceramides exhibit stronger antitumor activity and immunostimulating activity than beta-galactosylceramide.
However, when the galactosylceramide is administrated as a medicine, we expect that glycosyl bond is hydrolyzed by enzyme so as galactosidase which exist in a lysozome (Chen et al., Biochem. Biophys. Acta. 1993, 1170, 53-61). C-glycosides, that oxygen atom on a glycoside bond were exchanged to carbon atom, has been known as a stable sugar derivatives on a glycosidase metabolism (Linhardt et al., Tetrahedron. 1998, 54, 9913-9959; Levy et al., The Chemistry of C-Glycosides, Pergamon:Oxford, 1995; Postema et al, C-Glycoside Synthesis, CRC Press: Boca Raton, 1995). In addition, S-glycoside which exchange oxygen atom to sulfur atom on the glycoside bond (Rahman et al, In Studies in Natural Products Chemistry, Elsevier: New York, 1991; Vol. 8, 315-317; Defaye et al, J. Carbohydr. Chem. (UK) 1998, 30, 159-166.) and N-glycosides which oxygen atom were replaced by nitrogen atom (Stunkel et al., Prog. Leukocyte Biol. 1989, 9, 575-579.) have been also known.
As a synthesis of the C-glycosides [which] with oxygen on the glycoside bond of a galactosyl ceramide were replaced by carbon atom, synthesis of the beta-C-galactosyl ceramide has been only report (Dondoni et al., J. Org. Chem. 1991, 64, 5557-5564). However, synthesis of a alpha-C-galactosyl ceramide (alpha-compound) has not been reported. Owing to stabilities against alpha-galactosidase, the alpha-compounds which have alpha-C, N, or S-glycoside bond are expected more effective than the alpha-O-galactoside that is decomposed by a alpha-galactosidase. Thus, those compounds have a potent anti-cancer activity and an immunostimulating activity, furthermore, are stable against hydrolysis with glucosidase, acid, and base, and also able to keep at a room temperature for a long time.
3. Problems to be Solved by the Invention
The object of the present invention is the provision of the glycolipid derivatives exhibiting potent antitumor activity and immunostimulating activity, and having alpha-C, N, or S-glycoside bond for allowing to stand at room temperature for a long time, Thus, the glycolipid derivatives exhibit potent antitumor activity and immunostimulating activity than a known compound, and furthermore it is able to save at room temperature for long time and continue the activity for long time.
4. Methods for Solution of the Problems
As a result of that research a glyoclipid derivatives for the purpose of synthesis of anti-tumor agent and immunostimulating agent, we found that a glycolipid derivatives which is described in the general formula (I), exhibits a potent anti-tumor effect and immunostimulating effect.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides medical composition which containing the general formula (I) and its pharmaceutically acceptable salt as active ingredient.
wherein W represents carbon chain from 9 to 17 which containing double bond or hydroxy group occasionally; X represents carbon chain from 11 to 25 which containing double bond or hydroxy group occasionally; Y represents —(CH
2
)
a
—CH═CH—(CH
2
)
a
—, —(CH
2
)
a
—(a,a′ denotes an integer of 0-5 and a+a′ is 5 and under [.]), —S(O)
0-2
CH
2
—, —NHCH
2
—,; Z represents —CO—, —SO
2
—; R represents —CH
2
OH, —CO
2
H, —CH
2
OCH
2
CO
2
H, —CH
2
OSO
3
H; R
0
represents —OH, —NH
2
, —NHA
c
.
A preparing method of general formula (I) in the present invention are examplified and not restrict the disclosed invention. And, each sign are as mentioned above.
(A) Synthesis of the Ceramide Moiety
I. The ceramide precursor (A-1) is prepared by Schmidt's method (Liebigs Ann. 1995, 755-764) using D-galactose as a starting material. A primary hydroxy group of the compound (A-1) is tritylated, followed by benzylation of the secondary hydroxy group, and the conpound (A-2) is obtianed.
(wherein W
1
is a carbon chain of C8 to C16 and it contains saturated position as the case may be.)
An azide group of the compound (A-2) is reduced by hydrogenatoin, or triphenylphosphine and water, thus the amino compound (A-3) is obtained.
The generated amino group is carried out amidation or sulfonylation in the presence of base, and the compound (A-4) or (A-5) are obtained, respectively. Furthermore, the compound (A-3) is condenced by coupling reagents (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl salt (WSCDI) et cetera), and the compound (A-4) is also able to obtain.
The compound (A-4) or (A-5) are reacted with acid for detritylation, to yield the compound (A-6) or (A-7). Then the generated hydroxy group is oxidized (Swern oxidation (J. Org. Chem. 1978, 43, 2482) etc), to yield the aldehyde compound (A-8) or (A-9).
II. The compound (A-2) is reacted with acid for detritylation, followed by a reduction (PPh
3
/H
2
O etc) of an azide group, to yield the compound (A-10). Then amino group of the compound (A-10) is protected with Boc group, followed by an oxidation of the primary hydroxy group (Swern oxidation (J. Org. Chem. 1978, 43, 2482) etc), to yield the aldehyde compound (A-11).
III. A primary hydroxy group of the compound (A-12) is carried out methanesulfonylation or bromination, to yield the compound (A-13).
(B) Synthesis of the Sugar Moiety
A cyano group of galactosylcyano compound (B-1) is reduced by Lopex's procedure (J. Carbohydr. Chem. 1987, 6, 273-279), to yield the alcohol compound (B-2).
A primary hydroxy group of the compound (B-—
2
) is carried out tosylation followed by iodation, to yield the compound (B-3). Then it is reacted with triphenylphosphine, to yield the compound (B-4).
The compound (B-4) is reacted with base (n-butyl lithium, potassium fluoride, etc), to yield the compound (B-5).
(C) Coupling Reaction with the Sugar Moiety and the Ceramide Moiety
I. The ceramide compound (A-8) and (A-9) which was prepared by the method (A), is carried out Wittig reaction with the compound (B-5) which was prepared by the method (B), to yield the compound (C-1) or (C-2) Then, those are reacted with sodium metal in liquid ammonia to yield the compound (C-3) or (C-4) Furthermore, those are hydrogenated to yield the compound (C-5) or (C-6). As another method, the compound (C-1) and (C-2) are directly hydrogenated to yield the compound (C-5) or (C-6).
II. The ceramide compound (A-11) which was prepared by the method (A), is carried out wittig reaction with the compound (B-5) which was prepared by the method (B), to yield the compound (C-7). Then, it is reacted with a sodium metal in liquid ammonia to yield the compound (C-8). Furthermore, it is hydrogenated to yield the compound (C-9). As another method, the compound (C-7) is directly hydrogenated to yield the compound (C-9).
The compound (C-8) or (C-9) is reacted with acid for deprotection to yield the compound (C-10) or (C-11), then the amino group is carried out amidation or sulfonylation to yield the compound (C-3, (C-4), (C-5), or (C-6).
III. The ceramide compound (A-13) which was prepared by the method (A), is glycosylated with the sugar derivatives (C-12) or (C-13) in th

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