C-glycosides and preparation of thereof as antidiabetic agents

Details C-glycosides and preparation of thereof as antidiabetic agents C-glycosides and preparation of thereof as antidiabetic agents

2001-01-23

2003-09-30

Ponda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S001110, C536S124000

Reexamination Certificate

active

06627611

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention regarding to new C-glycosides which are useful for the treatment and/or prevention of diabetes and a pharmaceutical composition containing these compounds as active ingredients. And this invention is also including the method of preparation of C-glycosides.
Current Technology
The anti-diabetic compounds which modulates energy valance and glucose levels in the body are required recently.
The Na
+
-glucose cotransporter (SGLT) located on the chorionic membrane of the intestine and the kidney. Glucose is absorbed in the investive and the kidney mediated by SGLT.
The mechanism of inhibiting SGLT provides a novel approach to treat and/or prevent of diabetes. Because the inhibitory effect on SGLT may be excrete extra glucose into urine and as a result, prevent chronic hyperglycemia (Welch, C. A. et al., J.Natr., 1989,119(11)1698).
Phlorizin, O-glycosides, is reported as a specific inhibitor of SGLT. And the series of O-glycosides are synthesized and reported the anti-diabetics activity of these compounds (Hanga, M.et al., Chem.Pharm.Bull.1998,46(1)22, Tokukai 11-021243).
These series of O-glycosides, however, would be cleaved by glycosidase exsists in intestine when orally administrated.
And it is reported that phloretine, the aglycone of phlorizin, inhibit facilitated-type glucose transporter. For example, intravenously injection of to rats result the reduction of glucose levels in rat brain (Stroke,1983,14,388).
To overcome the stability against glycosidases, acids and bases, the chemistry of C-glycosides which replace of internal oxygen atom to carbone atom are reported (R. J. Linhardt.et al.,Tetrahedron, 1998, 54,9913., D. E. Levy,The Chemistry of C-Glycosides.Pergamon; Oxford,1995., M. H. D. Postema, C-Glycoside Synthesis.CRC Press;Boca Raton.1995). However, it is not reported that C-glycosides has strong SGLT inhibitor, so far.
The Subject of the Invention
The present invention concerns metabolic and hydrolytic stable C-glycosides compounds. These C-glycosides excrete extra glucose into urine and show hypoglycemic activity and a pharmaceutical composition containing these compounds as active ingredients. The present invention also includes the methods of preparing these C-glycosides compounds.
A Solution to the Invention
After elaborated to make C-glycosides which metabolic and hydrolytic stable for an anti-diabetics drug, the inventors found that new compounds as show general formula (I) had shown potent anti-diabetic activities and fulfilled this invention. Namely, the invention is the compounds as shown in general formula (I) and its pharmaceutically acceptable salts and a composition containing these compounds as active ingredients.
SUMMARY OF THE INVENTION
A novel C-glycosides and preparation of thereof as the treatment and/or prevention agent of diabetes and the blood glucose lowering agent are provided.
DETAILED DESCRIPTION OF THE INVENTION
It is that the compounds as shown in general formula (I) and its pharmaceutically acceptable salts.
Namely, the invention is the compounds as shown in general formula (I) and its pharmaceutically acceptable salts and a composition containing those compounds as active ingredients.
wherein: with the provisos that
R
1
is H, OH, lower alkyl, O-lower alkyl or
R
2
is H, —COO-lower alkyl,
or
R
5
is —CH
2
OH, —CH
2
OCO
2
-lower alkyl,
—CH
2
OSO
3
H, —COOH or —COONa;
wherein: A is
(with the provisos that X is oxygen atom, nitrogen atom or sulfur atom
R
3
is lower alkyl when m=0, and is lower alkyl, —OH or —O-lower alkyl when m=1, . . . means saturated or unsaturated carbon bond;
m is 0 or 1;
n is 0, 1 or 2;
above mentioned-lower alkyl means C
1
-C
5
.)
Enforcement of Invention
48 compounds are exemplified as follow, but the invention is not limited to these compounds.
TABLE 1
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
1
135-136
−1.59(1, Py.)

2
226-228
−23.60(1, Py.)

3
>250
−24.80(0.5, Py.)

4
195-196
−40.19(1, Py.)

5
120-121
−35.80(1, Py.)

6
120-121
−10.80(1, Py.)

7
189-190
−42.00(0.1, Py.)
TABLE 2
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
8
228-229
+57.19(1, Py.)

9
137-138
−10.57 (0.643, CHCl
3
)

10
181-183
−66.13(0.5, Py.)

11
239-242
−70.90(0.55, Py.)

12
183-185
−68.08(0.05, Py.)

13
236-239
−59.41(0.5, Py.)

14
226-228
−46(0.1, Py.)
TABLE 3
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
15
245-248
−28.0(0.1, Py.)

16
198-199
+1.19(1, Py.)

17
194-196
−44(0.1, Py.)

18
217-220
−60(0.1, Py.)

19
276-279
−72(0.1, Py.)

20
256-257
−86.00(1, Py.)

21
103-105
−2.39(0.5, Py.)
TABLE 4
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
22
226-228
−23.60(1, Py.)

23
112-113
−16.19(1, Py.)

24
89-90
−8.20(1, Py.)

25
175-176
−23.60(0.5, Py.)

26
191-192
+10.40(1, Py.)

27
118-119
−12.80 (0.5, CH
2
Cl
2
)

28
194-196
−52.0(0.1 , Py.)
TABLE 5
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
29
131-132
−15.59(1.0, Py.)

30
66-71
−20(0.1, Py.)

31
216-217
−44.80(1, Py.)

42
71-73

43
115-117

44
177-179

45
220
TABLE 6
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
46
77-79

47
113-114
−18.39 (0.5, MeOH)

48
 262
−11.60 (0.5, MeOH)

49
  128-128.5
+2.80 (1.0, MeOH)

50
>220

51
103-105
+4.79 (1, CHCl
3
)

52
85-87
−8.00 (1, CHCl
3
)
TABLE 7
Compound
Structure
mp (° C.)
[&agr;]D
23
/(c, solv.)
53
58-60
−18.39 (1, CHCl
3
)

54
227-228
−10.00 (1, CH
3
OH)

55
80-83
+10.46 (1, CHCl
3
)

56
amorphous
−1.19 (1, CHCl
3
)

57
118-120
−2.00 (1, CHCl
3
)

58
199-201
−9.20 (1.0, MeOH)
Typical preparations of the compounds of general formula (I) according to the invention are shown, but the invention is not limited to those examples.
The preparations of the compound of general formula (I).
(1) In case of R
2
is all hydrogen atoms.
The compounds can be obtained by means of the following diagram (wherein R
1
, R
4,
A
1
, m, and n have the above-mentioned meaning): The compound of general formula (II) is converted to the compound of general formula (I) by the aldol reaction with aldehyde compound of general formula (IV), and followed by the catalytic hydrogenation of double bond of general formula I.
(2) In case of R
1
is —OH, R
2
is —H, or —COOCH
3
.
The compounds can be obtained by means of the following reaction diagrams (wherein A, m, and n have the above-mentioned meaning): The phenolic hydroxy groups of the above-mentioned (I) is protected by allyl group, and then reacted with methyl chloroformate in the presence of base to obtain the compound of general formula (V). After removal of allyl groups of the compound (V) by the Pd catalyst, followed by the catalytic hydrogenation of double bond, if necessary, the compound of general formula (VI) is obtained.
(3) In case of R
1
is —OH, R
2
is —H or
and R
5
is
The compound can be obtained by means of the following reaction diagrams (wherein A and m have the above-mentioned meaning): The compound of general formula (I) is reacted with succinic anhydride in pyridine to obtain the compounds of general formula (XVII) and/or (XVIII).
(4) In case of R
2
is all hydrogen atoms, R
5
is CH
2
OH and R
1
is
The compounds can be obtained by means of the following reaction diagram (wherein A
1
and m have the above-mentioned meaning): The phenolic hydroxy group of the compound of general formula (I) is reacted with 4-bromomethyl-5-methyl-1,3-dioxolene in the presence of base, to obtain the compound of general formula (XIX).
The preparations of the compound of general formula (II).
(a) In case of m=0
The compound can be obtained by means of the following reaction diagram (wherein R
1
and n have the above-mentioned meaning, X is halogen (Br, F, etc.), leaving group such as CF
3
.CO.O—, and Bn

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