Xanthine derivative
The present invention discloses a xanthine derivative having the structure of the following general formula (I) or a pharmaceutically acceptable salt thereof; further discloses a preparation method for the xanthine derivative or a pharmaceutically acceptable salt thereof; and further discloses the use of the xanthine derivative or a pharmaceutically acceptable salt thereof. Through experiments of DPP-IV activity inhibition experiments in vitro, impact on glucose tolerance in normal mice and impact on blood glucose in spontaneous diabetic mice, it proves that the compounds and pharmaceutically acceptable salts thereof show good DPP-IV inhibition activity, can be applied to prepare medicines for treating dipeptidyl peptidase IV-related diseases, and more particularly, can be applied to the use of medicines for treating type II diabetes or diseases of abnormal glucose tolerance.
1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof:
wherein: R 1 is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom or cyano group.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that R 1 is substituted at the 5-position of (1,3-benzothiazol-2-yl)methyl.
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that R 1 is selected from hydrogen atom, fluorine atom or chlorine atom.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that the compound is:
5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that the compound is:
6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that the compound is:
7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that the pharmaceutically acceptable salt is formed by the compound and an acid selected from: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.
8. The compound or a pharmaceutically acceptable salt thereof according to claim 7 , characterized in that the acid is p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid.
9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , characterized in that the compound or the pharmaceutically acceptable salts thereof is:
1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-amino-piperidin-1-yl]-xanthine;
1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-amino-piperidin-1-yl]-xanthine;
1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-amino-piperidin-1-yl]-xanthine;
1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-amino-piperidin-1-yl]-xanthine hydrochloride; or
1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-amino-piperidin-1-yl]-xanthine hydrochloride.
10. A preparation method of the compound or a pharmaceutically acceptable salt thereof according to claim 1 , comprising the following steps:
Step 1: at room temperature, a starting raw material a is reacted with a raw material A to give an intermediate b;
wherein, in the raw material A, X 1 is a leaving group;
Step 2: at room temperature, the intermediate b is further subjected to a substitution reaction with a raw material B to give an intermediate c;
wherein, in the raw material B, X 2 is a leaving group;
Step 3: under heating condition, the obtained intermediate c is reacted with (R)-3-tert-butoxycarbonyl aminopiperidine, to give an intermediate d;
Step 4: at room temperature, the obtained intermediate d is subjected to deprotection under acid condition, to give the target compound I as a free base;
and
Step 5, as an optional step: at room temperature, the obtained target compound I is further reacted with an acid (HA), to prepare the corresponding salt e;
and
R1 is defined in claim 1 .
11. A method for treating dipeptidyl peptidase IV related diseases comprising administering a compound or a pharmaceutically acceptable salt thereof of claim 1 to a subject in need thereof, wherein the dipeptidyl peptidase IV related disease is type II diabetes or diseases of abnormal glucose tolerance.
12. The method of claim 10 , X 1 is Cl, Br or I.
13. The method of claim 10 , wherein X 2 is Cl, Br or I.
14. The method of claim 10 , wherein the acid in step 4 is hydrochloric acid or trifluoroacetic acid.
15. The method of claim 10 , wherein the acid in step 5 is p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid.
16. The method of claim 10 , wherein said room temperature is 10-25° C.
17. The method of claim 10 , wherein said heating condition is 50-100° C.