Inhibitors of D-amino acid oxidase (DAAO) and uses thereof
Provided herein are compounds of Formula (I) and uses thereof for inhibiting the activity of D-amino acid oxidase (DAAO) or treating diseases or disorders associated with DAAO, such as a central nervous system (CNS) disorder, obesity, diabetes, or hyperlipidemia. Also provided in the present disclosure are methods of synthesizing the Formula (I) compounds described herein.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 5 to 8 membered monocyclic ring system, which optionally comprises at least one heteroatom selected from the group consisting of N, O, P, and S;
each of R1, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , independently, is absent, or of the formula:
wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is present
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C 1 - 3 alkyl, halogen, —CN, —NO2, —SH, −S(C 1-3 alkyl), —NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl)2, and −O(C 1-3 alkyl); and
wherein
n is 0 or 1;
m is 1, 2, 3, 4, or 5; and
the total number of galloyl moieties is an integer of 15 to 35, inclusive.
2. The compound of claim 1 , wherein Ring A is:
3. The compound of claim 2 , wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , independently, is of the formula:
or absent.
4. The compound of claim 3 , wherein the compound of Formula (I) is of the formula:
and R 1 , R 2 , R 3 , R 4 , and R 5 are each selected from the group consisting of:
5. The compound of claim 3 , wherein the compound of Formula (I) is of the formula:
and R 1 , R 2 , R 3 , R 4 , and R 5 are each selected from the group consisting of:
6. A composition comprising the compound of claim 1 and a carrier.
7. The composition of claim 6 , wherein the composition is a pharmaceutical composition, a nutraceutical composition, a health food, or a medical food.
8. A method for preparing the compound of claim 1 , comprising:
(a) providing a compound of formula (Ia)
wherein R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 6′ , R 7′ , and R 8′ , independently, are each —OH, —NH 2 or absent;
wherein at least one of R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 6′ , R 7′ , and R 8′ is present; and
wherein Ring A is a 5 to 8 membered monocyclic ring system, which optionally comprises at least one heteroatom selected from the group consisting of N, O, P, and S;
(b) reacting the compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo [d][1,3]dioxole-5-carbonyl chloride, to allow conjugation of 7-(allyloxy)-2,2-diphenylbenzo [d][1,3]dioxole-5-carbonyl chloride to one or more of R 1′ , R 2′ , R3′, R4′, R5′, R 6′ , R 7′ , and R 8′ of the compound of formula (Ia), thereby producing a first intermediate; and
(c) de-protecting the ally! groups and the cyclic acetal groups in 7-(allyloxy)-2,2-diphenylbenzo [d][1,3]dioxole-5-carbonyl chloride that is conjugated to the compound of Formula (Ia) to obtain the compound of claim 1 .
9. The method of claim 8 , wherein step (c) is performed by:
(c1) de-protecting the allyl groups;
(c2) de-protecting the cyclic acetal groups.
10. The method of claim 9 , further comprising, prior to step (c2), repeating the process consisting of steps (b) and (c1) for 3-7 times.
11. The method of claim 8 , wherein Ring A is:
12. The method of claim 8 , wherein the compound of formula (Ia) is glucose.
13. The method of claim 12 , the glucose is in α form or in β form.
14. The method of claim 8 , further comprising purifying the compound of claim 1 produced after step (c).
15. The compound of claim 1 , which is of the formula:
or a pharmaceutically acceptable salt thereof.