N-alkyl tryptanthrin derivative, preparation method for same, and application thereof
An N-alkyl tryptanthrin derivative, a preparation method for same, and an application thereof are provided. The structure of the derivative is as represented by formula I. The N-alkyl tryptanthrin derivative can serve as a highly active IDO inhibitor, for use in preparing a medicament for prevention and/or treatment of a disease having a pathological characteristic of an IDO-mediated tryptophan metabolic pathway.
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein Z is absent or F;
T 1 is
T 2 is H or unsubstituted C 1 -C 3 alkyl
X and Y are independently substituted or unsubstituted C 1 -C 5 alkyl or substituted or unsubstituted C 1 -C 5 halogenated alkyl;
or X and Y are independently substituted or unsubstituted C 1 -C 5 alkylene, and X and Y are linked by —CH 2 —, —O—, or —N(Ra)—, wherein
Ra is H or substituted or unsubstituted C 1 -C 3 alkyl; and
when a group is substituted, the substituent group is selected from the group consisting of C 1 -C 5 alkyl, trifluoromethyl, and halogen.
2. The compound of formula (I) of claim 1 , wherein Z is F.
3. The compound of formula (I) of claim 1 , wherein X is substituted or unsubstituted C 1 -C 3 alkyl; and Y is substituted or unsubstituted C 1 -C 3 alkyl.
4. The compound of formula (I) of claim 1 , wherein X and Y together with the adjacent N atom form the following structures:
5. The compound of formula (I) of claim 1 , wherein the compound is:
6. A preparation method for a compound of formula (I), wherein the method comprises the following steps (a)-(c):
(a) oxidizing the compound of formula II to form the compound of formula III;
(b) reacting the compound of formula III with fluoric isatin or isatin thereby forming the compound of formula IV; and
(c) substituting the compound of formula IV thereby forming the compound of formula I;
wherein in each formula, R 1 and R 2 are independently selected from the group consisting of H, Br and I, provided that R 1 and R 2 are not simultaneously H;
T 1 is
T 2 is H or unsubstituted C 1 -C 3 alkyl; and
Z is absent or F.
7. A pharmaceutical composition, comprising:
the compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
8. A method for treating a disease related to tryptophan metabolism disorder selected from the group consisting of cancer, Alzheimer's disease, cataracts, depression, anxiety disorders, AIDS, autoimmune disease, and mental disorders in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 7 .
9. The method of claim 8 , wherein the compound of formula (I) is:
10. A method of inhibiting indoleamine 2,3-dioxygenase (IDO) activity, the method comprising contacting the compound of formula (I) of claim 1 with IDO, thereby inhibiting IDO activity.
11. The method of claim 10 , wherein the compound of formula (I) is