US 9,809,822 B2
Triptolide derivatives and preparation method and use thereof
Ge Zhang, Kowloon (HK); Aiping Lu, Kowloon (HK); Cheng Wang, Kowloon (HK); Cheng Lu, Kowloon (HK); Jun Lu, Kowloon (HK); and Biao Liu, Kowloon (HK)
Appl. No. 15/100,092
Filed by Hong Kong Baptist University, Kowloon (HK)
PCT Filed Dec. 11, 2013, PCT No. PCT/CN2013/001551
§ 371(c)(1), (2) Date May 27, 2016,
PCT Pub. No. WO2015/085447, PCT Pub. Date Jun. 18, 2015.
Prior Publication US 2016/0362691 A1, Dec. 15, 2016
Int. Cl. C12N 15/115 (2010.01); A61K 47/48 (2006.01); A61K 31/7088 (2006.01); A61K 31/585 (2006.01); C07J 73/00 (2006.01)
CPC C12N 15/115 (2013.01) [A61K 31/585 (2013.01); A61K 31/7088 (2013.01); A61K 47/48092 (2013.01); C07J 73/003 (2013.01); C12N 2310/16 (2013.01); C12N 2310/351 (2013.01); C12N 2320/30 (2013.01)] 19 Claims
1. A triptolide derivative, being a compound of the Formula (I):

OG Complex Work Unit Drawing
R1=H or OH;
R2=H or OH;
R3=H or OH;
R4=H or OH;
R5=H or OH;
R6=H or OH;
R7=H or OH;
G is O or NH;
A is —CO—, —CO—(CH2)n—CO—, —CH═CH—CO—, —CH═CH—(CH2)n—CO—, —CH(OH)-Ph-CO—, CH(OH)-Ph-(CH2)n—CO—, —CH2-Ph-(CH2)n—CO—, —CO—NH—CO—, —CO—NH—(CH2)n—CO—, —CH2—CH═CH—CO—, —CH2—CH═CH—(CH2)n—CO—, —CO—CH2—, —CO—O—(CH2)n—CO—, —SO2-Ph-CO—, or —SO2-Ph-(CH2)n—CO—; wherein 1≤n≤14; (CH2)n further comprises a substituent selected from straight or branched alkyl, alkenyl, aralkyl, or alkyl aryalkyl, aryl, halogen, group with a heteroatom, heterocycle substituting one or more H in the (CH2)n, the alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl; the alkenyl is selected from vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, or the E, Z isomers thereof; the aralkyl and the alkyl aralkyl is selected from benzyl, diphenylmethyl, tolyl methyl, triphenylmethyl, cinnamyl, phenethyl, styryl, phenylbutyl and neophenyl; the aryl is selected from phenyl, diphenyl, tolyl, methylbenzyl, 4,2,6-trimethylphenyl, cumenyl, di(tert-butyl) phenyl, anthryl, indenyl, naphthyl, haloaryl, haloaryl alkylphenoxy, tolyloxy, xylyl alkoxy, 2,4,6-tris tolyloxy and cumene oxy, diphenyl, anilino, toluidino, tosyl, allyl benzyl or phenyl, furanyl, pyridyl, 2-pyridyl (pyridin-2-yl), indol-1-yl, chloromethylbenzyl or phenyl, trifluoromethylbenzyl or phenyl, hydroxybenzyl or phenyl, methoxybenzyl or phenyl, ethoxybenzyl or phenyl, ethoxymethoxybenzyl or phenyl, allyloxybenzyl or phenyl, phenoxybenzyl or phenyl, acetoxybenzyl or phenyl, benzoyloxy benzyl or phenyl, methylthiobenzyl or phenyl, phenylthio benzyl or phenyl, tolylthio benzyl or phenyl, methylaminobenzyl or phenyl, dimethylaminobenzyl or phenyl, ethylaminobenzyl or phenyl, diethylaminobenzyl or phenyl, acetamidobenzyl or phenyl, carboxybenzyl or phenyl, methoxycarbonyl benzyl or phenyl, ethoxycarbonyl benzyl or phenyl, phenoxycarbonyl benzyl or phenyl, chlorophenoxycarbonyl benzyl or phenyl, N-cyclohexylcarbamoyloxy benzyl or phenyl, allyloxycarbonyl benzyl or phenyl, carbamoyl benzyl or phenyl, N-methylcarbamoyl benzyl or phenyl, N,N-dipropyl carbamoyl benzyl or phenyl, N-phenyl-carbamoyl-benzyl or phenyl, nitrobenzyl or phenyl, cyanobenzyl or phenyl, S-benzyl or phenyl, sulfate benzyl or phenyl, phosphonyl benzyl or phenyl, phosphate benzyl or phenyl and morpholino benzyl or phenyl; the halogen comprises fluorine, chlorine, bromine or iodine; the group with the heteroatom is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, isobutylthio, tert-butylthio, methylsulfinyl, ethylsulfinyl, isopropyl sulfinyl, methylsulfonyl, ethylsulfonyl, isopropyl sulfonyl; the heterocycle is selected from pyridine, quinolone, thiophene, furan, oxazole, tetrazole, thiazole, imidazole, pyrazole, or indole;
B is an aptamer, and the aptamer is AS1411 or Sgc8c;
M is O or OH;
Z is O;
X is O;
wherein A is connected with M, Z or X.
12. A method for treating cancer comprising administering the triptolide derivative according to claim 1 to a subject in need thereof, wherein said cancer is selected from pancreatic cancer, renal cancer, small cell lung cancer, brain cancer, neural cancer, bone cancer, leukemia, lymphoma, intestinal cancer, uterine cancer, breast cancer, liver cancer, prostate cancer, skin cancer, and melanoma.