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Anti-tumor compound containing triazole heterocyclic structure and application thereof

A triazole and compound technology, applied in the field of medicinal chemistry, can solve the problems of limited clinical activity, bone loss, unsatisfactory performance of amonafide, etc., and achieve strong anti-tumor activity and good selectivity

Inactive Publication Date: 2010-01-20
DALIAN UNIV OF TECH
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

However, in the human clinical trials of mitonafide, it was found that it has very serious central nervous system (CNS) toxicity, and its clinical activity is limited; the performance of amonafide in clinical trials is not satisfactory, causing bone marrow suppression, vomiting, Side effects such as rash and moderate phlebitis
[0003] Triazole compounds can be used as aromatase inhibitors, angiogenesis inhibitors, enzyme inhibitors, etc. to exert anti-cancer effects. Anastrozole, Letrozole and Vorozole, which are currently used in clinical practice, are the third generation of aromatase inhibitors, which are highly effective and reversible. , specificity and other characteristics, but its long-term use has the risk of bone loss and osteoporosis

Method used

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  • Anti-tumor compound containing triazole heterocyclic structure and application thereof
  • Anti-tumor compound containing triazole heterocyclic structure and application thereof
  • Anti-tumor compound containing triazole heterocyclic structure and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthesis of N-[3'-(4-phenyl-[1,2,3]-triazole)-propyl]-4-morpholinyl-1,8-naphthalimide (compound 1):

[0025] (1) 2.77 g of 4-bromo-1,8 naphthalene anhydride (0.01 mol) was added to 20 ml of ethylene glycol monomethyl ether, and 2.6 ml of morpholine was added thereto. The temperature was raised, refluxed, and the reaction was followed by thin plate chromatography until the reaction was complete, left standing overnight, filtered, and the solid was weighed to be 2.16 g, and the yield was 76.5%.

[0026]

[0027] (2) Take 2 g of the product synthesized in step (1), add it to 30 ml of absolute ethanol, and then add 0.69 g of n-propanolamine (0.7 ml). The temperature was raised, refluxed, and the reaction was followed by thin-plate chromatography until the reaction was complete, left standing, and filtered to obtain 2.0 g of a yellow solid.

[0028]

[0029] (3) get 1.5 grams of the product synthesized by step (2), add in 15ml of ethyl acetate, slowly drip 0.8ml of P...

Embodiment 2

[0038] Synthesis of N-[3'-(4-phenyl-[1,2,3]-triazole)-propyl]-4-thiomorpholine-1,8-naphthalimide (Compound 2) :

[0039] Except for replacing the morpholine ring with thiomorpholine, other synthesis and purification methods are the same as in Example 1, to obtain the target compound 2

[0040] 1HNMR(d6-CDCl 3 , 400MHz): δ (ppm): 2.46 (m, 2H), 2.97 (t, J 1 =4Hz, J 2 =4.4Hz, 4H), 3.50(t, J 1 =4.4Hz, J 2 =4.0Hz, 4H), 4.31(t, J 1 =6.4Hz, J 2 =6.8Hz, 2H), 4.54(t, J 1 =6.8Hz, J 2 =7.2Hz, 2H), 7.22(d, J=8.0Hz, 1H), 7.32(t, J 1 =6.8Hz, J 2 =7.6Hz, 1H), 7.42(t, J 1 =7.6Hz, J 2 =7.6Hz, 2H), 7.71(t, J 1 =8.0Hz, J 2 =7.6Hz, 1H), 7.80(d, J=8.0Hz, 2H), 8.04(s, 1H), 8.36(d, J=8.4Hz, 1H), 8.51(d, J=8.0Hz, 1H), 8.59 (d, J=7.2 Hz, 1H).

[0041] HR-MS (m / z): C 27 H 25 N 5 O 2 S, calculated: 483.1729, found: 483.1728.

Embodiment 3

[0043] Synthesis of N-[3'-(4-phenyl-[1,2,3]-triazole)-propyl]-4-hexahydropyridine-1,8-naphthalimide (compound 3):

[0044] Except for replacing the morpholine ring with hexahydropyridine, other synthesis and purification methods are the same as those in Example 1, to obtain the target compound 3

[0045] 1HNMR(d6-CDCl 3 , 400MHz): δ (ppm): 1.89 (m, 4H), 2.45 (m, 2H), 3.24 (t, J 1 =4.0Hz, J 2 =4.4Hz, 4H), 3.73(m, 2H), 4.31(t, J 1 =6.4Hz, J 2 =6.4Hz, 2H), 4.54(t, J 1 =7.2Hz, J 2 =6.8Hz, 2H), 7.17(d, J=8.4Hz, 1H), 7.32(t, J 1 =7.2Hz, J 2 =7.2Hz, 1H), 7.42(t, J 1 =7.6Hz, J 2 =7.2Hz, 2H), 7.68(t, J 1 =8.0Hz, J 2 =7.6Hz, 1H), 7.80(d, J=8.0Hz, 2H), 8.04(s, 1H), 8.39(d, J=8.4Hz, 1H), 8.49(d, J=8.4Hz, 1H), 8.58 (d, J=7.2 Hz, 1H).

[0046] HR-MS (m / z): C 28 H 27 N 5 O 2 , Calculated: 465.2165, Measured: 465.2162.

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Abstract

The invention discloses a class of anti-tumor compounds containing a triazole heterocyclic structure and an application thereof, belonging to the technical field of medicinal chemistry. The compounds containing the triazole heterocyclic structure introduce quintuple 1,2,3-triazole ring in the form of side chains through the amino condensation, bromination, nitrine substitution, link reaction and other reactions on the basis of naphthalimide parent structure, select tetrazolium salt reduction to test 7721 hepatocellular in the experiment of inhibiting proliferation of tumor cells, and also select sulfonyl rhodamine B protein staining method to test MCF-7 breast cancer cells. The experiment results show that the anti-tumor compounds have wide anti-tumor activity and good inhibition effect on the normal growth of tumor cells derived from different tissues of liver cancer, breast cancer and the like.

Description

technical field [0001] The invention relates to a class of antitumor compounds containing triazole heterocyclic structures and applications thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Naphthalimide compounds with nitrogen-containing heteroatom substituents introduced into aromatic rings have good anticancer activity, among which amonafide (N-(β-dimethylaminoethyl)-3-amino- 1,8-Naphthalimide) (Malviya V K, Liu P Y, Alberts D S, et al. Am. J. Clin. Oncol., 1992, 15: 41-44.) and mitonafide (N-(β-dimethylformaldehyde) (Brana M.F, Santos A., Roldan C.M., et al.Eur.J.Med.Chem.Chim.Ther., 1981, 16 , 207-212) has entered phase II clinical trials. The compounds can effectively inhibit the growth of tumor cells, and the mechanism of action is to intercalate between the base pairs of DNA, inhibit the synthesis of DNA and RNA, and inhibit topoisomerase II, thereby achieving the purpose of inhibiting tumors. However, in human clinica...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D401/12A61K31/5377A61K31/541A61K31/473A61K31/496A61P35/00G01N33/15G01N21/31
Inventor 李晓莲赵雯雯
Owner DALIAN UNIV OF TECH
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