Preparation of 3,7,10-tri-substuent hetero nitrogen silicon tricyclic and 5-Fu combined substance and its use in pharmacy

A technology of three substitutions and conjugates, which is applied in the fields of compounds of group 4/14 elements of the periodic table, active ingredients of silicon compounds, antineoplastic drugs, etc. Low fat and other problems

Inactive Publication Date: 2007-04-11
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to its significant metabolism and low lipophilicity, the bioavailability of 5-fluorouracil is low, which affects the anti-tumor efficacy, and its therapeutic dose is close to the toxic dose

Method used

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  • Preparation of 3,7,10-tri-substuent hetero nitrogen silicon tricyclic and 5-Fu combined substance and its use in pharmacy
  • Preparation of 3,7,10-tri-substuent hetero nitrogen silicon tricyclic and 5-Fu combined substance and its use in pharmacy
  • Preparation of 3,7,10-tri-substuent hetero nitrogen silicon tricyclic and 5-Fu combined substance and its use in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment 1

[0034] γ-[N-[1-oxo-2-[1-(5-fluoro-uracilyl)]ethyl]amino]azasilatricyclo(1)

[0035] 0.5g (2.66mmol) compound A (where R 1 hydrogen) and DCC 1.0g and p-nitrophenol 0.4g (2.88mmol) were added to dry 15ml DMF, heated to 40°C, reacted for 1h, added compound B (where R 2 , R 3 , R 4 hydrogen) 0.62g (2.66mmol), reacted for more than 24 hours, filtered to remove the urea compound generated, the filtrate was concentrated, the residue was purified by silica gel column chromatography [chloroform: methanol = 20: 1], and acetone: petroleum ether = 1:4 recrystallization, 0.29g white solid was obtained, yield: 27.1%, m.p.168-170℃. 1 H-NMR (CDCl 3 )δ: 10.64 (s, 1H, 6-fluorouracil), 7.83 (d, 1H, 3-fluorouracil), 7.28 (s, 1H, -CONH), 4.39 (s, 2H, -NCH 2 CO), 3.67(t, 6H, -Si(OCH 2 -) 3 ), 3.12(q, 2H, -CONHCH 2 CH 2 ), 2.82(t, 6H, -N(CH 2 ) 3 ), 1.52 (m, 2H, -CH 2 CH 2 CH 2 ), 0.25 (m, 2H, -CH 2 Si).ESI-MS(70V): 403.5[M+H] +.Anal.Calcd for C 15 h 23 N 4 o 6 FSi*0.25H 2 O(40...

specific Embodiment 2

[0036] 3,7,10-Trimethyl-γ-[N-[1-oxo-2-[1-(5-fluoro-uracilyl)]ethyl]amino]azasilatricyclo(2)

[0037] According to the preparation method of compound (1), drop into 0.5g (2.66mmol) compound A (wherein R 1 hydrogen) and DCC 1.0g and p-nitrophenol 0.4g (2.88mmol) were added to dry 15ml DMF, heated to 40°C, reacted for 1h, added compound B (where R 2 , R 3 , R 4 For methyl) 0.73g (2.66mmol), obtain 0.38g white solid 2, yield: 32.2%; m.p.162~164 ℃. 1 HNMR (CDCl 3 ) δ: δ: 10.54 (s, 1H, 6-fluorouracil), 7.80 (d, 1H, 3-fluorouracil), 7.38 (s, 1H, -CONH), 4.32 (s, 2H, -NCH 2 CO), 3.57(m, 6H, -Si(OCH 2 -) 3 ), 3.02(q, 2H, -CONHCH 2 CH 2 ), 2.75(m, 6H, -N(CH 2 ) 3 ), 1.49 (m, 2H, -CH 2 CH 2 CH 2 ), 1.23(m, 9H, -Si(OCHCH 3 ) 3 ), 0.24 (m, 2H, -CH 2 Si). ESI-MS: 445.7 [M+H] + .AnalCalcd for C 18 h 29 N 4 o 6 FSi(444.51): C 48.64, H 6.57, N 12.61; Found: C 49.01, H 6.83, N 12.82

specific Embodiment 3

[0038] γ-[N-[1-oxo-2-[1-(5-fluoro-uracilyl)]propyl]amino]azasilatricyclo(3)

[0039] According to the preparation method of compound (1), drop into 0.5g (2.47mmol) compound A (wherein R 1 is methyl) and DCC 1.0g and p-nitrophenol were added to dry 15ml DMF, heated to 40°C, reacted for 1h, added compound B (where R 2 , R 3 , R 4 for hydrogen) 0.58g (2.66mmol), to obtain 0.19g white solid 3, yield: 18.4%, m.p.158~160℃. 1 H-NMR (CDCl 3 )δ: 10.44 (s, 1H, 6-fluorouracil), 7.68 (d, 1H, 3-fluorouracil), 7.18 (s, 1H, -CONH), 4.09 (m, 1H, -NCHCO), 3.60 (t, 6H ,-Si(OCH 2 -) 3 ), 3.10 (q, 2H, -CONHCH 2 CH 2 ), 2.78(t, 6H, -N(CH 2 ) 3 ), 1.69 (m, 3H, -NCHCH 3 CO), 1.50 (m, 2H, -CH 2 CH 2 CH 2 ), 0.22 (m, 2H, -CH 2 Si).ESI-MS(70V): 417.2[M+H] + .Anal.Calcd for C 16 h 25 N 4 o 6 FSi*0.5H 2 O(425.46): C 45.17, H 6.15, N 13.17; Found: C 45.39, H 6.26, N 13.53

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Abstract

The present invention relates to conjugate of 3, 7, 10-trisubstituent silatrane and 5-FU, which may be used in preparing medicine for treating leukemia, liver cancer, rectum cancer, gastric cancer, breast cancer and other tumors, and has the structural formula as shown.

Description

technical field [0001] The present invention relates to the design and synthesis of a combination of 3,7,10-trisubstituent azasilatricyclic and 5-FU with anti-tumor activity, which is used to prepare and treat leukemia, liver cancer, rectal cancer, gastric cancer and breast cancer , malignant lymphoma and other tumor diseases. Background of the invention [0002] Cancer is a kind of disease that seriously endangers human health, with high incidence and high mortality. Conventional cancer treatment methods mainly include surgery, radiation therapy and chemotherapy. Surgical therapy and radiation therapy are mainly local treatment methods. It is suitable for early treatment of malignant tumors. Chemotherapy is suitable for systemic treatment, and has a better therapeutic effect on advanced or diffuse tumors. In recent years, with the advent of various anticancer drugs, chemotherapy has become one of the main methods for the treatment of malignant tumors, but many drugs hav...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18A61K31/695A61P35/00
Inventor 郭平叶发青胡黎川刘剑敏周丽萍黄可新周红宇杨新宇李永吴迪
Owner WENZHOU MEDICAL UNIV
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