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Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof

A kind of technology of farnesyl thiosalicylic acid and derivatives, which is applied in the application field of preparing antitumor drugs

Inactive Publication Date: 2012-05-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention discloses a class of furazan nitrogen oxide NO-donor FTA derivatives with medicinal value and pharmaceutically acceptable salts thereof. There is no report on this type of compound so far

Method used

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  • Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof
  • Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof
  • Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Preparation of 2-[(4-benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]ethylamine (1a)

[0160] Dissolve 3mL (50mmol) ethanolamine and 1.85g (5mmol) 2-oxo-3,4-diphenylsulfonyl-1,2,5-oxadiazole in 20mLTHF, cool in an ice bath, and drop into 2.5mol / L NaOH solution 2 mL, react at room temperature for 0.5 h, add 1 mL of 2.5 mol / L NaOH solution, continue to stir until the raw materials are completely reacted, pour 80 mL of water, extract with dichloromethane (3×20 mL), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate , recrystallized from methanol / water to obtain 0.93 g of white solid (1a), yield 66%, mp: 102-104°C.

[0161] N-{2-[(4-Benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]ethyl}farnesylthiosalicylic acid amide (I 1 ) preparation

[0162] Dissolve 18.0 g (0.50 mmol) FTA and 14.0 mg (0.65 mmol) DCC in 15 mL anhydrous CH 2 Cl 2 , stirred at room temperature for 30 minutes, added 0.18g (0.60mmol) 1a and a catalytic amount of DMAP, reacted at r...

Embodiment 2

[0164] Preparation of N-{[2-(4-Benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]ethoxy}piperazine (1b)

[0165] Referring to the preparation method of 1a, a light yellow solid was obtained from hydroxyethylpiperazine with a yield of 55%, mp: 90-92°C.

[0166] 3-{4-[3-[(4-Benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]propoxy]-1,4-dioxobutoxy }farnesyl methyl thiosalicylate (I 2 ) preparation

[0167] N-{[2-(4-Benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-)oxygen]ethoxy}piperazinylfarnesylthiosalicylic acid imide ( I 2 ) preparation

[0168] Refer to I 1 The preparation method is prepared by the reaction of FTA and 1b, a colorless transparent oil, and the yield is 61%. IR (KBr, cm -1 ) v: 2926, 1731, 1648, 1551, 1454, 1371, 1167; 1 H NMR (CDCl 3 , 300MHz): δ8.05(d, 2H, J=7.8Hz, Ar-H), 7.75(m, 1H, Ar-H), 7.61(m, 2H, Ar-H), 7.38(m, H, Ar-H), 7.28(m, 3H, Ar-H), 5.28(m, 1H, SCH 2 C H ), 5.08(m, 2H, 2×CH 2 C H =CCH 3 ), 4.58(t, 2H, J=5.1Hz, C H 2 O), 3.84(d, 2H, J=4.5Hz, N...

Embodiment 3

[0170] Preparation of 4-[(4-benzenesulfonyl-5-oxo-1,2,5-oxadiazole-3-)oxy]-2-butyn-1-ol (1c)

[0171] Referring to the preparation method of 1a, a white solid was obtained from 2-butynediol with a yield of 63%, mp: 110-112°C.

[0172] {4-[(4-Benzenesulfonyl-5-oxo-1,2,5-oxadiazol-3-)oxy]-2-ynyl}farnesyl butyl thiosalicylate (I 3 ) preparation

[0173] Refer to I 1 The preparation method is prepared by the reaction of FTA and 1c, a colorless transparent oil, the yield is 65%, IR (KBr, cm -1 ) v: 2934, 1724, 1618, 1548, 1453, 1357, 1167; 1 H NMR (CDCl 3 , 300MHz): δ8.06(d, 2H, J=7.8Hz, Ar-H), 8.01(d, 1H, J=7.8Hz, Ar-H), 7.74(t, 1H, J=7.2Hz, Ar -H), 7.62(m, 2H, Ar-H), 7.47(t, 1H, Ar-H), 7.33(m, 1H, Ar-H), 7.20(m, 1H, Ar-H), 5.33( m, 1H, SCH 2 C H ), 5.12(m, 4H, 2×CH 2 C H =CCH 3 , COOCH 2 ), 5.00(s, 2H, OCH 2 ), 3.60 (d, 2H, J=7.2Hz, SC H 2 ), 1.88-2.04 (m, 8H, 2×CHC H 2 C H 2 CH), 1.48-1.68 (m, 12H, 4×CH=CC H 3 ); ESI-MS (m / z): 651 [M+H] + .

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Abstract

The invention discloses a nitric oxide (NO) donor-type farnesyl thiosalicylic acid (FTA) derivative, and pharmaceutically acceptable salt, a preparation method and medical application thereof. The FTA derivative is a compound obtained by carrying out heterozygosis on a NO donor furazan nitrogen oxide and Ras protein inhibitor FTA by an ester bond or an amido bond. Pharmacological test results show that the FTA derivative can reserve the Ras protein inhibiting activity of FTA and simultaneously releases high-concertration NO to induce cancer cell apoptosis and enhance the inhibiting action on cancer cell proliferation; compared with the FTA, the FTA derivative has more excellent anti-tumor activity, and therefore, the compound can be suitable for treating various clinical malignant tumours.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a class of nitric oxide donor type farnesyl thiosalicylic acid derivatives and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their The medical application, especially the application in the preparation of antineoplastic drugs. Background technique [0002] All-trans farnesylthiosalicylic acid (abbreviation: FTA, trade name: Salirasib), as a new farnesyltransferase-based Ras protein inhibitor, can competitively replace F-Ras and F-Ras mutant proteins with Galectin binds and inhibits Ras-induced downstream signaling pathways (including Raf and P13K signaling pathways) and mTOR (stimulator of tumorigenesis, which can rely on or independently open P13K signaling pathways), thereby inhibiting the growth of tumor cells. Studies have shown that FTA can inhibit cell proliferation and migration of various...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12C07D271/08A61K31/625A61P35/00A61P35/02
Inventor 张奕华凌勇赖宜生叶小磊季晖彭司勋
Owner CHINA PHARM UNIV
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