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Dupa-indenoisoquinoline conjugates

A technology of indenoisoquinoline and conjugates, which is applied in the field of targeting ligand-cytotoxic drug conjugates, and can solve the problems of use discount, disappointing results, tumor tolerance and the like

Inactive Publication Date: 2016-08-24
PURDUE RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Current types of treatment include hormone therapy and chemotherapy, but both have disappointing and sometimes harmful results, making them less useful
The efficacy of chemotherapy in cancer treatment is often limited by two main factors: side effects and the emergence of tumor resistance (Soudy et al., J. Med. Chem. 2013, 56, 7564-7573)

Method used

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  • Dupa-indenoisoquinoline conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0308] Example 1: N-[4-(benzyloxy)benzylidene]-3-bromo-1-propanamine (54)

[0309] 3-Bromopropylamine hydrobromide (3.56 g, 16.2 mmol) was diluted in CHCl 3 (50mL) and Et3 in N (1.64g, 16.2mmol). The mixture was stirred for 5 minutes, then compound 53 (3.00 g, 14.1 mmol) and Na 2 SO 4 (4.02g, 28.3mmol). The mixture was stirred at room temperature for 16 h, then washed with H 2 O (100 mL x 3) and brine (100 mL) washes. The organic layer was washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give product 54 (4.69 g, 100% + residual solvent) as a light yellow syrup. IR (film) 2839, 1645, 1605, 1509, 1246, 1166, 830cm -1 ; 1 H NMR (300MHz, CDCl 3 )δ8.26(s, 1H), 7.68(dd, J=1.8 and 6.9Hz, 2H), 7.45-7.33(m, 5H), 7.02(dd, J=1.9 and 6.9Hz, 2H), 5.11(s , 2H), 3.74(dt, J=0.9 and 6.2Hz, 2H), 3.51(t, J=6.6Hz, 2H), 2.27(m, 2H); ESIMS m / z (relative intensity) 332 / 334(MH + , 100 / 97).

Embodiment 2

[0310] Example 2: cis-4-carboxy-3,4-dihydro-N-(3-bromopropyl)-3-[4-(benzyloxy)phenyl]-7-nitro-1(2H )-isoquinolones (55)

[0311] Schiff base 54 (4.69 g, 14.1 mmol) was diluted in CHCl at 0 °C 3 (50 mL) and added anhydride 58 (2.80 g, 13.5 mmol). The red mixture was stirred at 0 °C for 2 h, then allowed to warm to room temperature and stirring continued for 2 h. Filter the milk-orange mixture and wash with CHCl 3 The residue was washed to give the product 55 (5.18 g, 71%) as an off-white solid: mp 140-141 °C. IR (film) 3076, 1727, 1630, 1525, 1347, 1187, 738cm -1 ; 1 H NMR (300MHz, DMSO-d 6 )δ8.71 (d, J=2.6Hz, 1H), 8.39 (dd, J=2.6 and 6.0Hz, 1H), 7.92 (d, J=8.2Hz, 1H), 7.40-7.30 (m, 5H), 6.92-6.83(m, 4H), 5.19(d, J=6.4Hz, 1H), 5.03(d, J=6.3Hz, 1H), 4.98(s, 2H), 3.90(m, 1H), 3.59(m , 2H), 3.03(m, 1H), 2.16(m, 1H), 2.04(m, 1H); ESIMS m / z (relative intensity) 415 ([MH–COOH–Br] + , 100); MH + HRESIMS calculated value: 539.0818, measured value: 539.0812.

[0312] Scheme 8...

Embodiment 3

[0314] Example 3: 6-(3-bromopropyl)-9-hydroxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (1)

[0315] Dilute cis acid 56 (0.50 g, 0.93 mmol) in SOCl 2 (50mL) and stirred at room temperature for 16h. The resulting yellow solution was evaporated to dryness. The yellow syrup was diluted in 1,2-dichloroethane (50 mL) at 0 °C and stirred for 15 minutes, followed by the addition of AlCl 3 (0.25 g, 1.85 mmol). The black mixture was heated at reflux for 2 h then evaporated to dryness. The remaining residue was washed with CHCl 3 (100mL) diluted with HCl 6N (100mL), H 2 O (100 mL x 3) and brine (100 mL) washes. The organic layer was washed with anhydrous Na 2 SO 4 dried, filtered and concentrated, adsorbed onto SiO 2 above, and with CHCl 3 Eluted flash column chromatography (SiO 2 ) to give product 1 (57 mg, 15%) as a red solid: mp 281-283 (decomposition) °C. IR (film) 3273, 1659, 1613, 1531, 1345, 1270, 755cm -1 ; 1 H NMR (300MHz, DMSO-d 6 )δ10.82(s, 1H), 8.83(...

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Abstract

A targeting ligand-cytotoxic drug conjugate, for example, a DUPA-Indenoisoquinoline conjugate, which is useful for treating cancers, e.g., prostate cancer is disclosed in the invention.

Description

[0001] Statement of Government Interest [0002] This invention was made with government support under CA089566 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0003] The present invention relates to targeting ligand-cytotoxic drug conjugates, such as DUPA-indenoisoquinoline conjugates, which are useful in the treatment of cancer, such as prostate cancer. Background of the invention [0004] Prostate cancer is the second leading cause of cancer death in the United States (after lung cancer in the first place), with an estimated 240,890 new cases and 33,720 deaths in 2011 (Siegel et al., CA Cancer J. Clin .2011, 61, 212-236). Current types of treatment include hormone therapy and chemotherapy, but both have disappointing and sometimes harmful results, making them less useful. The efficacy of chemotherapy in cancer treatment is often limited by two main factors: side effects and the emergence of tumor r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K47/30A61K31/47
CPCA61K31/473A61K47/542A61K47/65A61P13/08A61P35/00A61P43/00
Inventor M·S·库什曼P·S·刘T·X·阮
Owner PURDUE RES FOUND INC
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