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Antitumoral compounds

A compound, selected technology, applied in the field of ascidians

Pending Publication Date: 2019-12-27
PHARMA MAR U
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Despite positive results in the clinical application of chemotherapy, in the field of ascidin compounds there is great interest in identifying new compounds with optimal activity profiles, selectivity for tumors, reduced systemic toxicity, and / or improved pharmacokinetic properties. research is still open

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0830] A)

[0831] To a solution of 1 (0.5 g, 0.80 mmol) in acetic acid (20 mL, 0.04 M) was added L-tryptophanol (2-S) (533 mg, 3.0 mmol, Sigma-Aldrich). The reaction mixture was stirred at 23°C for 16 hours, then the acetic acid was evaporated. Add saturated NaHCO 3 aqueous solution with CH 2 Cl 2 Extract the mixture. through anhydrous Na 2 SO 4 The combined organic layers were dried, filtered and concentrated in vacuo. Flash column chromatography (hexane:EtOAc, 1:1) gave compound 3-S (616 mg, 97%) and 3a-S (12 mg, 2%).

[0832] 3-S

[0833] R f =0.50 (hexane:EtOAc, 1:1).

[0834] 1 H NMR (300MHz, CDCl 3 ): δ7.71(s,1H),7.36(dd,J=7.9,1.0Hz,1H),7.27(dd,J=8.2,0.9Hz,1H),7.13(ddd,J=8.3,7.0,1.2 Hz,1H),7.03(ddd,J=8.0,7.0,1.0Hz,1H),6.62(s,1H),6.26(d,J=1.4Hz,1H),6.04(d,J=1.3Hz,1H ),5.75(s,1H),5.14(dd,J=11.7,1.2Hz,1H),4.60(s,1H),4.41(s,1H),4.36-4.24(m,2H),4.21(d, J=2.7Hz, 1H), 3.82(s, 3H), 3.52(s, 1H), 3.50-3.47(m, 1H), 3.45(dq, J=8.4, 2.2Hz, 1H), 3.35(t, J =10.1Hz,1H...

Embodiment 2

[0854] A)

[0855] To a solution of 1 (0.5 g, 0.80 mmol) in acetic acid (20 mL, 0.04 M) was added D-tryptophanol (2-R) (533 mg, 3.0 mmol, Sigma-Aldrich). The reaction mixture was stirred at 23°C for 16 hours, then the acetic acid was evaporated. Add NaHCO 3 saturated aqueous solution with CH 2 Cl 2 Extract the mixture. Anhydrous Na 2 SO 4 The combined organic layers were dried, filtered and concentrated in vacuo. Flash column chromatography (hexane:EtOAc, 1:1) gave compound 3-R (479 mg, 75%).

[0856] R f =0.44 (hexane:EtOAc, 1:1).

[0857] 1 H NMR (400MHz, CDCl 3 ): δ7.61(s,1H),7.39(d,J=7.8Hz,1H),7.29(d,J=9.6Hz,1H),7.12(t,J=7.3Hz,1H),7.03(t ,J=7.3Hz,1H),6.60(s,1H),6.25(s,1H),6.03(s,1H),5.75(s,1H),5.04(d,J=11.7Hz,1H),4.62 (s,1H),4.37(s,1H),4.32-4.25(m,1H),4.22(d,J=2.7Hz,1H),4.19-4.09(m,1H),3.82(s,3H), 3.77(s,1H),3.64(d,J=9.0Hz,1H),3.49-3.41(m,2H),3.02-2.90(m,2H),2.60-2.52(m,2H),2.45(d, J=14.7Hz, 2H), 2.40(s, 3H), 2.28(s, 3H), 2.22-2.14(m, 2H), 2.18(s, 3H), 2.1...

Embodiment 3

[0866] Example 3 Synthesis of Allyl N-[(R)-(2-amino-3-(1H-indol-3-yl)propyl)]carbamate (9-R)

[0867]

[0868] A)

[0869] CH 3 To the solution of CN (42 mL, 4 mL / mmol) was added di-tert-butyl dicarbonate (4.6 g, 20.8 mmol). The reaction mixture was stirred at 23°C for 3 hours and concentrated in vacuo. Flash column chromatography (CH 2 Cl 2 :CH 3 OH from 99:1 to 85:15) gave 5-R (2.2 g, 73%).

[0870] R f =0.5(CH 2 Cl 2 :CH 3 OH, 9:1).

[0871] 1 H NMR (400MHz, CDCl 3 ):δ8.13(s,1H),7.67(dd,J=7.8,1.1Hz,1H),7.38(dd,J=8.1,1.3Hz,1H),7.29-7.10(m,2H),7.06( s,1H),4.82(s,1H),4.00(s,1H),3.71(dd,J=11.0,3.8Hz,1H),3.62(dd,J=11.0,5.5Hz,1H),3.01(d , J=6.7Hz, 2H), 2.14(s, 1H), 1.44(s, 9H).

[0872] B)

[0873] To 5-R (2.4g, 8.2mmol) in CH 2 Cl 2 (50 mL, 6 mL / mmol) were added phthalimide (2.7 g, 18.2 mmol), triphenylphosphine (4.8 g, 18.2 mmol), and the mixture was cooled at 0°C. CH with addition of diethyl azodicarboxylate 2 Cl 2 solution (25 mL, 3 mL / mmol) for 15...

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Abstract

A compound of general formula I, wherein X, R1-R4 take various meanings, is applied to the treatment of cancer.

Description

technical field [0001] The present invention relates to ectascidins, especially synthetic analogues of ectascidins 736 (ET-736), pharmaceutical compositions containing them, their preparation methods and their use as antitumor agents. Background technique [0002] Escidina is a very potent antineoplastic agent isolated from the marine tunicate-mangrove sea squirt (Ecteinascidia turbinata). One of the compounds, ET-743, has the following formula: [0003] [0004] The compound is used under the International Nonproprietary Name (INN) as the anticancer drug trabectedin in patients who have failed or are unsuitable for treatment with anthracyclines and ifosfamide It was subsequently used in the treatment of patients with advanced and metastatic soft tissue sarcoma (STS), and in combination with pegylated liposomal doxorubicin for the treatment of recurrent platinum-sensitive ovarian cancer. [0005] Escidin 736 (ET-736), first discovered by Rinehart, is characterized by a ...

Claims

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Application Information

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IPC IPC(8): C07D515/22A61P35/00A61K31/4995
CPCC07D515/22A61P35/00C07B2200/07Y02P20/55A61K31/4995
Inventor 马里亚·德尔·卡门·库瓦斯马昌特A·弗兰切斯凯·索洛索瓦伦丁·马丁内斯巴拉萨
Owner PHARMA MAR U
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