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Macrocyclic compounds and uses thereof

A compound and heterocyclic group technology, applied in the field of novel macrocyclic compounds, can solve the problems of unreported tumor vascular remodeling and anti-CAF active anti-cancer drugs

Pending Publication Date: 2020-08-21
PRESIDENT & FELLOWS OF HARVARD COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, no anticancer drugs with tumor vascular remodeling effect and anti-CAF activity have been reported

Method used

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  • Macrocyclic compounds and uses thereof
  • Macrocyclic compounds and uses thereof
  • Macrocyclic compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0344] (4aR,5aS,6R,8aS,9aR)-2,2-di-tert-butyl-6-methyloctahydrofuro[2',3':5,6]pyrano [3,2-d][1,3,2]dioxasilin-7-ol

[0345]

[0346] Compound A-1 obtained by the method written in Organic Letters (2009), 11(2), 409-412 at -78°C for 30 min in a nitrogen atmosphere: (4aR, 5aS, 6R, 8aS, 9aR) -2,2-Di-tert-butyl-6-methylhexahydrofuro[2',3':5,6]pyrano[3,2-d][1,3,2]dioxa To a solution of silacyclohexatrien-7(8aH)-one (A-118.5g, 54.0mmol) (CAS number; 1095280-04-8) in toluene (275mL) was added DIBAL (70.2mL, 70.2mmol, 1.0 M toluene solution). The reaction mixture was then stirred at -78°C. After 90 min, the reaction was carefully quenched with MeOH (4.37 mL) at -78 °C, then the cooling bath was removed. Saturated sodium potassium tartrate tetrahydrate solution (300 mL) was added to the reaction mixture and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was ext...

Embodiment 2

[0348] (4aR,6S,7S,8aR)-6-((S)-but-3-en-2-yl)-2,2-di-tert-butylhexahydropyrano[3,2-d] [1,3,2]dioxasiacyclohexatrien-7-ol (Compound A-2)

[0349]

[0350] To a suspension of methyltriphenylphosphonium bromide (73.30 g, 205.2 mmol) in THF (200 mL) was added potassium tert-butoxide (17.27 g, 153.9 mmol) over 10 min at -5 °C under nitrogen atmosphere, then Stir at -5 °C for 60 min. A solution of the crude lactol described in Example 1 in THF (40 mL) was transferred to the reaction mixture over 10 min at -5°C, then stirred at -5°C for 1 hour and at room temperature for 1 hour. The reaction mixture was quenched with ice water (400 mL), then diluted with TBME (400 mL) and the layers were then separated. The aqueous layer was extracted with TBME (400 mL). The combined organic extracts were washed with brine (400 mL), washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was suspended with heptane / EtOAc=1 / 1 (100 mL). The resulting suspension ...

Embodiment 3

[0353] (4aR,6S,7S,8aR)-6-((S)-but-3-en-2-yl)-2,2-di-tert-butyl-7-((tert-butyldimethylformazol Silyl)oxy)hexahydropyrano[3,2-d][1,3,2]dioxasiacyclohexatriene (Compound A-3)

[0354]

[0355] Compound A-2 as described in Example 2: (4aR,6S,7S,8aR)-6-((S)-but-3-en-2-yl)-2 was prepared at 0°C under nitrogen atmosphere , 2-di-tert-butylhexahydropyrano[3,2-d][1,3,2]dioxasilacyclohexatrien-7-ol (9.85g, 28.8mmol) in DCM ( 150 mL) was added 2,6-lutidine (6.68 mL, 57.5 mmol) and tert-butyldimethylsilyl triflate (9.25 mL, 40.3 mmol). The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether. The organic layer was successively washed with 0.5N HCl aqueous solution, saturated NaHCO 3 aqueous solution, then washed with brine. The combined organic layers were subjected to MgSO 4 Dry, filter (a small amount of SiO2 ) and concentrated under reduced pressure. Flash chromatography of the residue on ...

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Abstract

The present invention provides novel compounds (e.g., compounds of Formulae (I), (II), (III), (IV)) having tumor vascular remodeling effect and / or anti-CAF (Cancer Associated Fibroblasts) activity, orpharmaceutically acceptable salts thereof, optionally in a pharmaceutically acceptable carrier, and a medical uses thereof.

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Applications U.S.S.N. 62 / 586,416, filed November 15, 2017, and U.S.S.N. The contents are incorporated into this application by reference. technical field [0003] The present invention provides novel macrocyclic compounds with tumor vascular remodeling effect and anti-CAF (cancer-associated fibroblast) activity. The compounds are useful, for example, in treating cancer or inhibiting tumor growth in a subject. Background technique [0004] Halichondrin (e.g., halichondrin B) is an anticancer agent originally isolated from the marine sponge Halichondriaokadai (see, for example, D. Uemura et al., "Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge" J.Am.Chem.Soc., 107,4796(1985)), and subsequently found in Axinellasp., Phakellia carteri and Lissodendoryxsp. . The total synthesis of Halichondrin B was published in 1992 (for example, se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22A61P35/00A61K31/357
CPCC07D493/22A61P35/00A61P35/04
Inventor Y.岸吉良和信伊藤宪
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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