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Enzyme-triggered carbon monoxide releasing molecules

A compound and selected technology, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, organic active ingredients, etc., can solve problems such as limited application and difficult control

Active Publication Date: 2020-03-31
GEORGIA STATE UNIV RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these reactions are not easy to control, or ultraviolet light must be used to activate the molecules, which limits their use as drugs

Method used

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  • Enzyme-triggered carbon monoxide releasing molecules
  • Enzyme-triggered carbon monoxide releasing molecules
  • Enzyme-triggered carbon monoxide releasing molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] Example 1: Synthesis of compound 1.11a

[0225]

[0226] N 2 , compound 1.12a (2.0 g, 14.5 mmol) and imidazole (1.5 g, 21.7 mmol) were dissolved in anhydrous dimethylformamide (DMF) (10 mL). Then, tert-butyldiphenylchlorosilane (TBDPSCl) (4.2 g, 15.2 mmol) was added dropwise at room temperature. The resulting mixture was further stirred at room temperature for 1 hour. Then, the mixture was poured into water and extracted with ethyl acetate (3 x 40 mL). The obtained organic layer was washed with anhydrous Na 2 SO 4 dry. After filtration and concentration, the residue was triturated with hexanes and the resulting precipitate was filtered to afford the title compound 1.11a. Yield: 90%. 1 H NMR (CDCl 3 ):δ8.16(s,1H),7.66(d,J=6.8Hz,4H),7.51–7.39(m,6H),7.24(t,J=7.2Hz,1H),7.05(d,J= 7.6Hz, 2H), 6.90(t, J=7.2Hz, 1H), 3.92(t, J=5.2Hz, 2H), 2.98(t, J=5.2Hz, 2H), 1.13(s, 9H). 13 C NMR (CDCl 3 ): δ155.8, 135.6, 132.0, 130.9, 130.1, 128.4, 127.9, 126.9, 120.4, 117.1, 66...

Embodiment 2

[0227] Embodiment 2: Synthesis of compound 1.10a

[0228]

[0229] To a solution of compound 1.11a (1.5 g, 4 mmol) in anhydrous DMF (25 mL) was added NaH (191 mg, 4.8 mmol) in portions at 0°C. The resulting mixture was then stirred at 0 °C for a further 0.5 h before methoxymethyl chloride (MOMCl) (480 mg, 6 mmol) was added dropwise. The resulting mixture was further stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 x 40 mL). The resulting organic layer was washed with brine and washed with anhydrous Na 2 SO 4 dry. After filtration and concentration, the obtained residue was purified on a silica gel column to obtain compound 1.10a as a colorless oil (yield: 90%). 1 H NMR (CDCl 3 ): δ7.76–7.61(m,4H),7.54–7.37(m,6H),7.28–7.20(m,2H),7.17–7.06(m,1H),6.99(td,J=7.4,1.1Hz ,1H),5.14(s,2H),3.96(t,J=7.2Hz,2H),3.40(s,3H),3.05(t,J=7.2Hz,2H),1.13(s,9H). 13 C NMR (CDCl 3 ): δ155.4, 135.6, 134.0, 131.4, 129....

Embodiment 3

[0230] Embodiment 3: Synthesis of compound 1.9a

[0231]

[0232] To a solution of compound 1.10a (1.0 g, 2.4 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was added tetramethylethylenediamine (TMEDA) (417 mg, 3.6 mmol) at 0 °C, followed by 2 Next, n-butyllithium (n-BuLi) (1.8 mL, 3.6 mmol, 2M in hexane) was added dropwise. The resulting solution was stirred at room temperature for an additional 1 hour. The obtained brown solution was cooled to -78°C, then ethyl chloroformate (520 mg, 4.8 mmol) was added dropwise. A white precipitate formed immediately. The resulting mixture was stirred while slowly warming to room temperature (about 1 hour). The reaction mixture was then poured into saturated NH 4 Cl solution and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 dry. After filtration and concentration, the obtained residue was purified on a silica gel column to obtain compound 1.9a as a colorless oil (yiel...

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Abstract

The present invention generally relates to carbon monoxide releasing compounds and compositions, and their use as carbon monoxide prodrugs. The compounds disclosed herein contain a cyclopentadienone moiety, a non-reactive dienophile, and an enzyme-cleavable tethering moiety connecting the cyclopentadienone moiety to the non-reactive dienophile. Cleavage of the enzyme-cleavable tethering moiety results in conversion of the non-reactive dienophile to a reactive dienophile.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application 62 / 518,467, filed June 12, 2017, which is incorporated herein by reference in its entirety. [0003] Statement Regarding Rights to Inventions Made Under Federally Sponsored Research and Development [0004] This invention was made with government support under Grant No. CA 180519 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Carbon monoxide (CO) is a well known deadly poisonous gas. However, CO is also an important member of the gastransmitter family of signal transduction molecules in mammalian systems, as important as NO and H 2 S is equal. NO is the first gaseous small molecule biomessenger identified in mammals. Nitroglycerin (glyceryl trinitrate) is used as an exogenous source of NO and is the most widely used drug for vasodilation and treatment of cardiac di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/122A61K31/166A61K31/235A61K31/5375
CPCA61K31/42A61P9/00A61P29/00C07D321/10C07C225/06C07D265/30
Inventor 季兴跃王炳和
Owner GEORGIA STATE UNIV RES FOUND INC
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