WO2016085224A2 - Radical oxyde nitrique de carbène n-hétérocyclique et son application - Google Patents

Radical oxyde nitrique de carbène n-hétérocyclique et son application Download PDF

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Publication number
WO2016085224A2
WO2016085224A2 PCT/KR2015/012624 KR2015012624W WO2016085224A2 WO 2016085224 A2 WO2016085224 A2 WO 2016085224A2 KR 2015012624 W KR2015012624 W KR 2015012624W WO 2016085224 A2 WO2016085224 A2 WO 2016085224A2
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alkyl
aryl
chemical formula
nitric oxide
heteroaryl
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PCT/KR2015/012624
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English (en)
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WO2016085224A3 (fr
Inventor
Eunsung Lee
Kimoon Kim
Junbeom PARK
Hayoung SONG
Youngsuk Kim
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Institute For Basic Science
Postech Academy-Industry Foundation
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Priority claimed from KR1020150161748A external-priority patent/KR101657054B1/ko
Application filed by Institute For Basic Science, Postech Academy-Industry Foundation filed Critical Institute For Basic Science
Publication of WO2016085224A2 publication Critical patent/WO2016085224A2/fr
Publication of WO2016085224A3 publication Critical patent/WO2016085224A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
    • C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms

Definitions

  • the present invention relates to an N-heterocyclic carbene nitric oxide radical, and an application thereof, and more particularly, to an N-heterocyclic carbene nitric oxide radical for effectively delivering nitric oxide, and an application thereof.
  • a number of diseases are characterized by insufficient production of nitric oxide, and are associated with insufficient production of nitric oxide, and many experiments and clinical research have proved that the insufficient production of nitric oxide is associated with major cardiovascular risk factors such as hyperlipidemia, diabetes, hypertension, smoking, and atherosclerosis.
  • a dysfunctional nitric oxide (NOS) synthase pathway is regarded as an early marker for various cardiovascular disorders.
  • Endothelial dysfunction may be obtained from reduced production of nitric oxide or increased decomposition of nitric oxide, and in specific aspects, the endothelial dysfunction may be defined as the inability to produce nitric oxide (NO).
  • the endothelial dysfunction refers to physiological dysfunction of normal biochemical processes performed by cells (the innermost lining of the heart and the lymph vessels) forming membranes on an inner surface of all blood vessels including endothelial, artery or vein, and is associated with several cardiovascular disorders including atherosclerosis.
  • an effective material which is well known in targeted delivery to pulmonary circulation may be suction-type nitric oxide.
  • the suction-type nitric oxide requires a specific suction device which may cause an economic burden to patients.
  • the present applicators completed the present invention with objects of providing a novel N-heterocyclic carbene nitric oxide radical for effectively delivering nitric oxide, an economical synthesis method thereof, and an application thereof.
  • An object of the present invention is to provide an N-heterocyclic carbene nitric oxide radical for effectively delivering nitric oxide.
  • Another object of the present invention is to provide a method for producing an economically desired N-heterocyclic carbene nitric oxide radical without forming by-products causing toxicity.
  • Another object of the present invention is to provide an application of the N-heterocyclic carbene nitric oxide radical according to the present invention which is usable as a source providing nitric oxide to other carbine compound by using the N-heterocyclic carbene nitric oxide radical.
  • N-heterocyclic carbene nitric oxide radical represented by Chemical Formula 1 below:
  • R 1 and R 2 are each independently (C1-C30)alkyl, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C6-C30)aryl or (C3-C30)heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be each independently further substituted with at least one selected from the group consisting of (C1-C30)alkyl, halo(C1-C30)alkyl, halogen, cyano, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C1-C30)alkoxy, (C6-C30)aryloxy, (C6-C30)aryl, (C6-C30)ar(C1-C30)alkyl, (C1-C30)alkyl(C6-C30)aryl, (C3-
  • Z 1 is -C(R 3 )- or -N-, wherein R 3 is hydrogen or (C1-C30)alkyl.
  • Z 1 may be -N-.
  • R 1 and R 2 may be each independently an aryl group selected from phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenyl, crycenyl, naphthacenyl, and fluoranthenyl, and the aryl group may be each independently further substituted with at least one selected from the group consisting of (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro, and hydroxy, but the present invention is not limited thereto.
  • N-heterocyclic carbene nitric oxide radical may be represented by Chemical Formula 2 below, but the present invention is not limited thereto:
  • Ar 1 and Ar 2 are each independently an arylene group selected from phenylene, naphthylene, biphenylene, terphenylene, anthrylene, indenylene, fluorenylene, phenanthrylene, triphenylenylene, pyrenylene, perylenylene, crycenylene, naphthacenylene, and fluoranthenylene,
  • R 11 and R 12 are each independently selected from hydrogen, (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro and hydroxy, and at least one of R 11 and R 12 has a substituent other than hydrogen at an ortho position of the arylene group on the basis of -N- of imidazole; and
  • p and q are each independently selected from integers of 1 to 3.
  • N-heterocyclic carbene nitric oxide radical may be represented by Chemical Formula 3 below, but the present invention is not limited thereto:
  • R 13 to R 18 are each independently selected from hydrogen, (C1-C7)alkyl, halo(C1-C7)alkyl, halogen, cyano, (C1-C7)alkoxy, nitro, and hydroxy, and at least one of R 13 , R 15 , R 16 and R 18 has a substituent other than hydrogen.
  • N-heterocyclic carbene compound represented by Chemical Formula 4 below:
  • R 1 and R 2 are each independently (C1-C30)alkyl, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C6-C30)aryl or (C3-C30)heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be each independently further substituted with at least one selected from the group consisting of (C1-C30)alkyl, halo(C1-C30)alkyl, halogen, cyano, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C1-C30)alkoxy, (C6-C30)aryloxy, (C6-C30)aryl, (C6-C30)ar(C1-C30)alkyl, (C1-C30)alkyl(C6-C30)aryl, (C3-
  • Z 1 is -C(R 3 )- or -N-, wherein R 3 is hydrogen or (C1-C30)alkyl.
  • Z 1 may be -N-.
  • R 1 and R 2 may be each independently an aryl group selected from phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenyl, crycenyl, naphthacenyl, and fluoranthenyl, and the aryl group may be each independently further substituted with at least one selected from the group consisting of (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro, and hydroxy, but the present invention is not limited thereto.
  • N-heterocyclic carbene compound may be represented by Chemical Formula 5 below, but the present invention is not limited thereto:
  • Ar 1 and Ar 2 are each independently an arylene group selected from phenylene, naphthylene, biphenylene, terphenylene, anthrylene, indenylene, fluorenylene, phenanthrylene, triphenylenylene, pyrenylene, perylenylene, crycenylene, naphthacenylene, and fluoranthenylene,
  • R 11 and R 12 are each independently selected from hydrogen, (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro and hydroxy, and at least one of R 11 and R 12 has a substituent other than hydrogen at an ortho position of the arylene group on the basis of -N- of imidazole; and
  • p and q are each independently selected from integers of 1 to 3.
  • the N-heterocyclic carbene nitric oxide radical according to the present invention may be an effective source of nitric oxide, and may be stable in vivo and may help to restore homeostasis of nitric oxide.
  • the N-heterocyclic carbene nitric oxide radical according to the present invention may be present in a stable form at room temperature (23) and may effectively supply nitric oxide by external heat source, and a release rate thereof may be easily controlled according to kinds and temperature range of the heat source. Further, it is expected that nitric oxide provided from the N-heterocyclic carbene nitric oxide radical is effectively usable for treating, preventing, and curing conditions related with insufficiency of nitric oxide.
  • N-heterocyclic carbene nitric oxide radical With the method for producing the N-heterocyclic carbene nitric oxide radical according to the present invention, by-products causing toxicity may not be formed, and the economically desired N-heterocyclic carbene nitric oxide radical may be produced, which provides industrial benefits.
  • N-heterocyclic carbene nitric oxide radical may be pyrolyzed by external heat source to effectively produce nitric oxide, and may be effectively used as a source providing nitric oxide to the other carbene compound.
  • FIG. 1 is graphs illustrating results obtained by measuring crystal structures of compounds produced by Example 1 (IPrNO) and Example 2 (IMesNO) by x-ray diffraction (XRD).
  • FIG. 2 is graphs obtained by comparing and analyzing electron paramagnetic resonance (EPR) spectra of compounds produced by Examples 1 to 4.
  • EPR electron paramagnetic resonance
  • FIG. 3 is graphs illustrating cyclic voltammograms of the compounds produced by Examples 1 and 2.
  • FIG. 4 illustrates a device used in Examples 3 and 4.
  • the present invention provides an N-heterocyclic carbene nitric oxide radical represented by Chemical Formula 1 below:
  • R 1 and R 2 are each independently (C1-C30)alkyl, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C6-C30)aryl or (C3-C30)heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be each independently further substituted with at least one selected from the group consisting of (C1-C30)alkyl, halo(C1-C30)alkyl, halogen, cyano, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C1-C30)alkoxy, (C6-C30)aryloxy, (C6-C30)aryl, (C6-C30)ar(C1-C30)alkyl, (C1-C30)alkyl(C6-C30)aryl, (C3-
  • Z 1 is -C(R 3 )-( ) or -N-( ), wherein R 3 is hydrogen or (C1-C30)alkyl.
  • Cycloalkyl used herein means a fully saturated and partially unsaturated hydrocarbon ring of 3 to 9 carbon atoms, and includes a case in which aryl or heteroaryl is fused.
  • aryl used herein, which is an organic radical derived from aromatic hydrocarbon by removal of one hydrogen, includes single or fused ring system suitably including 4 to 7 ring atoms, preferably, 5 or 6 ring atoms in each ring, and even includes a form in which a plurality of aryls are connected to each other by a single bond.
  • aryl may include phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like, but the present invention is not limited thereto.
  • alkyl alkoxy, and other substituents including “alkyl” part used herein may include all linear or branched types including 1 to 7 carbon atoms or 8 to 30 carbon atoms.
  • the N-heterocyclic carbene nitric oxide radical according to the present invention may be used as a bioavailable nitric oxide source, may provide nitric oxide at a high yield from external heat source, and may be utilized for diseases requiring sufficient level of nitric oxide (NO).
  • NO nitric oxide
  • occurrence of harmful active gases such as nitrous oxide (N 2 O) may be minimized, such that nitric oxide may be converted at a high yield.
  • Z 1 is preferably -N-, but the present invention is not limited thereto.
  • R 1 and R 2 may be each independently aryl selected from phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenyl, crycenyl, naphthacenyl, fluoranthenyl, and the like, and the aryl may be each independently further substituted with at least one selected from the group consisting of (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro, hydroxy, and the like, but the present invention is not limited thereto.
  • N-heterocyclic carbene nitric oxide radical may be represented by Chemical Formula 2 below:
  • Ar 1 and Ar 2 are each independently an arylene group selected from phenylene, naphthylene, biphenylene, terphenylene, anthrylene, indenylene, fluorenylene, phenanthrylene, triphenylenylene, pyrenylene, perylenylene, crycenylene, naphthacenylene, and fluoranthenylene,
  • R 11 and R 12 are each independently selected from hydrogen, (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro and hydroxy, and at least one of R 11 and R 12 has a substituent other than hydrogen at an ortho position of the arylene group on the basis of -N- of imidazole; and
  • p and q are each independently selected from integers of 1 to 3.
  • N-heterocyclic carbene nitric oxide radical may be represented by Chemical Formula 3 below, but the present invention is not limited thereto:
  • R 13 to R 18 are each independently selected from hydrogen, (C1-C7)alkyl, halo(C1-C7)alkyl, halogen, cyano, (C1-C7)alkoxy, nitro, and hydroxy, and at least one of R 13 , R 15 , R 16 and R 18 has a substituent other than hydrogen.
  • the N-heterocyclic carbene nitric oxide radical which is a high purity nitric oxide source may be synthesized from an N-heterocyclic carbene compound in a simple and economical way. Further, the present invention may obtain a high purity product due to excellent reaction efficiency, thereby maximizing productivity.
  • the present invention provides a method for producing the N-heterocyclic carbene nitric oxide radical, including: preparing an N-heterocyclic carbene nitric oxide radical represented by Chemical Formula 1 below by reacting an N-heterocyclic carbene compound represented by Chemical Formula 4 below with nitric oxide:
  • R 1 and R 2 are each independently (C1-C30)alkyl, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C6-C30)aryl or (C3-C30)heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be each independently further substituted with at least one selected from the group consisting of (C1-C30)alkyl, halo(C1-C30)alkyl, halogen, cyano, (C3-C30)cycloalkyl, (C3-C30)heterocycloalkyl, (C1-C30)alkoxy, (C6-C30)aryloxy, (C6-C30)aryl, (C6-C30)ar(C1-C30)alkyl, (C1-C30)alkyl(C6-C30)aryl, (C3-
  • Z 1 is -C(R 3 )- or -N-, wherein R 3 is hydrogen or (C1-C30)alkyl.
  • Z 1 may be -N- in order to implement high yield within a short period of time with higher reactivity.
  • R 1 and R 2 may be each independently an aryl group selected from phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenyl, crycenyl, naphthacenyl, fluoranthenyl, and the like, and the aryl group may be each independently further substituted with at least one selected from the group consisting of (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro, hydroxy, and the like, but the present invention is not limited thereto.
  • N-heterocyclic carbine compound may be represented by Chemical Formula 5 below, but the present invention is not limited thereto:
  • Ar 1 and Ar 2 are each independently an arylene group selected from phenylene, naphthylene, biphenylene, terphenylene, anthrylene, indenylene, fluorenylene, phenanthrylene, triphenylenylene, pyrenylene, perylenylene, crycenylene, naphthacenylene, and fluoranthenylene,
  • R 11 and R 12 are each independently selected from hydrogen, (C1-C10)alkyl, halo(C1-C10)alkyl, halogen, cyano, (C1-C10)alkoxy, nitro and hydroxy, and at least one of R 11 and R 12 has a substituent other than hydrogen at an ortho position of the arylene group on the basis of -N- of imidazole; and
  • p and q are each independently selected from integers of 1 to 3.
  • the reaction may be performed at -80 to 40°C.
  • the reaction may be performed by mixing each reaction product at -80 to 0, and then reacting the obtained mixtures at room temperature (23) to 40, but the present invention is not limited thereto.
  • reaction may be performed for 10 minutes to 5 hours, and when Z 1 is -N-, reactivity is excellent while high purity is maintained, such that a desired N-heterocyclic carbene nitric oxide radical may be obtained by performing the reaction for 10 minutes to 1 hour.
  • the present invention provides a method for producing nitric oxide by pyrolyzing the N-heterocyclic carbene nitric oxide radical represented by Chemical Formula 1 below.
  • the pyrolyzing of the method for producing nitric oxide according to an exemplary embodiment of the present invention may be performed at 80 to 200°C, preferably, 80 to 150 in view of energy efficiency, more preferably, 80 to 120, but the present invention is not limited thereto.
  • a chemical structure of the target compound was confirmed by NMR (model: Bruker DRX 500 spectrometer), electron impact mass spectrometry (electron-impact GC/MS spectrum), and electron paramagnetic resonance (model: Bruker X-band A200 spectrometer), and electrical chemical performance was measured and determined by cyclic voltammograms (Princeton Applied Research (PAR) 273A potentiostat).
  • NMR model: Bruker DRX 500 spectrometer
  • electron impact mass spectrometry electron-impact GC/MS spectrum
  • electron paramagnetic resonance model: Bruker X-band A200 spectrometer
  • IPr (1a) 1,3-bis-(2,6-diisopropylphenyl)imidazolylidene (IPr (1a), 1.00 g, 2.57 mmol, 1.00 equiv) dissolved in 25 mL of toluene was added to a 40 mL vial, and a temperature of the obtained solution was decreased to be -78 °C.
  • Nitric oxide (1.00 equiv) in a gas form was supplied to the solution several times, and it was confirmed that the color of the solution was changed from colorless to dark brown.
  • the solution was heated to 23 °C and reacted for 1 hour.
  • the solvent was removed under vacuum to obtain a solid.
  • FIG. 1 a crystal structure of the target compound (2a) by x-ray diffraction (XRD) was illustrated in FIG. 1.
  • ERP signal and intensity thereof were confirmed at 23 °C by dissolving 0.1 mg of the target compound (2a) in 1.0 mL of benzene in the glove box in which a nitrogen atmosphere is maintained (see FIG. 2).
  • electrode potential was measured by scanning electron potential of an electrode from 1.2 up to -0.8 at a scan rate of 0.1V/sec with respect to the reference electrode Ag/AgCl(KCl 3.5M) in acetonitrile including the target compound (2a) (1.2 mM) in 0.1 M NBu 4 BF 4 .
  • FIG. 3 The results thereof were shown in FIG. 3.
  • FIG. 3 a crystal structure of the target compound (2b) by x-ray diffraction (XRD) was illustrated in FIG. 1, electron paramagnetic resonance (EPR) spectrum thereof was measured and illustrated in FIG. 2, and cyclic voltammogram thereof was measured and illustrated in FIG. 3.
  • XRD x-ray diffraction
  • a device illustrated in FIG. 4 was installed, and the compound 2a (5.0 mg, 12.1 ⁇ mol) produced by Example 1 was added to a first tube.
  • the compound 1a (0.50 mg, 1.3 ⁇ mol) dissolved in 0.5 mL of benzene was added to a second tube.
  • the device was maintained in a vacuum state, and the second tube was maintained at -78 °C.
  • the first tube was heat treated at 120 °C for 1 hour, and the second tube was maintained at 23 °C.
  • the electron paramagnetic resonance (EPR) spectrum of the solution of a second tube was measured (See FIG. 2).
  • Example 4 was performed by the same method as Example 3 except for using a compound 1b (0.50 mg, 1.6 ⁇ mol) instead of using the compound 1a (0.50 mg, 1.3 ⁇ mol) in Example 3. Then, the electron paramagnetic resonance (EPR) spectrum of a solution of the second tube was measured (See FIG. 2).
  • EPR electron paramagnetic resonance
  • the compound 2a generates a reversible oxidation-reduction reaction and the compound 2b generates an irreversible oxidation-reduction reaction.

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Abstract

Cette invention concerne un radical oxyde nitrique de carbène N-hétérocyclique, et une de ses applications, et plus particulièrement, un radical oxyde nitrique de carbène N-hétérocyclique permettant d'administrer efficacement un oxyde nitrique en une quantité recherchée en un court laps de temps, un procédé de production d'un radical oxyde nitrique de carbène N-hétérocyclique, et une de ses applications.
PCT/KR2015/012624 2014-11-25 2015-11-24 Radical oxyde nitrique de carbène n-hétérocyclique et son application WO2016085224A2 (fr)

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