Aliphatic Nitro Ketones

Hurd, Charles D.; Nilson, May E.

doi:10.1021/jo01125a018

Cited by 64 publications

(25 citation statements)

References 8 publications

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“…2,2-Dimethoxypropanediol (12). To a solution of dihydroxyacetone dimer (15.0 g, 0.05 mmol) in dried methanol (200 ml) was added trimethyl orthoformate (17.5 g, 0.16 mol) and p-toluenesulfonic acid (0.06 g).…”

Section: Methodsmentioning

confidence: 99%

“…The basic skeleton of neonicotinoid is constructed from an amidine or a guanidine conjugated to a powerful electron-withdrawing group like a nitro or cyano one; consequently, the amidinyl (guanidyl) nitrogen atoms are partially positive. [8][9][10] By referring to the well-examined hydrolytic cleavage of 1,3-diacyl and related structures 11,12) as represented by the reaction, RCOCH 2 COR + H 2 O ! RCOOH + RCOCH 3 , we predicted that such aaminoketone as R 1 R 2 NCH 2 COCH 3 could give R 1 R 2 NCH 3 in a similar fashion, if the amine part were positively charged like the nitrogen atoms in the neonicotinoid skeleton.…”

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confidence: 99%

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Prodrug-Oriented Molecular Design of Neonicotinoids: Preparation of Imidacloprid-Related 5,5-Dimethoxy-1,3-diazacyclohexane Derivatives and Their Insecticidal Activity

Kagabu

Hibi

Nishimura

2005

Bioscience, Biotechnology, and Biochemistry

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Prodrug-oriented molecular design was attempted for the potent acyclic neonicotinoid insecticide, clothianidin (1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine). Molecules bearing a CH 2 COCH 2 bridge linking the 1,3-NH ends of clothianidin or their acetals would possibly be hydrolyzed, regenerating the mother compounds. This strategy was used to prepare seven acetals of clothianidin-based molecules that combined 2-chloro-5-thiazolylmethyl, 6-chloro-3-pyridylmethyl or 3-tetrahydrofurfuryl with a nitroimine, cyanoimine or nitromethylene group. The key intermediate, 1,3-diamino-2,2-dimethoxypropane, was prepared from the dihydroxyacetone dimer in four steps. A selected acetal showed a characteristic nerve-impulse pattern for neonicotinoids on an excised American cockroach ganglion, although the neuroblocking activity was fairly low. Some acetals were highly insecticidal against the pea aphid at 0.8-20 ppm 7 days after a spray treatment, this being in a contrast to their far weaker activity by injection into American cockroaches. The biological results suggest that the intrinsic insecticidal activities of the acetals are weak, but would exhibit enhanced activity if hydrolyzed in an external environment.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Prodrug-Oriented Molecular Design of Neonicotinoids: Preparation of Imidacloprid-Related 5,5-Dimethoxy-1,3-diazacyclohexane Derivatives and Their Insecticidal Activity

Kagabu

Hibi

Nishimura

2005

Bioscience, Biotechnology, and Biochemistry

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“…Silica gel column chromatography was performed using Silicycle silica gel (70-230 mesh). Glycerol trinitrate [Marken et al, 1977], 3,4-bis(benzenesulfonyl)furoxan (7) [Kelly et al, 1977], 4-bromo-1-butanol (10) [Nguyen et al, 2000], nitroacetone (17) [Hurd and Nilson, 1955], 2-cyanoethyl 3-aminocrotonate (19) [Ogawa et al, 1993], benzofurazan-4-carboxaldehyde (25) [Heitzmann, 1987], 2-amino-1-nitroprop-1-ene (26) [Miri et al, 2000], and 2-cyanoethyl acetoacetate (27) [Yiu and Knaus, 1997] were prepared according to procedures reported in the literature. All other reagents were purchased from Aldrich Chemical (Milawukee, WI).…”

Section: Methodsmentioning

confidence: 99%

Syntheses, calcium channel agonist‐antagonist modulation effects, and nitric oxide release studies of [3‐(Benzenesulfonyl)furoxan‐4‐yloxy]alkyl 1,4‐Dihydro‐2,6‐dimethyl‐5‐nitro‐4‐(2‐trifluoromethylphenyl, benzofurazan‐4‐yl, 2‐, 3‐, or 4‐pyridyl)‐3‐pyridinecarboxylates

Nguyen

McEwen

et al. 2002

Drug Development Research

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A group of racemic 1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylates possessing either a C-4 2-trifluoromethylphenyl (22-24), benzofurazan-4-yl (42-44), 2-pyridyl (45-47), 3-pyridyl (48-50), or 4-pyridyl (51-53), substituent in conjunction with a nitric oxide donor C-3 ester [3-(benzenesulfonyl)furoxan-4-yloxy]alkyl substituent were synthesized using modified Hantzsch reactions. Compounds 45-53 having a C-4 2-, 3-, or 4-pyridyl substituent exhibited more potent in vitro calcium channel antagonist activity (IC 50 's in the 0.46 to 5.23 mM range) on guinea pig ileum longitudinal smooth muscle (GPILSM) than related analogs having a C-4 2-trilfuoromethylphenyl (22-24) or benzofurazan-4-yl (42, 44) substituent (IC 50 Z 29.91 mM). The point of attachment of the pyridyl ring (2-, 3-, or 4-), and the length of the C-3 ester alkyl spacer [-CH 2 (CH 2 )n, n ¼ 1-3], were not determinants of smooth muscle calcium channel antagonist activity. Replacement of the C-3 ester methyl substituent of Bay K 8644, or the ester isopropyl substituent of the 4-(pyridyl) isomers 4a-c by a [3-(benzensulfonyl)furoxan-4-yloxy]alkyl moiety retained the desired calcium channel agonist (positive inotropic) effect on guinea pig left atrium (GPLA). Compounds having C-4 3-pyridyl (48-50), or 4-pyridyl (51-53), substituents were the most potent cardiac positive inotropes (EC 50 's in the 3.02 to 19.74 mM range) relative to the reference drug Bay K 8644 IC 50 ¼ 0.77 mM). The % nitric oxide released in vitro in the presence of L-cysteine for this group of compounds was higher (36-74% range) than for the reference drug glycerol trinitrate (20%). A quantitative structure-activity analysis showed an inverse correlation between a molecular weight (MW) descriptor and % nitric oxide released. Model hybrid (calcium channel modulation, nitric oxide donor) compounds that show dual cardioselective agonist (positive inotropic)/smooth muscle selective antagonist activities constitute a novel type of 1,4-dihydropyridine calcium channel modulator that provides a potential drug design concept targeted toward the treatment of congestive heart failure, and is a useful probe to study the structure-function relationship of calcium channels. Drug. Dev. Res. 56:1-16, 2002.

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“…Preparative silica gel thin layer chromatography (PTLC) was performed using Camag Kieselgel DF-5 plates, 1.0 mm in thickness. Nitroacetone (6) [Hurd and Nilson, 1955], 2-nitrooxyethyl 3-aminocrotonate (7a) [Ogawa et al, 1993], nitrooxyalkyl acetoacetates (10a-c) [Ogawa et al, 1993], and 1,3-dinitrooxy-2-propyl acetoacetate (10d) [Iqbal and Knaus, 1996] were prepared according to the literature procedures. In vitro calcium channel antagonist and agonist activities were determined using protocols approved by the Health Sciences Animal Welfare Committee at the University of Alberta.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

Miri

McEwen

Knaus

2000

Drug Development Research

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A group of racemic nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates 8a-o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a-o exhibited weaker calcium antagonist activity (10 -5 to 10 -7 M range) than the reference drug nifedipine (IC 50 = 1.43 × 10 -8 M). Compounds 8 possessing a C-4 R 1 = 2-pyridyl substituent were always more potent than the approximately equiactive analogs having an R 1 = 3-pyridyl, 4-pyridyl or 2-CF 3 -C 6 H 4 -substituent, within each subgroup of nitrooxyalkyl compounds [R 2 = -(CH 2 ) n ONO 2 (n = 2, 3, 4) or -CH(CH 2 ONO 2 ) 2 ]. Although the length of the R 2 = -(CH 2 ) n ONO 2 substituent (n = 2-4) was not a determinant of smooth muscle calcium antagonist activity when the C-4 R 1 -substituent was 2-pyridyl, when R 1 was a 3-pyridyl, 4-pyridyl, or 2-CF 3 -C 6 H 4 -substituent, the relative potency order with respect to the R 2 = -(CH 2 ) n ONO 2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)-2-pyridyl 3a by a -(CH 2 ) n ONO 2 (n = 2-4) moiety increased calcium antagonist activity on GPILSM by 8-fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)-3-pyridyl 3b, (±)-4-pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R 2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4-dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8bc), or the methyl (8d) group by a -CH 2 CH 2 ONO 2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C-4 substituent was 2-CF 3 -C 6 H 6 -(8d) > 3-pyridyl (8b) ≈ 4-pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure-function relationship of calcium channels. Drug Dev. Res. 51:225-232, 2000.

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Aliphatic Nitro Ketones

Cited by 64 publications

References 8 publications

Prodrug-Oriented Molecular Design of Neonicotinoids: Preparation of Imidacloprid-Related 5,5-Dimethoxy-1,3-diazacyclohexane Derivatives and Their Insecticidal Activity

Prodrug-Oriented Molecular Design of Neonicotinoids: Preparation of Imidacloprid-Related 5,5-Dimethoxy-1,3-diazacyclohexane Derivatives and Their Insecticidal Activity

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

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