4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, a new class of cardiotonic agents

Ra, Schnettler; Rc, Dage; Jm, Grisar

doi:10.1021/jm00354a017

Cited by 58 publications

(25 citation statements)

References 3 publications

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“…116 Several other companies sought selective phosphodiesterase inhibitors, enoximone being developed at the Merrell Dow Research Center in Cincinnati after it was discovered that imidazole had some activity. 117 It was less potent than milrinone.…”

Section: Milrinonementioning

confidence: 99%

Drugs Originating from the Screening of Organic Chemicals

Sneader

2005

Drug Discovery

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Section: Milrinonementioning

confidence: 99%

Drugs Originating from the Screening of Organic Chemicals

Sneader

2005

Drug Discovery

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“…Yield 2.9 g (57%); mp 158-160°; 1 Compound 10 (1.36 g, 4 mmoles) was dissolved in methylene chloride (20 ml) under nitrogen atmosphere. N-E t h y l d i i s opropylamine (EDIA) (0.72 ml, 4 mmoles) was added to the reaction mixture followed by addition of ethoxy or benzyloxy methyl chloride (4 mmoles).…”

Section: -[(4-tert-butyl-5-iodo-1h-imidazol-2-yl)thio]acetamide (10)mentioning

confidence: 99%

“…Yield 1.14 g (72%); mp 95-97°; 1 3,5-Dimethylthiophenol (0.13 ml, 1 mmole) was dissolved in dimethylformamide (10 ml), and sodium hydride (44 mg, 1 mmole) was added to the solution portionwise under ice cooling. After stirring for 0.5 hour, compound 11 b (0.46 g, 1 mmole) was added portionwise to the reaction mixture under ice cooling, and the reaction mixture was left to be stirred at room temp.…”

Section: -[ ( 4 -T E Rt-b U T Y L -1 -E T H O X Y M E T H Y L -5 -I Omentioning

confidence: 99%

Studying the synthesis of 4‐tert‐butyl‐1,3‐dihydroimidazol‐2‐ones and their corresponding thiones

Loksha

Pedersen

El‐Barbary

et al. 2003

Journal of Heterocyclic Chem

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4 -t e rt-Butyl-1,3-dihydroimidazol-2-ones and 1,3-dihydroimidazol-2-thiones were synthesized from 1-amino-3,3-dimethylbutanone and subjected to alkylation reactions. The latter compounds were S-alkylated with iodoacetamide under alkaline conditions. The N 1 ,N 3 -unsubstituted derivative was iodinated and subsequently alkylated with alkylation reagents which previously have been used for the synthesis of anti-HIV active imidazoles. Unfortunately, the present products were devoid of activity against HIV.J. Heterocyclic Chem., 40, 593(2003).1,3-Dihydroimidazol-2-ones are used as cardiotonic agents [1-4] and 1-substituted 1,3-dihydroimidazole-2-thione derivatives are used for the treatment of thyroid disorder [5], arthritis [6,7] and cardiovascular disorders [8,9]. 1-Substituted 1H-imidazole derivatives are used as H I V-1 reverse transcriptase inhibitors [10,11]. In addition, anti-inflammatory activities [12] and, more recently, antioxidant properties [13] have been reported as well. In the present report, we are exploring the chemistry of t e rtbutyl substituted imidazoles which could be possible intermediates for the synthesis of imidazole derivatives with potential activity against HIV. We found t e rt -b u t y l derivatives interesting because an ethyl or an isopropyl group seems to be a prerequisite for activity against HIV of both AG1549 (5-(3,5-dichlorophenyl)thio-4-isop r o p y l -1 -( 4 -p y r i d y l ) m e t h y l -1H-i m i d a z o l -2 -y l m e t h y l carbamate) [11 ] and in SJ-3366 (1-(3-cyclopenten-1-yl)-m e t h y l -6 -( 3 , 5 -d i m e t h y l b e n z o y l ) -5 -e t h y l -2 , 4 -p y r i m i d i n edione) [14].α-Aminoketone hydrochlorides were heated with potassium cyanate to give 4-alkyl-1,3-dihydroimidazol-2-ones 1a,b as previously described by Lawson (methyl, ethyl, and cyclohexyl, respectively). Compound 4 a has previously been prepared by Doney and Altland [17] by the same synthetic procedure. The potassium salt of compounds 4a-c were treated with 2-iodoacetamide to afford 2-(1-alkyl-5-tert-butyl-1H-imidazol-2-ylsulfanyl)acetamides 5a-c (Scheme 1). This is an effective way to prepare N 1 ,S-dialkylated-1H-dihydroimidazol-2-thiones 5 a -c which have a substituent in the 2-position with some resemblance to the one in AG1549.2-[(4-tert-Butyl-1H-imidazol-2-yl)thio]acetamide 6 was synthesized by reaction of the potassium salt of the commercial available 4-t e rt-b u t y l -1 , 3 -d i h y d r o i m i d a z o l e -2 -thione 1c with 2-iodoacetamide in methanol. Compound 6 was coupled with dimethylsulfamoyl chloride to get 2-[(4-t e rt-b u t y l -1 -d i m e t h y l s u l f a m o y l -1 H -i m i d a z o l -2 -yl)thio]acetamide 7. It was attempted to introduce a cyclohexylthio substituent to the 5-position of 7 by lithiation with n-butyl lithium at -78° followed by addition of cyclohexyl disulfide. However, the product was elucidated to be

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“…17 The most important compound in this series is (Figure 1), a selective phosphodiesterase inhibitor, has a significant inotropic and vasodilating properties that have proved useful in the postoperative management of infants and children having cardiac surgery. 18,19 Effects of phosphodiesterase (III/IV)-inhibitors and cytokines on mechanical properties of neutrophilic granulocytes in neonates and adults have been studied.…”

Section: Introductionmentioning

confidence: 99%

A simple synthesis of 4-aroyl-5-methyl-1H-imidazol-2(3H)-one derivatives (Enoxymone analogues) from aryl methyl ketones via enaminones

Bezenšek¹,

Grošelj²,

Stare³

et al. 2013

Arkivoc

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Dedicated to Professor Rosa M. Claramunt on the occasion of her 65th anniversary AbstractAryl methyl ketones 1a-e gave with N,N-dimethylacetamide dimethylacetal (DMADMA) (E)-1-aryl-3-(dimethylamino)-but-2-en-1-ones 2a-e. Substitution of the N,N-(dimethylamino) group in the reaction with ammonium acetate afforded the corresponding (Z)-3-amino-1-aryl-but-2-en-1-ones 3a-e. In the reaction of 3a-e with diethyl azodicarboxylate intermediates 4a-e were formed, which were, in most cases without isolation, cyclized into ethyl (5-aroyl-4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)carbamates 5a-e. Hydrolysis of the ester group, followed by the decarboxylation and deamination of intermediates 6a-c,e produced 4-aroyl-5-methyl-1H-imidazol-2(3H)-ones 7a-c,e.

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4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, a new class of cardiotonic agents

Cited by 58 publications

References 3 publications

Drugs Originating from the Screening of Organic Chemicals

Drugs Originating from the Screening of Organic Chemicals

Studying the synthesis of 4‐tert‐butyl‐1,3‐dihydroimidazol‐2‐ones and their corresponding thiones

A simple synthesis of 4-aroyl-5-methyl-1H-imidazol-2(3H)-one derivatives (Enoxymone analogues) from aryl methyl ketones via enaminones

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