Synthesis and Analgesic Activity of N ,6-Diaryl-4-hydroxy-4-methyl-2-oxocyclohexane-1-carboxamides and Their Dehydration
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hesis and Analgesic Activity of N,6-Diaryl-4-hydroxy4-methyl-2-oxocyclohexane-1-carboxamides and Their Dehydration Products N. V. Nosovaa, A. A. Sokolova, O. N. Geina, V. L. Geina,*, A. N. Yankinb, S. E. Danilovс, and M. V. Dmitrievd a Perm
State Pharmaceutical Academy, Perm, 614990 Russia Research University ITMO, St. Petersburg, 197101 Russia с St. Petersburg State University, St. Petersburg, 199034 Russia d Perm State National Research University, Perm, 614990 Russia *e-mail: [email protected]
b National
Received April 23, 2020; revised April 23, 2020; accepted April 30, 2020
Abstract—A series of new N,6-diaryl-4-hydroxy-4-methyl-2-oxocyclohexane-1-carboxamides was obtained through the reaction of N-arylamides of acetoacetic acid with benzalacetone and 4-chlorobenzalacetone under basic conditions (KOH) in methanol at room temperature. Increasing of the amount of potassium hydroxide used in the reaction led to the formation of dehydration products, namely N,6-diaryl-4-methyl-2-oxocyclohex3-ene-1-carboxamides. The latter were also formed by using unsubstituted acetoacetamide and N-methylacetoacetamide. The synthesized compounds were tested for analgesic activity. Keywords: acetoacetic acid N-arylamides, benzalacetone, 4-chlorobenzalacetone, N,6-diaryl-4-hydroxy4-methyl-2-oxocyclohexane-1-carboxamides, analgesic activity
DOI: 10.1134/S1070363220090017 The synthesis of cyclohexanones attracts the attention of researchers both in theoretical and practical aspects. This is due to the fact that the cyclohexanone fragment is the main structural unit of a number of widely used natural and synthetic drugs [1, 2]. The best-known representative of this class is camphor (Scheme 1), a structural terpenoid found in camphor laurel oil (Cinnamomum camphora) and used as an analeptic drug [3]. Functionalized cyclohexanone derivatives are used as fluorescent agents [4] and have anthelmintic [5], antiinflammatory [6], antibacterial [7–9], anticonvulsant [10], antitumor [11, 12], antiviral [13] and herbicidal activity [14]. Some of them are phosphodiesterase inhibitors and can be used as anti-inflammatory agents for the treatment of chronic obstructive pulmonary disease [15, 16]. There are a number of well-known drugs containing a cyclohexanone fragment in their structure (Scheme 1). For example, ketamine and methoxetamine are noninhalation anesthetics that exhibit analgesic activity [17, 18], while naloxone and naltrexone are opioid receptor antagonists [19, 20]. Tetracycline is a broad-spectrum
antibiotic [21], and cyclovalon is a synthetic choleretic drug, which in addition to the main effect (bile formation) also has an anti-inflammatory effect [22]. Earlier, we have obtained derivatives of 2-acetyl-4hydroxy-5-methyl-3-phenyl-1-cyclohexanone and alkyl 4-hydroxy-4-methyl-2-oxo-6-phenylcyclohexane-1carboxylates [23] through the reaction of benzalacetone with acetylacetone and acetoacetic acid esters, respectively, under basic catalysis. In addition, their reactions with N-nucleophilic reagents have been performed [24] and antimi
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