Synthesis of 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-carboxylic acids corresponding nitriles, and related bridged lactones, hemiketals, lactams, amines, amidoximines, and amidines (5,10-epoxymethano and 5,10-iminomethano compounds)
Abstract:Synthesis of d]cycIoheptene-10-carboxyIic Acids, Corresponding Nitriles, and Related Bridged Lactones, Hemiketals, Lactams, Amines, Amidoximes, and Amidines (5,10-Epoxymethano and 5,10-Iminomethano Compounds)
“…At this point, deprotection with HCl in dioxane furnished the α-aminohydroxyamidines 43 − 44 . Alternatively, hydrogenolysis of the N−O bond and deprotection with HCl in dioxane gave the aminomethylamidine analogues 45 − 46 . 4 …”
3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
“…At this point, deprotection with HCl in dioxane furnished the α-aminohydroxyamidines 43 − 44 . Alternatively, hydrogenolysis of the N−O bond and deprotection with HCl in dioxane gave the aminomethylamidine analogues 45 − 46 . 4 …”
3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
“…[9] In particular, the preparation of compounds 3 a (X = N, W = H, Y = CH 2 , Z= CH 2 , R and R 1 = H) and 4 a-b (X = CH, W = NR 2 R 3 , R 2 is respectively CH 3 and H, R 3 = CH 3 , Z = CH 2 , R and R 1 = H) is described in detail.The tetracyclic derivative 3 a was synthesized as shown in Scheme 1. Starting from the known [10] 5-oxo-10,11-dihydro-5Hdibenzo[a,d]cycloheptene-10-carbonitrile (5), the alkylation reaction was performed with lithium bis(trimethylsilyl)amide in the presence of 1,3-dimethyl-2-imidazolidinone and ethylbromoacetate to afford racemic a-alkylated nitrile 6 in moderate yield. The reduction of both the nitrile and ketone functionalities via catalytic hydrogenation, followed by spontaneous cyclization in situ of the resulting amine and the ester side chain, gave lactam 7.…”
Sleep deprivation is well documented to result in physiologic stress and mood disorders (depression, irritability and anxiety), and sleep disturbances are among the most prevalent clinical problems and physical signs of depression.[1] Nonspecific pharmacotherapy available for sleep disorders currently falls into four categories: GABA receptor agonists, over-the-counter antihistamines, melatonin receptor agonists and sedating antidepressants. However, benzodiazepine and non-benzodiazepine GABA A receptor agonists all share a common adverse effect profile related to the drug class, including daytime somnolence, dizziness, headache and memory impairment.[2] Hence, there is still a medical need for the development of new drugs with improved efficacy for the treatment of sleep disorders.It has been suggested that brain histamine is involved in the regulation of the sleep/awake cycle, arousal, cognition and memory, mainly through the histamine H 1 receptor, producing a reduction of sleep latency both in preclinical [3] and clinical studies.[4] In parallel, selective blockade of the serotonin 5-HT 2A receptor has been proved in both preclinical [5] and clinical studies [6] to be efficacious in reducing wake after sleep onset, increasing slow-wave sleep and total sleep time, therefore, providing consolidation of sleep. On the other hand, pharmacological studies have shown that mirtazapine (1) and mianserin (2), two noradrenergic and specific serotonergic antidepressants (NaSSAs), act by blocking 5-HT 2A receptors, [7] and their broad pharmacological profile is characterized by a potent H 1 antagonistic activity. [8] As part of a program aimed at discovering novel chemical entities useful for the treatment of various sleep disorders, the model compounds mirtazapine (1) and mianserin (2) were used to design novel tetracyclic derivatives (see general template 3-4; Figure 1). This template is characterized by the presence of a spiro junction connecting the classical tricyclic core, suitably substituted, to a fourth exocycle ring with the nitrogen atom that can either be endo (3, X= N, W = H) or exo (4, X = CH, W = NH(CH 3 ) and N(CH 3 ) 2 ) with respect to that ring.To the best of our knowledge, the synthesis of compounds 3 has never been described, while the synthetic route to prepare compounds 4 has recently been reported by us in a patent application. [9] In particular, the preparation of compounds 3 a (X = N, W = H, Y = CH 2 , Z= CH 2 , R and R 1 = H) and2 is respectively CH 3 and H, R 3 = CH 3 , Z = CH 2 , R and R 1 = H) is described in detail. The tetracyclic derivative 3 a was synthesized as shown in Scheme 1. Starting from the known [10] 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-carbonitrile (5), the alkylation reaction was performed with lithium bis(trimethylsilyl)amide in the presence of 1,3-dimethyl-2-imidazolidinone and ethylbromoacetate to afford racemic a-alkylated nitrile 6 in moderate yield. The reduction of both the nitrile and ketone functionalities via catalytic hydrogenation, followed by spo...
“…riety of bridged dibenzsuberans have been reported. [1][2][3] During the course of our investigation into the reactions of dibenzocycloheptenone (1) we discovered an interesting and, what we believe to be, novel reaction. 0 1 When 1 was treated with anhydrous hydrazine at elevated temperature, a stable product was isolated whose infrared spectrum lacked a carbonyl absorption and elemen-tal composition indicated an addition of hydrazine without concomitant loss of water.…”
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
