- Synthesis of spiro[cycloalkane-pyridazinones] with high Fsp3 character
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Background: Nowadays, in course of the drug design and discovery much attention is paid to the physicochemical parameters of a drug candidate, in addition to their biological activity. Disadvantageous physicochemical parameters can hinder the success of a drug candidate. Objective: Lovering et al. introduced the Fsp3 character as a measure of carbon bond saturation, which is related to the physicochemical paramethers of the drug. The pharmaceutical research focuses on the synthesis of compounds with high Fsp3 character. Method: To improve the physicochemical properties (clogP, solubility, more advantageous ADME profile, etc.) of drug-candidate molecules one possibility is the replacement of all-carbon aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen atom containing systems, such as pyridines and pyridazines, etc. The other option is to increase the Fsp3 character of the drug candidates. Both of these aspects were considered in the design the new spiro[cycloalkanepyridazinones], the synthesis of which is described in the present study. Results: Starting from 2-oxaspiro[4.5]decane-1,3-dione or 2-oxaspiro[4.4]nonane-1,3-dione, the corresponding ketocarboxylic acids were obtained by Friedel-Crafts reaction with anisole or veratrole. The ketocarboxylic acids were treated by hydrazine, methylhydrazine or phenylhydrazine to form the pyridazinone ring. N-Alkylation reaction of the pyridazinones resulted in the formation of further derivatives with high Fsp3 character. Conclusion: A small compound library was obtained incorporating compounds with high Fsp3 characters, which predicts advantageous physico-chemical parameters (LogP, ClogP and TPSA) for potential applications in medicinal chemistry.
- Für, Csilla Sepsey,Riszter, Gergo,Gerencsér, János,Szigetvári, áron,Dékány, Miklós,Hazai, László,Keglevich, Gy?rgy,B?lcskei, Hedvig
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p. 731 - 744
(2020/06/22)
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- Eco-friendly conjugate hydrocyanation of α-cyanoacrylates using potassium hexacyanoferrate(II) as cyanating reagent
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The conjugate hydrocyanation of α-cyanoacrylates through chemoselective 1,4-addition to synthesise α,β-dicyanopropanoates by one-pot two-step procedure using potassium hexacyanoferrate(II) as an eco-friendly cyanide source, benzoyl chloride as a promoter
- Zhang, Yu-Peng,Hu, Xiao-Chun,Li, Zheng
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p. 596 - 603
(2015/04/14)
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- 2-aza-4-(alkoxycarbonyl)spiro[4,5]decan-3-one
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2-Aza-4-(alkoxycarbonyl)spiro[4,5]-decan-3-one and a process for the production of it, starting either from cyclohexylidene malonic acid esters or cyclohexylidene cyanoalkylates. The cyclohexylidene malonic acid ester is reacted with hydrocyanic acid in t
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- Antiarthritic and suppressor cell inducing activity of azaspiranes: Structure-function relationships of a novel class of immunomodulatory agents
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Spirogermanium (1;8,8-diethyl-N,N-dimethyl-2-aza-8-germaspiro[4.5]decane-2-propanamin e dihydrochloride) is a potent cytotoxic agent in vitro which has demonstrated limited activity in experimental animal tumor models. Subsequently, it has been reported that spirogermanium has antiarthritic and suppressor cell-inducing activity. We have synthesized a series of substituted 8-hetero-2-azaspiro[4.5]decane and 9-hetero-3-azaspiro[5.5]undecane analogues of spirogermanium to identify the heteroatom requirements for in vivo antiarthritic and suppressor cell-inducing activity. This structure-activity relationship study has identified that appropriately substituted silicon and carbon analogues of spirogermanium retain both antiarthritic and immunosuppressive activity, with the 8,8-dipropyl (carbon) analogue being among the most active. Following the identification of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine dihydrochloride (9) as more active analogue than spirogermanium, a series of 8,8-dipropyl analogues with various amine substituents were synthesized. A number of these analogues had activity similar to that of 9. A correlation between activity in the adjuvant arthritic rat and the ability to induce suppressor cells (r = 0.894, p0.001) suggests an association between the two pharmacologic effects. While the precise biochemical mechanism(s) for the pharmacological activity is unclear, these data suggest that compounds within this series, e.g., N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine dihydrochloride, may provide effective therapy in diseases of autoimmune origin and/or the prevention of rejection in tissue transplantation.
- Badger,Schwartz,Picker,Dorman,Bradley,Cheeseman,DiMartino,Hanna,Mirabelli
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p. 2963 - 2970
(2007/10/02)
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- Synthesis of 4,4-Disubstituted 2,3-Dicyano-5-imino-2-pyrrolines. Reaction of Alkylidenemalononitriles with Trimethylsilyl Cyanide
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The reaction of alkylidenemalononitriles with trimethylsilyl cyanide in the presence of KCN/18-crown-6 gave 4,4-disubstituted 2,3-dicyano-5-imino-2-pyrrolines in high yields.
- Chatani, Naoto,Hanafusa, Terukiyo
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p. 2134 - 2135
(2007/10/02)
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