Abstract:Die Aminolyse des Cyanketen-0,N-Aceta-Gemisches 1 Z/E mit den Aminen 2a,b fiihrt zu den E-konfigurierten primar/sekundiiren Cyanketenaminalen 3a,b. Durch Reaktion von 3a,b mit den 1.3-Biselektrophilen 4, 6a,b, 9 HCI, 12, 13,15a,b, 17 und 19 lassen sich die N2-substituierten 2-Aminonicotinonitrile 5, 7, 8, 10, 11, 14, 16 und 20 herstellen. Umsetzung der 2-Aminonicotinonitrile mit a-Phenylethylrest in Position 2 (14b, 16a, 8a, 20b, 5 und 8b) mit Polyphosphorsaure fuhrt zu den primiiren 2-Aminonicotinonitrile Zla… Show more
“…Next, the ester moiety of 3l was replaced by a nitrile group. Although a direct conversion of 3l to 11 is laborious, this compound was easily accessible by reaction of ( E ) ( RS ) 3-amino-3-[(1-phenylethyl)amino]acrylonitrile ( 10 ) with 1,4-benzoquinone ( 1 ) at room temperature in ethanol, giving ( RS ) 5-hydroxy-2-[(1-phenyl)ethylamino]-1 H -indole-3-carbonitrile ( 11 ) in good yields (Scheme ). 1 Synthesis of 2-Amino-5-hydroxyindoles ( 3 ) via the Nenitzescu Reaction a a Reagents and conditions: (a) amine ( 6a − m ), EtOH, reflux, 48 h; (b) amine ( 6n , o ), toluene, reflux; (c) 1,4-benzoquinone ( 1 ), EtOH, rt, 50 min; (e) NaH, dimethyl sulfate, DMF, reflux, 1 h. 2 Synthesis of ( RS ) Methyl and ( RS ) Ethyl 2-[(1-Phenylethyl)amino]-1 H -indole-3-carboxylate ( 9a , b ) a a Reagents and conditions: (a) NCS, N,N ‘-dimethylpiperazine, CH 2 Cl 2 , 0 °C, 2 h, (b) trichloroacetic acid, ( RS )-phenylethylamine ( 6l ), rt, 2 h. 3 .…”
Compounds that inhibit 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of leukotrienes (LTs), possess potential for the treatment of inflammatory and allergic diseases as well as of atherosclerosis and cancer. Here we present the design and the synthesis of a series of novel 2-amino-5-hydroxyindoles that potently inhibit isolated human recombinant 5-LO as well as 5-LO in polymorphonuclear leukocytes, exemplified by ethyl 2-[(3-chlorophenyl)amino]-5-hydroxy-1H-indole-3-carboxylate (3n, IC(50) value congruent with 300 nM). Introduction of an aryl/arylethylamino group or 4-arylpiperazin-1-yl residues into position 2 of the 5-hydroxyindoles was essential for biological activity. Whereas the 4-arylpiperazin-1-yl derivatives were more potent in cell-free assays as compared to intact cell test systems, aryl/arylethylamino derivatives inhibited 5-LO activity in intact cells and cell-free assays almost equally well. On the basis of their 5-LO inhibitory properties, these novel 2-amino-5-hydroxyindoles represent potential candidates for the pharmacological intervention with LT-associated diseases.
“…Next, the ester moiety of 3l was replaced by a nitrile group. Although a direct conversion of 3l to 11 is laborious, this compound was easily accessible by reaction of ( E ) ( RS ) 3-amino-3-[(1-phenylethyl)amino]acrylonitrile ( 10 ) with 1,4-benzoquinone ( 1 ) at room temperature in ethanol, giving ( RS ) 5-hydroxy-2-[(1-phenyl)ethylamino]-1 H -indole-3-carbonitrile ( 11 ) in good yields (Scheme ). 1 Synthesis of 2-Amino-5-hydroxyindoles ( 3 ) via the Nenitzescu Reaction a a Reagents and conditions: (a) amine ( 6a − m ), EtOH, reflux, 48 h; (b) amine ( 6n , o ), toluene, reflux; (c) 1,4-benzoquinone ( 1 ), EtOH, rt, 50 min; (e) NaH, dimethyl sulfate, DMF, reflux, 1 h. 2 Synthesis of ( RS ) Methyl and ( RS ) Ethyl 2-[(1-Phenylethyl)amino]-1 H -indole-3-carboxylate ( 9a , b ) a a Reagents and conditions: (a) NCS, N,N ‘-dimethylpiperazine, CH 2 Cl 2 , 0 °C, 2 h, (b) trichloroacetic acid, ( RS )-phenylethylamine ( 6l ), rt, 2 h. 3 .…”
Compounds that inhibit 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of leukotrienes (LTs), possess potential for the treatment of inflammatory and allergic diseases as well as of atherosclerosis and cancer. Here we present the design and the synthesis of a series of novel 2-amino-5-hydroxyindoles that potently inhibit isolated human recombinant 5-LO as well as 5-LO in polymorphonuclear leukocytes, exemplified by ethyl 2-[(3-chlorophenyl)amino]-5-hydroxy-1H-indole-3-carboxylate (3n, IC(50) value congruent with 300 nM). Introduction of an aryl/arylethylamino group or 4-arylpiperazin-1-yl residues into position 2 of the 5-hydroxyindoles was essential for biological activity. Whereas the 4-arylpiperazin-1-yl derivatives were more potent in cell-free assays as compared to intact cell test systems, aryl/arylethylamino derivatives inhibited 5-LO activity in intact cells and cell-free assays almost equally well. On the basis of their 5-LO inhibitory properties, these novel 2-amino-5-hydroxyindoles represent potential candidates for the pharmacological intervention with LT-associated diseases.
“…Treatment of imidate/ketene-O,N-acetal mixtures 7a and 7b respectively with (±)-1-phenylethylamine (14) in ethanol at room temperature afforded the primary/secondary ketene aminal 15, whose existence in the E-configuration was established by NOE-measurements (Scheme 4). Scheme 5 shows that cyclocondensation of ketene aminal 15 with phenylpropinal (11), acetylacetone (12) and trimethinium salt 13 in boiling ethanol-acetic acid yielded N-(1-phenylethyl)-substituted phenyl 2-aminopyridine-3sulfonates 16a-c. A planned deprotection of the 1-phenylethylgroup in 16a-c was managed by treatment with polyphosphoric acid at 60 °C [12][13][14] yielding pyridines 3a,j,k ( Table 2). Phenyl carbamoylmethanesulfonate (6) was prepared based upon the method described by Hinman et al 11 The syntheses of b-aminovinylketones were carried out according to a literature method.…”
A series of phenyl 2-aminopyridine-3-sulfonates 3 has been synthesized starting from phenyl cyanomethanesulfonate (5). Pinner reaction with 5 gave phenoxysulfonylketene aminal 4K which was cyclocondensed with a series of C 3 -biselectrophiles to yield the title compounds, which are of pharmaceutical and medicinal interest.
“…The IR spectra were obtained (KBr disk) on a Perkin Elmer/1650 FT-IR instrument. 1 H NMR spectra were measured on a Varian 400 MHz spectrometer for solutions in (CD 3 ) 2 SO using SiMe 4 as internal standard. Mass spectra were recorded on a Varian MAT 112 spectrometer.…”
Section: Methodsmentioning
confidence: 99%
“…and dry ethanol (100 ml) and then heated for 12 h. The solution was then poured into iced water and the resultant precipitate was collected and recrystallized from the appropriate solvent. 4a: mp 190 °C, yield 67%; max (KBr)/cm 1…”
Section: Methodsmentioning
confidence: 99%
“…Imino esters are highly reactive compounds and are extensively utilized as reactants or reaction intermediates since their imino and ester functions are suitably situated to enable reactions with common bidentate reagents to form a variety of heterocyclic compounds. 1,2 Moreover, the active hydrogen atom on C-2 of these compounds can also take part in a variety of condensation and substitution reactions. As part of a medicinal chemistry program in our laboratories, the syntheses of several substituted pyridine-2(1H)-thiones were required.…”
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