Ritter reaction of tertiary alcohols with chloroacetonitrile and subsequent cleavage of chloroacetyl group in the resulting chloroacetamide with thiourea is an efficient procedure for synthesis of tert-alkylamines.The reaction of nitriles or hydrogen cyanide with in situ generated carbocations giving N-tert-alkylamides (Ritter reaction 1 ) is one of the few methods for introduction of the amino functionality at a tertiary carbon atom. Nevertheless the synthesis of tert-alkylamines via the Ritter reaction is limited to the use of the highly toxic hydrogen cyanide (HCN) because the formyl group in resulting formamide can be easily cleaved by either acidic or basic hydrolysis. 1b-d In contrast to formamides, N-tertalkylacetamides undergo retro-Ritter reaction during acidic hydrolysis 1a,2 and can be cleaved only by drastic alkaline hydrolysis 1a,d or by a two step procedure involving O-alkylation of acetamide with triethyloxonium tetrafluoroborate. 3In connection with the development of a series of 1,3,5-alkyl-substituted cyclohexylamines acting as N-methyl-Daspartate receptor antagonists, 4 we searched for a convenient approach toward tert-alkylamines avoiding the use of hazardous hydrazoic acid or HCN. We turned our attention to chloroacetamides as precursors of tert-alkylamines taking into account the smooth cleavage of the chloroacetyl group with thiourea. 5 Synthesis of N-tert-alkylchloroacetamides by the Ritter reaction with chloroacetonitrile (ClCH 2 CN) has already been reported. 1c Herein we report an extension of this reaction to the synthesis of tert-alkylamines.The Ritter reaction with ClCH 2 CN was carried out with structurally diverse tertiary alcohols 1a-g (Scheme). Typically, high yields of chloroacetamides 2a-f (Table 1) were obtained showing that amide formation with ClCH 2 CN is at least as efficient as with HCN or MeCN. 6 In the case of 1-phenylcyclohexanol (1g), formation of amide 2g was not observed; instead, 1-phenylcyclohexene was isolated as the major product. The poor ability of cyclohexanol 1g to form the corresponding amides in the Ritter reaction with PhCN and HCN has been reported previously and is apparently due to the low electrophilicity of the intermediate carbenium ion. 7 4-Phenylpiperidin-4-ol (1e) reacts efficiently with MeCN,8 and this was also found to be the case with ClCH 2 CN. SchemeTable 1 Yields of Chloroacetamides 2 and tert-Alkylamines 3 a a Satisfactory microanalyses obtained: C ±0.47, H ±0.16, N ±0.19. b Isolated in the base form due to high hygroscopicity of dihydrochloride. RR 1 R 2 CX X = NHCOCH 2 Cl Yield (%) X = NH 3 + Cl − Yield (%) 2a, 86 3a, 89 2b, 84 3b, 80 2c, 95 3c, 85 2d, 78 3d, 84 2e, 73 3e, 74 b 2f, 91 3f, 61 2g, − 3g, -

A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor's transmembrane domain was visualized.

A virtual screening study towards novel noncompetitive antagonists of the metabotropic glutamate receptor 1 (mGluR1) is described. Alignment-free topological pharmacophore descriptors (CATS) were used to encode the screening compounds. All virtual hits were characterized with respect to their allosteric antagonistic effect on mGluR1 in both functional and binding assays. Exceptionally high hit rates of up to 26 % were achieved, confirming the applicability of this virtual screening concept. Most of the compounds were found to be moderately active, however, one potent and subtype selective mGluR1 antagonist, 13 (IC(50): 0.362 microM, SEM +/-0.031; K(i): 0.753 microM, SEM +/-0.048), based on a coumarine scaffold was discovered. In a following activity optimization program a series of coumarine derivatives was synthesized. This led to the discovery of potent (60, IC(50): 0.058 microM, SEM +/-0.008; K(i): 0.293 microM, SEM +/-0.022) and subtype selective (rmGluR5 IC(50): 28.6 microM) mGluR1 antagonists. From our homology model of mGluR1 we derived a potential binding mode within the allosteric transmembrane region. Potential interacting patterns are proposed considering the difference of the binding pockets between rat and human receptors. The study demonstrates the applicability of ligand-based virtual screening for noncompetitive antagonists of a G-protein coupled receptor, resulting in novel, potent, and selective agents.

No abstract