- N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-substituted benzamides: Synthesis and dopamine D-2 and D-3 receptor binding affinities
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In an attempt to develop substituted benzamide antagonists that may be selective for the D-3 receptor, we have investigated the effects of a cyclopropylmethyl group. The compounds differed in the substitutions present in the aromatic ring and the pyrrolidine ring. Binding affinities were carried out by using 3H-spiperone and SF9 cell lines expressing the rat recombinant D-3 dopamine receptor subtype. Type A compounds, containing a 3- fluoropropyl group in the aromatic ring (fallypride and its N- cyclopropylmethyl analog) exhibited high affinities for D-2 compared to D-3 sites (fallypride: 0.023 nM for D-2 and 0.19 nM for D-3; N-cyclopropyl analog: 0.048 nM for D-2 and 0.36 nM for D-3); type B compounds, containing a 5-bromo substituent in the aromatic ring, N-cyclopropyl analog of FLB 457 showed very high potency for D-2 sites (K(i) = 0.003 nM); while type C compounds, ((S)-N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-5-chloro-4- cyclopropylcarbonylamino-2-methoxybenzamide), was able to show a 17-fold selectivity for D-3 over D-2 receptor subtypes.
- Yang, Zhi-Ying,Mukherjee, Jogeshwar
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- EFFICIENT STEREOCONSERVATIVE SYNTHESIS OF 1-SUBSTITUTED (S)- AND (R)-2-AMINOMETHYLPYRROLIDINES AND INTERMEDIATES THERETO
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Stereoconservative method for preparation of an (R)- or (S)-isomer of the compound of the formula I with at least 95% optical purity wherein R1 is a hydrogen atom, a saturated or unsaturated lower alkyl group, a cycloalkyl group, or a group (CH2)m Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group including 1) O,N-dialkylation, directly or stepwise of (R)- or (S)-proline 2) aminolysis 3) reduction to formation of the (R)- or (S)-isomer of the compound of the formula I, and new intermediates II and III in optical active form obtained by the reaction steps above and wherein R2 is defined as R1 above.
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- Efficient Stereoconservative Syntheses of 1-Substituted (S)- and (R)-2-Aminomethylpyrrolidines
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Three-step stereoconservative syntheses of chiral 1-substituted 2-aminomethylpyrrolidines with high optical purities from D- or L-proline are described.The key intermediates, 1-substituted prolinamides, were obtained by N,O-dialkylation of proline followed by ammonolysis or by 1-alkylation of prolinamide.Reduction furnished the optically pure (about 99percent e.e.) pyrrolidine derivatives, which are useful as intermediates in the preparation of antipsychotic substituted benzamides.
- Hoegberg, Thomas,Raemsby, Sten,Stroem, Peter
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p. 660 - 664
(2007/10/02)
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