No abstract

Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.

We have previously described a series of antagonists that showed high potency and selectivity for the NK(1) receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here we show that alteration of the 2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK(1) receptor affinity for the various conformational forms has facilitated the development of a detailed NK(1) pharmacophore model.

Addition of o-iodobenzoyl chlorides to imines affords Nacyliminium ions, perhaps in equilibrium with a-chlorobenzamides, as adducts. Reaction of the adducts with 1.1 equivalents of phenyllithium at -78 °C followed by warming to ambient temperature induces an intramolecular Wurtz-Fittig coupling to afford 2,3-dihydroisoindolones in excellent yields.The reaction of acid chlorides with imines affords adducts 3 which may be represented formally as the N-acyliminium ions 3a or the corresponding a-chloroamides 3b derived from 1,2-addition across the imine C-N bond. 1 Such adducts of imines and a variety of acylating agents, which include acid chlorides and anhydrides, have been proposed as intermediates in the synthesis of a number of different heterocycles. 2 This has included several complex natural products containing heterocycles as substructures. 3 Reaction of acid chlorides with simple imines has also been used in a method to protect a secondary amide. 4 Our interest in preparing isoindolones prompted speculation that adducts 3 derived from the addition of o-iodobenzoyl chlorides to imines might be readily cyclized under reductive coupling conditions to afford 2,3-dihydroisoindolon-1-ones (Scheme 1). Thus, generation of an anion or anion equivalent ortho to the benzoyl carbonyl group in the benzoyl chloride/imine adduct 3 should provide an intermediate poised to cyclize to an isoindolone. 5 We proposed that the desired cyclization might be induced by forming the ortho-lithio derivative 4 from the oiodobenzoyl chloride/imine adduct 3, by lithium-iodide exchange. 6 Such a reaction would be similar in principle, to the Wurtz-Fittig-type cyclization of a,w-dihaloalkanes induced by tert-butyllithium, which was described by Bailey and co-workers. 7 We were also encouraged by our previous work utilizing lithium-iodide exchange to generate internally functionalized aryllithium reagents, in the presence of imines, as method to prepare isoindolones. 8 Direct nucleophilic couplings to form a bond between the carbon a to nitrogen and the ortho-C-aryl carbon to form an isoindolone ring are rare (5, formation of red bond). 9Scheme 1 (a) Addition of acid chlorides to imines to form N-acyliminium salts 3a and/or chloroamides 3b; (b) lithium-iodide exchange-induced cyclization to form isoindolone 5 A representative adduct 3 was prepared by adding o-iodobenzoyl chloride to a THF solution of butylidenebutylamine 2, (R 1 = Pr, R 2 = Bu, R 3 = H) at -25 °C. After stirring for 10 minutes at -25 °C, the resulting solution was cooled to -78 °C and phenyllithium (1.1 equivalent) was added dropwise. The cooling bath was removed immediately, and the mixture was warmed to ambient temperature. Isoindolone 5 (R 1 = Pr, R 2 = Bu, R 3 = H) was isolated in a 90% yield. The reaction was very clean, with only a minor amount of a single by-product being detected. The by-product was identified as N-[(1E)-1-butenyl]-N-butylbenzamide, presumably arising from some minor competing b-elimination from the acid chloride/imine adduct 3 (R 1 = Pr, R 2 = Bu,...

Pyrrol‐3.4‐dicarbonsäuren (I) liefern über die Anhydride (II) mit Aminen die Amidcarbonsäuren (III), die zu den Imiden (IV) cyclisiert und weiter zu (V) hydriert werden.

Samarium(III) tris [hexamethyldisilazide] (Sm[(Me 3 Si) 2 N] 3 = Sm [HMDS] 3 ) promotes the direct conversion of an ester admixed with an amine into the corresponding carboxamide under exceptionally mild conditions (£0°C) and in high yields. Only a slight excess of amine and the lanthanide complex are required to effect complete conversion of the ester into the amide. Esters with acidic a-hydrogens undergo a competing Claisen-like condensation along with the desired conversion into amides.

Tris[hexamethyldisilazide] and Amines. -Lanthanum and samarium tris(hexamethyldisilazide) efficiently promote the reactions of aromatic esters with amines. -(CAMPBELL*, J. B.; SPARKS, R. B.; DEDINAS, R. F.; Synlett 2011, 3, 357-360, http://dx.doi.org/10.1055/s-0030-1259508 ; CNS Discovery Res., AstraZeneca Pharm., Wilmington, DE 19850, USA; Eng.) -Mais 23-066