Heterocyclic replacements for

A second patent application appeared in 2005, in which a series of pyrrolo[l,2-b]pyridazine-5,6-dicarboxylates was disclosed [31]. Several of the described compounds (exemplified by structure 8) were reported to have IC50 values of < 0.5 iM against DGAT-1. Various hydrophobic and amino substitutions at positions 4 and 7, and 2, respectively, were tolerated on the heterocyclic ring, along with heterocyclic replacements for the 6-substituted ethyl carboxylate. 

There are also some couplings in which hydrazones are formed but for which the azo tautomer is not detectable and probably does not exist. This is the case in some coupling reactions involving methyl groups of aromatic heterocycles (see, for example, 12.48 and 12.49 in Sec. 12.5). Replacement of a methyl proton by an arylazo group (Scheme 12-3) would result in an azo compound containing an sp3-hybridized — CH2 — group (12.1). The latter is less stable than the tautomeric hydrazone (12.2), in which there is a n-n orbital overlap from the heteroaromatic to the aromatic system. 

The betaine-type formula (6) has not been found to be acceptable for the general representation of meso-ionic heterocycles, but in view of the recent advocacy of the symbolism depicted in formula 7 some further comment is necessary. Although we originally used this symbolism in the representation of the sydnones, we subsequently recommended its replacement by 5 because this is in accord with current practice. Our present view is that the use of a special symbol (7) is not justified it is too vague to be useful, and in any case it can cause misunderstanding if formulas of type 8 with e=f are used as well as those of type 7 with e—f. The general formula 5 has much to commend it for discussion of type A and type B five-membered meso-ionic heterocycles and for the correlation of corresponding structural features of these two types (Tables I and II). 

The tetrazole moiety is an excellent bioisosteric replacement for a carboxylic acid, being a small, polar, acidic heterocycle. 

Heterocycles were explored as replacements for the nonphenolic ring (Table 3) [19]. Unsubstituted thiazoles, pyridines, and thiophenes gave active agonists, but with little or no selectivity. While an TV-methyl imidazole had little if any opioid agonist activity in this series, often additional substituents on the heterocycles provided potent compounds with delta opioid receptor selectivity. For instance, compound 34, a thiophene with a diethyl carboxamide, displayed selective delta opioid receptor agonism (although no binding selectivity was observed). 

Terminal perfluoroolefins have two fluorine atoms at the double bond. The carbon atoms of the latter bear a significant positive charge, and the nucleophilic agents easily replace the fluorine atoms at the multiple bond. The reactions of binucleophilic reagents with terminal perfluoroolefins form heterocyclic systems. The first step of the reaction involves a nucleophilic attack at the carbon atom of the double bond, generating a carbanion. The latter is stabilized by elimination of the fluoride ion and formation of a new double bond. Subsequent cyclization by the intramolecular attack of the nucleophilic center at the double bond leads to the formation of a heterocyclic system. For example, when a reaction mixture of hexafluoropropylene and sodium dialkylaminodithiocarbamate in dimethylacetamide is heated with aqueous sodium tetraphenylborate, one obtains the tetraphenylborate salt of 2-dialkylamino-4-trifluoromethyl-4,5-difluoro-l,3-dithiolan-2-yl (78JFC(12)193). This compound is formed by intramolecular cyclization of the S-nucleophilic center. 

Functionally-substituted disilanes are useful starting materials for silylenes, silicon containing heterocycles or for polymeric silicon-containing materials. The classical method to prepare functionalized disilanes is the cleavage of aryl groups by HCI/AICI3 [1] or by triflic acid [2]. An easier method is the introduction of chloro- or alkoxygroups by replacement of amino substituents. 

The finding that the 2-naphthalene moiety is a good surrogate for the isovanillin moiety (4-methoxy-3-hydroxyphenyl), fuelled the search for plausible replacements for the 3 -hydroxy-4 -methoxyphenyl (IsoV) B ring of Combretastatin A-4 other than the 2-naphthyl. Veirious heterocycles were considered, the most conservative choice being the indole ring in compound 14, fig. (7) [24]. 

Conformationally Constrained Analogs. Dermorphin analogs containing a local constraint were prepared by incorporation of a dipeptide mimetic in place of Phe -Gly". The Aba -Gly" (see Fig. 7.43) analog of dermorphin retains high affinity at [x receptors and potency in the GPI, whereas this structural modification increases S-receptor affinity and potency in the MVD 17- to 25-fold (892). A number of heterocycles are also tolerated as bond replacements for the Phe -Gly" peptide bond (893). 

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