Analogue preparation

The anticonvulsant activity of some 1,3-benzisoxazoles was discovered in routine testing. One of the more interesting of the subsequent analogues prepared was zonisamide (39). One of its syntheses starts with l,2-benzisoxazole-3-acetic acid (36) which is brominated and subsequently decarboxylated to give 37. Displacement of halogen in 37 with sodium bisulfite interestingly... 

It has square planar coordination (Pd-N 2.010-2.017 A) similar to the value of 2.009 A in the tetraphenylporphyrin analogue, prepared by a similar route. As with nickel, macrocycle complexes can be made by in situ template... 

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

A rather complex fused isoindoline (87) has been found to show good anorectic activity. This substance differs from other anorectic agents by not being a p-phenethylamine analogue. Preparation of this compound starts by reaction of a substituted benzoyl-benzoic acid (82) with ethylene diamine. The product (84) can be rationalized as being the aminal from the initially obtained monoamide 83. This is then subjected to reduction with lithium aluminum hydride... 

NATURAL PRODUCTS AND BIOLOGICALLY ACTIVE ANALOGUES PREPARED BY STEREOSELECTIVE ALDOL ADDITON OF DOUBLY DEPROTONATED (R)- AND (S)-HYTRA... 

Figure 10.1 Glu analogues prepared by AspAT-catalysed transamination...

AspAT has been shown to display a broad substrate spectrum. This chemoenzymatic procedure is, therefore, a very convenient way to prepare a variety of L-2,4-syn Glu analogues substituted at the 4-position by alkyl or functionalized substituents. Moreover, this catalyst has been used for the preparation of 4,4-disubstituted ° and (25,3R)-3-methyl Glu derivatives, as well as the cyclobutane analogues LCBG II-IV. The different Glu analogues prepared to date using this methodology are reported in Figure 10.1. 

The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene. A third very useful approach is cyclodehydration of 0-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate. However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfo-nyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point. 

Figure 10.55 Statistical rotaxane synthesis (a) product from solution and (b) analogue prepared in higher yield (6 %) on a solid support.

The excess of analogue preparations and the unnecessary diversity of trade names for one and the same drug make the pharmaceutical markets of some countries (e.g., Germany) rather perplexing. A critical listing of essential drugs is a prerequisite for optimal pharmacotherapy and would be of great value for medical practice. 

The first cadmium triazenide complex Cd(ArNNNAr)2 (Ar = p-CgH4-N02) was obtained by Meldola and Streatfeild in 1887 on adding ammoniacal CdCl2 to a hot alcoholic solution of the triazene (146). It was described as a steely blue crystalline material which turned red on drying and exploded on heating. The diphenyltriazene analogue, prepared more recently... 

High-energy density batteries having superior stability were prepared Morioka [1] using polynitroxyl radicals components, (I). Sulfur, (II), and boron, (III), free radical analogues prepared by Bannai [2] were also effective as secondary battery components. 

Tab. 2.1 Potency of balanol analogues prepared by Kolde et al. against PKA and PKC [69].

Numerous azido-substituted nucleosides have been evaluated as potential antitumour agents. De Clercq et al. found that of a series of 2 - and 3 -azidonucleoside analogues prepared and evaluated for antitumour activity against murine LI210 cells in vitro, the most potent derivative was 3 -azido-2, 3 -dideoxyadenosine (146), with 3 -azido-2, 3 -dideoxyguanosine (102), 3 -azido-3 -deoxyadenosine (147) and 2 -azido-2 -deoxycytidine (148) proving moderately active [170], the activity of the last compound having been reported previously [171, 172], AZT was also evaluated in this study... 

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