Selection product analogues

The benzannulation allows a facile incorporation of a hydrogen-bonding functionality, which complements the pharmacophore in naturally occurring indolocarbazoles. Orthogonally protected indolocarbazole nitrogen atoms allow a concise and selective glycoside formation en route to synthetic indolocarbazoles as natural product analogues. 

While the selection of an isotopically-labelled or analogue internal standard is relatively easy in quantitative bioanalysis, the situation is more complicated in multiresidue analysis. It is difficult to select appropriate analogue standards for a wide variety of target compounds, while isotopically-labelled standards are often not available for all target compounds. In addition, if one would introduce one standard per target compound, this would seriously limit the sensitivity of the method as it doubles the number of SRM transitions that have to be monitored. Another problem in multiresidue analysis is the selection of appropriate blanks for the production of the matrix-matched standards and the number of matrices that might have to be studied. When no adequate blank matrix is available, the standard addition method is the only way to achieve sufficiently accurate and precise results [123]. This method is time-consuming and labourious. 

Reactions involving one or more reactants enclosed separately or together, and in this way protected in big tailor-shaped cavities (resembling die Mobil process using zeolite cavities in the production of petrol from methanol) with varied kinetics, stereochemistry, and selectivity, are conceivable. Thus, new types of selective enzyme-analoguous reactions may be studied and used. 

Saturation of the aromatic ring of pentopril analogues is also consistent with ACE inhibition as demonstrated by the oral activity of indolapril (23). The necessary heterocyclic component (21) can in principle be prepared by catalytic perhydrogenation (Rh/C, HOAc) of the corresponding indole. A single isomer predominates. The product is condensed by amide bond formation with the appropriate alanylhomophenylalanyl dipeptide ester 20 to give 22. Selective saponification to 23 could be accomplished by treatment with HCl gas. Use of the appropriate stereoisomers (prepared by resolution processes) produces chiral indolapril [8]. 

The VACM-1 receptor is a membrane-associated protein with a single putative transmembrane domain that binds selectively AVP (XD — 2 nM), but cannot discriminate between VXR and V2R analogues. It is expressed in endothelial and medullary collecting duct cells and upon stimulation by AVP. It induces a mobilization of cytosolic-free Ca2+, decreases cAMP production and inhibits cellular growth via MAPK phosphorylation and p53 expression. The mechanism of action and physiological functions of this new receptor are not well understood, but it seems to participate in the regulation of AVP induced signal transduction pathways or of a yet unidentified peptide. 

In a similar fashion, the C - C hnked pyrazinone-triazoles were reacted with an excess of DMAD (3.5 equiv) under microwave irradiation conditions at a pre-selected temperature of 190 °C (Scheme 29). The reactions proceeded smoothly in o-DCB in 10-20 min, using a maximum irradiation power of 200 W. Differing from the C - O analogues, the C - C linked pyrazinone-triazoles generated the corresponding pyridinones as the exclusive products. 

GP 4] [R 5] Formaldehyde synthesis has been known at BASF for more than 100 years [1, 49-51,108]. Hence it was expected to be able to handle the synthesis of substituted analogue, an undisclosed methanol derivative, with the same processsing concepts, major problems not being anticipated. This expectation was still supported by first attempts with the tried and tested pan-like reactor concept (5 cm diameter), which were promising. At 50% conversion, a selectivity of 90% was achieved. However, transfer to production scale using a 3 m production reac-... 

Dithioacetal monoxides undergo Michael addition to acrylonitrile. The addition products are easily converted into y-ketonitriles 382 (equation 221). Benzenesulphinyl allylic carbanions 383 derived from the corresponding allylic sulphoxides react selectively at the y-position with a variety of cycloalkenones to give the l,4-adducts " (equation 222). Recently, Nokami and coworkers have synthesized some prostaglandin analogues via a three-component coupling process involving 1,4-addition of phenylsul-phinyl allylic carbanion (equation 223) . ... 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Thomas and co-workers [277] reported that irradiation of (382) with a 450 W high-pressure mercury lamp brought about photocyclisation to a constrained analogue (394). The structure of the product was elucidated through NMR and X-ray diffraction analysis. The compound retained high affinity for the CBi receptor (Xj = 48 nM) and good selectivity over the CB2 receptor (K[ — 3,340 nM). 

---