Early-phase analogues

Fig. 5.1 Angiotensin ATI receptor antagonists derived from losartan are early-phase analogues. Despite the similarity of the structures, it can be assumed that the corresponding discoveries were made independently. The first year in parentheses is the basic patent year, the second one is the year of the first launch.

As I look back at this experience, it was an awesome adventure to be alone, during and for an interval of time after this discovery, with the apparatus showing one new effect after another, when there was no one in the Illinois Physics Department experienced in NMR with whom I could talk. Little did the early NMR resonance community realize that the analogue of spin echo hidden memory contained in excited phases of all kinds of states of matter, including plasmas, would be obtained in the future by use of optical laser, electric, and acoustic pulses as well. And now today the use of spin echoes is a standard procedure for magnetic resonance imaging of the human body for medical diagnosis. 

Only two stable fluorine oxides are known. Except for an early investigation of the decomposition of F202, studies of decomposition kinetics have been confined to F20. There still remains considerable doubt concerning the mechanisms by which these two compounds decompose to their elements. Unlike its chlorine analogue, FO has defied spectroscopic detection in the fluid phases, although it is considered an important intermediate in many of the reactions of F20. 

Other fluoroazoles are emerging flutrimazole (for topical treatment) and voriconazole, which has a good diffusion in cephalorachidian liquid. Posoconazole (Phase III) is the fluoro analogue of itraconazole. The structural complexity (four chiral centers) of posoconazole is remarkable (Figure S.23). Albaconazole, CS-758, Syn-2869, and Azoline have the same structural core as voriconazole they are in the early stage of clinical development. ... 

Rheumatoid arthritis Tender, swollen joints, visual analogue scale for pain acute phase reactants (ESR, C-reactive protein), duration of early morning stiffness, preservation of function... 

Such was the state of the art when Amundson and Bilous s paper was published in the first volume of the newly founded A.I.CH.E. Journal (Bilous and Amundson, 1955). This for the first time treated the reactor as a dynamical system and, using Lyapounov s method of linearization, gave a pair of algebraic conditions for local stability. One of these corresponded to the slope condition of previous analyses, and there was a brief flurry of attempts to invest the other with a similarly physical explanation. For the global picture they introduced the phase plane (another feature of the theory of dynamical systems) and, with consummate skill, Bilous conjured the now classic figures from a Reeves electronic analogue computer. Even in this early paper, they had touched upon the consecutive reaction scheme A - B - C and had shown that up to five steady states might be expected under some conditions. 

Silylium ions R3Si+ are known to be more stable in the gas phase than their carbon analogues, which is due to the fact that silicon is more electropositive than carbon. It is easy to observe them by mass spectrometry or ion cyclotron resonance spectroscopy of triorganosilyl compounds. [5] However, their existence in solvent phases is difficult to prove and, therefore, is still a matter of dispute. Early attempts to synthesize silylium ions in solution with methods successful in the preparation of carbocations were not successful. [78] The lack of stability of R3Si+ in solution was attributed to the strong tendency of Si to form hypercoordinated compounds, in which Si has five or even six bonding partners. [79]... 

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