Early Compounds

At the very end of the eighteenth century, Tassaert—a French chemist so obscure in the history of chemistry that his first name remains unknown—observed that ammonia combined with a cobalt ore to yield a reddish-brown product. This was most likely the first known coordination compound. Throughout the first half of the nineteenth century, many other, often beautifully crystalline examples of various cobalt ammonates were prepared. These compounds were strikingly colored, and the names given to them—for example, roseo-, luteo- (from the Latin luteus, meaning deep yellow ), and purpureocobaltic chlorides—reflected these colors. 

The Cobalt Ammonate Chlorides (Data Available to Blomstrand, Jorgensen, and Werner) 

In the second half of the century, other ammonates, particularly those of chromium and platinum, were prepared. Despite various attempts, however, no theoretical basis was developed to account satisfactorily for these wondrous compounds. 

In 1869 Christian Wilhelm Blomstrand first formulated his chain theory to account for the cobalt ammonate chlorides and other series of ammonates. Blomstrand, knowing that the fixed valence of cobalt was established at 3, chained together cobalt atoms, divalent ammonia groups, and monovalent chlorides to produce a picture of 

Representations of the cobalt ammonate chlorides by Blomstrand and Jorgensen (o) Blomstrand s representation of C0CI3 6NH3 (b) Jorgensen s representations of four members of the series with the iridium substituted for the intended cobalt in compound (4). (Adapted from F. Basolo and R. C. Johnson, Coordination Chemistry, 2nd edition, p.6. Copyright 1986. Reprinted by permission of Science Reviews 2000 Ltd., www.sciencereviews2000. co.uk.) 

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The very simple nitroimidazole azomycin (52-2) is one of the very early compounds uncovered by the extensive search for antibacterial agents produced by Streptomyces fermentation. Its development as an antibiotic drug was probably... 

It is important that herbicides used for weed control in crops are selective to that crop. Early compounds used the inability of the foliage of upright cereal crops to retain a great deal of spray as the basis of their selectivity and this was successful in many situations although it must be remembered that the alternative to weed control with inadequately selective herbicides was hand weeding or no weed control at all. 

It has to be accepted therefore that the level of risk in early compounds is extreme and this reduces only gradually until studies in quite large populations have been tested. Consequently the evaluation of a compound or other kind of asset must be realistically limited to what it is actually possible to know at the time, and acted upon accordingly. 

Early work in the area of crown ether biological mimics was reported by Vogtle and coworkers (Tummler, 1977). These early compounds were made in an effort to duplicate natural ion carriers in the sense that they could complex biologically important ions for transport. The early, two-dimensional crowns (such as 5) and non-cyclic polyethers gave way to the three-dimensional ciyptands (6), which generally complexed ions more tightly but which lack the dynamics of podands, crown ethers, or lariat ethers. 

Once the medicinal properties of I and II were appreciated, the inevitable synthesis of carbamate analogs followed. The anticholinesterase activity of physostigmine- and eserine-related synthetics suggested their possible use as Insecticides but tests of early compounds failed, due to the quaternary ammonium barrier to penetration of the insect cuticle present in them. 

While many early compounds were tested as mixtures of enantiomers, when these compounds were made stereoselectively or separated, one enantiomer was usually more potent. For instance, the (+)-enantiomer of BW373U86 (containing the R stereochemistry at the benzhydryl position, S stereochemistry at the 2 position of the piperazine, and R stereochemistry at the 5 position) was significantly more potent at both the delta and mu opioid receptors (Table 4). 

The evidence then is that, for rifamycin and other ansamycins, biosynthesis diverts at a so-far unidentified (but early) compound in the shikimic acid pathway to give 3-amino-5-hydroxybenzoic acid (91) (as its CoA ester). This compound then yields, on the one hand, the mitomycins [e.g. porfiromycin (88)1 and, on the other, the CoA ester of P8/1-OG (92), which then affords diverse metabolites such as rifamycin B (87) and actamycin (86) (cf. ref. 83 for a detailed scheme). 

Since 1917, only 11 new endoparasiticides have been developed for use in the horse. Many of the early compounds had very narrow spectra of activity and/or high potential for toxicity such that they have become obsolete. Febantel, levamisole, trichlorfon, dichlorvos, phenothiazine and carbon disulfide are no longer used routinely in the horse (Lyons et al 1999). 

The useful biological properties of paclobutrazol have inspired further chemical synthesis of azole structures, culminating with the discovery of a series of tertiary alcohol compounds. The original synthetic strategy was conceived as a disconnection and reconnection analysis from paclobutrazol (Figure 5). These early compounds were good fungicides and further optimisation in this area has led to the commercial introduction of two products flutriafol and recently hexaconazole. 

Typical Hi antagonists are not particularly structurally reminiscent of histamine Early compounds often had side-effects caused by actions at other receptors such as that for acetylcholine, but their main drawback is antagonism of Hi receptors in the CNS, leading to drowsiness. Promethazine (Phenergan) has such strong... 

Schmiedberg (1886) first reported that urethane (ethyl carbamate) produces rapid and deep narcosis in dogs. (The drug was subsequently used as a veterinary anesthetic.) More alkyl esters were soon introduced as hypnotics or anesthetics. For example, hedonal, which is more active than urethane, was introduced by Dreser7 (1899) as a fixed anesthetic for intravenous use. Figure 12-10, illustrates some early compounds, such as urethane and hedonal, which are only of historical interest, along with several others that, while still available, are rarely used in the United States. 

A third generation of antidepressants will be needed to advance into an era of higher selectivity to yield even safer and especially more effective compounds. The roadblock may well be still insufficient neurochemical knowledge. Even though the second-generation drugs discussed are safer than were the early compounds, their impact therapeutically... 

A second immediate success was in DMPK. When a project team working on ITK realized that their early compounds had safety problems due to inhibition of P-450, the ITK team collaborated with the SYK team who had had the same issue and had resolved it after a 2-year effort. ITK was able to benefit from the recent knowledge that was gained in solving the SYK problem. As a result, ITK required 6 months less to successfully design lead compounds without P-450 inhibition liabilities. 

Information regarding pharmaookinetio and metabolic disposition is limited, because this early group of compounds was not studied in depth. Only later, with second-generation Hi antihistamines, and/or when issues of potential toxicity have arisen concerning some of the early compounds, has the metabolio disposition been examined more completely. Thus, the available information oonoerning the metabolism on these early antihistamines is sparse. 

Diarylmethylene groups (benzhydryl substituents, as in diphenhydramine) are attached to one of the nitrogen atoms, and an alkyl or aralkyl substituent is attached to the other nitrogen. Early compounds, such as cyclizine, chlorcyclizine, meclizine, buclizine, and hydroxyzine, have been widely used as antihistamines and as agents for treatment of motion sickness, because they have useful central antiemetic effects. 

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