ARAES

Compounds containing two primary amino groups attached to a benzene ring can be prepared by the reduction of dinitro compounds and of nitroanilines, usually with tin or stannous chloride and hydrochloric acid or with iron and very dilute hydrochloric acid. / ara-diamines may also be obtained by the reduction of aromatic amino-azo compounds (e.g., p-aminodimethylanihne from methyl orange, see Section IV,78). p-Phenylenediamine may also be prepared from p-nitroacetanilide reduction with iron and acid yields p-amino-acetaniUde,.which may be hydrolysed to the diamine. 

This equation is formally similar to the p+(T+ relationship, Sf being related to p+, and b being a parameter whose value depends on the values of cr+ for meta- and ara-methyl groups b = o-+/(cr+ — o-+)]. 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

Table III-94 5-Ara kylthiazoles with one substituent on the aryl group...

As indicated in Figure 5.18,/>ara- lT2 can exist in only even/states and ortho- ll2 in odd J states. At temperatures at which there is appreciable population up to fairly high values of J there is roughly three times as much ortho- as there is para- l2- Flowever, at very low temperatures at which the population of all rotational levels other than J= 0 is small IT2 is mostly in the para form. 

D. Cho, R. Warrington Jr., A. Pisano, H. Bau, C. Friedrich,. ara-Almonte, and. Liburdy, eds.. Micromechanical Sensors, Mctuators and Systems, American Society of Mechanical Engineers, New York, 1991. 

S. Iyer and co-workers, Eesearch Toward More Poweful Explosive, technical report ARAED-TR-89010, ARDEC, Picatinny Arsenal, N.J., June 1989. 

Table 1. Temperature Dependenee of the Equilibrium Ortho-, / ara-Hydrogeu Compositiou, ...

P-D-Arabinofuranosylcytosine [147-94-4] (ara-C, 16), C H N O, reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephaUtis (33), although several negative results have also been reported (34) (Fig. 2). Ara-C, also known as cytarabine, is quite toxic and is only recommended for very severe viral infections. It is rapidly deaminated in humans to the relatively inactive ara-U Ara-C is converted in the cell to the 5 -monophosphate by deoxycytidine kinase, followed by formation of the corresponding di- and triphosphate. The triphosphate has been shown to inhibit DNA polymerase. 

The 3, 5 -cyclic phosphate of ara-C has shown significant antiviral activity in vivo with an efficacy greater than that exhibited by ara-C itself (35). It was speculated that the 3, 5 -cycHc phosphate moiety may inhibit the deamination of ara-C, thus causiag the iacreased in vivo potency. A number of derivatives of ara-C have been prepared ia an effort to improve on antiviral activity and to reduce the toxicity. One such derivative is 2 - uoro-5-iodo-l-p-D-arabiQofuranosylcytosiae [69123-90-6] (FIAC, 17), synthesized (36) ia 1979. It is active against certain DNA vimses. FIAC,... 

Purine Nucleoside Derivatives. A number of purine nucleoside analogues are also found to be active against several DNA vimses (Fig. 3). The clinically active antiviral drug ara-A (9-P-D-arabinofuranosyladenine [5536-17-4] vidarabine, 23) is active against a number of DNA vimses in vivo and also inhibits certain RNA tumor vimses which repHcate through a DNA intermediate (43). Ara-A, was first synthesized in 1960 (44) and later... 

Ara-A-5 -monophosphate [29984-33-6] (ara-AMP), C2QH24N OyP, is more water-soluble than ara-A, and therefore can be used in higher dosage during the first hours of treatment of viral infections. Ara-AMP has been shown to decrease virion-associated DNA polymerase concentrations in ground squirrels carrying ground squirrel hepatitis vims. The hypoxanthine derivative, ara-HxMP [54656-49-4] (24) is more water-soluble, appears to have a similar antiviral spectmm to ara-A, and is considerably less toxic (48). 

Topical apphcation of ara-HxMP, C2QH23N40gP, significantly inhibited the development of keratitis-induced HSV-1, HSV-2, or vaccinia vims in the eyes of rabbits. Ara-HxMP also significantly controlled the development of HSV-1 or vaccinia viral-induced encephaUtis in mice and was also active in preventing equine abortion viral deaths in hamsters. Clinical trials with ara-HxMP have not yet been reported. 

Ara-A is phosphorylated in mammalian cells to ara-AMP by adenosine kinase and deoxycytidine kinase. Further phosphorylation to the di- and triphosphates, ara-ADP and ara-ATP, also occurs. In HSV-1 infected cells, ara-A also is converted to ara-ATP. Levels of ara-ATP correlate directly with HSV rephcation. It has recently been suggested that ara-A also may exhibit an antiviral effect against adenovims by inhibiting polyadenylation of viral messenger RNA (mRNA), which may then inhibit the proper transport of the viral mRNA from the cell nucleus. 

It is likely that ara-HxMP similarly exerts its antiviral activity in the form of the triphosphate, ara-HxTP, since ara-HxTP inhibits HSV-1 DNA polymerase (49). Another possible explanation of the antiviral activity of ara-HxTP is that it is metaboHcaHy converted to ara-AMP. In fact, it has been shown at Wellcome Research Laboratories that ara-HxMP is a substrate for adenylosuccinate synthetase, and that the resulting arabinofuranosyladenylosuccinate is cleaved to ara-AMP by adenylosuccinate lyase (1). The selective action of ara-A against HSV appears to be a consequence of the preferential inhibition of ara-ATP against HSV-1 and HSV-2 polymerases. Ara-ATP also inhibits normal cellular DNA polymerases, which may be the reason for its cellular toxicity. Also, it has been observed that ara-A is incorporated uniformly throughout the HSV-1 genome, which may result in defective viral DNA (50). 

The antiviral activity of (5)-DHPA in vivo was assessed in mice inoculated intranasaHy with vesicular stomatitis vims ( 5)-DHPA significantly increased survival from the infection. (5)-DHPA did not significantly reduce DNA, RNA, or protein synthesis and is not a substrate for adenosine deaminase of either bacterial or mammalian origin. However, (5)-DHPA strongly inhibits deamination of adenosine and ara-A by adenosine deaminase. Its mode of action may be inhibition of Vadenosyl-L-homocysteine hydrolase (61). Inhibition of SAH hydrolase results in the accumulation of SAH, which is a product inhibitor of Vadenosylmethionine-dependent methylation reactions. Such methylations are required for the maturation of vital mRNA, and hence inhibitors of SAH hydrolase may be expected to block vims repHcation by interference with viral mRNA methylation. 

Acyclovir is more effective the more serious the disease and the earher it is given. It has been shown to be efficacious when used systemicaHy in the prophylaxis of HSV infections in immunosuppressed patients, ie, bone marrow transplant recipients (67). Acyclovir therapy appears to be superior to ara-A in the treatment of herpes simplex encephaUtis in humans (68). 

Moderate in vivo antiherpes vims activity was demonstrated by 9-P-Dxylofuranosylguanine [27462-39-1] (xylo-G, 38), C qH N O, and the 5 -mono-and 3, 5 -cycHc phosphates of (38), although none was as active as ara-A (89). Generally, guanine base-modified analogues of acyclovir are less active than acyclovir because they are not readily phosphorylated by herpes thymidine kinase. 

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