Oxatriazole Derivatives

GEA-3162 spontaneously generates NO when dissolved [93, 94]. GEA-3163 inhibited ADP-induced platelet aggregation and induced a dose-dependent increase in cyclic GMP in platelets. The increase in cGMP was potentiated by phosphodiesterase-5 inhibitor, zaprinast, and inhibited by oxyhemoglobin [94]. 

---

Oxatriazole derivatives are usually prepared by the cyclization of A-nitrosohydrazines as illustrated by the synthesis of 3-alkyl-1,2,3,4-oxatriazolium-5-olates 764 from semicarbazides via nitrosation (Scheme 330) . 

In some cases mesoionic systems have proved to be valuable precursors for 1,2,3-triazoles bearing latent functionalities. Thus, the oxatriazole derivative (314) decompsoes to an intermediate azide, which can be intercepted, e.g. by tolane, forming triazole (315) (68CB536). In a related photoreaction, the sydnone derivative (316) gives a 2/7-1,2,3-triazole (31 by way of an intermediate nitrilimine (317). The reaction mechanism has been studied by N-labelling ( ) (78HCA1477). 

Scheme 6.22 Acylation and nitrosation of 5-amenate derivatives of mesoionic 1,2,3,4-oxatriazoles.

Scheme 6.23 Ring-opening reactions of mesoionic 5-olate and 5-amenate 1,2,3,4-oxatriazoles to nitrosohydrazine derivatives.

Meso-ionic 3-alkyl-l,2,3,4-oxatriazol-5-ones (271) are obtained by the nitrosation of 1-alkyl semicarbazides, RNHNHCONHj. At low temperatures, the intermediate A-nitroso derivatives (272) can be isolated, which cyclize on heating. An alternative synthetic route is illustrated by the formation of meso-ionic 3-methyl-l,2,3,4-oxatriazol-5-one (271, R = Me) from A-nitroso-iV-methylhydrazine (273) and phosgene. ... 

The dipole moment of the A-phenyl derivative (271, R = Ph) in benzene solution is 6.14 D, ° which may be compared with the molecular orbital calculations by Sundaram and Purcell which give a value of 5.3 D for the meso-ionic l,2,3,4-oxatriazol-5-one heterocyclic ring moment. 

Treatment of the JV-nitrosocyanides (283)198 or the W-nitrosoguanyl-hydrazines (284)199 with hydrogen chloride yielded the 1,2,3,4-oxatriazolium chlorides (285, X = Cl), which with aqueous sodium bicarbonate gave the meso-ionic l,2,3,4-oxatriazol-5-imines (277, R2 = H).198 Nitrosation of these compounds (277, R2 = H) gave the interesting JV-nitroso compounds (277, R2 = NO), and acylation gave the JV-acyl derivatives (277, R2 = RCO).198... 

This chapter covers the literature from mid-1995 to mid-2007. Recent advances include the preparation of the first A2-l,2,3,4-oxatriazolines 7 by intramolecular [3+2] cycloaddition (Section 6.08.9), synthesis of mesoionic derivatives 4 using bromonitroformaldehyde iV-arylhydrazones as the starting materials (Section 6.08.9), and detailed studies of the biologically active mesoionic oxatriazoles in the context of their nitric oxide donating capabilities (Section... 

Although 1,2,3,4-oxatriazole and its 5-methyl-substituted derivative are unknown compounds, the equilibrium between ring-closed 1 (R = H or Me) and ring-open forms 17 and 18 has been examined theoretically (Equation 1) <2000CPL276, 2005CRV3561>. 

No molecular ions appear in the electron ionization (El) spectra of mesoionic 1,2,3,4-oxatriazoles 4 and 6 or their derivatives. Instead, [M+ —30] peaks are observed due to loss of nitric oxide <1979J(P1)747, 1999CHE363>. The typical fragmentation pathway for such compounds and their analogues is summarized in Scheme 1 <1984CHEC(4)579, 1996CHEC-II(4)679>. In their fast atom bombardment (FAB) spectra, intact molecular ion peaks are observed for the A2-l,2,3,4-oxatriazolines 23 114 [M+H] and 24 142 [M+H] <2002HAC307>. 

The chemistry of 1,2,3,4-thiatriazoles was covered previously in 32 pages in CHEC(1984) <1984CHEC(6)579> together with data on 1,2,3,4-oxatriazoles, and in 40 pages in CHEC-II(1996) <1996CHEC-II(4)691>. Older reviews were mentioned in the introductions to these two texts. The synthetic aspects of 1,2,3,4-thiatriazole derivatives and the isomeric 1,2,3,5-thiatriazoles were recently reviewed by Begtrup <2004HOU833>. 

An N-nitroso derivative of (87 R1 = H, R = Ph) has been prepared (71CPB559). It is thermally unstable, decomposing to give a high yield of mesoionic 3-phenyl-l,2,3,4-oxatriazol-5-one (equation 66). 

With one nitrogen and one oxygen or sulfur as azole 1,2-locants, ortho-fused derivatives are classified as isoxazolo- and isothiazolo-azines with the same heteroelements as azole 1,3-locants the fused derivatives are classified as oxazolo- and thiazolo-azines. With two nitrogens the compounds are oxadiazolo- or thiadiazolo-azines which are subdivided further according to the relative locations of the azole heteroatoms. This approach can also be extended to fused oxatriazole and thiatriazole. These systems, however, are omitted from this discussion since little work has hitherto been reported. 

Oxatriazolium-5-aminides (9) are structurally related to sydnon-imines (3). As with sydnonimines, the 5-imine derivatives are stable only as salts or in their N-acylated forms. 3-Cyclohexyl-1,2,3,4-oxatriazole-5-imine hydrochloride was first synthesized by Finnegan and Henry in 1965 [55]. The biological activity was reported by Masuda et al. in 1971 [56]. Oxatriazole-5-imines (9) have been reported to be an important class of NO donors and potent antiplatelet, fibrinolytic, thrombolytic, and bronchiectatic agents [57]. However, an extensive investigation of the NO-releasing and other biologi-... 

N-Morpholino-W-nitrosoaminoacetonitril as a nitric oxide ( N0) donor (Bohn and SchOnafin-GER 1989, Feelisch et al. 1989) formed from N-ethoxycarbonyl-3-morphlinosydnonimine (molsi-domin) via 3-morphlinosydnonimine by 02 formation is a safe vasodilator in man, but a potential nasal carcinogen in the rat, probably due to the vast smooth endoplasmic reticulum with its cytochrome P450 (Hadley and Dahl 1982, Adams etal. 1991). The question whether the new series of mesoionic 3-aryl substituted oxatriazole-5-imine derivatives (Lahteenmaki et al. 1998) have the same side effects is outstanding. 

The novel oxatriazole-type NO-donors (GEA compounds) are mesoionic 3-aryl substituted oxatri-azole-5-imine derivatives releasing NO. They have vasodilator, antiplatelet and fibrinolytic activities (CoRELL et al. 1994, Karup et al. 1994, Kankaan-... 

---