Antagonists Thromboxane

Figure 11.3 (a) Thromboxane A2 (TXA2). Note The locants given are those of the dioxan ring only and not those for the complete molecule. They are used for reference purposes only (see text), (b) Examples of some of the thromboxane antagonists developed by ICI... 

The aldehyde below waa needed by 1C1 when they were developing a thromboxane antagonist, Two-group disconnection gives a 2-halo-aldehyde that can be made from bobutyraldehyde. 

The next compound was needed by I Cl when chemists there were developing a thromboxane antagonist to inhibit blood clot formation. You can immediately spot the 1,3-relationship between the ester and the hydroxyl group, so 1,3-diO disconnection is called for. 

Nanimiya S, Okuma M, Ushikubi F. Binding of aradioicxlinated 13-azapinane thromboxane antagonist to platelets correlation with antiaggregatory activity in different spedes. Br J Pharmacol 1986 88 323-31... 

The cyclohexanone (S3), an intermediate for the synthesis of thromboxane antagonists, has been prepared by a combination of phosphine oxide- and phosphonium ylide-based olefinations.30 Reaction of the lactone (50) with methoxymethyldiphenylphosphine oxide anion gave a poorly characterized adduct (presumably (51)) which on reduction with sodium borohydride, followed by treatment with sodium hydride gave the vinyl ether (52) in 80% overall yield from (SO) (Scheme 8). Further modification gave the required cyclohexanone (53). 

J. M. Lawlor and M. B. Macnamee, Tetrahedron Lett., 1983, 24, 2211. The product is a thromboxane antagonist developed by the then ICI and described in S. Lee and G. Robinson, Process development, Oxford University Press, Oxford, 1995, pp. 27-37. 

A good equivalent for the ester enolate d synthon is a P-dicarbonyl compound, because it can easily be disconnected to diethyl malonate and an alkylating agent, thromboxane antagonist intermediate synthesis... 

In suitable cases the application of stoichiometric chiral auxiliaries may be advantageous even on the industrial kilogram-scale. Scheme 49 provides as an example the synthesis of a thromboxane antagonist (ICI D1542) via the Evans aldol strategy [114]. Thus, the chiral auxiliary 49-1 is converted into the amide 49-3 and then submitted to a boron mediated aldol addition leading to 49-4 in dias-tereomerically pure crystalline form. The auxiliary is removed by reduction and... 

H-1 antihistamines [26], gliclazide [27], or thromboxane antagonists [28] could be well resolved. Derivatized CDs often exhibit improved chiral recognition properties [29]. //eptaA K(2,3-di-0-acetyl)-p-CD is able to resolve a series of pharmacologically active phenethylamines with their structures systematically varied [30],[31],[32]. Similar results have been reported for hydroxypropyl- as well as for permethylated P-CD [33] and perphenylearbamated P-CD to resolve atenolol [34],... 

Coker, S.J. and Parratt, J.R. (1985). AH23848, a thromboxane antagonist, suppresses ischaemia and reperfusion-induced arrhythmias in anaesthetized greyhounds. Br. ]. Pharmacol, 86, 259-264... 

Katsura, M., Miyamoto, T., Hamanaka, N., Kondo, K., Terada, T., Ohgaki, Y., Kawasaki, A. and Tsuboshima, M. (1983). In vitro and in vivo effects of new powerful thromboxane antagonists (3-alkylamino pinane derivatives). Adv. Prostagl Thrombox. Leuk. Res., 11, 351-357... 

Narumiya, S., Okuma, M. and Ushikubi, F. (1986). Binding of a radioiodinated 13-azapinane thromboxane antagonists to platelets Correlation with antiaggregatory activity in different species. Br. ]. Pharmacol, 88, 323-331... 

Rybicki, J.P., Venton, D.L. and LeBreton, G.C. (1983). The thromboxane antagonist, 13-azaprostanoic acid, inhibits arachidonic acid-induced Ca release from isolated platelet membrane vesicles. Biochim. Biophys. Ada, 751, 66-73... 

A number of 7 oxabicyclo[2.2.1]heptane prostaglandin analogues were synthesized and evaluated as potential thromboxane synthetase inhibitors or thromboxane antagonists. Several of the compounds tested were shown to be TXA2 antagonists, judged from platelet aggregation and thromboxane inhibition tests. Two of the compounds also inhibited arachidonic acid induced bronchoconstriction [266]. 

The intramolecular hydroarylaion and hydroalkenylation methodology has provided novel routes to the core unit of the quinolizidine-based homopnmiliotoxin alkaloids (Scheme 40) and the conformationally restrained analogs of the combined thromboxane antagonist/synthase inhibitor GR85305f (Scheme 41). 

A typical example for the significance of aliphatic amines in the pharmaceutical industry is the analysis of amylamine and tert-butylamine. Both amines are intermediates in the synthesis of a thromboxane antagonist, while tert-butyl-amine also serves as a counterion of drug components. Amylamine and tert-butylamine can be eluted with methanesulfonic acid from an lonPac CS14 cation exchanger and detected by suppressed conductivity, but different eluent concentrations are used to account for the different affinities of the two amines toward the stationary phase [462]. Moreover, amine retention can be controlled by a small amount of acetonitrile in the mobile phase. In both cases, it is fortunate that the respective drug components are soluble in water and thus can be... 

Scheme 3.19 Preparation of a qrclohexanone intermediate for synthesis of thromboxane antagonists.

---