Potassium compounds activation

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

A small fraction of the hydrocarbons decompose and deposit on the catalyst as carbon. Although the effect is minute ia terms of yield losses, this carbon can stiU significantly reduce the activity of the catalyst. The carbon is formed from cracking of alkyl groups on the aromatic ring and of nonaromatics present ia certain ethylbenzene feedstocks. It can be removed by the water gas reaction, which is catalyzed by potassium compounds ia the catalyst. Steam, which is... 

Fig. 7.27 Structure of minoxidil a compound metabolized by sulphotransferases to a potassium channel activator.

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

The potassium channel activator cromakalim is a mixture of trans-con-figured compounds. What relationship do these two stereoisomers have to each other ... 

Potassium channel activators (KCAs), or openers, are a group of compounds that have aroused considerable pharmaceutical interest during the last decade as smooth muscle relaxants. Following the publication in 1986 [1] of this novel mechanism of action for cromakalim (1), virtually every major pharmaceutical company has initiated a programme to study the mechanism of action and structure-activity relationships (SAR) of this group of compounds, particularly benzopyrans related to cromakalim (1) and its active 35, 4/ enantiomer, levcromakalim (2) [2],... 

The white saline potassium compound KCsHs was obtained by Thiele as early as 1901 by the action of the metal on a solution of cyclopentadiene in benzene 191) compounds of all the alkali metals except francium have now been made by the interaction of the metal and the hydrocarbon in liquid ammonia (SS). They are without exception colorless salts which decompose immediately, with consequent discoloration, on exposure to the atmosphere. They are dissociated to a large extent in polar solvents, and the Na-C bond has been estimated as 50 ionic 205). They are insoluble in nonpolar solvents, and in solvents which contain active hydrogen (e.g., water) they at once undergo hydrolysis according to the equation... 

The other alkali metals have been less extensively studied. The propagation rates of polystyrylsodium, -potassium, -rubidium and -cesium have been measured in benzene and cyclohexane [72, 73]. The sodium compound still shows half order kinetics in active centre concentration and is presumably associated to dimers. The rates for the rubidium and cesium compounds are directly proportional to the concentrations of the active chains which are presumably unassociated in solution. Absolute kp values can be determined from the propagation rate in this case. Poly-styrylpotassium shows intermediate behaviour (Fig. 11), the reaction order being close to unity at a concentration of the potassium compound near 5 x 10 M and close to one half at concentrations around 10" M. It could be shown by viscosity measurements that association was absent in the low concentration range. In this system both K2 and kp can be measured. The results are summarized in Table 2. The half order reactions show a large increase in kpK between lithium and potassium which... 

One other system has been studied in which there is evidence of lack of association of active centres at high dilutions [76] the propagation rate of polybutadienyl potassium in cumene at —30°C. At concentrations about 10" M the rate appears to be first order in potassium compound with a rate coefficient of about 7 x 10 1 mole" see . ... 

C (cf. styrene —75°C) and is negative above this temperature. The potassium compound gives only evidence for one species with a constant activation energy of 5.2 kcal mole" between —60 and +10°C the proportion of solvent separated pairs must be negligible. 

Bergmann, R., and Gericke, R., Synthesis and antihypertensive activity of 4-(l,2-dihydro-2-oxo-l-pyridyl)-2//-l -benzopyrans and related compounds. New potassium channel activators, J. Med. Chem., 33, 492, 1990. 

These anionic ring opening polymerizations are usually carried out either in bulk or in solution. A host of catalyst types are active. For synthetic references using specific catalysts, the reader is referred to several excellent sources (4,7,31,32). Representative catalysts include hydroxides, alcoholates, phenolates, silanolates, siloxanolates, mercaptides of the alkali metals, organolithium and potassium compounds, and quaternary ammonium and phosphonium bases and their silanolates and siloxanolates. Some physical characteristics of linear oligomers are given in Table 5 (10). 

NH4)6Mo7024 and supported on TiCb. These two catalysts are able to lower the soot oxidation temperature from 825-875 K to 600 K, thus being active in the temperature range of interest. Moreover, they are the most active catalysts reported so 6r. Yuan et at. [10] give a posable explanation for tte increase in activity in soot oxidation afrer addition of a potassium compound to a TiOa supported copper catalyst (i.e. stabilization of the support material). In three recent publications [11, 12, 13] we have presented various q)erimental details concerning the soot oxidation activity of the Cu/K/Mo/Cl catalyst. 

Reaction 1 appears to result solely in termination. In hydrogenolysis experiments with various chelates we have observed precipitation of lithium hydride in all cases at room temperature. Attempts to generate chelated LiH in situ by adding hydrogen during ethylene polymerization also caused a rapid, irreversible loss of activity. Since there is no evidence that lithium hydride can add to ethylene under moderate polymerization conditions, it is unlikely that any significant chain transfer occurs via this mechanism. Potassium alkyls readily eliminate olefin with the formation of metal hydride, and sodium alkyls do so at elevated temperatures (56). It was noted earlier that chelation of lithium alkyls makes them more like sodium or potassium compounds, so it is quite probable that some termination occurs by eliminating LiH. It is conceivable that this could be a chain transfer mechanism with more reactive monomers than ethylene because addition to lithium hydride would be more favorable. 

Other compounds which have been in development include several cardiovascular agents such as the antihypertensives Cadralazine (193), a hydrazinopyridazine derivative, GYKI-12743 (194), a peripheral post synaptic al/a2 antagonist, and the potassium channel activator EDM-57283 (195),... 

This reaction is suppressed by addition of an equimolal amount of lithium methylamide, which has little catalytic activity but inhibits decomposition of the potassium compound. 

The results of the tests on residues from total gasification of coal indicate that potassium compounds (K2CO3 and KC1) in the residues retained most of their activity in increasing the production of methane, lost part of their capability of increasing hydrogen production, and inhibited carbon monoxide production. The addition of 1.14 grams of catalyst-free residue had very little effect on either methane or total gas production (experiment 220 vs. 167). 

More recently a new class of drugs for treating hypertension has been discovered that relaxes smooth muscle by activating potassium channels. Precisely this novel mechanism involves an enhancement in the outward movement of potassium ions through channels in the membranes of vascidar smooth muscle cells, ultimately leading to relaxation of the smooth muscle. Hence, these compounds may be termed as potassium channel activators. 

Synthesis of aromatic ethers has been performed under solvent-free phase-transfer catalysis conditions by reaction of several aryl halides with potassium methoxide or phenoxide in the presence of a catalytic amount of 18-crown-6. The specific MW effects were shown to be very dependent on the nucleophile and on the structure of the aromatic compound (activated or nonactivated, chloride or fluoride) (Eq. (56), Table 4.17) [96, 142]. 

The Frunze etal. mechanism has much in common with the alkali lactamolytic mechanism of Champetier and Sekiguchi, except for the formation of the above-shown complex. Frunze et al. also believe that probably a single mechanism exists for the anionic polymerization of lactams that they describe as ion coordinative Tht contributions of various mechanisms via ion pairs or via free ions depend upon the nature of the alkali metal counterion and upon their capacity to coordinate with electron-donating compounds (activator and monomer). The growth of ion pairs may mainly be expected from a lithium counterion, while growth by free anions may be expected from potassium or cesium. 

Besides the one-pot process described above, the White Reagent catalyzes a chelate-controlled oxidative Heck arylation between a wide range of a-olefins and organoborane compounds in good yields and with excellent regio-and stereoselectivities (Figure 6). Unlike other Heck arylation methods, no Pd-H isomerization is observed under the mild reaction conditions. Aryl boronic acids, styrenylpinacol boronic esters, and aryl potassium trifluoroborates (activated with boric acid) are all compatible with the general reaction conditions. 

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