V. D. Akamsin

Selective Blockade of Locomotor Muscles by Uracil-Containing Tetraalkylammonium Acetylcholinesterase Inhibitors

The ratio between muscle-relaxing and lethal doses of onium cholinesterase inhibitors characterizes the selectivity of their effect on the locomotor muscles and the corresponding level of “pharmacological safety” ( LD 50 / ED 50 ). The greatest selectivity is characteristic of oxazyl (ambenonium), whereas the lowest selectivity is exhibited by the majority of cholinesterase inhibitors [1]. Taking into account the fact that the specific effect of cholinesterase inhibitors lasts insufficiently long, the search for ways of increasing the selectivity of their effect is a topical problem.

Two-fragment α-adrenolytics. 4. Synthesis of phosphorylated derivatives of 2-aryloxyethylamines and N-phenylpiperazine

The reactions of 3-chloropropylphosphonates, 3-chloropropylthiophosphonates, or 3-chloropropylphosphinates with 2-aryloxyethylamines or N-phenylpiperazine afford the corresponding 3-(2-aryloxyethylamino)propylphosphonates and -phosphinates or 3-(4-phenylpiperazin-1-yl)propylphosphonates and -phosphinates. The compounds obtained exhibit α-adrenolytic and hypotensive activities, the latter being found to depend on the substituents at the P atom.

Synthesis of pyrimidinophanes containing nitrogen atoms in polymethylene bridges

The reactions of 1,3-bis(ω-bromobutyl- or -pentyl)-6-methyluracil with 1,3-bis(ω-ethylaminobutyl- or -pentyl)-6-methyluracil afforded pyrimidinophanes containing N atoms in bridging polymethylene chains. Individual geometric isomers of pyrimidinophanes were isolated. The structure of one of these isomers was established by X-ray diffraction analysis. Quaternization of the bridging N atoms with o-nitrobenzyl bromide gave rise to water-soluble pyrimidinophanes.

Synthesis and pharmacological activity of ω-(4-phenylpiperazin-1-yl)alkylthiopyrimidines

Previously we have reported on the synthesis of double-fragment adrenoblockers containing a tetracoordinated phosphorus atom in various environments [1 – 4]. It was established that maximum hypotensive activity was inherent in compounds with a nitrogen atom of the adrenolytic fragment separated by three methylene groups from the phosphorus atom. In continuation of these investigations, we have synthesized and characterized a series of N-phenylpiperazine derivatives containing a mercaptopyrimidine cycle, which plays the role of a fragment favoring an increase in the affinity of compounds to adrenoreceptors of blood vessels. In the first step, we used the reaction of 2-( -bromoalkylthio)-4,6-dimethylpyrimidines (I – VII) with N-phenylpiperazine (VIII) in DMF in the presence of K2CO3 in order to obtain the corresponding 4,6-dimethyl-2-[ -(4-phenylpiperazin-1-yl)alkylthio]pyrimidines (IX – XV) (Scheme 1).

Synthesis and biological activity of α,ω-Bis(ammonio)alkalis containing oxopyrimidinyl radicals

It was reported that some compounds belonging to the class of pyrimidine-containing onium structures exhibit large therapeutic breadth (defined as the ratio LD50 ED50) [1], which is unusual of such anticholinesterase agents, and high (to within six orders of magnitude) selectivity with respect to acetylcholinesterase as compared to butyrylcholinesterase [2, 3]. In contrast, phosphorylated pyrimidines exhibit no such highly specific action and behave as trivial organophosphorus inhibitors, which is evidence of the insignificant role of the meta-diazine cycle in this particular case [4]. Onium salts are widely used in clinics as peripheral myorelaxants and cholinesterase inhibitors [5 – 9]. It is commonly accepted that the best prospects may be related to nondepolarizing onium structures of the cyclobutonium and truxilonium types, which have antagonists and are characterized by relatively high “pharmacological safety” indices corresponding to a therapeutic breadth of LD50 ED50 > 10.0 [8]. On the other hand, the very low sensitivity to onium inhibitors observed for cholinesterases of invertebrates [9] may ensure a sufficiently high level of “ecological safety” of such structures (LC50 > 10.0 – 100.0 M). In this context, we have synthesized and characterized a series of , -bis[ -(3,6-dimethyluracil-1-yl)alkylmethylammonio]alkanes (I – IX) and , bis[ -(2-amino-6-methylpyrimidiny-4-oxy)alkyldimethylammonio]alkanes (X – XIII). These compounds are structurally analogous to hexamethonium and decamethonium, which contain pyrimidine cycles at various distances from the onium groups. Compounds I – IX were synthesized using reactions of 1,6-bis(dimethylamino)hexane or 1,10-bis(dimethylamino)decane with the corresponding 1-bromoalkyl-3,6-dimethyluracils on boiling in anhydrous methyl ethyl ketone (MEK). m = 6 (I – V), 10 (VI – IX); n = 2 (I, VI), 4 (II, VII), 5 (III), 6 (IV, VIII),

Reactions of 1,3-bis(ω-bromoalkyl)-6-methyluracils with 2-(dialkylamino)ethylphosphonates and 2-(dialkylamino)ethyl phosphates

Abstract1,3-Bis(4-bromobutyl)-6-methyluracil reacts with diethyl 2-(dimethylamino)ethylphosphonate to form a bisquaternary ammonium salt, whereas the reaction of 1,3-bis-(6-bromohexyl)-6-methyluracil with diethyl 2-(diethylamino)ethyl phosphate gives 1,3-bis-[(6-diethoxyphosphoryloxy)hexyl]-6-methyluracil and 1,1,4,4-tetraethylpiperazinium dibromide.

Two-fragment α-adrenolytics: 2. Synthesis of alkyl(phenyl)[ω-(N-phenylpiperazino)alkyl]phosphine oxides

A method for the synthesis of hypotensive alkyl(phenyl)[ω-(N-phenylpiperazino)alkyl]-phosphine oxides by reacting alkyl(ω-haloalkyl)phenylphosphine oxides withN-phenylpiperazine was elaborated. Phenyl[γ-(N-phenylpiperazino)propyl]propylphosphine oxide reacts with alkyl halides to give [γ-(N-alkyl-N′-phenylpiperazinio)propyl]phenyl(propyl)oxophosphine halides.

Synthesis and Biological Activity of Some Mono- and Bis-ω-Ammonioalkyluracil Bromides

Compounds possessing anticholinesterase activity have been found in a series of mono- and bis-tetraalkylammonium derivatives containing uracil cycles at various distances from onium groups. These compounds are subdivided into high/moderate toxicity (in mice) and low/zero toxicity (in daphnia). Under the functional loading conditions (treadmill test in mice upon i.p. drug injection), compounds with an alkylammonium chain length of n = 5 are more effective and less toxic than the reference drugs (proserine [neostigmine] and BW284c51) and induce the development of a clearly pronounced myorelaxant effect with a duration of not less than 5 days with ED50 = 0.06 – 0.13 µM/kg and LD50/ED50 = 20.0 – 188.0.

Synthesis and Myorelaxant Activity of 1,3-Bis(5-ammoniopentyl)-6-methyluracil Dihalides

A series of 1,3-bis(5-ammoniopentyl)-6-methyluracil dihalides with the anticholinesterase type of activity have been synthesized and characterized with respect to toxicity and myorelaxant activity. The obtained compounds exhibit high toxicity with respect to mice and belong to the class of low/practically zero toxicity with respect to daphnia. Under conditions of functional loading (treadmill running test) in mice, the compounds with small-volume electron-acceptor substitutes (F, NO2, CN, CH2 OCH3, C(O)OCH3 etc.) at the quaternary nitrogen atoms in the benzyl radical are more effective (upon intraperitoneal injection) and safer than the reference drugs (proserine and BW284c51) and induce the development of a clearly pronounced myorelaxant effect with a duration of no less than 1 day with ED50 = 0.04 – 0.09 µ-M/kg and LD50/ED50 up to 56.25.