Zoltán Tuba

Synthesis and structure - Activity relationships of neuromuscular blocking agents

The first use of neuromuscular blocking agents (muscle relaxants) in clinical practice (1942) revolutionised the practice of anaesthesia and started the modern era of surgery. Since 1942 introduction of tubocurarine (18) neuromuscular blocking agents have been used routinely to provide skeletal muscle relaxation during surgical procedures allowing access to body cavities without hindrance from voluntary or reflex muscle movement. After the introduction of tubocurarine and the depolarizing suxamethonium chloride (4) (1949) several nondepolarizing steroidal and nonsteroidal neuromuscular blocking agents with different onset time and duration of effect were introduced e.g. gallamine triethiodide (1) (1949), methocurine (2) (1949), alcuronium chloride (3) (1963), pancuronium bromide (9) (1968), vecuronium bromide (11) (1982), pipecuronium bromide (10) (1982), atracurium besylate (5) (1982), doxacurium chloride (6) (1991), mivacurium chloride (8) (1992), rocuronium bromide (12) (1994) cisatracurium besylate (7) (1996), and rapacuronium bromide (13) (2000). SZ 1677 (14) a steroid type nondepolarizing neuromuscular blocking agent under development (preclinical phase). This review article deals with a comprehensive survey of the progress in chemical, pharmacological and, in some respects, of clinical studies of neuromuscular blocking agents used in the clinical practice and under development, including the synthesis, structure elucidation, pharmacological actions, structure activity relationships studies of steroidal and nonsteroidal derivatives.

Palladium-catalysed aminocarbonylation of steroidal 17-iodo-androst-16-ene derivatives in N,N′-dialkyl-imidazolium-type ionic liquids

The use of [bmim]+[BF4]−, [bmim]+[PF6]− and [emim]+[PF6]− ionic liquids as solvents in homogeneous catalytic aminocarbonylation of 17-iodo-5α-androst-16-ene at atmospheric carbon monoxide pressure has been investigated. It has been proved that after the extraction of the product with toluene, the ionic liquid–catalyst mixture could be recycled several times. Although there was a loss of catalytic activity in the further cycles, even 94% conversion can be achieved after the fifth run by using [bmim]+[BF4]− ionic liquid. The conversion depended strongly both on the properties of the ionic liquid and those of the catalyst. The activities of the in situ palladium(0) catalysts prepared from Pd(OAc)2 and various phosphine ligands (PPh3, TPPTS, DPPBA) have been compared. The method can be effectively used for the aminocarbonylation of other steroids with 17-iodo-16-ene functionality.

Facile Synthesis of Steroidal Phenyl Ketones via Homogeneous Catalytic Carbonylation

Steroidal phenyl ketones were synthesised in high yields by palladium-catalysed carbonylation reactions of 17-iodo-androst-16-ene derivatives in the presence of NaBPh4 under mild reaction conditions. Alkenyl bromides or enol triflates gave lower yields in the same reaction.

Homogeneous catalytic dehalodimerization of 17-iodo-Δ16 steroids

Abstract 17-Iodo- Δ 16 steroids undergo selective dimerization and carbonylative dimerization in the presence of palladium catalysts in dimethylformamide which result in 16–17′-coupled dienes and 17-carboxylic anhydrides, respectively. Moderate to good yields have been obtained for both types of dimers.

Synthesis and biological activity of a new progestogen, 16-methylene-17α-hydroxy-18-methyl-19-norpregn-4-ene-3,20-dione acetate

The progestational activity of second- and third-generation progestins in oral contraceptives were markedly increased by addition of an 18-methyl group. A new progestin, the 18-methyl analog of Nestorone, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3,2 0-dione acetate (10), was synthesized. The relative binding affinity and biologic activity of 10 was compared with Nestorone, levonorgestrel, and progesterone using a binding assay for rat progesterone receptors, the Clauberg assay in the rabbit, and by assessing pregnancy maintenance in the rat. These studies, as summarized in Table 4, show that 10 is three to ten times more potent than Nestorone. The addition of the 18-methyl group to Nestorone markedly increased its potency as noted above, but is unlikely to change its rate of delivery from sustained release systems. 10 should be ideally suited for administration by implants or small skin patches.

Palladium-catalyzed homogeneous coupling reactions of steroids with organostannanes

Direct and carbonylative coupling reactions of various steroid derivatives possessing iodo- and bromo-alkenyl moiety (17-iodo-androst-16-ene, 1, 17-bromoandrost-2,16-diene, 2, 17-iodo-4-aza-4-methylandrost-16-en-3-one, 3, 17-iodo-4-azaandrost-16-en-3-one, 4) with vinyltributylstannane and ethynyltributylstannane were carried out in the presence of various palladium catalysts. While carbonylation took place only with vinyltributylstannane, 17-vinyl-, and 17-ethynyl-delta 16 steroids were produced via direct coupling with vinyltributylstannane and ethynyltributylstannane, respectively. Activities of some catalysts based on Pd(0) and Pd(II) precursors were compared, and Pd(PPh3)4 was found to be superior to other complexes in most cases. In the coupling of 17-iodoandrost-16-ene with organostannanes Pd2(dba)3 + 8 AsPh3 in situ catalyst was found to be even more effective.

Synthesis of new formyl and aminomethyl steroids via homogeneous catalysis

New formyl-pregene, formyl-androstene and the corresponding aminomethyl derivatives are synthesised selectively via hydroformylation with a rhodium–phosphine catalyst prepared in situ.

FACILE, HIGH-YIELDING SYNTHESIS OF STEROIDAL CROWN ETHERS VIA PALLADIUM-CATALYZED CARBONYLATION REACTION

17-Carboxamido-androstanes possessing crown ether moieties attached to the amide functionality were synthesized from the corresponding 17-iodo-androsta-16-enes in palladium-catalyzed homogeneous aminocarbonylation reaction.

Facile, high-yielding synthesis of novel pentacyclic steroids

Abstract Novel androstane-based skeletons were synthesized in a facile one-pot reaction of 17-iodo-androsta-16-ene, vinyltributylstannane and functionalised olefins. The palladium-catalysed coupling reaction was followed by Diels-Alder reaction resulting in the formation of an unsaturated six-membered E-ring.

Functionalization of the estrone skeleton via homogeneous coupling and hydroformylation reactions

Abstract The estrone triflate (3-trifluoromethylsulfonate-estra-1,3,5(10)-triene-17-one) was vinylated by use of vinyltributyltin in the presence of palladium catalysts. The rhodium- and platinum-catalysed hydroformylation of the vinylated aromatic steroid gave the pure epimer 3-(2′-formylethyl)-estra-1,3,5(10)-triene-17-one.