M. P. Dolgikh

Neurotropic activity of lambertianic acid adducts with N-substituted maleinimides

Terpenoids of the labdane series have been extensively studied as potential drugs. In particular, forskolin and a derivative of this labdanoid were used for the treatment of glaucoma [1]. It was also reported that labdanoids showed fungistatic and antibacterial activity [2, 3], produced a cytostatic effect [4], inhibited biosynthesis of cholesterol [5], suppressed thrombocyte aggregation [6], and exhibited antilipoxygenase action [7]. Recently, we have established [8] that lambertianic acid (I) – a readily available labdanoid contained in siberian cedar (Pinus sibirica R. Mayr.) – is a potential neurotropic agent [9]. Synthetic nitrogen-containing derivatives of lambertianic acid exhibit pronounced nootropic properties [10 – 12].

Pharmacological Activity of Complexes of Nonsteroidal Antiinflammatory Drugs with Glycyrrhizic Acid Obtained by Liquid- and Solid-State Synthesis

The use of solid-state technologies in the pharmaceutical industry significantly increases the possibilities of creating both original drugs and new forms of the preparations. At the Institute of Solid State Chemistry and Mechanochemistry, a new technology for obtaining dispersed solid systems of pharmacologically active compounds based on impact-wear processing of a powder mixture of the initial substances in special mills [1] was developed. Recently, this technology was used to develop a new rapidly soluble form of aspirin [2]. We have studied the possibility of using the new method for obtaining dispersed solid preparations of nonsteroidal antiinflammatory drugs (NSAIDs) with -glycyrrhizic acid (GA). GA is a biologically active triterpene glycoside extracted from roots of licorice (Glycyrrhiza sp.), known to exhibit high antiinflammatory activity without the complications typical of NSAIDs [3 – 5]. Previously, it was established that molecular complexes of GA with acetylsalicylic acid (ASA), orthophen (ORT), and butadione exhibit a lower toxicity and a less pronounced ulcerogenic effect than the same drugs without GA [6, 7]. The purpose of this study was to determine the average lethal doses (LD50), evaluate the ulcerogenic action, and assess the antiinflammatory effect of GA – ASA and GA – ORT complexes obtained by solid-state synthesis and compare these properties to those of the analogous compounds synthesized by conventional chemical synthesis in solution. EXPERIMENTAL CHEMICAL PART

Antioxidant Properties of Aurole (Tyrosol C)

Data on the antioxidant properties of the total extract from roots of Rhodiola rosea L. and Rhodiola iremelica Boriss have been repeatedly reported in the literature [1, 2]. An individual compound isolated from the gold root extract in the Vorozhtsov Institute of Organic Chemistry (Novosibirsk) was identified as 4-(2 -hydroxyethyl)phenol. This compound (also known as tyrosol) relieves mental and physical fatigue, enhances memory, and favorably influences the overall physical state [3, 4]. Commercially, tyrosol is known as an intermediate product in the synthesis of -choline, some cardiovascular drugs, and biologically-active polymers [8]. On the Russian pharmaceutical market, tyrosol is available in the form of liquid (ethanol extract) and tabletized preparations of gold root. However, natural Rhodiola plantations are difficult to access, the plants have to grow for 3 – 5 years before collection, and the yield of tyrosol upon extraction does not exceed 0.1% [9]. For these reasons, a scheme of tyrosol synthesis was developed and the experimental production of a substance called aurole (from Greek aurum for gold) was organized at the Vorozhtsov Institute of Organic Chemistry (Novosibirsk). It was established that aurole possesses membrane-stabilizing and adaptogenic properties [10]. The purpose of this study was to assess the antioxidant properties of aurole in comparison with some other natural antioxidants ( -tocopherol, ubiquinone Q10, phylloquinone, quercetin) and synthetic phenols used as medicinal preparations (dibunol, chroman C1).

Synthesis and Evaluation of Ulcerogenic Activity of Instant Disperse Solid Systems Based on Acetylsalicylic Acid and Biologically Active Licorice Components

Despite obvious achievements in the field of creating modern analgesics and anesthetics, the administration of preparations based on acetylsalicylic acid (ASA) increases, including drugs available without prescription [1]. In connection with this uncontrolled use of salicylates, there is an increase in the incidence of gastrointestinal tract disorders in patients with various diagnoses [2, 3]. In order to reduce the risk of such complications, special medicinal forms of ASA were developed, including parenteral, rectal, and transdermal systems, which allow the local irritant ASA action upon the mucous membrane of the stomach to be decreased. For peroral administration, there are special tablets dissolving in the intestinal tract (enteric-coated drugs such as aspirin cardio, aspilyte, bufferin) and instant (including effervescent) tablets characterized by increased ASA bioaccessibility (ascalcin, anopyrin, Alka-Seltzer, aspirin UPSA, etc.) [4, 5]. The instant tablet compositions contain acid-neutralizing additives (typically sodium bicarbonate) capable of reducing the irritant ASA action upon the mucous membrane of the stomach. However, even the new ASA forms for peroral administration retain more or less pronounced ulcerogenic properties [6]. An alternative approach to the problem of reducing the ulcerogenic affect of ASA derivatives is to create complex drugs containing active antiulcer agents. The advantages of this approach were confirmed in our previous investigations, where it was demonstrated that the synthesized complexes of -glycyrrhizic acid (GRA) with ASA produce a 5 – 8 times lower ulcerogenic effect as compared to that of pure ASA [7]. Wide possibilities for progress in this direction are opened by developing drugs based on instant disperse solid systems (DSS), which may contain various biologically active compounds and drugs. An advantage of DSS is increased solubility and bioaccessibility of slightly soluble pharmacologically active compounds, which is achieved at the expense of dispersion and enhanced intermolecular interaction of DSS components. A new method of DSS production developed at the Institute of Solid State Chemistry and Mechanochemistry (Novosibirsk) is based on the impact-wear mechanical processing of the initial components in special mills. This processing leads to comminution of the components followed by their aggregation into composite DSS composed of particles with a highly developed contact surface [8]. Previously, this method was used to obtain a domestic instant form of aspirin called aspinat, which is comparable in efficacy with imported buffered aspirin preparations. The purpose of this study was to create and characterize with respect to the ulcerogenic effect a series of instant complex DSS containing ASA, calcium carbonate, and biologically active licorice components possessing antiulcer activity. The licorice components represented phenolic compounds (flavonoids and coumarins extracted from a plant raw material) [9], GRA, and its monoammonium salt [10].

Synthesis and analgesic activity of pyrrolidinomorphinan derivatives

Diels-Alder reactions of (-)-thebaine with N-substituted maleimides have been used to obtain cycloadducts possessing α-facial stereoselectivity. The 3-O-and 6-O-demethylated derivatives as well as the products of complete and partial reduction of carbonyl groups in the pyrrolidinedione moiety were also obtained. Some of the synthesized compounds have proved to be promising analgesics. The introduction of the bromine atom into the aryl moiety favors prolongation of the analgesic effect.

Synthesis and antiinflammatory and antiulcer properties of glycyrrhetic acid derivatives containing fragments of amino acids or their methyl ethers

Glycyrrhizic and glycyrrhetic acids, as well as their derivatives, exhibit a broad spectrum of biological effects, including high antiinflammatory and antiulcer activity [ 1 4]. Below we report on the results of investigation of the antiinflammatory and antiulcer properties of a series of new derivatives o f glycyrrhetic ( I a Id ) and 3[3-acetylglycyrrhetic (IIa, IIb, I I IaI I ld) acids containing fragments of aminocarboxylic acids and their methyl ethers:

Formation of salts with hydrobromic acid determines the antiarrhythmic effect of lappaconitine derivatives.

265 The diterpene alkaloid lappaconitine ( I ) in the form of hydrobromide has been widely recognized as an antiarrhythmic drug (Allapinin) produced in Russia. Allapinin is recommended for treating supraventricular and ventricular extrasystoles, paroxysms, atrial fibrillation and flutter, paroxysmal supraventricular and ventricular tachycardia, and arrhythmia against the background of myocardial infarction [1–3]. There are no published data on the effect of structural changes in the lappaconitine molecule on antiarrhythmic activity, in particular, the role of the saltforming acid component is not discussed. We studied lappaconitine base ( I · Bas ), hydrochloride ( I · HCl ), hydrobromide (Allapinin) ( I · HBr ), and acid succinate ( I · SuÒ ), as well as clathrates of lappaconitine base, hydrochloride, and hydrobromide with glycyrrhizic acid (GA, IV ) ( I · Bas-IV , I · HCl-IV , and I · HBr-IV ). The molecular composition of the clathrates corresponded to a I : IV ratio of 1 : 4.

SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF THE OXIDIZED FRACTIONS OF ARABINOGALACTAN FROM SIBERIAN LARCH (Larix sibirica L.)

Aqueous solutions of arabinogalactan from Siberian larch (Larix sibirica L.) were subjected to oxidative destruction by a hydrogen peroxide – molecular oxygen system. The obtained high- and low-molecular-weight fractions of oxidation products were characterized by chemical and spectral methods and tested for pharmacological activity. The results of experiments on animals showed evidence for significant antiulcer and antiinflammatory properties of the preparations studied.

A new group of highly active analgesic of the morphinan family.

Synthetic transformations of the alkaloid thebaine are widely used in opioid drug production [1]. In the past two decades, much attention has been given to thebaine derivatives containing added carbonyl groups and heterocycles [2–9]. Of particular interest are the thebaine derivatives with N-containing heterocycles annealed to the C ring, of which some are selective ligands for δ [5, 6] and χ [7–9] opioid receptors. To synthesize 7,8-pirrolidino-6,14-endoethenotetrahydrothebaine derivatives, N-substituted maleimides were allowed to react with thebaine in diene reactions, and the adducts were subjected to further transformations. We tested more than 20 compounds of this type; the results allow us to speak of a new group of highly active analgesics. Three compounds with the following common formula are the most promising in this group:

Pharmacokinetics of the New Phenolic Antioxidant SO-3

Structurally-hindered phenolic compounds are widely used as antioxidants and stabilizers in various organic materials [1]. In this respect, most promising compounds are found among phenols containing tert-butyl groups in ortho positions. Antioxidants of this type are readily synthesized by cheap methods and are characterized by high efficacy and low toxicity [2, 3]. Of special interest are biand polynuclear analogs combining the properties of antioxidants and thermostabilizers [4]. A special technology for the synthesis of polyfunctional bisphenol antioxidants [5] was developed at the Novosibirsk Institute of Organic Chemistry (NIOC) of the Russian Academy of Sciences. In particular this technology was used for the synthesis of bis[3-(3,5-de-tert-butyl-4-hydroxyphenyl)propyl] sulfide (SO-3) – an antioxidant compound possessing a number of technological and working properties exceeding those of monoand bisphenols widely used at present [6]. Previously [7], we demonstrated that SO-3 (LD 50 = 15,000 mg) produced neither local nor general toxic action upon experimental animals and affected neither embryogenesis nor post-birth development in rats. The purpose of this study was to measure by HPLC the pharmacokinetics of SO-3 upon peroral introduction of the antioxidant in rats.