D. N. Lazareva

Synthesis and Antiinflammatory Activity of 3-Thiabis(cyclohexanecarboxylic) Acid Derivatives

The class of antiinflammatory drugs includes a group of sulfur-containing organic compounds such as metiazinic acid, tinoridine (kenfamin), tiaramide (solantol), etc. However, all these drugs give rise to side effects, including gastrointestinal tract disorders. A pronounced antiinflammatory activity was reported for patented cyclic hydroxysulfones [1], the most active of which was 3-hydroxytetrahydrothiophene-1,1-dioxide (3-hydroxysulfolan). The results of investigations carried out in the Laboratory of New Drugs at the Institute of Organic Chemistry (Ufa) showed that most of the synthetic sulfones possess a more or less pronounced antiinflammatory activity. The maximum activity was observed for dihydroxysulfolan, producing, in contrast to most of the known antiinflammatory sulfur-containing compounds, no ulcerogenic action. The purpose of this work was to synthesize and characterize a series of new 3-thiabis(cyclohexanecarboxylic) acid derivatives. The condensation of piperylene (Ia) with acrylic acid nitrile (II) was conducted by the method described in [2 – 4] to obtain 2-methyl-1,2,5,6-tetrahydrobenzonitrile (IIIa) with a yield of 90%. As was previously established by A. A. Petrov and A. F. Sapozhnikova for an initial mixture containing cis and trans forms of piperylene in a 50 : 50 ratio, the condensation with acrylonitrile at 130 – 135°C involves only the trans form, whereas the cis form does not enter the reaction at this temperature. However, a complete condensation takes place at 180°C, when the cis to trans conversion obviously takes place. We conducted the condensation process with a cis– trans mixture for 12 h at 140°C; the unreacted cis-piperylene was distilled off. The synthesis was conducted according to the following scheme. I – V: R = Me (a), H (b); VI: R = Me (a – c), H (d); R = C4H8NO (a, b, d), C5H10N (c); X = H (a), Na (b – d).

Synthesis and immunotropic activity of pyrimidine derivatives. Part. IV. Synthesis and immunotropic and antiinflammatory activity of pyrimidine acyclonucleosides

Compounds I V (Table 1) were obtained by interaction of 6-methyluracil or 5-hydroxy-6-methylumcil with epichlorohydrin (ECI-I) in the presence of catalytic amounts of potassium carbonate in DMF at 7 0 80~ [ 4 9]. It was established that alkylation of 6-methyluracil by ECH leads to the formation, in addition to compound I, of 1-(2-hydroxy-3-chloropropyl)-6-methyluracil (I1) at a yield of 8%. The proposed positions of substituents were confirmed by the UV spectroscopic data: pH 1, L~n = 245 nm, Lmax = 257 nm; pH 7, ~min = 245 mat, Xmax = 260 nm; pH 12,. L~, = 247 nm, Xm~x = 265 rim. Insignificant variation of the absorption maximum in the UV spectrum of compound 1I, observed when the pH value is changed from 1 to 12, is indicative of the substitution at position I.

Synthesis and antiinflammatory activity of 9-thiabicyclo[3.3.1]nonane derivatives

In the previous works of this series [1 -3 ] we have demonstrated that derivatives of 2,2-dicyclohexylsulfide, 2,5-dim ethylene1-thiacyclopentane, and 13-thiabicyclo [8.2.1 ]-5tridecene exhibit antiinflammatory activity in combination with low toxicity. The purpose of this work was to synthesize new compounds belonging to the group of 9-thiabicyclo[3.3.1]nonane derivatives (I XVI) and study their antiinflammatory properties. Sulfides I IV, IX, X, XIII and XIV were obtained by the reaction of 2,6-dichloroor 1,5-dimethyl-2,6-dichloro-9thiabicyclo[3.3.1]nonane [ 4 6] with morpholine or piperidine using a procedure described in [7]. Oxidation of these sultides with hydrogen peroxide led to the corresponding sulfoxides. The proposed structures were confirmed by the data of IR and NMR spectroscopic measurements and elemental analyses. The IR spectra of compounds I XVI contain characteristic absorption bands in the following regions: 600660 cml (stretching vibrations of C-S bonds), 1110 1120 cmi (v C-O-C), 1240 era1 (v CN), 2520, 2560, 2670 cm-1(v NH+), and 1020 1040 cmt (v SO) [8]. Signals in the IH NMR spectra were assigned according to the reference data [9, 10].

Synthesis and antiinflammatory activity of 13-thiabicyclo[8.2.1]tridec-5-ene. Communication 2

The goal of this work is to synthesize novel 13-thiabicyclo[8.2. I ]tridec-5-enes (I VIII) exhibiting antiinflammatory activity and possessing low toxicity. The reaction of 2,9-dichloro-13-thiabicyclo[8.2. l]tridec5-ene [I] with morpholine or piperidine gave compounds I and I!, which were converted to their derivatives III VIII by the action of H202 and HCI. The yields of the desired products are 50 100%.

Synthesis and anti-inflammatory activity of 2,5-dimethyl-1-thiacyclopentane

The reaction of 2,5-di(chloromethyl)-l-thiacyclopentane (I) (obtained by the procedure reported in [1] 4) with morpholine or piperidine gives 2,5-di(morpholinomethyl)(II) or 2,5-di(piperidinomethyl)-l-thiacyclopentane (III). Corresponding dihydrochlorides IV VII are obtained by treatment of compounds II and III with hydrochloric acid or by oxidation of these compounds with hydrogen peroxide in the presence of I N HCI. The treatment of compounds VI and VII with an aqueous ammonia solution results in 2,5-di(morpholinomethyl)-l-thiacyclopentane-l-oxide (VIII) and 2,5di(piperidinomethyl)-l-thiacyclopentane-l-oxide (IX). The structures and purity of the products are confirmed by IR and ~H NMR spectra, and by elemental analysis data.

Synthesis and antiinflammatory activity of 13-thiabicyclo[8.2.1]tridec-5-ene

The goal of this work is to synthesize novel 13-thiabicycio[8.2.1]tridec-5-enes exhibiting antiinflammatory activity and possessing low toxicity. The reaction of 2,9-dichloro13-thiabicyclo[8.2.1 ]tridec5-ene with morpholine or piperidine [1] gave compounds I and II, which were converted to their sulfoxide derivatives VII and VIII by the action of H202 and HCI (compounds VII and VIII were converted to free bases V and VI with aqueous ammonia). The yields of the desired products are 50 100%.

Synthesis and biological activity of new thebaine derivatives

The works of Bentley [4-7] marked the beginning of the search for medically promising thebaine derivatives [4-7]. The availability of this alkaloid, the impossibility of its direct use as a drug, as well as the unquestionable success of investigative searches in the last two decades, have stimulated the continual interest of chemists and pharmacologists in this compound. A whole series of extremely interesting preparations have been obtained based on converting products of the diene synthesis, formed by reacting thebaine with alkene and alkyne dienophiles.

Synthesis and immunotropic activity of pyrimidine derivatives. 2

As part of our continuing studies of new pyrimidine derivatives and analysis of their immunotropic properties, we have developed a method for synthesizing alkylthio derivatives of 6-methyluracil and their platinum-containing complexes. Cis-diamminodichloroplatinum [1] is known to have antiinflammatory activity and to reduce DNA synthesis; this agent is used in the treatment of breast, prostate, and ovary tumors. Platinum-containing complexes of uracil are also known [2-4]. However, their immunotropic properties have not been studied. With the purpose of synthesizing N-alkylpyrimidines with functional substituents in the alkyl chain, and to study their immunotropic properties, we investigated the interaction of the sodium salt of 6-methyluracil with 13-chloroethylisobutylsulfide. Interaction of the sodium salt of 6-methyluracil with 13-chloroethylisobutylsulfide at a ratio of 1:1 for 5 h in a water--benzene environment at 90-100 ~ produced a mixture of monoalkyl derivatives (compounds Ia and Ib; yield 68.8 %); 3-isobutylthioethyl-6methyluracil, compound Ib, was purified from the mixture by crystallization from water. The position of the substituent in 3-isobutylthioethyl-6-methyluracil was determined by UV spectroscopy at pH 1-12: p H I )kmi n 231.65 Xma x 262.50 pH 7 Xmi n 231.85 Xma x 262.50 pH 12 ~kmi n 245.65 Xma x 281.15 The UV absorption peak gave a bathochromic shift of 18.65 as the pH changed from 1 to 12, which is typical for uracils substituted at a third nitrogen atom of the ring [5-7]. Thus, the substituent must be located in position 3, so that compound Ib is 3-isobutylthioethyl-6-methyluracil. The presence of a methyl group in position 6 of the pyrimidine ring significantly reduced the rate of N(1)-alkylation, which is probably due to steric factors; we were unable to obtain compound Ia in pure form. At a ratio of 6-methyluracil, NaOH, and/3-chioroethylisobutylsulfide of 1:2:2, we obtained 1,3-bis-(isobutylthioethyl)-6methyluracil (compound II) at a yield of 57.4%. Product purity was confirmed by IR, UV, and 1Hand 13C-NMR spectroscopy, and by elemental analysis and TLC.

Complexes of β-glycyrrhizinic acid with nonsteroidal antiinflammatory drugs as novel transport forms

The well known nonsteroidai antiinflammatory drugs (NAID) which are used extensively in medical practice, such as acetyisalicylic acid (ASA), butadione, orthofen (voltaren), brufen, and indomethacin, have a number of side effects, in particular uicerogenic effects in the gastrointestinal tract, ieukopenia, and allergic effects [i]. The use of these drugs in clinical medicine is also frequently restricted by their low water solubility.