HETEROCYCLES

■ Contents

■ Spectamines A and B, Possible Inhibitors of Superoxide Anion Production of Macrophages from Cassia spectabilis

Tsunashi Kamo,* Kentaro Maehara, Kazuya Sato, and Mtsuru Hirota

*Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan

Abstract

Two novel piperidine alkaloids were isolated from an African legume, Cassia spectabilis, and identified as the O-benzoyl (1, named spectamine A) and O-acetyl (2, named spectamine B) derivatives of (+)-iso-6-cassine (3). The absolute configurations of 1-3 were established to be (2R,3R,6R) using the modified Mosher’s method. Compound (1) inhibited the superoxide anion production of macrophages, while it did not quench the superoxide anion which is produced by xanthine oxidase at a concentration of 25 μM.

■ Synthesis and Cytotoxic Activity of N-Acetylated Triindolylmethanes

Jun Li, Bing Guang, Liangbing Wang, Bogang Li, and Guolin Zhang*

*Chengdu Institute of Biology, The Chinese Academy of Sciences, Chengdu 610041, China

Abstract

Triindolylmethanes or N-acetylated triindolylmethanes were synthesized with high yields by treating indoles with indole-3-carboxaldehydes in acetic acid and acetic anhydride. In vitro screening showed that bis(indole-3- yl)-(N-acetylindole-3’-yl)methane (3a) and bis(2-methylindole-3-yl)-(N-acetyl- indole-3’-yl)methane (3b) possessed moderate cytotoxic activity against Lu-04 cell line with GI₅₀ of 19 μM and 33 μM, respectively.

■ Hydrolysis of N,N-Dimethylenamines. Stereospecific Synthesis of Their Enol and Enol Ester Derivatives

Lovro Selic, Simona Golic Grdadolnik, and Branko Stanovnik*

*Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, SI-1000 Ljubljana, Slovenia

Abstract

Stereospecific conversions of dimethylaminomethylidene group in various (Z)-alkyl 2-[(2,2-disubstituted ethenyl)-amino]-3-dimethylaminopro-pe-no-ates into their hydroxymethylidene and benzoyloxy methylidene derivatives were achieved in moderate to good yields. The difference between pathway to enol esters and (fused)pyrrole-2-carboxylate derivatives is clarified.

■ Synthesis of 6-Substituted Imidazo[4,5-d]pyridazin-7-ones

Paul J. Gilligan* and Rajagopal Bakthavatchalam

*Discovery Chemistry, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, U. S. A.

Abstract

A novel synthesis of 6-substituted imidazo[4,5-d]pyridazin-7-ones is described, which employs 1,2-disubstituted 4-aroylimidazole-5-carboxylates as key intermediates.

■ Synthesis and Dopamine Receptor Binding of Some Pyrazolo[3’,4’:6,7]azepino[5,4,3-cd]indoles

Peter Gmeiner, Harald Hübner, Kayed A. Abu Safieh, Ismail I. Fasfous, Mustafa M. El-Abadelah,* Salim S. Sabri, and Wolfgang Voelter

*Chemistry Department, Faculty of Science, University of Jordan, Amman 11942, Jordan

Abstract

A synthesis of some substituted pyrazolo[3’,4’:6,7]azepino[5,4,3-cd]indoles is described and their affinities to dopamine receptors were evaluated. The tested compounds (3a-d and 4a,b) showed micromolar affinity to the bovine D1 receptor subtype and the human D₂, D₃ and D₄ receptor isoforms.

■ 4-Hydroxycoumarin and Related Systems: Sitoselectivity of the Mitsunobu Reaction with Prenyl Alcohols

Giancarlo Cravotto,* Gian Mario Nano, Giovanni Palmisano,* and Silvia Tagliapietra

*Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, via P. Giuria 9, I-10125 Torino, Italy

Abstract

The Mitsunobu reaction leads to the formation of new C-C bonds between prenyl alcohols and 1,3-dicarbonyl compounds like 4-hydroxycoumarin or its nitrogen isoster. Buchapine was obtained through a one-pot procedure from 4-hydroxy-2-quinolone and dimethylallyl alcohol.

■ Synthesis and COX-2 Inhibitory Activities of Rutaecarpine Homologues

Hyeun Wook Chang, Seung Ill Kim, Hejin Jung, and Yurngdong Jahng*

*College of Pharmacy, Yeungnam University, Kyongsan 712-749, Korea

Abstract

Homologous series of rutaecarpine were prepared by structurally modifying the C-ring and were evaluated their inhibitory activities on COX-2. The inhibitory activity on COX-2 increased with the increase of methylene unit while the selectivity on COX-2 over COX-1 decreased to lead a loss in trimethylene bridged system.

■ Synthesis of 2-(5-Amidinobenzoxazol-2-yl)-5-(4-amidinophenyl)furan and 2-(5-Amidinobenzoxazol-2-yl)-5-(4-amidinophenyl)thiophene to Test a DNA Minor Groove Dimer Binding Model

Adalgisa Batista-Parra, Sheela Venkitachalam, W. David Wilson, and David W. Boykin*

*Department of Chemistry, Georgia State University, University Plaza, Atlanta, GA 30303, U.S.A.

Abstract

Two new bis-amidines were synthesized, characterized and tested to probe the structural requirements for a DNA minor groove dimmer binding model.

■ Novel Synthesis of 5-Oxomorpholine Derivative by Cyclization of Δ¹-Dehydrodipeptide

Dai Yoshioka, Keiji Inoue, Yasuchika Yonezawa, and Chung-gi Shin*

*Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

A convenient synthesis of novel 6-disubstituted 5-oxomorpholine-3- carboxylate derivatives (5) by stereoselective cyclization of Δ¹-dehydrodipeptides, Boc-ΔVal-L-AA-OMe (AA=Ser, Thr, HyVal) with t-BuOCl or N-halosuccinimide is described. Furthermore, the configuration of 5 was determined by single crystal X-Ray analysis.

■ Nitrothioquinanthrenes and Their S-Oxides

Maria J. Maslankiewicz* and Tadeusz Glowiak

*Institute of Chemistry, University of Silesia, Szkolna 9, 40-006 Katowice, Poland

Abstract

The reaction of dithiinodiquinolines (1) or (5) with an excess of nitrating mixture at 0-5 °C led within 3 days to the mixtures of nitrothioquinanthrene S-oxides (3a-d) or nitroisothioquinanthrene S-oxides (7a, b). Sulfoxides (3a-d) were reduced to sulfides (4a, b) with KI / aq. HCl system. Sulfides (4a, b) were reoxidised to sulfoxides (3a-d) with nitrating mixture. Structure of compounds (3a, 4a, b, 7b) was assigned by means of 1D and 2D ¹H and ¹³C NMR spectral techniques. The structural conclusions were supported by an X-Ray analysis of 8-nitrothioquinanthrene 7-oxide (3a).

■ Oxidative Cyclization of Dithiobiuret under Basic Condition and Theoretical Tautomeric Studies of 5-Amino-2,3-dihydro-1,2,4-thiadiazole-3-thione

Nam Sook Cho,* Young Hoon Kim, Mi Sun Park, Eun Hee Kim, Sung Kwon Kang, and Chang-moon Park

*Department of Chemistry, College of Natural Sciences, Chungnam National University, Taejon 305-764, Korea

Abstract

The oxidative cyclization of dithiobiuret under basic conditions (NaOH-H₂O₂ or CH₃CO₃H) afforded bis(5-amino-1,2,4-thiadiazolyl) 3,3’-disulfide (5), oxidative dimer form of 5-amino-3-mercapto-1,2,4-thiadiazole (3b). The theoretical tautomeric study (ab initio calculations) shows that the most stable tautomeric form of 3 is 5-amino-3-mercapto-1,2,4-thiadiazole (3b) among the four possible tautomers. Thus, 3b is speculated as an intermediate of the formation of the compound (5).

■ Water-soluble Melatonins: Syntheses of Melatonins Carrying a Glycosyl Group at the 1-Position

Takako Iwaki, Yasuaki Fujita, Fumio Yamada, and Masanori Somei*

*Faculty of Pharmaceutical Scicences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan

Abstract

1-(β-D-Xylopyranosyl)- (2a), 1-(β-D-glucopyranosyl)- (2b), 1-(β-D-galactopyranosyl)- (2c), and 1-(α-D-arabinopyranosyl)melatonins (3b) are prepar-ed as water-soluble melatonins starting from melatonin.

■ Dependence of Ring Size on Conditions in Cyclization of 4-Methylaminobenzoic Acid by Dichlorotriphenylphosphorane

Isao Azumaya,* Takao Okamoto, Imabeppu Fumiaki and Hiroaki Takayanagi

*School of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

4-Aminobenzoic acid was effectively coupled by dichlorotriphenylphosphorane to give cyclized aromatic amides with various ring sizes. Major compounds were trimer and hexamer. The ratios and yields of the compounds obtained by the reaction depended on the reaction conditions.

■ Improved, Efficient Synthesis for Multigram-Scale Production of PSB-10, a Potent Antagonist at Human A₃ Adenosine Receptors

Joachim Burbiel, Mark Thorand, and Christa E. Müller*

*Pharmaceutical Institute Poppelsdorf, University of Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany

Abstract

The reported synthesis of PSB-10 (8-ethyl-4-methyl-2-(2,3,5-trichlorophenyl)-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one), a potent A₃-selective adenosine receptor antagonist, gives only moderate yields and is not suitable for the production of PSB-10 on a multi-gram scale. Attempts to develop alternative routes and an improved procedure suitable for preparing large quantities of PSB-10, required for pharmacological studies, are described.

■ (+)-Viniferol D, a New Stilbenetrimer from the Stem of Vitis vinifera ‘Kyohou’

Yoshiaki Takaya, Kenji Terashima, Ke-Xu Yan, and Masatake Niwa*

*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan

Abstract

A new stilbenetrimer named (+)-viniferol D having a bicyclo[5.3.0]decane ring system was isolated from the stem of Vitis vinifera ‘Kyohou’ and the structure was elucidated on the basis of the spectral evidence. The biogenesis was also discussed.

■ Design and Synthesis of a Novel Cyclophane as Host for Biologically Relevant Phosphates

Koichi Metori and Muneharu Miyake*

*College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan

Abstract

A novel water-soluble cyclophane bearing 4-dimethylaminopyridinium groups on the alkyl chains as blanches of 6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine skeleton was synthesized in order to investigate the ability as macrocyclic enzyme models to incorporate biologically relevant phosphates.

■ Synthesis of 4-Substituted Indolizidin-9-one Amino Acid Derivatives

Christelle Lamazzi, Sylvie Carbonnel, Pierre Calinaud, and Yves Troin*

*Laboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de Clermont-Ferrand, Université Blaise Pascal, BP187, 63174 Aubiére Cedex, France

Abstract

Synthesis of 4-substituted indolizidin-9-one amino acid by cyclization of pipecolic acid derivatives has been described.

■ Microwave-assisted Synthesis of Aryl and Heteroaryl Derivatives of Benzimidazole

Haitao Yu, Hirohisa Kawanishi, and Hideko Koshima*

*Department of Applied Chemistry, Faculty of Engineering, Ehime University, 3 Bunkyo-cho, Matsuyama, 790-8577 Ehime, Japan

Abstract

A series of benzimidazoles containing aryl and heteroaryl substituents were efficiently and quickly synthesized by condensation of 1,2-phenylenediamine with carboxylic acids in the presence of polyphosphoric acid under microwave irradiation.

■ Synthesis and Reactions of 4-Chloro-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

Yutaka Azuma,* Mieko Morone, Kouki Nagayama, Yurie Kawamata, and Asuko Sato

*Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

The chlorination of 1,2-dihydro-4-hydroxy-6-methyl-2-oxo-3-pyridinecarbonitrile (2) with a mixture of POCl₃ and PCl₅ in CHCl₃ gave 4-chloro-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile (3) in good yield. Compound (3) reacted with alkyl- and arylamines to give the corresponding 4-alkylamino- and 4-arylamino-3-pyridinecarbonitriles (6 and 7).

■ An Efficient Conversion of Catechine into 3,4-trans-Leucocyanidin

Toyohiko Kikuchi, Masato Nishimura, Atsushi Hoshino, Yasumasa Morita, Shigeru Iida, Norio Saito, and Toshio Honda*

*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Catechine was efficiently converted into 3,4-trans-leococyanidin by seven steps involving an acetoxylation at the benzylic position of catechine pentabenzyl ether, followed by hydrolysis, oxidation, deprotection, and stereoselective reduction, successively.

■ Synthesis, Structural Analysis and Reactivity of 1,3-Oxathiane Derivatives

Anamaria Terec, Ion Grosu,* Gérard Plé, Luminita Muntean, and Sorin Mager

*Equippe de Fonctions Azotées et Oxygénées, IRCOF, Université de Rouen, F-76821 Mont saint Aignan, France

Abstract

The methods of synthesis, the configurational and conformational aspects of the stereochemistry and the main spectral properties and reactions of 1,3-oxathiane derivatives are reviewed.