Gottfried Heinisch

4 Pharmacologically Active Pyridazine Derivatives. Part 2

Publisher Summary This chapter focuses on pharmacologically active pyridazine derivatives. This chapter describes that the cardiovascular diseases occupy first place as causa mortis in civilized countries continues to influence strongly the research in the field of bioactive pyridazine derivatives, as shown by the enormous number of patents and papers dealing with pyridazines useful as cardiovascular drugs. Cardiovascular active pyridazines are divided into the following classes: cardiotonics (including pyridazines exhibiting both positive inotropic and systemic vasodilator activity—that is, inodilators), coronary vasodilators, antiarrhythmics, cardioselective P-blockers, antihypertensive agents, antihypotensive agents, and hypocholesterolaemic agents. The increasing interest in the chemistry and in biological activities of pyridazines as observed within the past 15 years has resulted in the development of a wide variety of interesting novel drugs and pharmacological tools. It is hoped that this chapter will not only facilitate the access to the literature on pharmacologically interesting pyridazines but also stimulate further research in this field.

2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: A novel class of antitumor agents

Here we describe the effects of novel benzoxazol‐2‐yl and benzimidazol‐2‐yl hydrazones derived from 2‐pyridinecarbaldehyde and 2‐acetylpyridine. The IC50 values for inhibition of cell proliferation in KB‐3‐1, CCRF‐CEM, Burkitts lymphoma, HT‐29, HeLa, ZR‐75 and MEXF276L by most of the novel compounds are in the nanomolar range. In colony‐forming assays with human tumor xenografts the compounds 2‐actylpyridine benzoxazol‐2‐ylhydrazone (EPH52), 2‐acetylpyridine benzoimidazol‐2‐ylhydrazone (EPH61) and 2‐acetylpyridine 1‐methylbenzoimidazol‐2‐ylhydrazone (EPH116) exhibited above‐average inhibition of colon carcinoma (IC50 = 1.3–4.56 nM); EPH52 and EPH116 also exhibited above‐average inhibition of melanoma cells. As shown with human liver microsomes, EPH116 is only moderately metabolized. The compound inhibited the growth of human colon cancer xenografts in nude mice in a dose‐dependent manner. Thiosemicarbazones derived from 2‐formylpyridines have been shown to be inhibitors of ribonucleotide reductase (RR). The following results show that RR is not the target of the novel compounds: cells overexpressing the M2 subunit of RR and resistant to the RR inhibitor hydroxyurea are not cross‐resistant to the novel compounds; inhibition of RR occurs at 6‐ to 73‐fold higher drug concentrations than that of inhibition of cell proliferation; the pattern of cell cycle arrest in S phase induced by the RR inhibitor hydroxyurea is not observed after treatment with the novel compounds; and a COMPARE analysis with the related compounds 2‐acetylpyrazine benzothiazol‐2‐ylhydrazone (EPH95) and 3‐acetylisoquinoline benzoxazol‐2‐ylhydrazone (EPH136) showed that the pattern of these compounds is not related to any of the standard antitumor drugs. Therefore, these novel compounds show inhibition of colon cancers and exhibit a novel mechanism of action.

Investigations on the Mechanism of Action of the Novel Antitumor Agents 2‐Benzothiazolyl, 2‐Benzoxazolyl, and 2‐Benzimidazolyl Hydrazones Derived from 2‐Acetylpyridine

2‐Acetylpyridine hydrazone derivatives of benzothiazole, benzoxazole, and benzimidazole were found to exhibit potent cytotoxic activity against the growth of suspended leukemia and lymphomas. They were also active in a number of solid tumor screens, e.g. HeLa uterine carcinoma, SOS bone osteosarcoma, lung MB9812, lung A549, Mcf‐7 breast growth. In L1210 lymphoid leukemia cells the compounds preferentially inhibited RNA synthesis followed by DNA synthesis at 100 μM after 60 min. The reduction of de novo purine synthesis by the compounds at the regulatory sites PRPP‐amido transferase, IMP dehydrogenase and dihydrofolate reductase was responsible for the suppression of nucleic synthesis. Other minor sites where the agents have metabolic effects were thymidylate synthetase and thymidine kinase which would be additive with the overall inhibition of cell growth. The ct‐DNA studies suggest that the compounds also interacted with the DNA molecule itself, probably affecting template activity.

Thiazolyl and benzothiazolyl hydrazones derived from α-(N)-acetylpyridines and diazines: synthesis, antiproliferative activity and CoMFA studies

Summary The synthesis of a series of thiazolyl and benzothiazolyl hydrazones derived from α-( N )-acylpyridines, -quinolines, -isoquinolines, -pyridazines, -pyrimidines, and -pyrazines is reported. The stereochemistry of these compounds was determined by NMR spectroscopic methods. The antiproliferative activity of the novel compounds was quantified in tissue culture (melanoma, breast carcinoma, colon adenocarcinoma, epitheloid cervix carcinoma, Burkitts lymphoma, leukemia, and hydroxyurea sensitive and resistant myelogenous leukemia sublines). All compounds exhibited profound antiproliferative activity, in particular against Burkitts lymphoma cells. Out of this series, compounds 6b, 7b, 7c, 8c and 8i were found to be 13–900 times more potent than hydroxyurea and no cross-resistance to hydroxyurea was observed. A predictive 3D-QSAR model using the CoMFA approach was established.

Synthesen und Reaktionen von Pyridazinderivaten, 11. Mitt.: 5-Acyl-4-pyridazincarbonsäurrester als „key intermediates” für 4-Acylpyridazine und 4-Alkyl-bzw. 4-Arylpyridazino[4,5-d]pyridazin-1 (2H) one

A convenient general method of preparing 4-acylpyridazines (4) is reported. It involves homolytic acylation of ethyl-4-pyridazinecarboxylate yielding ethyl-5-acyl-4-pyridazinecarboxylates (2) which easily can be converted to4 by alkaline hydrolysis followed by decarboxylation. The hitherto unknown pyridazino[4,5-d]pyridazine-1 (2H) ones bearing an alkyl- or arylsubstituent on C-4 (5a-g) were prepared in quantitative yields by reaction of2 with hydrazine.

Pyridazines. IIIL: The configuration of novel thiosemicarbazone derivatives of pyridazinecarbaldehydes and alkyl pyridazinyl ketones

Determination de la structure et de la configuration des derives de thiosemicarbazones contenant un groupement pyridazinyl-3, pyridazinyl-4 ou pyridyl-2 par spectrometrie RMN 1 H et 13 C

Pyridazines. XXIV: Application of radicalic ethoxycarbonylation to the synthesis of pyridazine mono- and polycarboxylic acid esters

Abstract Reactivity of pyridazines 1 , 2 , 3 , 16 towards ethoxycarbonylradical (generated by redox decomposition of oxyhydroperoxide of ethylpyruvate) was studied. Application of this type of homolytic substitution for synthesis of hitherto not accessible pyridazine carboxylic acid esters 6 , 8 , 9 , 12 , 13 , 14 , 15 , 17 is demonstrated. In addition improved synthesis of diethyl 4,5-pyridazinedicarboxylate ( 5 ) is proposed.

Synthesen und reaktionen von pyridazinderivaten, 1. Mitt.: a) Eine neue synthese der pyridazin-4-carbonsäure, b) Darstellung und reaktionen von 3-oxo-3-(4′-pyridazinyl)-propionsäureäthylester

Pyridazine-4-carboxylic acid is prepared in high yield by catalytic hydrogenation of 3.6-dichloropyridazine-4-carboxylic acid.Claisen condensation of its ethyl ester with ethyl acetate yields ethyl 3-oxo-3-(4′-pyridazinyl)-propionate (6), the condensation reactions of which with urea, thiourea, phenylhydrazine and hydroxylamine are described. 4-Acetylpyridazine is prepared from6.

Darstellung C-4-substituierter Pyridazine durch homolytische Alkylierung bzw. Acylierung

Abstract4-Benzyl-pyridazine (2) is prepared by homolytic benzylation of pyridazine (1). Oxidation of2 with KMnO4 or SeO2 yields 4-benzoyl-pyridazine (3). On treatment with NaBH4,3 is reduced quantitatively to the corresponding carbinol4. Reaction of protonated1 with benzoyl radicals affords mainly 4,5-dibenzoyl-pyridazine (5). The structures are proved by1H-NMR-, IR- and mass spectra.

The Inhibitory Activity of Diazinyl-Substituted Thiourea Derivatives on Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Starting from 2-(2-aminoethyl)pyridine, a series of N-diazinyl-N′-[2-(2-pyridyl)ethyl]thioureas was prepared via the (2-pyridyl)ethylisothiocyanate and was screened as non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors. Derivatives bearing a 3-pyridazinyl or a 4-pyrimidinyl moiety turned out to be the most potent compounds. However, they exhibited less activity than nevirapine or trovirdine.