Antiparasitic 5-nitrothiazoles and 5-nitro-4-thiazolines. 4

Abstract

The synthesis and biological properties of some 2-heteroylimino-5-nitro-4-thiazoline-3-acetamides (I, R is heterocyclic) and some l-(carbamoylmethyl)-l-(5-nitro-2-thiazolyl)ureas (IV, R is NHR1) together with the corresponding ring N-substituted [3-(carbamoylmethyl)-5-nitro-4-thiazolin-2-ylidene]ureas (I, R is NHR1) are described. I and/or IV are prepared by treatment of a DMF solution of the Na salt of the appropriate amide or urea I11 with several haloacetamides. Various I and some IV have significant antischistosome properties.The synthesis of some schistosomicidal 2-acylimino-5-nitro-4-thiazoline-3-acetamides I in which R is alkyl, alkoxy, aryl, or aryloxy and Z is NRlR2 or alkoxy has been described earlier.2 I t was shown in this study that thiazolines I possessed very pronounced activity against the Puerto Rican strain of Schistosoma mansoni in experimentally infected mice. However, no compound appeared to be curative in S. mansoni infected rhesus monkeys, although slight to strong temporary egg suppression was observed when various I were administered in gavage doses of 50-100 mg/kg per day for 10 days. In addition, it was not found possible to draw any strict structure-activity relationships within the thiazoline series I. n N CH&O Z I n The present paper is concerned with the synthesis of thiazoline-3-acetamides I in which R is heterocyclic or NHRl (R1 is E t or allyl). These compounds were prepared in order to attempt to delineate further structure-activity relationships existing in compounds of formula I and also hopefully to extend the potent antischistosome properties of I to primates, In particular, the preparation of ureas I in which R is NHRl was of interest, since it had been established that a wide variety of I-alkyl-3-(3-alkyl-5-nitro-4-thiazolin-2-ylidene)ureas I1 possessed potent activities against S. mansoni both in mice and monkey^.^ Chemistry. Thiazolines I in which Z is NRlR2 or alkoxy (Table I, 1-7, l(t14, 16-22, and 24-45) and the analogs 8 and 15 were obtained in 6-74% yield by alkylation of a DMF solution of the sodium salt of the thiazolylamide or -urea I11 with the appropriate bromo or chloro compound.While alkylation of I11 (R is heterocyclic) appeared (from the ir spectra2 of the crude reaction products) to afford little if any of the corresponding thiazole isomers IV, in most cases mixtures of ring N-alkylated ureas I ( R is NHR1) and exocyclic N-alkylated ureas IV (R is NHR1) were formed on alkylation of the appropriate 1-(5-nitro-2-thiazoly1)ureas I11 ( R is NHRl) under similar conditions. rn Iv Biology. The compounds described in the present communication were tested in mice against a Puerto Rican strain of S. mansonit by Drs. P. E. Thompson and W. P. Stucki and coworkers of Parke, Davis and Co., Ann Arbor, Mich. Several of the most active thiazolines were evaluated further against S. mansoni in rhesus monkeys. As in previous work, drugs were administered in a powdered ?For a description of test methods, see ref 4. diet for 14 days or by gavage for 5 days, and compounds exhibi...

1,1,3-Trisubstituted cyclobutanes containing thiazole and thiourea fragments

“…1 H NMR spectrum (CDCl 3 ), δ, ppm: 6.86-7.06 (3H, m, Ar-H); 5.95 (1H, s, =CH-S, thiazole); 5.48 (2H, s, NH 2 ); 3.52 (1H, quint, J = 8.80, CH, cyclobutane); 2.76-2.80 (4H, m, the alicyclic protons of tetralin); 2.33-2.55 (4H, m, CH 2 , cyclobutane); 1.81-1.84 (4H, m, alicyclic protons of tetralin); 1.54 (3H, s, CH 3 ). 13 C NMR spectrum, δ, ppm: 170.60 (C (1) ), 157.85 (C (2) ), 152.09 C (3) ), 42.55 (C (4) ), 40.18 C (5) ), 32.66 C (6) ), 31.50 C (7) ), 31.05 (C (8) ), 138.87 C (9) ), 136.18 (C (10) ), 131.04 (C (11) ), 127.52 (C (12) ), 124.30 (C (13) ), 102.27 (C (14) ), 25.35 (C (15) ), 25.31 (C( 16) 2-Amino-4-(3-mesityl-3-methylcyclobutyl)thiazole (3b) was synthesized like compound 3a except that the product was crystallized from aqueous methanol (1:4). Yield 65%.…”

Antimicrobial activity studies of the metal complexes derived from cyclobutane‐substituted thiazole carbamate ligands

“…Electronic spectra in the 200-to 900-nm range were obtained on a CECIL CE 5502 UV-Vis spectrophotometer. Magnetic susceptibilities were carried out by the Gouy method using Hg[Co(SCN) 4 ] as calibrant on a Sherwood Scientific magnetic susceptibility balance (Model MK 1) at room temperature (20…”

“…It is well known that 3-substituted cyclobutanecarboxylic acid derivatives exhibit anti-inflamatory and antidepressant activities, and also liquid crystal properties [3]. Various thiazole derivatives have shown herbicidal, anti-inflamatory, antimicrobial, or antiparasitic activity [4]. However, the syntheses and physiochemical properties of 1,1,3-trisubstituted cyclobutane thiazoles and their carbamate derivatives have not been reported so far.…”

Cyclobutane‐substituted diacetamido sulfides and 2,5‐diacylthiophenes

“…It is well known that 3-substituted cyclobutane carboxylic acid derivatives exhibit antiinflammatory and antidepressant activities [4,5] and liquid crystal properties [6]. Various thiazole derivatives show herbicidal [7], antiinflammatory [8,9], antimicrobial [10], or antiparasitic activity [11].…”