Amino-1,2,4-thiadiazoles properties

Diamino-1,2,4-thiadiazoles of type (361) have been patented for use in the treatment of hypertension <82EUP44266), while 5-amino-1,2,4-thiadiazoles such as (362) are claimed to be useful for treating autoimmune diseases and in the prevention of graft rejection. Compounds of type (362) also have antirheumatic properties and are, in particular, useful in the treatment of rheumatoid arthritis and immune diseases such as systemic lupus <91EUP455356). 

A number of phenolic ethers of this series show the expected properties. 5-Amino-3-ethoxy-l,2,4-thiadiazole is considerably more soluble in water than its 3-methoxy homolog (3.24 and 0.76 g/100 ml, respectively).88 Their ultraviolet spectra resemble those of the 3-alkyl (or aryl)-5-amino-l,2,4-thiadiazoles.88 3-Alkoxy(or aryloxy)-l,2,4-thiadiazoles are more sensitive towards acids than are the 3-alkyl(or aryl) analogs.88... 

D. Amino-1,2,4-thiadiazoles 1. 3- and 5-Amino-1,2,4-thiadiazoles a. Physical Properties. 3-Substituted 5-amino-1,2,4-thiadiazoles are generally stable, colorless, odorless compounds.6,88,86,128 Their thermal stability (as reflected by their melting points), solubility, and resistance to acids are influenced by the nature of the 3-substituent. 5-Alkoxy-3-amino-l,2,4-thiadiazoleB sublime without decomposition.83... 

Although 3-amino-l,2,4-thiadiazoles (e.g. the 5-phenyl homolog) fail to yield nitrosamines under the usual conditions,126 5-nitrosamines are well known.81, 5,190,191 Thus, 3-alkoxy-,8 3-alkylthio-,85 3-dialkyl-amino-,87 and 3-alkylsulfonyl-5-amino-86 (243) as well as 3-aryl-5-arylamino-l,2,4-thiadiazoles,74 on treatment with the calculated quantity of sodium nitrite in dilute mineral acid, or concentrated formic acid, yield crystalline nitrosamines (244). Their unusual stability has permitted a close study of their formation and properties. 170 Their positive Liebermann reaction85,87,170 and the results of their methylation (outlined in the reaction scheme) show that nitro-sation occurs in the side-chain and not in the nucleus.170... 

Thiadiazoles were first described in 1882 by Fischer and further developed by Busch and his coworkers. The advent of sulfur drugs and the later discovery of mesoionic compounds greatly accelerated the rate of progress in the field of thiadiazoles. Thiadiazoles carrying mercapto, hydroxy and amino substituents can exist in many tautomeric forms and this property is being intensively studied using modern instrumental methods. 

Azine approach. Diazotization of 2-amino-3-hydroxypyridines might be expected to yield the bicyclic ring system (631) by bond formation between the oxygen and the diazonium group in the first formed diazonium salt fused 1,2,3-thiadiazoles and -triazoles are formed by this type of reaction. Compounds prepared by this method, however, are highly unstable and have spectroscopic properties consistent with the pyridodiazooxide structure (630) (74CS(6)222>. 

Physical Properties of 1,3,4-Thiadiazoles. Ultraviolet spectra of some 2-benzylideneamino-5-phenyl-1,3,4-thiadiazoles have been reported. The n.m.r. spectral properties and conformational preferences of some open-chain and cyclic aromatic sulphides that contain 1,3,4-thiadiazole units, spectroscopic data of metal (Mn, Fe, Co, Ni, Cu, or Zn) chelates of iV-(5-phenyl-l,3,4-thiadiazol-2-yl)dithiocarbamic acids, conductometric and i.r. and Raman determinations on thirteen complexes of Zn, Cd, or Hg with 2-methyl-5-mercapto-1,3,4-thiadiazole, and thermogravimetry of some noble- and common-metal chelates of 5-amino-l,3,4-thiadiazole-2-thiol were also described, as well as the mass-spectral fragmentation of 2-phenyl-... 

By far the greatest number of monoazo dyes of this type are based on diazotized 5-amino-3-phenyl-l,2,4-thiadiazole. A great variety of examples, their structure and properties modulated by a suitable choice of couplers are the subject of numerous, often very substantial3928 patent specifications.393-424 An example of more than ordinary interest is (3-phenyl-1,2,4-thiadiazol-5-yl)- [4-(4,7,10,13-tetraoxa-1 -azacyclopentadecyl)phenyl] diazen... 

Reports are available of the screening of 1,2,4-thiadiazoles459 460 as systemic insecticides. 5-Alkoxy-3-trichloromethyl-1,2,4-thiadiazoles, the proved fungicides, have also insecticidal and acaricidal properties.461 1,2,4-Thiadia-zoles may act as chemosterilants462 5-amino-3-methyl(or methylthio)-1,2,4-thiadiazole are found to have this action in the housefly.463,464 5-Chloro-3-ethylthio-1,2,4-thiadiazole has nematocidal activity.465... 

Diamino-l,2,4-thiadiazole possesses radioprotective activity3, a correlation has been established466 between this property and a depressive effect on thymidine uptake on myelocytes, and on the rate of DNA synthesis in bone marrow and intestinal epithilium. The radioprotective activity of 5-amino-3-methylthio-l,2,4-thiadiazole has also been reported.467... 

Chemical Properties. - Cyclocondensation of 4-amino-1,2,3-thiadi-azoles with R1COCHR2COR3 gave 1,2,3-thiadiazolof3,4-aJpyrimidinium salts [317 R,R1, R2,R3 = mix of H,Me,Ph (for R2-R1< only)] in 17-7 yield333. 5-Amino-1,2,3-thiadiazole is converted to the Na or Ba salt of (318) with aqueous NaOH 1 or Ba(0H)2 8H2033, respectively. 5-Azido-4-carbethoxy-1,2,3-thiadiazole could not be prepared from NaN3 and the 5-chloro analogue the diazo compound (319) was isolated in 73 yield. Confirmation for (319) was derived from its spectral data and its thermolysis to ethyl a-... 

Properties of 1,2,4-Thiadiazoles. Proton n.m.r. spectroscopy of the products of the condensation of 5-amino-3-methyl-1,2,4-thiadiazole with nitriles RCN shows that they consist of an equilibrium mixture of (213a) and (213b), which does not occur with the corresponding 1,2,4-oxadiazoles. The structure of the product (214 X = O) obtained by the reaction of Hector s Base (214 X = NH) with mineral acid has been elucidated by means of X-ray crystallography.An... 

Chemical Properties.—5-Substituted 3-amino-l,2,4-thiadiazoles are very weak bases [pA"a = 0,8 0,3 for (45 R = Et)] aqueous solutions of their hydrochlorides are strongly acidic. On being acylated or sulphenylated, they yield mono-(46 X = Ac or o-NOaCeH4S) or di-acylamino-derivatives... 

Information is available concerning the cytostatic properties of 2-amino-1,3,4-thiadiazole and its acyl derivatives, and its 5-isopropyl and 5-butyl homologues. ... 

Similar effects, although with rather subtle differences, are also observed in the furazan and thiadiazole pyrimidine derivatives (91) and (92). These two molecules have quite different chemical properties, as evidenced both by the extremely facile nucleophilic substitution of the amino-group in (91), which is less easy in (92), and also by the ready photoaddition to the... 

Physical Properties.—The spectral properties of a series of 3-amino-4-aryl-5-aryl(or alkyl)-imino-4,5-dihydro-l,2,4-thiadiazoles are in accord with the proposed structures. The n.m.r. spectra indicate the preferred existence of the dihydro- rather than the tautomeric tetrahydro-thiadiazole structure. Mass spectral fragmentation patterns were proposed for these, and for compound (70). ... 

Chemical Properties.—Alkylation. Methylation of 2-amino-5-benzoyl-l,3,4-thiadiazole and its derivatives has been systematically examined. The direction of methylation, which occurs at the N-3 atom of the ring and the exocyclic amino-group, is influenced by the structure of the substrate, the nature of the reagent (Mel, Me2S04, or CH2N2), and the reaction conditions. 2-(Substituted amino)-l,3,4-thiadiazoline-5-thiones (104) are 5-methylated to (105) by one equivalent of methyl iodide, in the presence or absence of alkali. Further methylation occurs at N-3 or N-4, but may lead to mixtures, the composition of which depends on the ratio of the reactants and on the degree of substitution of the 2-amino-group in (105). At 190 C, (105 R = R = Me) isomerizes to (106) ... 

A series of azo-dyes (46), (47) incorporating the benzo-l,2,3-thiadiazole structure have been produced from the 5-amino-heterocycle by conventional methods, and their properties as dyes evaluated. ... 

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