TREA

5-heterocyclic-2,4-dialkyl-3H-1,2,4-triazole-3-thiones and their use as antidepressants

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Information

  • Patent Grant
  • 4952593
  • Patent Number
    4,952,593
  • Date Filed
    Thursday, July 23, 1987
    37 years ago
  • Date Issued
    Tuesday, August 28, 1990
    34 years ago
Information
Abstract
This invention relates to novel 5-R.sub.n -(Het)-2,4-di alkyl-3H-1,2,4-triazole-3-thiones, to the intermediates and processes for their preparation, and to their use as antidepressants.
Description
Claims
  • 1. A compound of the formula ##STR3## and the tautomers thereof, and the pharmaceutically acceptable salts thereof wherein
  • R is halogeno, C.sub.1-6 lower alkyl, C.sub.1-6 lower alkoxy, hydroxy or trifluoromethyl,
  • n is zero, 1 or 2,
  • R.sub.2 and R.sub.4 independently represent C.sub.1-6 lower alkyl, and "Het" represents a heterocyclic moiety selected from the group consisting of 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl.
  • 2. A compound of claim 1 wherein Rn-(Het)- is 2-, 3-, pyridyl.
  • 3. A compound of the formula ##STR4## wherein R is halogeno, C.sub.1-6 lower alkyl, C.sub.1-6 lower alkoxy, hydroxy or trifluoromethyl,
  • n is zero, 1 or 2,
  • R.sub.2 and R.sub.4 independently represent C.sub.1-6 lower alkyl, and "Het" represents a heterocyclic moiety selected from the group consisting of 2- or 3-thienyl, and the tautomers thereof, or a pharmaceutically acceptable salt thereof.
  • 4. A compound of claim 1 wherein each of R.sub.2 and R.sub.4 is methyl or ethyl.
  • 5. A compound of claim 1 wherein each of R.sub.2 and R.sub.4 is methyl.
  • 6. A compound of claim 1, said compound being 5-(4-pyridyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione.
  • 7. A compound of claim 3, said compound being 5-(2-thienyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione.
  • 8. A method of treating a patient in need of an antidepressant which comprises adminstering an effective amount of a compound of the formula ##STR5## wherein R is halogeno, C.sub.1-6 lower alkyl, C.sub.1-6 lower alkoxy, hydroxy or trifluoromethyl,
  • n is zero, 1 or 2,
  • R.sub.2 and R.sub.4 independently represent C.sub.1-6 lower alkyl, and "Het" represents a heterocyclic moiety selected from the group consisting of 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl, and the tautomers thereof, or a pharmaceutically acceptable salt thereof.
  • 9. A method of treating a patient in need of an antidepressent which comprises adminstering an effective amount of a compound of claim 3.
Parent Case Info

This is a continuation-in-part of application Ser. No. 792,367, filed Oct. 29, 1985, now abandoned. This invention relates to 5-aryl-2,4-dialkyl-3H-1,2,4-triazole-3-thiones, to the intermediates and processes for their preparation, to their pharmacological properties, and to their use as antidepressants. More specifically, this invention relates to compounds of the formula ##STR1## and the tautomers thereof, and the pharmaceutically acceptable salts thereof wherein R represents halogeno, C.sub.1-6 lower alkyl, C.sub.1-6 lower alkoxy, hydroxy, or trifluoromethyl, with n being zero, 1 or 2; each of R.sub.2 and R.sub.4 independently represents C.sub.1-6 lower alkyl; and "Het" represents a heterocyclic moiety. For R, halogeno preferably represents chloro or fluoro, and methyl and ethyl represent the preferred lower alkyl moieties, although all the straight, branched and cyclic manifestations thereof such as n-propyl, cyclopentyl, cyclohexyl and cyclopropyl are herein included. Lower alkoxy radicals include ethers having alkyl moieties of the C.sub.1-6 alkyl group defined above. When n is one, representing a mono-substituted heterocyclic moiety, the R-substituent is located on any of the carbon atoms of the heterocyclic moiety. When di-substituted, the two R substituents are both located on a carbon atom of the heterocyclic moiety. The tautomeric forms are included for each of the compounds embraced within formula I. Preferably R.sub.2 and R.sub.4 each represents an alkyl group selected from methyl and ethyl, but may represent any straight or branched alkyl chain. Representative of "Het" in formula I are such heterocyclic moieties as 2-, 3-, or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3- pyrrolyl, 6-isoquinolyl, 6-quinolyl and 3-quinolyl. Preferred is 4-pyridyl, with or without an R substituent, particularly when R.sub.n is a monochloro or monofluoro. State of the art salts formed with the heterocyclic moieties are generally employed, with the hydrochloride being one of convenience and general application. Such salts are formed by standard techniques well known in the art. The compounds of formula I may readily be prepared using processes and procedures analogously known in the art as seen by the following reaction scheme. ##STR2## wherein R.sub.2, R.sub.4, and R.sub.n -Het- are as previously defined. In step A, the preparation of the thiosemicarbazides (IV) is readily effected by reacting hydrazine (II) with an isothiocyanate (III) by contacting the reactants in a suitable solvent. The reaction is quite rapid and may be carried out at 0.degree. C. to room temperature. Although the reaction proceeds rapidly, the mixture may be left for up to 24 hours without significant decrease in yields. Reflux conditions may be employed but are not preferred Almost all solvents (with the exception of water and organic acids) may be used Anhydrous alcohols (preferably ethanol or methanol) are preferred although DMF, CHCl.sub.3, CH.sub.2 Cl.sub.2, THF and Et.sub.2 O may also be used. The required hydrazines and isothiocyanates are usually commercially available, but may be prepared by known techniques quite obvious to one of ordinary skill in the art. In Step B, the desired substituted thiosemicarbazides (VI) may be prepared by reacting the thiosemicarbazides (IV) with an R.sub.n -substituted-heterocyclic acid chloride (V) in an aprotic solvent such as pyridine, CHCl.sub.3, THF and the like. The acylation proceeds rather easily at temperatures ranging from 0.degree. C. to room temperature over periods of 3 to 24 hours, although elevated temperatures (e.g. reflux temperatures) may be employed Again, the acid halides (V) generally are commercially available but may also be prepared from the corresponding acids which are available from obvious starting materials. In Step C, the substituted thiosemicarbazides (VI) are subjected to a cyclization reaction which is effected by heating the compounds (VI) in an aqueous base, e.g. sodium bicarbonate or sodium hydroxide. Alcoholic bases may be utilized, but generally are less desirable. The reaction is conducted at about the reflux temperature of the solvent, preferably at about 65.degree.-100.degree. C. In practice, the thiosemicarbazides (VI) need not be purified for use in Step C so that even 1:1 mixtures with pyridine hydrochloride, produced as a byproduct when pyridine is employed as a solvent in Step B, may be used.

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Continuation in Parts (1)
Number Date Country
Parent 792367 Oct 1985