3- and 5-[3-(1-arylureido)]-1,2,4-triazoles

Abstract

Description

This is hydrazine triazinones ureido-triazoles which show effectiveness in the test can be considered to be active antihypertensive agents in humans.

Claims

1. A compound of the formula ##STR11## wherein:

X is oxygen or sulfur;

R₁ is phenyl, substituted phenyl, phenyl lower alkyl, or substituted phenyl lower alkyl;

R₄ is hydrogen, lower alkyl, lower alkanoyl, carboloweralkoxy, phenyl, or benzoyl;

R₆ is hydrogen or lower alkyl; and wherein: substituted phenyl or substituted phenyl lower alkyl means a phenyl group or a phenyl lower alkyl group, respectively, in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo lower alkyl, amino, lower alkanoyl, lower alkyl acylamino, hydroxy, carboloweralkoxy, phenyl lower alkoxy, lower alkyl acyloxy, cyano, halo lower alkoxy or lower alkyl sulfonyl;

and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of the formula ##STR12## wherein:

X is oxygen or sulfur;

R₁ is phenyl or phenyl in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, and halo lower alkyl;

R₄ is hydrogen, lower alkyl, carboloweralkoxy, phenyl, benzoyl, or lower alkanoyl;

R₆ is hydrogen; and the pharmaceutically acceptable acid addition salts thereof.

3. A compound of the formula ##STR13## wherein:

X is oxygen or sulfur;

R₄ is hydrogen, lower alkanoyl, carboloweralkoxy, or benzoyl;

R_a, R_b, R_c, R_d and R_e are hydrogen, halo, or halo lower alkyl;

provided that R_a and R_e are not both halo when R₄ is lower alkanoyl; and further provided that neither R_b nor R_d are trihaloloweralkyl when R₄ is hydrogen; and the pharmaceutically acceptable acid addition salts thereof.

4. A compound according to the formula ##STR14## wherein:

X is oxygen or sulfur;

R₁ is phenyl;

R₄ is hydrogen, lower alkyl, carboloweralkoxy, lower alkanoyl, phenyl or benzoyl; and the pharmaceutically acceptable acid addition salts thereof.

5. A compound according to the formula ##STR15## wherein:

X is oxygen or sulfur;

R_a, R_b, R_c, R_d and R_e are hydrogen, halo or lower alkyl; and the pharmaceutically acceptable acid addition salts thereof.

6. A compound according to the formula ##STR16## wherein:

X is oxygen or sulfur;

R₄ is carboloweralkoxy, benzoyl, or lower alkanoyl;

R_a and R_e are hydrogen, lower alkyl or trihaloloweralkyl;

R_b and R_d are hydrogen, halo, lower alkyl, or trihaloloweralkyl; and

R_c is hydrogen, halo or trihaloloweralkyl; and the pharmaceutically acceptable acid addition salts thereof.

7. A pharmaceutical composition comprising an effective blood pressure lowering amount of a compound selected from the group consisting of:

4-acetylhydrazino-1-phenyl-1,2-dihydro-1,3,5-triazin-2-one;

4-ethoxycarbonylhydrazino-1-phenyl-1,2-dihydro-1,3,5-triazin-2-one;

4-hydrazino-1-phenyl-1,2-dihydro-1,3,5-triazin-2-one;

4-methylhydrazino-1-phenyl-1,2-dihydro-1,3,5-triazin-2-one;

4-acetylhydrazino-1-(4-chlorophenyl)-1,2-dihydro-1,3,5-triazin-2-one;

4-benzoylhydrazino-1-(4-chlorophenyl)-1,2-dihydro-1,3,5-triazin-2-one;

1-(3-chlorophenyl)-4-hydrazino-1,2-dihydro-1,3,5-triazin-2-one;

1-(3-chlorophenyl)-4-methylhydrazino-1,2-dihydro-1,3,5-triazin-2-one;

4-hydrazino-1-(4-methylphenyl)-1,2-dihydro-1,3,5-triazin-2-one;

1-(4-methylphenyl)-4-phenylhydrazino-1,2-dihydro-1,3,5-triazin-2-one;

1-(2,6-dichlorophenyl)-4-hydrazino-1,2-dihydro-1,3,5-triazin-2-one;

4-acetylhydrazino-1-(2-chlorophenyl)-1,2-dihydro-1,3,5-triazin-2-one;

1-(2-chlorophenyl)-4-hydrazino-1,2-dihydro-1,3,5-triazin-2-one;

1-(4-chlorophenyl)-4-ethoxycarbonyl-hydrazino-1,2-dihydro-1,3,5-triazin-2-o ne;

1-(4-chlorophenyl)-4-hydrazino-1,2-dihydro-1,3,5-triazin-2-one;

1-(4-chlorophenyl)-4-methylhydrazino-1,2-dihydro-1,3,5-triazin-2-one;

4-acetylhydrazino-1-(3-chlorophenyl)-1,2-dihydro-1,3,5-triazin-2-one;

1-(3,4-dichlorophenyl)-4-hydrazino-1,2-dihydro-1,3,5-triazin-2-one;

4-acetylhydrazino-1-(3-dichlorophenyl)-1,2-dihydro-1,3,5-triazin-2-one;

4-methylhydrazino-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-1,3,5-triazin-2- one;

4-acetylhydrazino-1-(3-trifluoromethyl-(phenyl)-1,2-dihydro-1,3,5-triazin-2 -one;

4-hydrazino-6-methyl-1-phenyl-1,2-dihydro-1,3,5-triazin-2-one;

1-(4-methylphenyl)-4-phenylhydrazino-1,2-dihydro-1,3,5-triazin-2-one; and

1-(4-methoxyphenyl)-4-phenylhydrazino-1,2-dihydro-1,3,5-triazin-2-one.

3-[3-(1-phenylureido)]-1,2,4-triazole,

1-methyl-3-[-(1-phenylureido)]-1,2,4-triazole,

3-[3-(1-3-chlorophenyl)ureido)]-1,2,4-triazole,

3(5)-[3-(1-(3-chlorophenyl)ureido)]-1-methyl-1,2,4-triazole,

3-[3-(1-(4-methylphenyl)ureido)]-1,2,4-triazole,

1-phenyl-5-[3-(1-(4-methylphenyl)ureido)]-1,2,4-triazole,

3-[3-(1-(2,6-dichlorophenyl)ureido)]-1,2,4-triazole,

3-[3-(1-(2-chlorophenyl)ureido)]-1,2,4-triazole,

3-[3-(1-(4-chlorophenyl)ureido)]-1,2,4-triazole,

1-methyl-3(5)-[3-(1-(4-chlorophenyl)ureido)]-1,2,4-triazole,

3-[3-(1-(3,4-dichlorophenyl)ureido)]-1,2,4-triazole,

1-methyl-3(5)-[3-(1-(3-trifluoromethylphenyl)ureido)]-1,2,4-triazole,

5-methyl-3-[3-(1-phenylureido)]-1,2,4-triazole,

5-[3-(1-(4-methylphenyl)ureido)]-1-phenyl-1,2,4-triazole, and

5-[3-(1-(4-methoxyphenyl)ureido)]-1-phenyl-1,2,4-triazole,

in admixture with a pharmaceutical carrier.

8. A method of lowering blood pressure in humans and other animals, comprising administering thereto an effective blood pressure lowering amount of a compound of the formula according to claim 1 ##STR17## wherein:

R_x and R_z are either NHC(X)NHR₁ or R₆, provided that R_x and R_z are not both either NHC(X)NHR₁ or R₆ ;

X is oxygen or sulfur;

R₁ is phenyl or substituted phenyl;

R₄ is hydrogen, lower alkyl, lower alkanoyl, carboloweralkoxy, phenyl, or benzoyl;

R₆ is hydrogen or lower alkyl; and wherein:

substituted phenyl means a phenyl group in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo lower alkyl, amino, lower alkanoyl, lower alkyl acylamino, hydroxy, carboloweralkoxy, phenyl lower alkoxy, lower alkyl acyloxy, cyano, halo lower alkoxy or lower alkyl sulfonyl;

or a pharmaceutically acceptable acid addition salt thereof.

9. A pharmaceutical composition comprising an effective blood pressure lowering amount of a compound according to the formula ##STR18## wherein:

R_x and R_z are either NHC(X)NHR₁ or R₆, provided that R_x and R_z are not both either NHC(X)NHR₁ or R₆ ;

X is oxygen or sulfur;

R₁ is phenyl, substituted phenyl, heterocyclyl or substituted heterocyclyl;

R₄ is hydrogen, lower alkyl, cycloloweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, carboloweralkoxy, carbamoyl, phenyl, substituted phenyl, benzoyl, substituted benzoyl, phenyl lower alkyl, substituted phenyl lower alkyl, heterocyclyl or substituted heterocyclyl;

R₆ is hydrogen, lower alkyl, cycloloweralkyl, lower alkenyl lower alkynyl, phenyl loweralkyl or substituted phenyl loweralkyl; and wherein:

heterocyclyl means pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyl, morpholinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, thiamorpholinyl, trimethylene ethylene diaminyl or ethyleneiminyl;

substituted phenyl, heterocyclyl or benzyl means a phenyl, heterocyclyl or benzoyl group, in which one or more of the ring hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo lower alkyl, amino, lower alkanoyl, lower alkyl acylamino, hydroxy, carboloweralkoxy, phenyl lower alkoxy, lower alkyl acyloxy, cyano, halo lower alkoxy or lower alkyl sulfonyl;

or a pharmaceutically acceptable acid addition salt thereof; in admixture with a pharmaceutically acceptable carrier.

10. A process for the preparation of a 3-ureido-1,2,4-triazole of the formula ##STR19## comprising reacting a 1-R₁ -6-R₆ -4-L-1,3,5-triazin-one or thione of the formula ##STR20## with a hydrazine compound of the formula NH₂ NHR₄ ;

wherein:

R_x and R_z are either NHC(X)NHR₁ or R₆, provided that R_x and R_z are not both either NHC(X)NHR₁ or R₆ ;

X is oxygen or sulfur;

R₁ is phenyl, substituted phenyl, heterocyclyl or substituted heterocyclyl;

R₄ is hydrogen, lower alkyl, cycloloweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, carboloweralkoxy, carbamoyl, phenyl, substituted phenyl, benzoyl, substituted benzoyl, phenyl lower alkyl, substituted phenyl lower alkyl, heterocyclyl or substituted heterocyclyl;

R₆ is hydrogen, lower alkyl, cycloloweralkyl, lower alkenyl, lower alkynyl, phenyl loweralkyl or substituted phenyl loweralkyl; and wherein:

heterocyclyl means pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyl, morpholinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, thiamorpholinyl, trimethylene ethylene diaminyl or ethyleneiminyl; and

substituted phenyl, heterocyclyl or benzyl means a phenyl, heterocyclic or benzoyl group, in which one or more of the ring hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo lower alkyl, amino, lower alkanoyl, lower alkyl acylamino, hydroxy, carboloweralkoxy, phenyl lower alkoxy, lower alkyl acyloxy, cyano, halo lower alkoxy or lower alkyl sulfonyl.

11. A process according to claim 10 for the preparation of a compound of the formula ##STR21## wherein:

R_x and R_z are either ##STR22## or R₆ ; and

R_a, R_b, R_c, R_d, and R_e are hydrogen, halo, or halo lower alkyl.