Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-20
2001-02-20
Gerstl, Robert (Department: 1671)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S134000, C544S367000, C546S277100, C548S137000
Reexamination Certificate
active
06191152
ABSTRACT:
This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT/HU98/00005 which has an International filing date of Jan. 13, 1998, which designated the United States of America.
The invention refers to novel 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the compounds as active ingredient. The novel compounds have an influence on the circulatory system and the heart, as well as the central nervous system.
More specifically, the invention refers to novel 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole derivatives of the formula
wherein
R
1
represents a hydrogen atom, a C
1-4
alkyl group or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halo atom, a hydroxy group, a nitro group, a C
1-4
alkoxy group, a (C
1-4
alkyl)amino group and a di(C
1-4
alkyl)amino group;
or a group of the formula
wherein
Z stands for a hydrogen atom or a C
1-4
alkoxy group,
R
0
means a group of the formula Alk-NR
4
R
5
wherein
Alk is a C
1-6
straight or branched chain alkylene group,
R
4
and R
5
represent, independently, a hydrogen atom, a C
2-6
alkenyl group, a C
1-8
alkyl group optionally substituted by a substituent selected from the group consisting of a hydroxy group, a (C
1-4
alkyl)amino group, a di(C
1-4
alkyl)amino group, a phenyl group—wherein the latter can be substituted by 1 to 3 C
1-4
alkoxy group(s)—and a 5- or 6-membered saturated heterocyclic group containing one or more nitrogen atom(s) or a nitrogen and an oxygen atom and being linked through its nitrogen atom, said heterocyclic group being optionally substituted by a C
1-4
alkyl group, or
R
4
and R
5
form together with the adjacent nitrogen atom and optionally with one or more further nitrogen and/or oxygen and/or sulfur atom(s) a 5- to 10-membered saturated heterocyclic group optionally substituted by a C
1-4
alkyl group or a phenyl group which latter is optionally substituted by a C
1-4
alkoxy group,
one of R
2
and R
3
is an amino group, while the other stands for an amino group or a 5- to 10-membered saturated heterocyclic group containing one or more nitrogen and/or oxygen and/or sulfur atom(s) and being linked through its nitrogen atom, said heterocyclic group being optionally substituted by a C
1-4
alkyl group, a phenyl group or a halophenyl group, or the latter one of R
2
and R
3
means a group of the formula —SR wherein
R represents a C
1-8
alkyl group, a C
2-6
alkenyl group or a C
2-6
alkynyl group, wherein the alkyl group is optionally substituted by a phenyl group or a halophenyl group,
and optionally one or both amino group(s) is/are substituted by 1 or 2 substituent(s) selected from the group consisting of a C
1-6
alkyl group, a C
2-6
alkenyl group, a phenyl(C
1-4
alkyl) group or a halophenyl-(C
1-4
alkyl) group,
and pharmaceutically acceptable acid addition salts thereof.
1,3,4-Thiadiazole derivatives substituted in position 2 by a substituted morpholino group are described in European Patent Application No. 123 473. The known compounds have antitumor activity. 2-amino-1,3,4-thiadiazoles substituted by an aminoalkyl group in position 5 are known from WO 92/22541. 2-amino-1,3,4-thiadiazoles substituted by an aminoalkylmercapto group in position 5 are described in WO 92/22542. The known thiadiazole derivatives are suitable for the treatment of diseases of the central nervous system as well as hypertension.
The synthesis of 2-(3-methylthio-5-amino-1,2,4-triazol-1-yl)-1,3,4-thiadiazole derivatives bearing a further substituted mercapto group on the thiadiazole ring is described in J. Het. Chem., 30, 333-343 (1993) without any hint at the possible biological effects.
The aim of the invention is to prepare novel 1,3,4-thiadiazole derivatives having cardioprotective effect and/or influencing the central nervous system.
It was found that the above aim was achieved by the novel 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole derivatives of the formula I.
In the description and Claims, in the definition of the substituents, under a halo atom primarily a fluoro, chloro, bromo or iodo atom, preferably a fluoro, chloro or bromo atom is meant.
A C
1-4
alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group. Preferably, a C
1-4
alkyl group is a methyl, ethyl or isopropyl group.
A C
1-6
alkyl group can be, in addition to alkyl groups listed above, for example, a n-pentyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group etc.
A C
1-8
alkyl group can be, in addition to the alkyl groups listed above, for example a n-heptyl, 2-methylhexyl, n-octyl or 2,2-dimethylhexyl group etc.
A C
2-6
alkenyl group can be, for example, a vinyl, allyl, 3-buten-1-yl, 2-buten-1-yl, 3-penten-2-yl, 4-penten-2-yl, 3-hexen-1-yl, 4-hexen-1-yl, 5-hexen-1-yl, 2-hexen-1-yl group etc. Preferably, a C
2-6
alkenyl group is an allyl group.
A C
2-6
alkynyl group can be, for example, an ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 3-hexyn-1-yl or 5-hexyn-1-yl group etc. Preferably, a C
2-6
alkynyl group is a propargyl group.
Primarily, a C
1-4
alkoxy group is a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group.
Under a 5 to 10 membered saturated heterocyclic group a heterocyclic group containing one or more heteroatom(s) is meant, wherein the heteroatom(s) can be nitrogen and/or oxygen and/or sulfur atom(s), such as a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, imidazolidinyl, pyrimidinyl, pyrazolidinyl, hexamethyleneimine-1-yl, heptamethyleneimine-1-yl group etc. Preferably, the above heterocyclic group is a piperidinyl, piperazinyl or morpholine-1-yl group.
Under a 5- or 6-membered saturated hetero-cyclic group containing one or more nitrogen atom(s) or a nitrogen and an oxygen atom preferably a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group is meant.
Under a pharmaceutically acceptable acid addition salt an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid etc. or with a pharmaceutically suitable organic acid such as acetic acid, fumaric acid, lactic acid, malic acid, tartaric acid etc. is meant.
The invention includes any tautomer forms of the compounds of the formula I and the mixtures thereof.
A subgroup of the novel compounds of the formula I consists of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole derivatives and pharmaceutically acceptable acid addition salts thereof, wherein
R
1
represents a hydrogen atom, a C
1-4
alkyl group or a phenyl group optionally substituted by 1 to 3 substituent(s) selected from the group consisting of a halo atom, a hydroxy group, a nitro group, a C
1-4
allkoxy group, a (C
1-4
alkyl)amino group and a di(C
1-4
alkyl)amino group,
one of R
2
and R
3
is an amino group, while the other stands for an amino group or a 5- to 10-membered saturated heterocyclic group containing one or more nitrogen and/or oxygen and/or sulfur atom(s) and being linked through its nitrogen atom, said heterocyclic group being optionally substituted by a C
1-4
alkyl group, a phenyl group or a halophenyl group,
or the latter one of R
2
and R
3
means a group of the formula —SR, wherein
R represents a C
1-8
alkyl group, a C
2-6
alkenyl group or a C
2-6
alkynyl group, wherein the alkyl group is optionally substituted by a phenyl group or a halophenyl group,
and optionally one or both amino group(s) is/are substituted by 1 or 2 substituent(s) selected from the group consisting of a C
1-6
alkyl group, a C
2-6
alkenyl group, a phenyl(C
1-4
alkyl) group or a halophenyl(C
1-4
alkyl) group.
A further subgroup of the novel compounds of the formula I consists of 5-phenyl-2-(1,2,4-triazole-1-yl)1,3,4-thiadiazole derivatives of the formula
wherein
R
0
represents a group of the formula Alk-NR
4
R
5
,
wherein
Alk is a C
1-6
straight or branched chain alkylene group,
R
4
and R
5
mean, independently,
Barkoczy Jozsef
Berecz Gabor
Csorgo Margit
Drabant Sandor
Egyed Andras
Birch & Stewart Kolasch & Birch, LLP
Egis Gyogyszergyar Rt.
Gerstl Robert
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