Aminotriazole compounds

Details Aminotriazole compounds Aminotriazole compounds

2000-04-14

2001-06-12

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06245916

ABSTRACT:

The present invention relates to new aminotriazole compounds.
SUMMARY OF THE INVENTION
The compounds of the present invention have a novel structure characterised by the combination of an aminotriazole group, a hydrazide structure and an aromatic-type spacer. The compounds are used in the treatment of pathologies associated with the neuropeptide Y (NPY).
DESCRIPTION OF THE PRIOR ART
Various NPY receptor ligands have been described recently. By way of example, there may be mentioned cyclic peptide compounds (WO 9400486), amino acid compounds of arginine (WO 9417035) or non-peptide compounds (WO 9827063).
BACKGROUND OF THE INVENTION
The Neuropeptide Y (NPY) is a peptide of 36 amino acids, related to the peptide YY (PYY) and to pancreatic polypeptides (PP). Originally isolated from pig brain (Proc. Natl. Acad. Sci., 1982, 79, 5485), NPY is widely distributed in mammals at the level of the central and peripheral nervous systems. This neurotransmitter is present in high concentrations in nerve fibres of the brain, but also of the heart, the sympathetic ganglia, blood vessels and smooth muscles of the vas deferens and of the gastrointestinal tract. It is responsible for various physiological effects which are exerted via the intermediary of specific receptors (Y). The latter form a heterogeneous group, 6 sub-types of which have been identified to date: Y
1
to Y
6
(Pharmacological Reviews, 1998, 50, 143). NPY is involved in eating behaviour by strongly stimulating food intake (Proc. Natl. Acad. Sci., 1985, 82, 3940), or by exerting a regulatory role on the HPA (hypothalamic-pituitary-adrenal) axis (J. of Neuroendocrinol., 1995, 7, 273). It also exhibits anxiolytic and sedative properties (Neuropsychopharmacology, 1993, 8, 357), a strong vasoconstrictive ability (Eur. J. Pharmacol., 1984, 85, 519) which induces an increase in blood pressure, and also has an effect on the circadian rhythm (Neuroscience and Biobehavioral Reviews, 1995, 19, 349).
In addition to the fact that the compounds of the invention are new, they have demonstrated an in vivo inhibitory action on food intake and weight gain. That effect is exerted via the intermediary of binding to the NPY receptors. It will thus be possible to use the compounds of the invention in the treatment of pathologies in which an NPY receptor ligand is necessary, especially in the treatment of pathologies associated with eating behaviour disorders or energy balance disorders, such as diabetes, obesity, bulimia, anorexia nervosa, and also in the treatment of arterial hypertension, anxiety, depression, epilepsy sexual dysfunctions and sleep disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates especially to compounds of formula (I):
wherein
n is 0 or 1,
W represents a —CO— group or an S(O)
q
group wherein q is 0, 1 or 2,
the grouping
represents a group selected from:
Z represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group,
A represents a grouping selected from —A
2
—, —A
1
—A
2
—, —A
2
—A
1
— and —A
1
—A
2
—A
1
— wherein A
1
is an alkylene group and A
2
represents an optionally substituted phenylene, optionally substituted naphthylene, cycloalkylene, or optionally substituted heteroarylene group,
R represents a hydrogen atom, or an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group,
R
1
represents an alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl or optionally substituted heteroarylalkyl group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that
the term “alkyl” denotes a linear or branched group having from 1 to 6 carbon atoms,
the term “alkylene” denotes a linear or branched bivalent radical containing from 1 to 6 carbon atoms,
the term alkenyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 double bond,
the term alkynyl denotes a linear or branched group having from 2 to 6 carbon atoms and from 1 to 3 triple bond,
the term “aryl” denotes a phenyl, naphthyl, biphenyl, dihydronaphthyl or tetrahydronaphthyl group,
the term “heteroaryl” denotes an unsaturated or partially unsaturated mono- or bi-cyclic group having from 5 to 11 ring members, containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur,
the terms “phenylene” and “naphthylene” denote bivalent phenyl and naphthyl radicals, respectively,
the term cycloalkylene denotes a bivalent saturated cyclic radical having from 3 to 8 carbon atoms,
the term “heteroarylene” denotes a bivalent heteroaryl radical as defined hereinbefore,
the expression “optionally substituted” applied to the terms “aryl”, “arylalkyl”, “heteroaryl” or “heteroarylalkyl” means that those groups are substituted on their cyclic moiety by from 1 to 5 identical or different substituents selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, halogen, hydroxy, linear or branched perhalo-(C
1
-C
6
)alkyl, nitro, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), linear or branched (C
1
-C
6
)acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (C
1
-C
6
)alkyl groups), linear or branched (C
1
-C
6
)acylamino, linear or branched (C
1
-C
6
)alkoxycarbonyl, formyl, carboxy, sulpho, nitrile, linear or branched (C
1
-C
6
)aminoalkyl (optionally substituted on the nitrogen atom by one or two linear or branched (C
1
-C
6
)alkyl group), linear or branched (C
1
-C
6
)thioalkyl (optionally substituted on the sulfur atom by a linear or branched (C
1
-C
6
)alkyl group), or linear or branched (C
1
-C
6
)hydroxyalkyl (optionally substituted on the oxygen atom by a linear or branched (C
1
-C
6
)alkyl group),
the expression “optionally substituted” applied to the terms “phenylene”, “naphthylene” or “heteroarylene” means that those groups are substituted by from one to three identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, halogen, hydroxy, linear or branched perhalo-(C
1
-C
6
)alkyl, nitro, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), linear or branched (C
1
-C
6
)acyl, formyl, carboxy, linear or branched (C
1
-C
6
)alkoxycarbonyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two linear or branched (C
1
-C
6
)alkyl groups), linear or branched (C
1
-C
6
)acylamino and nitrile.
Among the heteroaryl groups preference is given to the pyridyl, furyl, thienyl and indolyl groups.
Among the heteroarylene groups preference is given to the pyridinylene and pyrazinylene groups.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid. etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
An advantageous aspect of the invention relates to compounds of formula (I) wherein n is 1.
Another advantageous aspect of the invention relates to compounds of formu

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