Hydrazide compounds

Details Hydrazide compounds Hydrazide compounds

2000-06-23

2001-08-07

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S419000, C514S423000, C514S448000, C546S279100, C546S316000, C548S492000, C548S537000, C549S072000

Reexamination Certificate

active

06271247

ABSTRACT:

The present invention relates to new hydrazide compounds.
DESCRIPTION OF THE PRIOR ART
Hydrazide compounds have been described in the literature (J. Org. Chem., 1971, 36, 1580) although no pharmacological property has been mentioned. Other compounds of related structure are used in the composition of photographic films (JP 02008833), or have been used in the formation of polymers that are used to prepare semipermeable membranes (J. Appl. Polym. Sci., 1992, 44, 1383).
The compounds of the present invention have a novel structure which imparts to them great affinity for neuropeptide Y receptors.
Ligands of those receptors 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 having a guanidine group (EP 448765, J. Med. Chem., 1994, 37, 2242).
BACKGROUND OF THE INVENTION
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 (Neuropsycho-pharmacology, 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 a structure which imparts to them great affinity for NPY receptors. It will thus be possible to use them 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 to compounds of formula (I):
R—NH—A—CO—NH—NH—(W)
n—Z
  (I)
wherein:
n is 0 or 1,
W represents a —CO— group or an S(O)
r
group wherein r is 0, 1 or 2,
Z represents a group selected from optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl,
R represents a group selected from
Z
1
—T—CO—
Z
1
—O—T—CO—
Z
1
—T—O—CO—
Z
1
—T—S(O)
q
—
wherein:
Z
1
represents an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group,
T represents a &sgr; bond or an alkylene, alkenylene or alkynylene group,
q represents an integer 0, 1 or 2,
A represents a linear or branched alkylene group having from 3 to 8 carbon atoms, a linear or branched alkenylene group having from 3 to 8 carbon atoms, a linear or branched alkynylene group having from 3 to 8 carbon atoms, an alkylenecycloalkylene group, a cycloalkylenealkylene group, an alkylenecycloalkylenealkylene group, an alkylenearylene group, an arylenealkylene group, an alkylenearylenealkylene group, a grouping
wherein B
1
represents an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or A forms with the nitrogen atom a grouping
wherein B
2
represents a saturated or unsaturated mono- or bi-cyclic system having from 5 to 11 ring members, optionally containing from 1 to 3 additional hetero atoms selected from nitrogen, oxygen and sulphur,
with the proviso that when simultaneously n is 0, A represents a grouping
B
1
being
a benzyl group, and Z represents an optionally substituted phenyl group, then R is other than a benzoyl 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, unless indicated otherwise,
the term “alkenylene” denotes a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 double bonds, unless indicated otherwise,
the term “alkynylene” denotes a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds, unless indicated otherwise,
the term “aryl” denotes a phenyl, naphthyl, dihydronaphthyl or tetrahydronaphthyl group, and the term “arylene” denotes a bivalent radical of the same type, 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 term “alkylenecycloalkylene” represents a grouping —A
1
—A
2
—, the term “cycloalkylene-alkylene” represents a grouping —A
2
—A
1
—, and the term “alkylenecycloalkylenealkylene” represents a grouping —A
1
—A
2
—A
1
, the term “alkylenearylene” represents a grouping —A
1
—A
3
—, the term “arylenealkylene” represents a grouping —A
3
—A
1
—, the term “alkylenearylenealkylene” represents a grouping —A
1
—A
3
—A
1
—, wherein A
1
is an alkylene group as defined hereinbefore, A
2
is a (C
4
-C
8
)cycloalkylene group, and A
3
is an arylene group as defined hereinbefore,
the expression “optionally substituted” applied to the terms “aryl”, “arylalkyl”, “heteroaryl” and “heteroarylalkyl” indicates 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, perhalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, nitro, linear or branched (C
1
-C
6
)acyl, linear or branched (C
1
-C
6
)alkylsulphonyl, and amino (amino optionally being substituted by one or two linear or branched (C
1
-C
6
)alkyl and/or linear or branched (C
1
-C
6
)acyl 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.
Advantageously, the invention relates to compounds of formula (I) wherein R represents a grouping Z
1
—T—CO, Z
1
preferably being an optionally substituted aryl group, and T preferably being an alkylene group or a bond.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R represents a grouping Z
1
—O—T—CO, Z
1
preferably being an optionally substituted aryl group, and T preferably being an alkylene group or a bond.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein R represents a grouping Z
1
—T—O—CO, Z
1
preferably being an optionally substituted aryl group, and T prefer

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