Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-23
2001-08-21
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S295000, C544S366000, C544S364000, C544S367000, C544S369000, C544S368000, C544S254000, C544S253000, C544S254000, C544S254000
Reexamination Certificate
active
06277853
ABSTRACT:
The present invention relates to novel heterocyclic compounds derived from indole piperazines as well as their method of preparation, the pharmaceutical compositions containing them and their use as medicament.
Serotonin or 5-hydroxytryptamine (5-HT) plays an important role both at the level of the nervous system and at the cardiovascular level. Serotoninergic receptors have been identified both at the central and peripheral level. It is generally accepted that serotonin plays an important role in various types of pathological conditions such as
certain psychiatric disorders such as anxiety, depression, aggressiveness, panic attacks, obsessive-compulsive disorders, schizophrenia, suicidal tendency,
certain neurodegenerative disorders such as Alzheimer's disease, Parkinsonism,
migraine, cephalagia, and
disorders linked to alcoholism
(cf. E. Zifa, G. Fillion, Pharm. Reviews, 44, 401, 1992; A. Moulignier, Rev. Neuro. (Paris) 150, 3-15, 1994; S. Langer, N. Brunello, G. Racagni, J. Mendlecvicz, “Serotonin receptor subtypes: pharmacological significance and clinical implications” Karger Ed.; (1992); B. E. Leonard, Int. Clin. Psychopharmacology, 7, 13-21 (1992); R. W. Fuller; J. Clin. Psychiatry, 53, 36-45 (1992); D. G. Grahame-Smith, Int. Clin, Psychopharmacology, 6. suppl. 4, 6-13, (1992).
The compounds according to the present invention are novel compounds having a very high affinity and a very good selectivity for the receptors commonly called 5-HT
1-like
and more particularly for the receptors called 5-HT
1B
and 5-HT
1D
.
The medicaments, alone or in combination with other therapeutic agents, including one or more active ingredients of the present invention find their use in the treatment, both curative and preventive, of diseases related to the dysfunction of the 5-HT-
1-like
receptors including the 5-HT
1B
and 5-HT
1D
receptors, to their deregulation, or to modifications of the activity of the endogenous ligand which is generally serotonin.
The compounds of the present invention are potent agonists, both at the level of their affinity and at the level of their intrinsic efficacy or activity, and selective agonists for the 5-HT
1B
and 5-HT
1D
receptors. The agonists for the 5-HT
1-like
receptors, and more particularly for the 5-HT
1B
receptors, exhibit a selective vasoconstrictive activity and find their use in the treatment of migraine and of vasospastic disorders (A. Doenicke et al., The Lancet, 1, 1309-1311, 1988; M. D. Ferrari, P. R. Saxena, Cephalalgia, 13, 151-165, 1993; S. J. Peroutka, Headache, 30, 5-11, 1990; M. A. Moskowitz, TiPS, 13, 307-311, 1992; W. Feniuk, P. P. Humphrey, M. S. Perren, H. E. Connor, E. T. Whalley, J. Neurol. 238, pp. 57-61, 1991; A. V. Deligonis, S. J. Peroutka, Headache, 31, 228-231, 1991).
The compounds of the present invention, which are for the most part potent and selective agonists for the 5-HT
1B
and 5-HT
1D
receptors, therefore find their use more particularly in the curative and prophylactic treatment of attacks of conventional migraine, with aura, of common migraine, without aura, vascular facial pain, chronic vascular cephalalgia and vasospastic disorders.
The prior state of the art in this field is illustrated in particular by:
patent applications EP-A2-0303507, WO 93/14087, WO 94/02460, WO 92/14708, and patents U.S. Pat. No. 4,839,377, GB-A-2124210 and GB-A-2162532 which describe sulfonamides derived from typtamines, including sumatriptan, as antimigraine drugs,
patent applications GB-A-2191488, GB-A-2185020 and GB-A-2168347 which describe alkylamides derived from tryptamine.
French patent applications FR-A-2,699,918 and FR-A-2,707,639 which describe novel indole compounds derived respectively from piperazines and arylamines as ligands for the 5-HT
1B
and
5
-HT
1D
receptors.
Application for patent of invention FR-A-2,724,933 which describes novel aromatic ethers derived from indole as ligands for the 5-HT
1D
receptors.
European patent applications EP-A-0313397, EP-A-0486666, EP-A1-0494774, EP-A-0494774, EP-A2-0497512, EP-A1-0501568, EP-A-0464558, EP-A1-0548813 and international applications WO 92/13856 and 93/11106 which describe heterocyclic derivatives derived from tryptamine as agonists for the 5-HT
1-like
receptors.
The present invention describes a novel class of piperazines derived from aminoindole which is distinguishable from all the closest prior art derivatives by their novel and different chemical structure, but also by their biological profile and their therapeutic potential since many compounds according to the present invention exhibit a very high affinity and selectivity for the 5-HT
1B
and 5-HT
1D
receptors, a remarkable efficacy and a particularly advantageous hemodynamic profile. The derivatives of the present invention therefore find their usefulness more particularly as active ingredients of medicinal compositions for the treatment of migraine and of various similar disorders.
The present invention relates to compounds of general formula (I).
in which, HET represents a heterocycle chosen from
R
1
and R
2
, which are identical or different, represent a hydrogen atom, R′
1
, CF
3
, CH
2
CF
3
, C
6
H
5
, CH
2
C
6
H
5
, OH, OR′
1
, SH, SR′
1
, Cl, F, Br, I, CN, NH
2
, NHR′
1
, NR′
1
R′
2
, NO
2
, NH—NH
2
, NH—NHR′
1
, NHOH, NHCO
2
R′
1
, NHCONH
2
, NHCONR′
1
R′
2
, NHSO
2
R′
1
, SO
2
R′
1
, SO
2
NH
2
, SO
2
NHR′
1
, COR′
1
, CO
2
R′
1
, CONH
2
, CONHR′
1
, CONR′
1
R′
2
which may be at the ortho or meta position on the aromatic ring,
R
3
and R
4
, which are identical or different, represent a hydrogen atom, a linear or branched carbon-containing radical comprising from 1 to 6 carbon atoms or a benzyl or phenethyl residue,
Y and Z, which are identical or different, represent CH or N,
X represents O, S or NR
7
,
R
5
, R
6
and R
7
, which are identical or different, represent a hydrogen atom, a linear or branched alkyl residue comprising from 1 to 6 carbon-atoms or a phenyl residue which is optionally substituted with a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, a halogen atom, CF
3
, OCH
3
, CN or NO
2
,
R′
1
and R′
2
, which are identical or different, represent a linear or branched alkyl group comprising from 1 to 6 carbon atoms or a phenyl residue which is optionally substituted with a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, Cl, Br, F, I, OCH
3
, OH, NO
2
, SCH
3
,
as well as their salts, solvates and bioprecursors which are acceptable for therapeutic use.
The expression “bioprecursors”
0
as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (I) but which, when administered to an animal or to a human being, are converted in the body to a compound of formula (I).
Among the compounds of general formula (I) which are included in the present invention, a class of compounds which is particularly appreciated corresponds to the compounds of general formula (I) in which R
1
, R
2
, R
3
and R
4
each represent a hydrogen atom.
Another class of compounds included in the present invention which is particularly appreciated corresponds to the compounds of general formula (I) in which HET represents a pyridyl or pyrimidyl residue.
A third class of compounds included in the present invention which is particularly appreciated corresponds to the compounds of general formula (I) in which HET represents a 5-membered heterocycle containing from 1 to 3 heteroatoms chosen from O, S or N.
Among the compounds of general formula (I) in the form of salts which are acceptable for therapeutic use, the salts formed by addition with inorganic acids, chosen from the hydrochlorides, hydrobromides, sulfates, fumarates, maleates, methanesulfonates and succinates, are preferred.
Other salts may be used in the preparation of the compounds of formula (I), for example the adducts with creatinine sulfate.
The present invention also relates to a method of preparing the compounds of general f
Halazy Serge
Perez Michel
Liu Hong
Pierre Fabre Medicament
Sage G. Patrick
Shah Mukund J.
The Firm of Hueschen and Sage
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