Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-06-07
2001-01-23
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S412000, C514S416000
Reexamination Certificate
active
06177450
ABSTRACT:
The present invention relates to the synergistic combination consisting of at least one antagonist of NK1 receptors and of at least one antagonist of NK2 receptors.
Substance P and neurokinin A are neuropeptides belonging to the tachykinin family. Tachykinins are endogenous ligands known for their ability to stimulate 3 types of receptors known as NK1, NK2 and NK3.
The effects of Substance P are mainly mediated by NK1 receptors. The effects of neurokinin A are mainly mediated by NK2 receptors.
Substance P is an undecapeptide which is implicated in many pathologies such as, for example, transmission of pain, disorders of the central nervous system, inflammatory or respiratory phenomena, and the like.
Neurokinin A is also implicated in numerous pathologies such as transmission of pain, arthritis, asthma, inflammatory phenomena, psychoses, tensional disorders, vesical disorders, cystites, and the like.
Until recently, despite research carried out and despite the abovementioned interest [M. R. Hanley, TINS, (5) 139 (1982)], no product acting specifically on Substance P or on neurokinin A and having a non-peptide structure had, in practice, been discovered.
Antagonists of NK1 receptors (antagonists of the effects of Substance P) are now known and described, especially in Patent Applications EP 429,366, EP 514,273, EP 514,275, WO 90/05525, WP 90/05729, WO 91/18899, WO 91/09844, WO 92/01688, WO 92/06079, WO 92/15585, WO 92/12151, WO 92/20661, WO 92/20676, WO 92/21677, WO 93/00330, WO 93/00331, WO 93/01159, WO 93/01169, WO 93/01165, WO 93/01170, WO 93/06099, WO 93/09116, WO 93/10073, WO 93/18023, WO 93/19064, WO 93/21155, WO 93/21181, WO 93/23380, EP 499,313, EP 394,989, EP 443,132, EP 482,539, EP 512,902, EP 517,589, EP 520,555, EP 522,808, EP 528,495, EP 532,456, EP 533,280, EP 536,817, EP 545,478, EP 559,538, XIIth Int. Symp. on Med. Chem., Basle, Sep. 13-17, 1992 or 3rd Meeting of the European Neuropeptide Club (Cambridge, Apr. 5-7, 1993).
Antagonists of NK2 receptors (antagonists of the effects of neurokinin A) are also known and described, especially in Patent Applications EP 428,434, EP 474,561, EP 512,901, EP 515,240, FR 2,678,267, WO 92/19254 or WO 93/14084.
J. L. Ellis et al., J. Pharmacol. Exp. Ther., 262(2), 646 (1992) mentions the combination of an antagonist of NK
1
receptors: CP 96345 and a peptide antagonist of NK
2
receptors (MEN 10376) but no study of the separate and then combined products was carried out and no synergy of action discovered.
C. A. Maggi, Br. J. Pharmacol., 103(2), 1535 (1991) describes the study of spantide and L-659,877 alone or in combination but, in as much as spantide is antagonist both of NK
1
and NK
2
receptors, this study could not make it possible to discover the advantage of a combination of an antagonist of NK
1
receptors and an antagonist of NK
2
receptors.
It has also been revealed that certain products are endowed with antagonist activity towards NK1 receptors and antagonist activity towards NK2 receptors: M. Murai et al., J. Pharm. Exp. Ther., 262(1), 403 (1992). However, none of these products has, until now, displayed a very high activity.
Until now, it had been supposed that the effects of antagonists of NK1 and NK2 receptors could act similarly and additively on certain functional groups. It has now been found that the effects of antagonists of NK1 receptors in combination with antagonists of NK2 receptors are potentiated, which opens a particularly advantageous route into therapeutic fields where Substance P and/or neurokinin A are involved.
As non-limiting examples, antagonists of NK1 receptors can be especially derivatives of the perhydroisoindole class, derivatives of the 2-substituted-3-aminoquinuclidine class, derivatives of the aminoazabicycloalkane class, derivatives of the 2-substituted-3-aminopiperidine class, derivatives of the 1-azabicyclo[3.2.2]nonan-3-amine class, derivatives of the N-alkylquinuclidinium salt class, derivatives of the pseudopeptide class, derivatives of the N,N-diacylpiperazine class, substituted aromatic derivatives, dialkylenepiperidino derivatives, quaternary salts of substituted piperidines, and the like.
By way of example, products of the class of perhydroisoindole derivatives can have the structure:
and their salts, when they exist, in which:
the R
1
symbol represents a phenyl radical optionally substituted by one or a number of halogen atoms or hydroxyl radicals, alkyl radicals which can optionally be substituted (by halogen atoms or amino, alkylamino or dialkylamino radicals), alkyloxy or alkylthio radicals which can optionally be substituted [by optionally substituted (by phenyl, hydroxyl or amino radicals) dialkylamino, alkylamino, amino or hydroxyl radicals, or dialkylamino radicals in which the alkyl parts form, with the nitrogen atom to which they are attached, a 5- to 6-membered heterocycle which can contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical)], or substituted by amino, alkylamino or dialkylamino radicals in which the alkyl parts can form, with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl radical, a naphthyl radical or a saturated or unsaturated, mono- or polycyclic heterocyclyl radical (5 to 9 carbon atoms) and one or a number of heteroatoms chosen from oxygen, nitrogen or sulphur, and optionally substituted by a halogen atom or by an alkyl or alkyloxy radical,
the R
2
symbol represents a hydrogen or halogen atom or a hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxyl, alkyloxycarbonyl, dialkylaminoalkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino radical,
the bicycle:
represents a perhydroisoindole or thiapyranopyrrole ring of general formula:
and the symbol X represents an oxygen or sulphur atom or a radical NR
6
in which R
6
is a hydrogen atom, an alkyl radical containing 1 to 12 carbon atoms and optionally substituted [by one or a number of carboxyl, dialkylamino, acylamino, alkyloxycarbonyl, alkyloxycarbonylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl radicals (it being possible for the alkyl portions of these substituents to themselves be substituted by dialkylamino or phenyl) or substituted by phenyl, substituted phenyl (substituted by halogen, alkyl, alkyloxy or dialkylamino), naphthyl, thienyl, furyl, pyridyl or imidazolyl radicals] or a dialkylamino radical, or else, if the ring is of formula (Ib) or (Ic), the symbol X represents an oxygen atom, or an NH radical, or else
the bicycle:
represents a perhydroisoindole or thiapyranopyrrole ring of general formula:
and the symbol X represents an oxygen atom.
In the general formulae (Ia) to (Ie):
the R symbols are identical and represent phenyl radicals optionally substituted by a halogen atom or by a methyl radical in the 2- or 3-position,
the R″ symbols are identical and represent hydrogen atoms or together form a bond,
the R
3
symbol represents a halogen atom or a hydroxyl radical and the R
4
symbol represents a hydrogen atom or, simultaneously with R
3
, represents a halogen atom,
the R′
3
symbol represents a phenyl radical optionally substituted in the 2-position by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the R′
4
symbol represents a fluorine atom or a hydroxyl radical, and the R
5
symbol represents a hydrogen atom or else the R′
4
and R
5
symbols represent hydroxyl radicals, or else the R′
4
symbol forms a bond with R
5
,
the R″
3
symbol represents a hydrogen atom and the R″
4
symbol represents a fluorine atom or a hydroxyl radical, or else the R″
3
symbol represents a phenyl radical optionally substituted in the 2-position by an alkyl or alkyloxy radical (1 or 2 carbon atoms), and the R″
4
symbol is a hydroxyl radical, or else the R″
3
and the R″
4
symbols together form an oxo radical,
the n symbol is an integer from 0 to 2; it being understood that the pr
Garret Claude
Montier Francois
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner
Jarvis William R. A.
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