Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-01-09
2001-06-19
Seaman, D. Margaret (Department: 1675)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S560000, C548S561000, C548S562000, C548S563000, C548S564000
Reexamination Certificate
active
06248765
ABSTRACT:
The present invention relates to new imidazole derivatives, to their preparation and also to their therapeutic applications as chemical compounds which are histamine H
3
receptor antagonists, agonists or partial agonists.
Histamine, in a known manner, an aminated base derived from histidine by decarboxylation, causes smooth muscle contraction, a secondary hypotension and phenomena resembling anaphylactic shock (oedema, urticaria, etc.) in man and in animals.
Histamine is also a chemical mediator released by some histaminergic cells.
Hence the interest which exists, in particular in the medical field, in being able to control histamine release, in particular in the case of disease, is readily understood.
This effect may be obtained by stimulation of the H
3
receptors (presynaptic autoreceptors), whereas blockade of the latter induces, on the contrary, an increase in histamine release, in particular at the cerebral histaminic neurons (Nature, 1983, 302:832). Moreover, it has become apparent more recently that the H
3
receptors also have a role as presynaptic heteroreceptors and, as such, they control, for example, the release of pro-inflammatory peptides in some tissues; their stimulation by H
3
agonists will enable anti-inflammatory, anti-asthmatic and antimigraine effects to be produced and will make it possible to combat glaucoma, sleep-associated problems, Alzheimer's disease, schizophrenia, depression, hypertension, dysfunctions of a sexual nature, and the like.
The H
3
receptors have been defined pharmacologically by evaluating the effect of stimulating them on the release of endogenous histamine from slices of rat brain (Nature 1987, 327: 117-123). In addition, other models of studies of the effectors of the H
3
receptor have been proposed since then (Physiol. Rev. 1991, 71: 1-51), but not all these models readily enable the effect of partial agonists of low intrinsic activity to be demonstrated, it being possible for the latter to be readily taken for antagonists. In point of fact, these partial agonists may be employed as medicinal products for indications similar to those of pure agonists, and not for indications for which antagonists are reserved. It is hence extremely important for the applications to make this distinction in a preclinical phase.
Moreover, Patent Application WO 93/14070 describes imidazole compounds displaying histamine H
3
receptor-antagonist properties, controlling the release and synthesis of histamine.
It is the purpose of the present invention to select, from the family of imidazole compounds described in the said Patent Application WO 93/14070, groups of compounds or compounds which are noteworthy for their high activity with respect to histamine H
3
receptors while being generally especially well suited as a result of their pharmacological properties to the preparation of medicinal products.
Moreover, the inventors of the present invention have developed a sensitive biological test enabling an agonist displaying low intrinsic activity to be clearly differentiated from a pure antagonist. They have, as a result, identified partial agonists having strong biological activity in vivo from among compounds which, on the basis of their chemical structure and their traditional test, were predicted to be antagonists. They have also synthesized imidazole derivatives having a stronger H
3
antagonist activity, in particular in vivo, than that of the compounds known hitherto, and this is likely to decrease the toxic effects or even the side-effects at the therapeutic doses, and accordingly to facilitate their clinical use.
Hence the present invention relates to chemical compounds which are histamine H
3
receptor agonists, partial agonists or antagonists, corresponding to the general formula:
in which:
the chain A represents an unbranched, branched or unsaturated alkyl group —(CH
2
)
n
— where n is an integer which can vary between 1 and 8 and preferably between 1 and 4; an unbranched or branched alkene group comprising from 1 to 8 carbon atoms and preferably 1 to 4 carbon atoms; an unbranched or branched alkyne group comprising from 1 to 4 carbon atoms;
the group X represents —OCONH—; —OCON(alkyl)-; —OCON(alkene)-; —OCO—; —OCSNH—; —CH
2
—; —O—; —OCH
2
CO—; —S—; —CO—; —CS—; amine; alkene;
the chain B represents an unbranched, branched or unsaturated lower alkyl comprising from 1 to 8 carbon atoms and preferably 1 to 5 carbon atoms; —(CH
2
)
n
(hetero atom)— where the hetero atom is preferably a sulphur or oxygen atom; n being an integer which can vary between 0 and 5, preferably between 0 and 4;
the group Y represents a phenyl group, unsubstituted or mono- or polysubstituted with one or more identical or different substituents selbcted from halogen atoms, OCF
3
, CHO, CF
3
, SO
2
N(alkyl)
2
, SO
2
N(CH
3
)
2
, NO
2
, S(alkyl), S(aryl), SCH
2
(phenyl), an unbranched or branched alkene, an unbranched or branched alkyne optionally substituted with a trialkylsilyl radical, —O(alkyl), —O(aryl), —CH
2
CN, a ketone, an aldehyde, a sulphone, an acetal, an alcohol, a lower alkyl, —CH═CH—CHO, —C(alkyl)═N—OH, —C(alkyl)═N—O(alkyl) and other keto derivatives, —CH═NOH, —CH═NO(alkyl), and other aldehyde derivatives, —C(alkyl)═NH—NH—CONH
2
, an O-phenyl or —OCH
2
(phenyl) group, —C(cycloalkyl)═NOH, —C(cycloalkyl)═N—O(alkyl), an optionally substituted heterocycle;
a heterocycle comprising a sulphur hetero atom; a cycloalkyl; a bicyclic group and preferably a norbornyl group; a phenyl ring fused to a heterocycle comprising a nitrogen hetero atom or to a carbocycle or a heterocycle bearing a keto function; an unbranched or branched lower alkyl comprising from 1 to 8 carbon atoms; an unbranched or branched alkyne comprising from 1 to 8 carbon atoms and preferably 1 to 5 carbon atoms; a linear or branched alkyl mono- or polysubstituted with phenyl groups which are either unsubstituted or mono- or polysubstituted; a phenyl alkyl ketone in which the alkyl group is branched or unbranched or cyclic; a substituted or unsubstituted benzophenone; a substituted or unsubstituted, unbranched or branched or cyclic phenyl alcohol; an unbranched or branched alkene; a piperidyl group; a phenylcycloalkyl group; a polycyclic group, in particular a fluorenyl group, a naphthyl or polyhydronaphthyl group or an indanyl group; a phenol group; a ketone or keto derivative; a diphenyl group; a phenoxyphenyl group; a benzyloxyphenyl group;
as well as their pharmaceutically acceptable salts, their hydrates, their hydrated salts, the polymorphic crystalline structures and the tautomeric forms of these compounds.
The antagonist, the agonist or partial agonist activity of these compounds may be readily verified by biological test methods, in particular those defined in the present invention.
The subject of the invention is also, by way of new compounds, those compounds of formulae Ia and Ib not known in the prior art, including Patent Application WO 93/14070.
According to the invention, group X representing an amine is understood to mean a secondary or tertiary amine.
The alkyl, alkene, alkyne, keto, aldehyde, cycloalkyl, S-alkyl, O-alkyl, phenyl alcohol and phenyl-cycloalkyl groups mentioned above as well as in the remainder of the description and the claims of the present patent comprise from 1 to 8 carbon atoms, and preferably 1 to 5.
Likewise, keto derivatives are understood to mean any oxime, alkyloxime, hydrazone, acetal, aminal, ketal, thione, carbazone or semicarbazone group and the thio analogues of these derivatives.
Likewise, by mono- or polysubstituted phenyl and/or benzophenone groups, it is understood to mean that these groups are substituted with one or more identical or different substituents selected from halogen atoms, OCF
3
, CHO, CF
3
, SO
2
N(alkyl)
2
, SO
2
N(CH
3
)
2
, NO
2
, S(alkyl), S(aryl), SCH
2
(phenyl), an unbranched or branched alkene, an unbranched or branched alkyne optionally substituted with a trialkylsilyl radical, —O(alkyl), —O(aryl), —CH
2
CN, a ketone, an aldehyde, a sulphone, an acetal, an alcohol, a lower alkyl
Arrang Jean-Michel
Bassem Sadek
Ganellin Charon Robbin
Garbarg Monique
Huls Annette
Bierman, Muserlian and Lucas
Institut National de la Sante et de la Recherche Medical
Seaman D. Margaret
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