Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-02-06
1994-08-30
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
A61K 31415, C07D23364, C07D23380
Patent
active
053429605
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds especially for therapeutic use as agonists of the histamine H.sub.3 receptor, to pharmaceutical compositions containing them and to the use of these compounds for producing a medicinal product.
The advantageous agonist properties with respect to the H.sub.3 histaminergic receptor of imidazolethylamine derivatives have been described in Patent Applications EP-A-0,214,058 and EP-A-0,338,939. These compounds are very potent in vitro since they act at nanomolar concentrations. They are also very active in vivo in rodents (rats or mice) in which they exert an inhibition of the synthesis and of the release of endogenous histamine from the brain and from various peripheral organs at doses close to 1 mg/kg: for example, the 50% effective dose of (R)-.alpha.-methylhistamine is 3 mg/kg orally (Arrang et al., Nature 1987, 327, 117-123; Garbarg et al., Eur. J. Pharmacol. 1989, 164, 1-11). This high activity in vivo is confirmed by the measurement of the plasma level of (R)-.alpha.-methylhistamine determined either by radioenzymatic assay (Garbarg et al., Eur. J. Pharmacol. 1989, 164, 1-11), or by a radioimmunoassay: at an oral dose of 3 mg/kg, plasma levels sufficient to stimulate the H.sub.3 receptor (>10 nM) are maintained for more than 6 hours.
However, by administering the same compound to a series of healthy volunteers at a dose of 175 mg per person, the Applicants observed that the plasma levels of (R)-.alpha.-methylhistamine which resulted from this administration were about 10 times lower than what was expected given the corresponding results obtained in rodents.
The Applicants have surprisingly discovered that by blocking the primary amine function of histamine derivatives, in particular among those described in the abovementioned European Patent Applications EP-A-0,214,058 and EP-A-0,338,939, compounds which are extremely active in vivo are obtained which are capable of being slowly hydrolyzed in a neutral medium to give the free derivative again. Similar results are obtained with all amines possessing a high affinity and selectivity for the histamine H.sub.3 receptor.
The subject of the invention is therefore a compound derived from an amine R-NH.sub.2, to the primary amine function of which a group which gives rise to a bond that is capable of being slowly hydrolyzed in a neutral medium is attached, R being such that the said amine possesses a high affinity for the histamine H.sub.3 receptor.
Compound is also understood as meaning the different isomeric forms as well as, where appropriate, the derivatives obtained by condensation of water as will be explained in greater detail later.
The amines R-NH.sub.2 to which the invention relates are more particularly the histamine derivatives, or more specifically the amines of the same chemical formula, described in the abovementioned Patent Applications EP-A-0,214,058 and EP-A-0,338,939, and which correspond to the formula: ##STR1## in which R.sub.5, R.sub.6 and R.sub.8 each denote a hydrogen atom or a methyl group, or alternatively R.sub.5 and R.sub.6, taken together, form a methylene group and R.sub.7 represents a hydrogen atom or a methyl or carboxyl group, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 not being capable of simultaneously denoting hydrogen.
Among the amines which correspond to this formula, the following may be mentioned in particular: particularly its stereoisomer R(-); (R.sub.5 =CH.sub.3 ; R.sub.6 =R.sub.7 =R.sub.8 =H); described by Gerhard and Schunack, Arc. Pharm. (Weinheim) 1980, 313, 709. (R.sub.5 =R.sub.7 =CH.sub.3 ; R.sub.6 =R.sub.8 =H); described by Schunack, Joint Meeting of the American Chemical Society, Div. of Med. Chem., and the American Society for pharmacology and experimental therapeutic, Boston, USA, 18-22 August, 1985. stereoisomers (R.sub.6 =CH.sub.3 ; R.sub.6 =R.sub.7 =R.sub.8 =H) described by Ganellin et al. in J. Med. Chem. 1973, 16, 616 (in racemic form) and by Schunack et al. in Frontiers in histamine research, C. R. Ganellin and J. C. Schwartz, ed. Pergamon Press, 1985, p. 39 (in th
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Arrang Jean-Michel
Garbarg Monique
Lecomte Jeanne-Marie
Lipp Ralph
Schunack Walter
Higel Floyd D.
Institut National de la Sante et de la Recherche Medicale
Societe Civile Bioprojet
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