Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-11-19
2000-10-31
Jarvis, William R. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31505
Patent
active
061403350
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR98/00765, filed Apr. 16, 1998.
The present invention relates to the use of mizolastine, 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidyl]methyl amino]-4-pyrimidinol or 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidyl]methyl amino]pyrimidin-4(1H)-one, and pharmaceutically acceptable salts thereof, for the preparation of a medicament intended for treating inflammatory diseases or inflammatory components of certain other diseases, associated with the 5-lipoxygenase route.
Mizolastine and pharmaceutically acceptable salts thereof are described in European Patent EP 0,217,700. Mizolastine is known as a histamine (H1) receptor antagonist and is used in the treatment of various allergic manifestations.
Certain documents which discuss mizolastine mention its effect in allergic inflammations associated with the release of histamine: Levrier et al., "Anti-anaphylactic activity of the novel selective histamine H1 receptor antagonist mizolastine in the rodent", Arzneimittelforschung, 45(5), 559-568 (1995); Leynadier et al., "Efficacy and safety of mizolastine in seasonal allergic rhinitis", Annals of Allergy, asthma and immunology, 76(2), 163-168 (1996); Pinquier et al., "Effect of mizolastine on experimental inflammation in human skin", Clinical pharmacology and therapeutics, 57(2), 169 (1995); Angel et al., "Powerful antihistamine properties of mizolastine in cutaneous oedema in the dog", Allergy, 51(31), 171 (1996).
In the cases described in these documents, these are inflammatory reactions induced indirectly by histamine (His), as described by R. Anderson et al. in "The in vitro effects of histamine and metiamide on neutrophil motility and their relationship to intracellular cyclic nucleotide levels", J. Immunol., 118, 1690-1697 (1977).
In effect, histamine (His) is not, strictly speaking, an inflammation mediator, but is involved in the physiological alteration during the established inflammatory processes. His is mainly released in response to stimulation with an antigen, to certain cellular inflammation factors or to physical stimuli. The direct role of His has been described and characterized in the allergic reactions, but only in acute phases of the allergy. His is not considered as being directly involved in initiating inflammation in delayed phases of the allergy (Tannenbaum et al. J. Immunol. 125, 325).
His is an amine which is essentially stored in the mastocyte and basophil cells. It is single-handedly capable of producing intradermal effects of vasodilation and of increasing local vascular permeability or of pain, i.e. only 3 of the 5 cardinal signs of inflammation. Thus, as regards the main inflammatory cells, i.e. the neutrophils (myeloid cells), histamine does not by itself modify the basal chemotaxis of these cells. Furthermore, His affects only the already-stimulated cellular chemotaxis which is associated with the intracellular increase in the level of cyclic adenosine 3',5'-monophosphate (cAMP), mainly by means of the agonist activity of the histamine H.sub.2 -receptor subtypes.
In contrast with His, leukotrienes play a key role in inflammatory responses and are involved in generating many different inflammatory pathologies.
More precisely, leukotrienes are in fact derived from a common precursor, leukotriene A4 (LTA4). The latter is formed only after an intermediate step in which hydroxyperoxyeicosatrienoic acid (5-HPETE) is synthesized by the action of 5-lipoxygenase (5-LO) on arachidonic acid (AA).
Thus, reduction of the 5-LO route is one possible way of inhibiting the production of the leukotrienes involved in the inflammatory processes (Bell et al., Journal of Lipid Meditors, 6, 259-264, 1993; R. M. McMillan and E. R. H. Wlaker, Trends Pharmacol. Sci., 13, 323-330, 1992).
It should also be pointed out that, further upstream, the primary sites of activation of arachidonic acid biosynthesis following an inflammatory stimulus are limited to the myeloid cells (neutrophils, eosinophils, etc.), (leading to 5-LO metabolites) a
REFERENCES:
patent: 4912219 (1990-03-01), Manoury et al.
Levrier, J. et al. "Anti-anaphylactic Activity of the Novel Selective Histamine H1 Receptor Antagonist Mizolastine in the Rodent", Drug Res., vol. 45, No. 5, 1995, pp. 559-568.
Leynadier, F. et al, "Efficacy and safety of mizolastine in seasonal allergic rhinitis", Annals of Allergy, Asthma and Immunology, vol. 76, No. 2, 1996, pp. 163-168.
Pinquier, J-L. et al, "Effect of mizolastine on experimental inflammation in human shin", Clinical Pharmacology and Therapeutics, vol. 57, No. 2, 1995, p. 169.
Angel, P. et al, "Powerful antihistamine properties of mizolastine in cutaneous oedema in the dog", Allergy, vol. 51, No. 31, 1996, p. 171.
Angel Itzchak
Arbilla Sonia
Even Luc
Goldhill Jonathon Marc
Pichat Philippe
Jarvis William R. A.
Sanofi-Synthelabo
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