Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Patent
1997-06-09
1998-12-08
Brouillette, D. Gabrielle
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
514272, 424449, A61K 600
Patent
active
058465529
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of international application PCT/FR95/01197 filed Sep. 19, 1995 which designated the U.S.
The present invention relates to the use as an active substance of 2,4-diaminopyrimidine 3-oxide or a salt thereof for the preparation of a therapeutic composition for pharmaceutical or veterinary application intended for the treatment of collagen maturation and structuring disorders.
To obtain bundles of native procollagen requires the hydroxylation of a certain number of prolyl and lysyl residues of preprocollagen within the rough endoplasmic reticulum, followed by the glycosylation of the hydroxylysyl residues in the Golgi apparatus. This maturation of collagen has been the subject of numerous studies.
Thus, minoxidil, namely 2,4-diamino-6-piperidino-pyrimidine 3-oxide, already described and used in the treatment of some types of hypertension and in the treatment of androgenic alopecia, has been the subject of numerous studies as a specific inhibitor of lysyl hydroxylase, an enzyme participating in the maturation of collagen.
In this connection, the studies of Murad et al., published in Arch. of Biochem. Biophys., Vol. 292, No. 1, pp. 234-238 (1992) and Vol. 308, No. 1, pp. 42-47 (1994), have, in effect, enabled it to be shown that the ability to inhibit lysyl hydroxylase necessitated the presence of a tertiary amine group located at the para position with respect to the N-oxide function of the 2,4-diamino-pyrimidine ring, and that this group preferably needed to be a piperidine group as in minoxidil.
In point of fact, it has now been established, surprisingly and quite unexpectedly, that 2,4-diamino-pyrimidine 3-oxide or 2,4-DPO (hereinafter), although it does not contain a tertiary amine group at the para position with respect to the N-oxide function of the 2,4-diaminopyrimidine ring, enables lysyl hydroxylase to be specifically inhibited.
This compound has already been described in WO 92/01437 as an active agent intended for the cosmetic treatment, by topical application, of hair loss. However, contrary to minoxidil, 2,4-DPO does not possess any antihypertensive effect, and is hence especially satisfactory from the standpoint of safety while having an inhibitory activity with respect to lysyl hydroxylase which is equal to or even greater than that of minoxidil .
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A demonstrates Relative Expression of mRNA at 3 h for C: Control, M: minoxidil, MS: Minoxidil sulphate, 2,4-DPO: 2,4-Diaminopyrimidine 3-oxide, LH: Lysylhydroxylase, PH: propylhydroxylase.
FIG. 1B demonstrates Relative Expression of mRNA, as in FIG. 1A, at 18 h.
The subject of the present invention is hence the use as an active substance of 2,4-DPO or a salt thereof for the preparation of a therapeutic composition for pharmaceutical or veterinary application intended for the treatment of collagen maturation disorders in man or animals.
Hereinafter, the expression "2,4-DPO" will mean not only 2,4-DPO itself but also a salt thereof as defined below.
Collagen maturation disorder should be understood, according to the invention, to mean any undesired accumulation of collagen, and in particular any structural disorder of the collagen matrix of the cutaneous tissue or bulbar conjunctiva; these disorders may be of spontaneous, traumatic or postoperative origin. Among these disorders, vitreoretinopathy, systemic scleroderma, ultraviolet-induced cutaneous thickening and cicatricial keloid may be mentioned in particular.
The use of 2,4-DPO according to the invention hence makes it possible to obtain, in particular, an aesthetic improvement in the patient undergoing treatment.
While, according to the invention, the treatment may be curative, it is nonetheless preferably used preventively, that is to say during the period in which structuring, and consequently the accumulation of collagen, takes place, this occurring, in particular, during the period of cicatrization.
2,4-DPO may be used for the preparation of a therapeutic composition presented in a form which can be administered topi
REFERENCES:
patent: 4421914 (1983-12-01), Okamura
patent: 5091522 (1992-02-01), Phillippe
Handa et al: "Minoxidil inhibits ocular cell proliferation and lysyl hydroxlase activity", Invest. Ophthalmol. Visual Sci., vol. 34, No. 3, 1993. pp. 567-575.
Handa et al: "Inhibition of cultured human RPE cell proliferation and lysyl hydroxlase activity by hydrogen derivatives of minoxdil.", Invest. Ophthamol. Visual Sic., vol. 35, No. 2, 1994, pp. 463-469.
Bernard Bruno
Breton Lionel
Galey Jean-Baptiste
Mahe Yann
"L'Oreal"
Brouillette D. Gabrielle
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