Aminopyri(mi)dine derivatives combined with amino acids, and pha

Details Aminopyri(mi)dine derivatives combined with amino acids, and pha Aminopyri(mi)dine derivatives combined with amino acids, and pha

1996-07-02

1998-09-01

Robinson, Douglas W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 19, 514256, 514275, 514774, 530331, 530345, A61K 3800, C07K 500

Patent

active

058011501

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR94/00753 filed Jun. 22, 1994.


BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention has for its object new synthetic compounds combining sulfur-containing or sulfur-free amino acids with aminopyrimidine and aminopyridine derivatives, as well as their addition salts with mineral or organic acids in the presence of amino groups, their processes for preparation, their pharmacological activities and the pharmaceutical compositions containing them.
2. Description of the Related Art
On the other hand, the salification of minoxidil by amino acids is disclosed by British patent 2 175 901. In this patent, a salt is formed between 5-oxoproline and the 2,4-diamino-6-piperidinopyrimidine-3-oxide (minoxidil).
Minoxidil is also disclosed in a patent WO-A-8 600 616 corresponding to an associative synthesis with alkoxy or alkoxycarbonyl compounds different from the amidic structures of the present claims.
At present, the minoxidil molecule is the base for our study and is known for its following properties: arterial pressure resulting from selective relaxation of the smooth muscle fibers of the peripheral arteries. in vivo growth of keratinocytes, and the growth of hair, in certain subjects having androgenic alopecy. The appearance of this phenomenon takes place after about four months (or more) of use of the product and varies as a function of the subjects. Minoxidil, when applied topically, is only slightly absorbed: an average quantity of 1.4% (for values ranging from 0.3 to 4.5%) of the applied dose reaches the blood stream.
The mechanism in the framework of fresh growth of hair will be based on the vasodilatory properties of the peripheral arteries of the hair-bearing skin. However, regrowth of hair requires prolonged treatment; the hairs formed are fragile and in particular the molecular weight of the keratines formed is less than that of normal strands.


SUMMARY OF THE INVENTION

The new compounds of the invention have a power of capturing free radicals which is higher, acting as such, and are of vasodilatory activity origin; they have a cutaneous penetration and retention in the skin which is substantially greater.
The original compounds disclosed for the first time and whose invention is claimed here, are aminopyrimidine and aminopyridine derivatives of formulas 1 to 4: ##STR1## wherein A represents either a nitrogen atom or an N-oxide group of the structure N.sup.+ --O--.sup.-. ##STR2## wherein X and Y represent hydrogen, a linear or branched alkyl group, possibly hydroxylated, an aryl group, an alkylaryl group, an amino alkyl group, an amino aryl group, a carboxyalkyl group, or a carboxyaryl group. possibly hydroxylated, an aryl group, an amino alkyl group, an amino aryl group, or a heterocyclic group; amino acids whose terminal or branched acid or amine functions can be free or combined with ester or amide groups. ##STR3## represents a cyclic structure either ##STR4## n being preferably 4 to 6 or ##STR5## wherein m is 2, B is a heteroatom, O, NH or amino substituted with a linear, branched or optionally hydroxylated alkyl group, or an aryl group, the amino function --NH--Y is an amine, Y being hydrogen, either in the form of mineral or organic salts, or in the form of an amide, Y having the structure CO--R.sub.4, R.sub.4 being identical to R.sub.2 excluding hydrogen.
These amides derive from monoamino, diamino and triamino-pyrimidines and from monoamino, diamino and triamino pyridines.
They result from the combination of either an aminopyrimidine or an aminopyridine and amino acids or sulfur-free peptides, such as for example glutamic acid, pyroglutamic acid, tyrosine, histidine, arginine, citrulline or sulfur-containing amino acids or peptides such as methionine, cysteine, S-methylcysteine, S-benzylcysteine, cystine, glutathion, or oxidized glutathion.
As an example could be cited the combination of minoxidil and amino acids or sulfur-free peptides, such as for example glutamic acid, pyroglutamic acid, tyrosine, histidine, arginine, citrulline or sulfur-con

REFERENCES:
patent: 4528135 (1985-07-01), Henninger et al.
patent: 4959475 (1990-09-01), Mills et al.
patent: 5124154 (1992-06-01), Babcock et al.
patent: 5328913 (1994-07-01), Murad et al.
R. B. Merrifield, Science vol. 150 Oct. '65 pp. 178-185.
Chemical Abstract No. 1988: 515976; Bennett et al., J. Bioact. Compat. Polym. (1988) 3(1) pp. 44-52.
Brunozzzi et al, Acta Therapeutica vol. 12 (1986) pp. 373-381.

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