WO1991000088A1

WO1991000088A1 - Novel use of 1-phenyl-2-aminoethanol derivatives as healing agents

Info

Publication number: WO1991000088A1
Application number: PCT/FR1990/000445
Authority: WO
Inventors: Michel Vaugon; Jean-Claude Plassard
Original assignee: Boehringer Ingelheim France
Priority date: 1989-06-23
Filing date: 1990-06-20
Publication date: 1991-01-10
Also published as: JPH04501568A; CA2035470A1; EP0431154A1; AU5953090A; FR2648709A1; KR920700627A

Abstract

The invention relates to a novel use in human or veterinary therapeutics on the one hand, and in cosmetic and dermopharmacology on the other, of a compound selected from the group consisting of a) 1-phenyl-2-aminoethanols of the formula (I), wherein R and R', identical or different, each represent a hydrogen atom, an alkyl group C1-C4, benzyl or α-phenethyl, Z represents an alkyl group C1-C5 or a cycloalkyl group C3-C6, and b) their non-toxic additive salts. The novel use in therapeutics relates to the field of wound-healing and the novel use in cosmetics or dermopharmacology relates to the dield of skin texture improvement.

Description

NEW DILIVATION OF 1-PHENYL -2-AMINOETHANOL DERIVATIVES AS MEDICINAL PRODUCTS

AREA OF INVEOTION

The present invention relates to a new use in both human and veterinary therapy of 1-phenyl-2-aminoethanol derivatives of formula I below, in which the phenyl ring contains at least one hydroxyl group, optionally etherified or esterified, as healing means.

It also relates to a composition useful in veterinary therapy, in human therapy and, where appropriate, in cosmetics and in dermopharmacy, containing at least one such derivative in combination with a quaternary ammonium and / or an anti-inflammatory agent.

Finally, it relates to the process for the preparation of such a composition. PRIOR ART

It is known that 1-phenyl-2-aminoethanol derivatives of the formula have already been described and proposed in human or veterinary therapy as adrenergic, sympathomimetic and / or active agents on the central nervous system (CNS)

in which

X represents OH or a C ₁ -C ₄ alkoxy group, Y represents H, OH or a C ₁ -C ₄ alkoxy group, X and Y attached to two adjacent carbon atoms of the phenyl ring can together form a methylenedioxy group,

R ₁ and R ₂ , which may be identical or different, each represent H, a C ₁ -C ₈ alkyl group, a hydroxyalkyl group, an aralkyl, piperonyl, 2-phenyl-2-hydroxyethyl group, R ₁ and R ₂ considered together which may form with the nitrogen atom to which they are linked an N-heterocyclic group saturated with 5 to 7 vertices such as pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, 4-methylpiperazino, 4- (2-hydroxyethyl) - piperazino, 4 -phenylpiperazino or hexamethyleneimino,

as well as their addition salts.

We know in particular from the Merck Index, 10th edition (1983), norfenenefrine [see pages 960-961; systematic nomenclature: 1- (3-hydroxyphenyl) -2-aminoethanol], octopamine [see page 971 and US-A-2585988; systematic nomenclature: 1- (4-hydroxyphenyl) -2-aminoethanol], normetanephrine [see page 962; systematic nomenclature: 1- (4-hydroxy-3-methoxyphenyl) -2-aminoethanol], as adrenergic means useful in human therapy, on the one hand, norepinephrine [see page 960; systematic nomenclature: 1- (3,4-dihydroxyphenyl) -2-aminoethanol], whose form 1 is presented as useful in human therapy (as an adrenergic agent) and in veterinary therapy (as a sympathetic agent), on the other hand, and bamethan [see page 138; systematic nomenclature: 1- (4-hydroxyphenyl) -2-butylaminoethanol], as a vasodilator useful in human therapy, on the other hand. In addition, other products of formula lo appear in the following patent documents:

- British patent GB-A-1043519 which describes compounds of formula Io, where X = OH or alkoxy, Y = H, R ₁ = C (CH ₃ ) ₃ and R ₂ = CH ₃ , as antidiuretic means;

- French patent FR-A-1 372 742 which describes the compound of formula lo, where X = 4-OCH ₃ , Y = 3-OCH ₃ , R ₁ = C (CH ₃ ) ₃ and R ₂ = H, in as a B-adrenergic receptor blocker;

- French patent FR-B-2 460668 which describes compounds of formula lo, where X = 4-OCH ₃ , Y = H, R ₁ = C ₁ -C ₄ alkyl or p-CH ₂ CHOH-C ₆ H ₄ = A (where A is H, CH ₃ or OCH ₃ ), and R ₂ = C ₅ -C ₈ alkyl with branched hydrocarbon chain, piperonyl or 2- (1-hydroxy-1-phenylpropyl), as means antidepressants or vasodilators;

- British patent application published GB-A-2 151 612 which describes compounds of formula lo, where X = OCH ₃ , Y = R ₁ = H, and R ₂ = C ₄ -C ₈ alkyl where said residue remains alkyl has a branched hydrocarbon chain, as agents active on the CNS (in particular, as antidepressants or sedatives) or the cardiovascular system (in particular as vasodilators).

We finally know that ketanserin, which corresponds to the systematic nomenclature of 3- [2- [4- (4-fluorobenzoyl) piperidino] -ethyl- (1H, 3H) -quinazoline-2,4-dione (specialty marketed under the brand name of "SUFREXAL" by the company JANSEN) has given good results as a healing medium in horses.

The aforementioned prior art neither describes nor suggests the use of the compounds of formula lo as healing agents for the treatment of wounds in humans and animals, on the one hand, and in cosmetics or dermopharmacy for skin care in humans, on the other hand. In addition, the compounds of formula I below according to the invention are structurally different from the above-mentioned ketanserin.

PURPOSE OF THE INVENTION

We just surprisingly found that some Compounds included in the above formula lo are particularly useful as healing agents, on the one hand, and as agents useful in cosmetics and dermopharmacy, on the other hand, when administered topically.

More precisely according to the invention, a new technical solution is proposed to solve the problem of wound healing. This new technical solution uses 1-phenyl-2-aminoethanol derivatives of formula I below.

OBJECT OF THE INVENTION

According to a first aspect of the invention, it is recommended, in accordance with said technical solution, a new use of a substance chosen from the group consisting of

(a) 1-phenyl-2-aminoethanols of formula

in which R and R ′, which are identical or different, each represent the hydrogen atom, a C ₁ -C ₄ alkyl group, benzyl, or α-phenethyl,

Z represents a C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl group, and

b) their non-toxic addition salts,

for obtaining a medicament intended for use in human and veterinary therapy as a cicatrizing agent administered locally on a wound.

According to a second aspect of the invention, a therapeutic composition is also recommended, useful both in humans and in animals for wound healing, said composition being characterized in that it contains, in association with a physiological excipient. acceptable (i) at at least one compound of formula I or one of its non-toxic addition salts, and (ii) a substance chosen from quaternary ammonium, anti-inflammatory agents and their mixtures.

According to a third aspect of the invention, a method of preparing said composition is also recommended.

According to yet another aspect of the invention, the use in cosmetics and dermopharmacy of the compounds of formula I and of their non-toxic addition salts, on the one hand, and of the compositions containing them, on the other hand, is recommended. go.

DESCRIPΠQN DEΓATTJ.ER OF THE INVENTION

As indicated above, the compounds of formula I are included in the general definitions of the products of formula lo, in particular when R = H or alkyl, R '= H, and Z is alkyl, or are derived therefrom when R' is different from H, and Z is a cycloalkyl group.

The alkyl groups which are involved in the definition of the groups R, R 'and Z are hydrocarbon residues with a straight or branched chain. In general, R and R ′ are protecting groups for the OH function in ether form.

From. suitable Z groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s.-butyl, t.-butyl, t.-butyl, n-pentyl, 2,2-dimethylpropyl groups, cyclopropyl, cyclopentyl and cyclohexyl.

The preferred compounds according to the invention include bamethan [systematic nomenclature: 1- (4-hydroxyphenyl) -2-butylaminoethanol] which is a compound of formula I where OR = 4-OH, R '= H and Z = n-butyl , on the one hand, and its non-toxic addition salts, in particular sulphate, on the other hand.

By addition salts is meant here the acid addition salts obtained by reaction of a free base of formula I with a mineral or organic acid, on the one hand, and the ammonium salts, on the other hand go. Among the acids which can be used to salify the free bases of formula I, mention may in particular be made of hydrochloric, hydrobromic, acetic, formic, propionic acids, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic, tartaric, aspartic, glutamic, methanesulfonic, p-toluenesulfonic. Among the compounds making it possible to obtain ammonium salts, mention may in particular be made of alkyl (especially C ₁ -C ₁₀ ), aryl or aralkyl halides, in particular bromides, chlorides and iodides.

In general, the acid addition salts are preferred to the ammonium salts.

The compounds of formula I and their addition salts can be prepared according to a method known per se by application of conventional reaction mechanisms.

In particular, they can be obtained according to any of the methods described in the aforementioned prior art, in particular US-A-2,585,988, GB-A-1043 519, FR-A-1 372742,

FR-B-2 460 668 and GB-A-2 151 612. The compounds of formula I, where R 'is alkyl, benzyl or α-phenethyl, can be obtained by etherification of the corresponding OH group before or after fixing of the NHZ group .

In no way limiting, a certain number of compounds which are suitable according to the invention have been recorded in table I below.

According to the invention, a therapeutic composition useful in humans and animals is recommended, in particular in any warm-blooded animal, such as mammals, for wound healing, which is characterized in that it contains, in combination with an excipient for physiologically acceptable local administration, at least one compound of formula I or one of its non-toxic addition salts, as a healing agent.

According to the invention, it is also recommended, a cosmetic or dermopharmaceutical composition useful in humans for improving the texture of the skin, which is characterized in that it contains, in combination with an excipient for physiologically acceptable local administration, at least a compound of formula I or one of its non-toxic addition salts, as an agent limiting the proliferation of fibroblasts.

Of course, in each of these therapeutic, cosmetic or dermopharmaceutical compositions, the active ingredient, namely the compound of formula I or one of its non-toxic addition salts, intervenes at a dose therapeutically, or respectively, cosmetically or pharmacologically effective.

In practical terms, the physiologically acceptable excipient of the therapeutic or cosmetic composition will be an excipient for local or topical use and will comprise an aqueous or oily liquid vehicle or else a vehicle of the oil-in-water or water-in-oil type . Among the vehicles which are suitable, mention may in particular be made of lotions, ointments and creams which are capable of containing other galenically useful fillers such as, in particular surfactants, preservatives, anti-W means and / or compounds (in particular salts) inorganic or organic to stabilize the pH or to give said composition hypertonic osmotic properties.

Advantageously, the healing therapeutic composition will contain (i) 60 to 1200 parts by weight of a healing substance chosen from the group consisting of the compounds of formula I and their non-toxic addition salts, and (ii) 0.05 to 35 parts by weight of a substance chosen from the group consisting of quaternary ammonium compounds, anti-inflammatory agents and their mixtures.

Preferably, said composition will contain (i) a compound of formula I in which one of its non-toxic salts and (ii) an anti-inflammatory agent, in association, where appropriate with (iii) a quaternary ammonium.

Among the quaternary ammonium compounds which are suitable, mention may be made of the halides (such as bromides and better the chlorides) of benzalkonium, cetylpyridinium, cetyltrimethylairmonium, cetyldimethylethylammonium, cetyldimethyl- (2-hydroxycyclohexyl) ammonium, benzethonium, methylbenzethonium as antiinfectious or antiseptic means, on the one hand, or as detergents for wounds such as thonzonium chloride and bromide, on the other hand. In practical terms, a quaternary ammonium acting as an antiseptic agent will be used, preferably benzalkonium chloride.

The anti-inflammatory agents used in the healing healing composition according to the invention are advantageously chosen from non-alkaloidal anti-inflammatory substances. Particularly suitable anti-inflammatory agents administered by the local route such as steroidal anti-inflammatory drugs and anti-inflammatory drugs derived from anthranilic acid, namely for example niflumic acid which corresponds to the systematic nomenclature of acid 2- [[3- (trifluoromethyl) phenyl] amino] -3-pyridinecarboxylic.

According to the invention, it is preferable to use an anti-inflammatory agent making it possible to avoid retraction of the wounds, for example a plant extract from a plant belonging to the family of compounds. In practice, we prefer more particularly use as anti-inflammatory agent according to the invention an extract of Calendula (French nomenclature: "marigold"; English nomenclature: "marigold") and better the mother tincture of Calendula obtained according to the indications of the French Pharmacopoeia, in particular from Calendula officinalis species.

According to the best mode of implementation of the healing healing composition of the invention, a composition is recommended which is characterized in that it contains, in association with an excipient for physiologically acceptable local administration,

(A) 60 to 1200 parts by weight of a healing substance chosen from the group consisting of the compounds of formula I, their non-toxic addition salts and their mixtures,

(B) 10 to 25 parts by weight of a substance chosen from the group consisting of quaternary ammonium compounds and their mixtures,

(C) 0.05 to 10 parts by weight of Calendula tincture. Advantageously, according to this best mode, such a composition will contain, as healing means (A), bamethan or one of its non-toxic addition salts, in particular sulphate, on the one hand, and minus a salt of a metal from groups I, IIa and Ilb of the periodic table in an amount sufficient to give a hypertonic composition, on the other hand.

In practice, said healing therapeutic composition will also contain

(D) 900 to 3000 parts by weight of an alkaline salt chosen from the group comprising sodium chloride, potassium chloride, calcium chloride, sodium sulfate, potassium sulfate, zinc sulfate, calcium sulfate and mixtures thereof;

(E) where appropriate, an antioxidant means in an appropriate amount; and or

(F) where appropriate, a wetting means in an appropriate amount. Among the antioxidant means (E) which can be used according to the invention, there may be mentioned in particular the alkali metal metabisulfite of group I of the periodic table, ascorbic acid and its metal salts with the metals of the groups I, Ila and Ilb of the Periodic Table, sorbitol, sorbates and gallates obtained with the said metals of groups I, Ila and Ilb, and their mixtures. The preferred antioxidant means is constituted by sodium metabisulfite, potassium metabisulfite, and better still by sodium ascorbate and potassium ascorbate. In general, 0.05 to 35 parts by weight of means will be used (E).

Among the wetting means (F) which can be used according to the invention, mention may in particular be made of glycols such as ethylene glycol and propylene glycol, lower C ₁ -C ₃ alkanols, such as methanol, ethanol, propanol and isopropanol, and mixtures thereof. The preferred wetting means according to the invention consists of ethylene glycol and better still propylene glycol. When the means (F) is used, it will intervene in an amount representing 1 to 20% by weight relative to the total weight of the composition, excipient included, and better still an amount representing 3 to 15% by weight.

In short, the healing composition will contain, in combination with an excipient for physiologically acceptable local administration,

(B) 10 to 25 parts by weight of a substance chosen from the group consisting of quaternary aiimσnium compounds and their mixtures,

(C) 0.05 to 10 parts by weight of calendula tincture,

(D) 900 to 3000 parts by weight of an alkaline salt chosen from the group comprising sodium chloride, potassium chloride, calcium chloride, sodium sulfate, potassium sulfate, zinc sulfate, calcium sulfate and their mixtures,

(E) where appropriate an antioxidant means, and

(F) if necessary, a wetting means.

The composition useful in cosmetics or in dermooharmacy according to the invention may be in a form analogous to that of the healing therapeutic composition. In particular, the composition useful in cosmetics and dermopharmacy may be an aqueous formulation, a gel or an ointment, comprising all of the means (A), (B), (C) (D) and, where appropriate (E) and / or (F); as a variant, the cosmetic composition comprising the means (A) or all of the means (A), (B), (C), (D) and, where appropriate (E) and / or F, may also comprise a corticosteroid.

According to another mode of formulation, provision may be made for the means (A) in association essentially with the means (C) or (D) to be housed in a film matrix progressively releasing the means (A) and any other means (C) and (D) associates; said matrix being capable of being biodegradable. According to this latter mode of formulation, the administration of the means (A) is carried out either at the level of the epidermis, or percutaneously or transdermally.

It is important during the process for preparing the composition according to the invention, in particular when it is aqueous, to incorporate a nonionic surfactant and better still a wetting means (F) to prevent the means (C) from is deposited on the wall of the preparation container and the means (A) and / or (B) do not precipitate in the presence of the means (D).

In this perspective, a process for the preparation of an aqueous therapeutic, cosmetic or dermopharmaceutical composition is recommended, comprising (i) a 1-phenyl-2-aminoethanol component of formula I and (ii) of Calendula tincture, said process being characterized in that we successively introduce into water

1) the tincture of Calendula as a medium (C), 2) a substance chosen from the group consisting of nonionic surfactants, wetting agents and their mixtures,

3) means (B) and (D), then

4 °) the means (A) in association with a means

antioxidant.

As a variant, a second method is recommended which is preferred according to the invention and comprises three stages for the preparation of the aqueous composition, said method being characterized in that it comprises

1 °) obtaining a first solution by successive incorporation in water

- antioxidant means (E),

- healing means (A),

- the means (D), and

- the means (C),

2) obtaining a second solution from

- wetting means (F), and

- the means (B),

then

3 °) the introduction of the second solution in the

first.

It has been found both from the therapeutic point of view in humans or warm-blooded animals as from the cosmetic and dermopharmaceutical point of view, that the use of a compound of formula I or of one of its salts non-toxic addition acts favorably on two types of skin cells: fibroblasts and keratocytes.

From the therapeutic point of view, it has been observed that the compounds of formula I and their non-toxic addition salts have a favorable action at the level of (i) the rate of healing, (ii) the evolution of the surface of the wounds. , and / or (iii) regeneration of the epidermal tissue during healing, following the interpretation of the rupture resistance test (extensiometry). In practice, it has been found that the composition containing the means (A) and (C) and in particular the therapeutic composition according to the best mode of implementation, which contains in water the means (A), (B), (C), (D) and, where appropriate, (E) and / or (F), exhibit synergistic properties conferring the aforementioned favorable effects at the level of (i) the speed of healing, (ii) the evolution of the surface of the wounds, and / or (iii) regeneration of the epidermal tissue during healing.

The compounds of formula I according to the invention have a protective effect with regard to the extension of the necrosis of the wound which is being treated. The aforementioned ketanserin stimulates the proliferation of fibroblasts; the compounds of formula I have an action on fibroblasts analogous to that of said ketanserin with the essential difference that, according to the invention, the reorganization of the underlying connective tissue is slowed down by decreasing the affinity of fibroblasts for screening collagen. By the expression "screening collagen" is meant the ability of collagen to form a network in which the linear collagen filaments are interconnected by a plurality of bridges to form a structure similar to the weft / warp structure of textiles.

The ideal resistance (to rupture) of wounds that is sought according to the invention is a compromise: it is necessary that said resistance is sufficient and that the embrittlement of the wounds is minimal. This compromise is obtained by the combination of formula I / Calendula tincture which makes it possible to reduce the decrease in breaking strength induced by the compound of formula I, thanks to the contribution of Calendula tincture (see table V). , without considerably increasing the embrittlement of the wound.

As the compounds of formula I improve the speed of healing and the evolution of the surface of the wounds, a slight decrease in the resistance to rupture of said wounds, compared to untreated animals or animals receiving only water containing of NaCl, paradoxically intervenes here as a beneficial effect at the level of regeneration of the conjunct tissue underlying tif due to the regulation of the natural proliferation of fibroblasts without inclusion of collagen capable of giving the retracted scar zones. In short, according to the invention, a regenerated smooth skin is obtained, devoid of keloids, with hair regrowth.

Corune indicated above, the cosmetic or dermopharmaceutical composition according to the invention which contains either the means (A) and, where appropriate, a corticosteroid, or the means (A), (B), (C), (D), and optionally a means (E) and / or (F) and, where appropriate, a corticosteroid, has a favorable effect on the epidermis by improving the texture of the skin and limiting the proliferation of fibroblasts. This is an important element in humans and animals (dogs, horses, etc.).

Other advantages and characteristics of the invention will be better understood on reading the following description of examples of the production of therapeutic preparations and of results of pharmacological tests. Of course, all of these elements are given by way of illustration and are in no way limiting. Examples of therapeutic preparations (also usable in cosmetics and dermopharmacy) which have been subjected to healing rate tests, to measurements of evolution of the surface of the wounds and to tests of extensiometry.

The tests in question were carried out by local application of compositions I-VII [examples 11-15 according to the invention and control (A) as well as a control batch (B) receiving no product] on standardized wounds produced in the adult male rat by tonsure of the back at the level of the spine, application for fifteen seconds of a hollow metal rod having an internal diameter of 1 cm and containing water brought to the boil by means of an immersed electrical resistance . Each wound thus produced was massaged for 30 seconds with a daily amount of 1.5 ml of water containing approximately 0.1 ml of preparation to be tested.

In a first series of tests, the healing speed was assessed by evaluating the average time for total closure of the experimental wounds. The results obtained are expressed, on the one hand, as a percentage of the corresponding value of the untreated wounds (lot B), and on the other hand, as a percentage change compared to the wounds treated with composition B (lot VI). The results obtained are recorded in Table III below.

The results of Table III show that the products of Examples 11 and 13 considerably improve the rate of healing.

Secondly, to assess the evolution of the wound surface, the areas under the surface / time curve were measured. The results expressed as indicated above are recorded in Table IV below.

The results of Table IV show that the composition of Example 13 leads to a significant improvement in the evolution of the surface of the wounds.

Third, we assessed the resistance of the wounds to rupture (extensiometry). The results obtained, which are expressed as indicated above, are reported in Table V below.

The results in Table V show that the tensile strength is inversely proportional to the concentrations of bamethan sulfate. The higher the concentration, the lower the breaking strength. It is noted in particular that the product of Example 13 (lot III) has a lower breaking strength than untreated wounds while the healing has been completed for four weeks and more. These results relating to resistance to rupture or extensiometry are in favor of a favorable decrease in the proliferation of fibroblasts.

All the results in Tables III-V show that the most advantageous composition according to the invention is that of Example 13. By way of complements, examples of compositions according to the invention obtained according to the so-called three-step process comprising obtaining a first solution and a second solution and then introduction of the second solution into the first solution.

Claims

1. Use of a substance chosen from the group consisting of

(a) 1-phenyl-2-aminoethanols of formula

in which R and R ′, which are identical or different, each represents the hydrogen atom, a C ₁ -C ₄ alkyl, benzyl or α-phenethyl group,

Z represents a C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl group, and

(b) their non-toxic addition salts, for obtaining a medicament intended for use in human and veterinary therapy as a healing agent administered locally on a wound.

2. Use according to claim 1, characterized in that the healing substance is 1- (4-hydroxyphenyl) -2-butyl-aminoethanol or one of its non-toxic addition salts.

3. Use according to claim 1, characterized in that the healing substance is 1- (4-hydroxyphenyl) -2-butylaminoethanol sulfate.

4. Therapeutic composition useful in humans and animals, in particular in any warm-blooded animal, such as mammals, for wound healing, which is characterized in that it contains, in combination with an excipient for physiologically acceptable local administration, at least one compound of formula I or one of its non-toxic addition salts, as a healing agent.

5. Therapeutic composition according to claim 4, characterized in that it contains (i) 60 to 1200 parts by weight of a healing substance chosen from the group consisting of the compounds of formula I and their non-toxic addition salts, and

(ii) 0.05 to 35 parts by weight of a substance chosen from the group consisting of quaternary ammonium compounds, anti-inflammatory agents and their mixtures.

6. Composition according to claim 5, characterized in that it contains

(i) 60 to 1200 parts by weight of a healing substance chosen from the group consisting of the compounds of formula I and their non-toxic addition salts, and

(ii) 0.05 to 10 parts by weight of tincture of Calendula as an anti-inflammatory substance.

7. Therapeutic composition according to claim 4, characterized in that it contains, in association with an excipient for physiologically acceptable local administration,

(C) 0.05 to 10 parts by weight of Calendula tincture.

8. Therapeutic composition according to claim 7, characterized in that it also contains

(D) 2000 to 3000 parts by weight of an alkaline salt chosen in particular from the group comprising sodium chloride, potassium chloride, calcium chloride, sodium sulfate, potassium sulfate, zinc sulfate , calcium sulfate and their mixtures.

9. Therapeutic composition according to any one of claims 7 and 8, characterized in that it contains in outraged

(E) an antioxidant means, and / or

(F) a wetting medium.

10. Use in cosmetics or dermopharmacy of a l-phenyl-2-aminoethanol derivative, characterized in that the cosmetic or dermopharmaceutical means improving the texture of the skin by limiting the proliferation of fibroblasts is chosen from the group consisting of

(a) 1-phenyl-2-aminoethanols of formula

Z represents a C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl group, and

(b) their non-toxic addition salts.

11. Cosmetic or dermopharmaceutical composition useful in humans for improving the texture of the skin, which is characterized in that it contains, in combination with an excipient for physiologically acceptable local administration, at least a compound of formula I or the one of its non-toxic addition salts, as an agent limiting the proliferation of fibroblasts.

12. A process for the preparation of an aqueous therapeutic, cosmetic or dermopharmaceutical composition comprising (i) a 1-phenyl-2-aminoethanol component of formula I according to claim 1, and (ii) of Calendula tincture, said process being characterized in that we successively introduce into water 1 °) the tincture of Calendula as a means (C), 2 °) a substance chosen from the group consisting of nonionic surfactants, wetting agents and their mixtures,

3) means (B) and (D), then

4) the means (A) in combination with an antioxidant means.

13. Process for the preparation of an aqueous therapeutic, cosmetic or dermopharmaceutical composition comprising (i) a 1-phenyl-2-aminoethanol component of formula I, according to claim 1, and (ii) of Calendula tincture, said process , which comprises three stages, being characterized in that it comprises

1 °) obtaining a first solution by successive incorporation in water

- antioxidant means (E),

- healing means (A),

- the means (D), and

- the means (C),

2) obtaining a second solution from

- wetting means (F), and

- the means (B),

then

3 °) the introduction of the second solution in the

first.