FR2648709A1 - NOVEL USE OF 1-PHENYL-2-AMINOETHANOL DERIVATIVES AS HEALING MEANS - Google Patents

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 alpha -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

NOVEL USE OF 1-PHENYL-2-AMINOETHANOL DERIVATIVES
AS CIVARIZING MEANS
FIELD OF THE INVENTION
The present invention relates to a new use in human as well as veterinary therapeutics of 1-phenyl-2-aminoethanol derivatives of formula I below, in which the phenyl ring contains at least one hydroxyl group which may be etherified or esterified, as cicatrizing means. .

 It also relates to a composition useful in veterinary therapy, in human therapy and, where appropriate, in cosmetics and 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 preparing such a composition.

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

in which
X represents OH or an alkoxy group
Y represents H, OH or an alkoxy group
X and Y attached to two carbon atoms
adjacent to the phenyl ring can form
together a methylenedioxy group,
R1 and R2, identical or different, represent
each H, a C1-C8 alkyl group, a group
hydroxyalkyl, aralkyl, piperonyl,
2-phenyl-2-hydroxyethyl, R1 and R2 considered
together that can form with the nitrogen atom
to which they are linked an N-heterocyclic group
saturated with 5-7 somnets such as pyrrolidino,
piperidino, morphol ino, thiomorpholino, piper
zino, 4-methylpiperazino, 4- (2-hydroxyethyl) -
piperazino, 4-phenylpiperazino or hexamethylene
imino, as well as their addition salts.

 In particular, the Merck Index, 10th edition (1983), norfénéfrine [see pages 960-961; systematic nomenclature: 1- (3-hydroxyphenyl) -2-aminoethanol], octopamine tcf page 971 and US-A-2,585,988; systematic nomenclature: 1- (4hydroxyphenyl) -2-aminoethanol], normetanephrine [cf page 962; systematic nomenclature: 1- (4-hydroxy-3-methoxyphenyl) -2-aminoethanol], as adrenergic means useful in human therapy, on the one hand, norepinephrine tcf page 960; systematic nomenclature: 1- (3,4-dihydroxyphenyl) -2-aminoethanol], whose form 1 is presented as useful in human therapeutics (as adrenergic means) and in veterinary therapy (as sympathomimetic means) on the other hand, and Bamethan, page 138; systematic nomenclature: 1- (4-hydroxyphenyl) -2-butylaminoethanol], as vasodilator means useful in human therapy, on the other hand finally.

On the other hand, other products of formula Io are found in the following patent documents - GB-A-1,043,519 which describes compounds of formula Io, where X = OH or alkoxy, Y = H, R1 = C (CH3) 3 and R2 = CH3, as antidiuretic means; the French patent FR-A-1 372 742 which describes the compound of formula Io, where X = 4-COH3, Y = 3-OCH3, R1 = C (CH3) 3 and R2 = H, as an inhibitor of S-adrenergic receptors; the French patent FR-B-2,460,668 which describes compounds of formula Io, where X = 4-OCH3, Y = H, R1 = C14 alkyl or p-CH2CHOH-C6H4-A (where A is H, CH3 or oCH3)> and R2 = alkyl in
C5-C8 with a branched hydrocarbon chain, piperonyl or 2- (1-hydroxy-phenylpropyl), as antidepressant or vasodilator means; British Patent Application GB-A-2 151 612 which describes compounds of formula Io, where X = OCH 3, Y w R 1 = H, and
R2 = C4-C8 alkyl, wherein said alkyl residue comprises a branched hydrocarbon chain, as active agents on the CNS (in particular, as antidepressants or sedatives) or the cardiovascular system (especially as vasodilators).

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

 The aforementioned prior art neither discloses nor suggests the use of the compounds of formula Io as healing agents for the treatment of wounds in humans and animals, on the one hand, and in cosmetics or dermopharmacy on the other hand. care of the epidermis in humans, on the other hand. In addition, the compounds of formula I below according to the invention are structurally different from the aforementioned ketanserine.

PURPOSE OF THE INVENTION
Surprisingly, it has been found that certain compounds included in formula Io above are particularly useful as healing agents on the one hand, and as useful agents in cosmetics and dermopharmacy, on the other hand, when they are administered topically.

 More precisely according to the invention, a new technical solution is proposed for solving the problem of wound healing. This new technical solution uses 1-phenyl-2-eminoethanol 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 ', identical or different,
each represent the hydrogen atom, a group
C1-C4 alkyl, benzyl, or o-phenethyl,
Z represents a C1-C5 alkyl group or
C3-C6 cycloalkyl, and
(b) their non-toxic addition salts, for obtaining a medicament for use in human and veterinary therapy as a wound healing agent administered locally to a wound.

 According to a second aspect of the invention, a therapeutic composition is also recommended, which is useful both in humans and in animals for the healing of wounds, said composition being characterized in that it contains, in association with a physiologically excipient. acceptable (i) at least one compound of formula I or one of its nontoxic addition salts, and (ii) a substance selected from quaternary ammoniums, anti-inflammatory agents and mixtures thereof.

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

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

DESCRIPTION DEZAILLg8 DB THE INVENTDON
As indicated above, the compounds of formula I are included in the general definitions of the products of formula Io, especially when R = H or alkyl, R '= H, and Z is alkyl, or derive therefrom when R' is different from H, and Z is a cycloalkyl group.

 The alkyl groups involved in the definition of the groups R, R 'and Z are linear or branched chain hydrocarbon radicals. In general, R and R 'are protecting groups of the OH function in ether form.

 Among the groups Z which are suitable, mention may especially be made of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-butyl, t-butyl and n-pentyl groups. dimethylpropyl, cyclopropyl, cyclopentyl and cyclohexyl.

Preferred compounds according to the invention include Bamethan [systematic nomenclature: 1- (4-hydroxyphenyl) -2-butylaminoethanol] which is a compound of Formula I wherein OR = 4H,
R '= H and Z = n-butyl, on the one hand, and its nontoxic addition salts, in particular sulphate, on the other hand.

 By addition salts is meant here acid addition salts obtained by reaction of a free base of formula I with an inorganic or organic acid, on the one hand, and the salts of aluminum, of somewhere else. Among the acids which can be used for salifying the free bases of formula I, mention may in particular be made of hydrochloric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, succinic, benzotcan, cinnamic, mandelic, citric, malic, tartaric and aspartic acids. , glutamic, methanesulfonic, p-toluenesulfonic. Among the compounds making it possible to obtain ammonium salts, there may be mentioned in particular alkyl halides (especially C1-C10), 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, especially US-A-2,585,988, GB-A-1,043,519, FR-A-1,372,742,
FR-B-2,460,668 and GB-A-2,151,612. The compounds of formula I, wherein R 'is alkyl, benzyl or -phenethyl, can be obtained by etherification of the corresponding OH group before or after fixing the NHZ group.

 In no way limiting it is noted in Table I below a number of compounds that are suitable according to the invention.

TABLE I

<tb> Product <SEP> OR <SEP> R '<SEP> Z
<tb> Ex <SEP> 1 <SEP> (a) <SEP> 4-OH <SEP> H <SEP> CH2CH2CH2CH3
<tb> Ex <SEP> 2 <SEP> (b) <SEP> 4-OH <SEP> H <SEP> C (CH3) 3
<tb> Ex <SEP> 3 <SEP> (a) <SEP> 3-OH <SEP> H <SEP> CH2CH2CH2CH3
<tb> Ex <SEP> 4 <SEP> (c) <SEP> 3-OH <SEP> H <SEP> CH (CH3) 2
<tb> Ex <SEP> 5 <SEP> (b) <SEP> 4-OH <SEP> H <SEP> cyclopropyl
<tb> Ex <SEP> 6 <SEP> (b) <SEP> 4-OCH3 <SEP> H <SEP> Cyclohexyl
<tb> Ex <SEP> 7 <SEP> (d) <SEP> 4-OCH3 <SEP> CH3 <SEP> CH2CH2CH2CH3
<tb> Ex <SEP> 8 <SEP> (b) <SEP> 2-OH <SEP> H <SEP> CH2CH2CH2CH2CH3
<tb> Ex <SEP> 9 <SEP> (b) <SEP> 3-OCH3 <SEP> CH3 <SEP> CH2CH2CH2CH3
<Tb>
Notes (a) sulfate (b) hydrochloride (c) hemifumarate (d) methanesulfonate
According to the invention, a therapeutic composition is recommended which is useful in humans and animals, in particular in any warm-blooded animal, such as mammals, for the healing of wounds, which is characterized in that it contains, in combination with a physiologically acceptable local administration excipient, 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 to use 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 a physiologically acceptable local administration excipient, at least a compound of formula I or a non-toxic addition salt thereof as an agent for 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 therapeutically or cosmetically dose. or dermopharmaceutically effective.

 In a practical way, the physiologically acceptable excipient of the therapeutic or cosmetic composition, will be an excipient for local or topical use and will include an aqueous or oily liquid vehicle or a vehicle of the emulsion type oil-in-water or water-in-oil . Among the suitable vehicles there may be mentioned lotions, ointments and creams which may contain other galenically useful fillers such as, in particular surfactants, preservatives, anti-UV means and / or compounds (especially inorganic or organic salts to stabilize the pH or to impart hypertonic osmotic properties to said composition.

Advantageously, the healing therapeutic composition will contain (i) 60 to 1200 parts by weight of a healing substance
selected 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 selected from
the group consisting of ammonium compounds
quaternary, anti-inflammatory agents and their
mixtures.

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

 Suitable quaternary ammonium compounds include halides (such as bromides and chlorides) of benzalkonium, cetylpyridinium, cetyltrimethylammonium, cetyldimethylethylammonium, cetyldimethyl, and the like. 2-hydroxycyclohexyl) aminoin, benzothononium, methylbenzethonium which are known as anti-infective or antiseptic means, on the one hand, or as detergent means for wounds such as chloride and thonzonium bromide, on the other hand . Conveniently, quaternary ammonium will be used as an antiseptic agent, preferably benzalkonium chloride.

 The anti-inflammatory agents involved in the healing therapeutic composition according to the invention are advantageously chosen from non-alkaloidal anti-inflammatory substances. In particular, locally-administered anti-inflammatory agents such as steroidal anti-inflammatory agents and anti-inflammatory agents derived from anthranilic acid, ie, niflumic acid, which corresponds to the systematic nomenclature of 2 - [[3- (trifluoroethyl) phenyl] amino] -3-pyridinecarboxylic acid.

 According to the invention it is preferred to use an anti-inflammatory agent to prevent the retraction of wounds, for example a plant extract of a plant belonging to the family of compounds. In a practical way, it is more particularly preferred to use as an anti-inflammatory agent according to the invention an extract of Calendula (French nomenclature "marigold") and better the mother tincture of Calendula which is obtained according to the indications of the present invention. French pharmacopoeia, especially from the species Calendula officinalis.

According to the best mode of implementation of the therapeutic healing composition of the invention, it is recommended a composition which is characterized in that it contains, in association with a physiologically acceptable local administration excipient,
(A) 60 to 1200 parts by weight of a healing substance selected from the group consisting of the compounds of formula I, their non-toxic addition salts and mixtures thereof,
(B) 10 to 25 parts by weight of a substance selected from the group consisting of quaternary ammonium compounds and mixtures thereof,
(C) 0.05 to 10 parts by weight of mother tincture of Calendula
Advantageously, according to this best mode, such a composition will contain, as a means of healing (A), bamethan or one of its non-toxic addition salts, in particular sulphate, on the one hand, and minus a salt of a metal groups
I, IIa and IIb of the Periodic Table in an amount sufficient to provide 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 selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium sulfate, potassium sulfate, zinc sulfate, calcium sulphate and mixtures thereof; and
(E) optionally an antioxidant means in an appropriate amount.

 The preferred antioxidant means is sodium metabisulfite, however any other antioxidant substance analogous to said metabisulfite may also be used.

In short, the healing composition will contain, in association with a physiologically acceptable local administration excipient,
(A) 60 to 1200 parts by weight of a healing substance selected from the group consisting of the compounds of formula I, their non-toxic addition salts and mixtures thereof,
(B) 10 to 25 parts by weight of a substance selected from the group consisting of quaternary ammonium compounds and mixtures thereof,
(C) 0.05 to 10 parts by weight of Calendula tincture,
(D) 9 to 3000 parts by weight of an alkaline salt selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium sulfate, potassium sulfate, zinc sulfate, calcium sulphate and mixtures thereof; and
(E) where appropriate an antioxidant means.

 The composition useful in cosmetics or dermopharmacy according to the invention may be in a form similar to that of the therapeutic healing composition. In particular the composition useful in cosmetics and dermopharmacy may be between an aqueous formulation, a gel or an ointment, comprising all the means (A), (B), (C) (D) and if appropriate (E); alternatively, the cosmetic composition comprising the means (A) or all the means (A), CB), (C), (D) and optionally (E) may further comprise a corticosteroid.

 According to another form of formulation, it can be provided that the means (4) in association essentially with the means (B), (C) or (D) is housed in a film matrix gradually releasing the means (A) and any other means (B), (C) and (D) associated; 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 essential, according to this method, to incorporate a nonionic surfactant to prevent the means (C) from being deposited on the wall of the preparation container and the means (A) and / or (B) do not precipitate in the presence of means (D).

 It has been found from the therapeutic point of view in humans or warm-blooded animals as well as from the cosmetic and dermopharmaceutical point of view that the use of a compound of formula I or a salt thereof Non-toxic addition acts favorably on two types of skin cells: fibroblasts and keratocvts.

 From a 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 cicatrization, (ii) the evolution of the wound surface and / or (iii) regeneration of the epidermal tissue during healing, following the interpretation of the tensile strength 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), have synergistic properties conferring the aforementioned favorable effects on (i) the rate of cicatrization, (ii) the evolution of the wound surface, and / or (iii) ) regeneration of the epidermal tissue during healing.

 The compounds of formula I according to the invention have a protective effect vis-à-vis the extension of the necrosis of the wound that is 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 the fibroblasts to weave collagen.

 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 weakening of the wounds are minimal. This compromise is obtained by the compound combination of formula I / tincture of Calendula which makes it possible to reduce the decrease in the breaking strength induced by the compound of formula I by the addition of tincture of Calendula (see Table V). , without significantly increasing the fragility of the wound.

 The compounds of formula I improve the healing rate and the evolution of the wound surface, a slight decrease in the breaking strength of said wounds, compared with untreated animals or animals receiving only water containing NaCl, paradoxically intervenes here as a beneficial effect in the regeneration of the underlying connective tissue due to the regularization of the natural proliferation of fibroblasts without inclusion of collagen likely to give retracted scarred areas. Briefly according to the invention there is obtained a smooth regenerated skin, free of keloids, with regrowth of hair.

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

 Other advantages and characteristics of the invention will be better understood on reading the following examples of embodiments of therapeutic preparations and pharmacological test results. Of course, all of these elements are given by way of illustration and are in no way limiting. Examples of therapeutic preparations (also useful in cosmetics and dermopharmacy) which have been subjected to cicatrization rate tests, wound surface evolution measurements, and test methods have been reported in Table II which follows. 'tensile testing.

 The tests in question were carried out by topical application of the compositions I-VII [Examples 11-15 according to the invention and control (A) as well as a control batch (B) receiving no product] on standard wounds carried out 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 electrical resistance submerged. Each wound thus made was massaged for 30 seconds with a daily quantity of 1.5 ml of water containing about 0.1 ml of test preparation.

TABLE II

Examples <SEP> Ex <SEP> 11 <SEP> Ex <SEP> 12 <SEP> Ex <SEP> 13 <SEP> Ex <SEP> 14 <SEP> Ex <SEP> 15 <SEP> A * <SEP> B **
<tb> (batch) <SEP> (I) <SEP> (II) <SEP> (III) <SEP> (IV) <SEP> (V) <SEP> (VI) <SEP> (VII)
<tb> Sulfate <SEP> from <SEP> bamethan <SEP> (a) <SEP> 0.12 <SEP> g <SEP> 0.12 <SEP> g <SEP> 0.12 <SEP> g <SEP > 1,2 <SEP> g <SEP> 1,2 <SEP> g <SEP> 0 <SEP> 0
<tb> Chloride <SEP> of <SEP> Benzalkonium <SEP> 0.02 <SEP> g <SEP> 0.02 <SEP> g <SEP> 0.02 <SEP> g <SEP> 0.02 <SEP > g <SEP> 0.02 <SEP> g <SEP> 0 <SEP> 0
<tb> Tincture <SEP> of <SEP> Calendula <SEP> 0 <SEP> 5 <SEP> ml <SEP> 0.5 <SEP> ml <SEP> 5 <SEP> ml <SEP> 0 <SEP> 0 <SEP> 0
<tb> chloride <SEP> of <SEP> sodium <SEP> 2,6 <SEP> g <SEP> 2,6 <SEP> g <SEP> 2,6 <SEP> g <SEP> 2,6 <SEP > g <SEP> 2.6 <SEP> g <SEP> 2.6 <SEP> g <SEP> 0
<tb> Water <SEP> QSP <SEP> 100 <SEP> ml <SEP> 100 <SEP> ml <SEP> 100 <SEP> ml <SEP> 100 <SEP> ml <SEP> 100 <SEQ> ml <SEP > 100 <SEP> ml <SEP> 0
<tb> Notes * first batch control (VI) receiving solution A containing sodium chloride; ** second control lot (VII) including untreated animals; (a) Product of Example 1 of Table I above.

 In a first series of trials, the healing rate was assessed by evaluating the mean total closing time of the experimental wounds. The results obtained are expressed, on the one hand, as a percentage of the corresponding value of untreated wounds (batch B), and, on the other hand, as a percentage of variation with respect to wounds treated with composition A (lot VI). The results obtained are recorded in Table III below.

TABLE III
HK3YEN TOTAL CLOSURE TIME FOR WOUNDS
Example Percentages by Percentage of Variation
(lot) atnc untreated wounds compared to the
product A
11 (I) 77 - 25
12 (II) 89 - 13
13 (III) 73 - 28
14 (rV) 91
15 (v) 105 + 3
A (VI) 102
The results in Table III show that the products of Examples 11 and 13 considerably improve the healing rate.

 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 given in Table IV below.

TABLE IV
EVOLUTION OF THE SURFACE OF WOUNDS

<tb> Example <SEP> Percentages <SEP> by <SEP> report <SEP> Percentage <SEP> of <SEP> varia
<tb><SEP> (batch) <SEP> to <SEP> wounds <SEP> no <SEP> treated <SEP> tion <SEP> by <SEP> report <SEP> to
<tb><SEP> product <SEP> A
<tb> 11 <SEP> (I) <SEP> 90 <SEP> - <SEP> 13
<tb><SEP> 12 <SEP> (II) <SEP> 95 <SEP> -8
<tb> 13 <SEP> (III) <SEP> 75 <SEP> - <SEP> 27
<tb><SEP> 14 <SEP> (IV) <SEP> 94 <SEP> -9
<tb> 15 <SEP> (V) <SEP> 90 <SEP> - <SEP> 13
<tb> A <SEP> (VI) <SEP> 103
<Tb>
The results of Table 1V show that the composition of Example 13 leads to a significant improvement in the evolution of the wound surface.

Thirdly, the resistance of the wounds to rupture (extensiometry) was appreciated. The results obtained, which are expressed as indicated above, have been recorded in Table V below. TABLE 3 V RESISTAZJCE OF WOUNDS AT BREAK

<tb> Example <SEP> Percentages <SEP> by <SEP> report <SEP> Percentage <SEP> of <SEP> varia
<tb><SEP> (batch) <SEP> to <SEP> wounds <SEP> no <SEP> treated <SEP> tion <SEP> by <SEP> report <SEP> to
<tb><SEP> product <SEP> A
<tb><SEP> li <SEP> (I) <SEP> 83 <SEP> - <SEP> 8 <SEP>
<tb><SEP> 12 <SEP> (II) <SEP> 79 <SEP> - <SEP> 12
<tb><SEP> 13 <SEP> (III) <SEP> 65 <SEP> - <SEP> - <SEP> 28
<tb><SEP> 14 <SEP> (rV) <SEP> 57 <SEP> - <SEP> 37
<tb><SEP> 15 <SEP> (V) <SEP> 57 <SEP> - <SEP> 37
<tb><SEP> A <SEP> (VI) <SEP> 90
<Tb>
The results in Table V show that the tensile strength is inversely oroportional to the concentrations of béthan sulfate. The higher the concentration, the lower the resistance to fracture. It is found in particular that the product of Example 13 (batch III) has a lower breaking strength than untreated wounds while healing has been completed for four weeks and

Claims (10)

1. Use of a substance chosen from the group consisting of (a) 1-phenyl-2-aminoethanols of formula in which R and R ', which may be identical or different, each represent a hydrogen atom, a group C1-C4 alkyl, benzyl or -phenethyl, Z represents a C1-C5 alkyl or C3-C6 cycloalkyl group, and b) their non-toxic addition salts, for the purpose of obtaining a drug for for use in human and veterinary therapy as a wound healing agent administered locally to a wound. 2. Use according to claim 1, characterized in that the healing substance is 1- (4-hydroxyphenyl) -2-butylaminoethanol 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.  Useful therapeutic composition in the human and animal, in particular in any warm-blooded animal, such as mammals, for the healing of wounds, which is characterized in that it contains, in combination with a vehicle for local administration physiologically acceptable, at least one compound of formula T 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  selected 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 selected from  the group consisting of ammonium compounds  quaternary, 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  selected 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 Calendula tincture  as an anti-inflammatory substance. 7. Therapeutic composition according to claim 4, characterized in that it contains, in combination with a physiologically acceptable local administration excipient,  (A) 60 to 1200 parts by weight of a healing substance selected from the group consisting of the compounds of formula I, their non-toxic addition salts and mixtures thereof,  (B) 10 to 25 parts by weight of a substance selected from the group consisting of quaternary ammonium compounds and mixtures thereof,  (C) 0.05 to 10 parts by weight of tincture of Calendula. 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 sulphate, potassium sulphate and zinc sulphate calcium sulphate and mixtures thereof. 9. Therapeutic composition according to any one of claims 7 and 8, characterized in that it also contains  (E) antioxidant means, especially sodium metahisulphite. 10. Use in cosmetics or dermopharmacy of a 1-phenyl-2-aminoethanol derivative, characterized in that the cosmetic or dermophanmaceueic 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

 in which R and R ', identical or different,  each represent the atone of hydrogen, a  C1-V4 alkylene group, benzyl or alpha-phenethyl,  Z represents a C 1 -C 5 alkyl group or  C3-C6 cycloalkyl, 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 a vehicle for physiologically acceptable local administration, at least one connotation of formula I or one of its non-toxic addition salts, as an agent limiting the proliferation of fibroblasts. A process for the preparation of an aqueous therapeutic, cosmetic or dermopharmaceutical composition comprising the means (A), (B), (C), (D) and (E) according to any one of claims 9 and 11, for administration local, said method being characterized in that the means (C), namely the dyeing of Calendula, 20) a non-ionic surfactant, are introduced successively into water (30). B) and (D), and 40) the means (A) in combination with an antioxidant.