WO2004032914A2

WO2004032914A2 - Use of a propargyl alcohol enantiomer for the treatment of dermatological disorders

Info

Publication number: WO2004032914A2
Application number: PCT/EP2003/008624
Authority: WO
Inventors: Jean-Claude Caron
Original assignee: Galderma Research & Development, S.N.C.
Priority date: 2002-08-20
Filing date: 2003-08-04
Publication date: 2004-04-22
Also published as: AU2003293295A1; AU2003293295A8; WO2004032914A3

Abstract

The invention relates to the specific use of a pure enantiomer of 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8tetrahydro-5,5,8,8tetramethyl-2-naphthyl)-1propynyl] benzoic acid in the S (+) configuration, of formula (I) below: or one of its salts, for preparing a pharmaceutical composition intended for use in human and/or veterinary medicine. The present invention also relates to a pharmaceutical composition comprising, in a physiologically acceptable carrier, at leas2-hydroxy4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 2-naphthyl)-1-propynyl] benzoic acid in the S (+) configuration, of formula (I), or one of its salts.

Description

USE OF A P OPARGYL ALCOHOL ENANTIOMER

The subject of the present invention relates to the use of the S(+) enantiomer of 2-hydroxy-4- [3- hydroxy-3- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2- naphthyl) -1-propynyl] benzoic acid for preparing a pharmaceutical composition intended for use in human and/or veterinary medicine.

In the context of the development of novel pharmaceutical active principles, the applicant has synthesized racemic organic molecules, in particular propargyl alcohols, of formula (II) below:

(ID

Such compounds have already been described in European Patent EP 0 661 258, which relates to bi- aromatic compounds exhibiting a propynyl unit of the family of retinoids having marked activity in the cell differentiation and proliferation fields, and also to their use in pharmaceutical compounds intended for use in human or veterinary medicine, or else in cosmetic compositions.

Subsequent to pharmacological studies which revealed unexpected properties of the enantiomer in the S(+) configuration of 2-hydroxy-4- [3-hydroxy-3- (5,6,7, 8-tetrahydro-5, 5,8, 8~tetramethyl~2-naphthyl) -1- propynyl] benzoic acid, the applicant proposes, in the present invention, the use of the enantiomer of formula

(I) below:

(»)

There is nothing in the prior art which pushed those skilled in the art to choose the racemate or one or other of the enantiomers.

In fact, studies of toxicity after topical or oral administration of the racemate and of the two enantiomers have not made it possible to show significant differences in rats and in dogs.

Similarly, several studies of activity measurements, carried out topically or orally, show no significant difference between the various enantiomers and their racemate.

It is, moreover, known that the use of an enantiomer involves difficulties in developing a process of chemical synthesis. Due to these difficulties, those skilled in the art were therefore rather inclined to use the racemic compound. In addition, since the activities and the toxicities do not exhibit any significant difference, this implies that the pharmacokinetic parameters will be similar.

Through analysis of the pharmacokinetic data of these two enantiomers, the applicant has noted, surprisingly, that the pharmacokinetic results for the two enantiomers obtained in rats and in dogs show significant differences in clearance, the ability of the organism to eliminate the enantiomer. The clearance of the enantiomer in the S configuration is 2- to 2.5- fold less than that of the enantiomer in the R configuration. This lower clearance therefore means that the enantiomer in the S configuration has a lower rate of elimination. The direct consequence of this difference is a greater total systemic exposure for the enantiomer in the S configuration. Furthermore, the applicant has noted that the enantiomer in the S configuration has a lower metabolism than the enantiomer in the R configuration. At equal toxicity, the enantiomer in the S configuration therefore exhibits the greatest exposure in the organism and has the greatest chance of reaching the tissue target in the form of a parent, and therefore active, product. The desired biological effect may therefore be obtained with a lower dose or a weaker dosage of the S enantiomer compared to the R enantiomer. These properties make the use of this enantiomer very advantageous .

The invention therefore relates to the selective use of the compound of formula (I) , 2- hydroxy-4- [3-hydroxy-3 - (5 , 6 , 7 , 8-tetrahydro-5,5,8,8- tetramethyl-2-naphthyl) -1-propynyl] benzoic acid in the S(+) configuration, or one of its salts, for preparing a pharmaceutical composition.

When the compound of formula (I) according to the invention is in the form of salts, they are preferably salts of alkali or alkaline earth metal, or, alternatively of zinc or of an organic amine. The invention also relates to the selective use of the compound of formula (I), 2-hydroxy-4- [3- hydroxy-3- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2- naphthyl) -1-propynyl] benzoic acid in the S(+) configuration, or one of its salts, for preparing a pharmaceutical composition intended to treat pathological conditions in the following fields:

1) for treating dermatological complaints associated with a keratinization disorder which has a bearing on cell differentiation and proliferation, in particular for treating common acne, comedo-type acne, polymorphic acne, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne such as solar, drug-related or occupational acne;

2) for treating other types of keratinization disorder, in particular ichthyosis, ichthyosiform states, Darrier's disease, palmoplantar keratoderma, leukoplasias and leukoplasiform states, and cutaneous or mucosal (buccal) lichen;

3) for treating other dermatological complaints with an inflammatory immunoallergic component, with or without a problem of cell proliferation, and in particular all forms of psoriasis, whether it is cutaneous, mucosal or ungual psoriasis, and even psoriatic rheumatism, or else cutaneous atopy, such as eczema or respiratory atopy or else gingival hypertrophy; 4) for treating all dermal or epidermal proliferations, whether benign or malignant or whether or not they are of viral origin, such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses, T lymphoma, and proliferations which may be induced by ultraviolet radiation, in particular in the case of basocellular and spinocellular epithelioma, and also any precancerous skin lesion such as keratoacanthomas ;

5) for treating certain ophthalmological disorders, in particular corneopathies ;

6) for preventing or curing stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; 7) for treating skin, disorders due to exposure to UN radiation, and also for repairing or combating ageing of the skin, whether this is photo- induced or chronological ageing, or for reducing actinic keratoses and pigmentations, or any pathological conditions associated with chronological or actinic ageing, such as xerosis; 8) for combating disorders of sebaceous function, such as hyperseborrhoea of acne or simple seborrhoea;

9) for treating pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo.

The subject of the present invention relates more particularly to the use of the enantiomerically pure alcohol, which is 2-hydroxy-4- [3-hydroxy-3- (5,6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthyl) -1- propynyl] benzoic acid in the S(+) configuration, of formula (I) below:

(I) or one of its salts, for preparing a pharmaceutical composition intended for the treatment of dermatological complaints, and in particular common acne, comedo-type acne, polymorphic acne, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne such as solar, drug-related or occupational acne, cutaneous, mucosal or ungual psoriasis, psoriatic rheumatism or cutaneous atopy, such as eczema, respiratory atopy or gingival hypertrophy, xerosis, hyperpigmentation, melasma, hypopigmentation or vitiligo.

In the present invention, the term "enantiomerically pure" is intended to mean a compound for which the chiral purity of the alcohol obtained is greater than 97%, preferably greater than 98%, and even more preferentially greater than 99%.

In a preferred variant of the use according to the present invention, the dermatological complaints are forms of acne.

A subject of the present invention is also a novel pharmaceutical composition intended in particular for the treatment of the abovementioned complaints, and which is characterized in that it comprises, in a ^' physiologically acceptable carrier, at least 2-hydroxy- 4- [3-hydroxy-3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl- 2-naphthyl) -1-propynyl] benzoic acid in the S(+) configuration of formula (I) below:

(I) or one of its salts. The composition according to the invention can be administered orally, enterally, parenterally, topically or ocularly. Preferably, the pharmaceutical composition is packaged in a form suitable for oral administration.

Via oral administration, the composition may be in the form of tablets, of gelatin capsules, or sugar-coated tablets, of syrups, of suspensions, of solutions, of powders, of granules, of emulsions, of suspensions of microspheres or nanospheres or of lipid or polymeric vesicles which allow controlled release. Via parenteral administration, the composition may be in the form of solutions or suspensions for infusion or for injection. Via oral administration, the compound according to the invention is generally administered at a daily dose of approximately 0.01 mg/kg to 100 mg/kg, preferably between 0.05 mg/kg and 20 mg/kg, of body weight, taken in 1 to^* 3 doses. In a particular embodiment according to the invention, the composition is administered orally and the concentration of enantiomerically pure alcohol of formula (I) is between 0.01 mg/kg and 100 mg/kg, preferably between 0.05 mg/kg and 20 mg/kg, of body weight, taken in 1 to 3 doses.

The compound is used systemically at a concentration generally of between 0.1% and 100% by weight, preferably between 1% and 50% by weight, relative to the weight of the composition. Via topical administration, the pharmaceutical composition according to the invention is more particularly intended for treating the skin and mucous membranes, and may be in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks, pomades, powders, impregnated pads, syndets, solutions, gels, sprays, foams, suspensions, sticks, shampoos or washing bases. It may also be in the form of suspensions of microspheres or nanospheres or of lipid or polymeric vesicles or of polymeric or gelled patches allowing a controlled release.

In a particular embodiment according to the invention, the composition is applied topically and the concentration of enantiomerically pure alcohol of formula (I) is between 0.00001% and 10%, preferably between 0.001% and 2%, advantageously 0.1%, by weight relative to the total weight of the composition. The composition according to the invention is particularly suitable for the treatment of dermatological complaints, preferably forms of acne.

The pharmaceutical compositions as described above may also contain inert additives, or even pharmacodynamically active additives as regards the pharmaceutical compositions, or combinations of these additives, and in particular: - wetting agents;

- flavour enhancers;

- preserving agents such as para-hydroxybenzoic acid esters; - stabilizers;

- moisture regulators;

- pH regulators;

- osmotic pressure modifiers;

- emulsifiers; - UN-A and UN-B screening agents;

- antioxidants;

- emollients;

- moisturizers.

Of course, those skilled in the art will take care to select the optional compound (s) to be added to these compositions such that the advantageous properties intrinsically attached to the present invention are not, or are not substantially, adversely affected by the envisaged addition. The invention relates more specifically to the use of the enantiomerically pure alcohol in the S(+) configuration of formula (I) below:

(I) or one of its salts, for preparing a pharmaceutical composition, said alcohol of formula (I) exhibiting pharmacokinetic parameters different from that of the racemic compound and of the enantiomer in the R configuration, and more particularly the alcohol of formula (I) exhibits a clearance significantly different from that of the racemic compound and of the enantiomer in the R configuration.

The following examples give a nonlimiting description of the studies of toxicity, of activity and of pharmacokinetics carried out with the racemic compound and the two enantiomers . A protocol for synthesis of the pure enantiomer in the S(+) configuration is also provided.

Example 1: 4-week toxicity study in rats

The racemic mixture and each one of the two enantiomers are suspended in carboxycellulose and then administered orally once a day for 28 days to three groups of Sprague-Dawley rats (10 males and 10 females per group) at doses of 0 (vehicle), 0.1, 0.5 and 1.5 mg.kg^.day^"1.

Clinical observations: In the three groups of rats, the clinical side effects observed are: hair loss from the dose of 0.1 mg.kg^"1, a skin irritation and a decrease in body weight gain from 0.5 mg.kg^"1.day^"1.

Histopathological observations :

Changes in the bone, observed at necropsy and confirmed on histopathological examination indicate greater epiphyseal ossification, a thickening and/or a disorganization and/or a loss of the epiphyseal plate. The other microscopic changes are restricted to changes in the skin, associated with a skin irritation, with slight hyperkeratosis and acanthosis.

These effects are observed from 0.1 mg.kg^"1.day^"1. The NOEL (No Effect Level Dose: maximum dose which induces no toxic effect) for the bone and skin changes was measured at less than 0.1 mg.kg^"1.day^"1 for the three compounds. Under the experimental conditions defined above, the racemic compound and the two enantiomers induce qualitatively and quantitatively the same toxic effects in accordance with those conventionally observed for compounds of the retinoid family.

Example 2; Study of the anti-inflammatory activity of the racemic compound and of its two enantiomers using tests of induction of keratinocyte proliferation in vivo induced by single topical application of TPA (100 μl at 0.05% in acetone)

The anti-inflammatory activity of the compounds tested is evaluated by analysing the modification of the inflammatory response induced after application of TPA, namely the decrease in oedema.

The test products are administered orally in 25% cremophore EL in a proportion of 10 ml/kg for seven days preceding the topical application of TPA (from D-7 to D-l) . The topical application of TPA at 0.05% in acetone takes place on DO of the study, on rats shaved 24 h beforehand.

Under these experimental conditions, the application of TPA at a concentration of 0.05% induces a clinically observable erythema 2 h after application of the TPA, which reaches a maximum at time 48 h post- application, representing a score of 3.75 + 0.16.

The cremophore administered from D-7 to D-l does not significantly modify the TPA-induced response. The racemic mixture, the S enantiomer and the R enantiomer, administered from D-7 to D-l at a dose of 3 mg/kg, significantly reduce the response induced by the topical application of TPA, respectively by 33% (p=0.0039), 29% (p=0.0074) and 30% (p=0.0054) at 24 h. At 48 h, the racemic mixture, the S enantiomer and the R enantiomer respectively reduce the TPA-induced erythema by 16% (p not significant) , 19% (p=0.0357) and 13% (p not significant). In this assay, the three products are equipotent.

Example 3 : Comparison of the pharmacokinetic profiles for the S enantiomer and for the R enantiomer in Sprague-Dawley rats (OFA ICO) after single intravenous administration at doses of 0.5, 1.5 and 5 mg.kg^"1

The pharmacokinetic parameters are determined by non-compartmental analysis (Kinetica™, SIMED) of the change in mean plasma concentrations as a function of time. The calculation of the AUCs (Area under the concentration curve. Cf. review of a technique for the estimation of area under the concentration curve in pharmacokinetic analysis, Therapy, 1993 Jan-Feb, 48 (1) , 1-5) (0-inf) is performed using the linear/logarithmic trapezium method.

These results indicate significant differences between the pharmacokinetic parameters of the two enantiomers. Since the clearance of the S enantiomer is in particular 2 to 2.5 times lower than that of the R enantiomer, this lower clearance therefore means that the enantiomer in the S configuration has a lower rate of elimination, and the systemic exposure (AUC) is therefore greater.

Example 4; Preparation of S- (+) -2 -hydroxy- 4- [3-hydroxy- 3- (5, 6, 7 , 8 - tetrahydro- 5 , 5 , 8, 8 - tetramethylnaphthalen- 2 - yl) -1 -propynyl] benzoic acid

The compound 1- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8- tetramethylnaphthalen-2-yl)prop-2-yn-l-ol (31.0 kg) of formula:

is brought into contact with Amano lipase PS 30

(6.2 kg) and vinyl acetate (11.0 kg) at a temperature below 40°C, in the presence of heptane (47 litres) . The mixture is heated at a temperature of approximately 36 to 40°C for 33 hours with mechanical stirring. The mixture is then cooled to a temperature of approximately 25/30°C. The enzyme in suspension is then filtered from the reaction mixture containing the acetate in the desired R configuration and the alcohol in the S configuration. The mixture is heated again at 40/50°C in order to evaporate at constant volume most of the solvents and reagents. A mixture of 108 kg of alcohol in the S configuration and acetate in the R configuration, in solution in heptane, is thus obtained.

Added to the heptane-based solution of S alcohol and R acetate obtained above are 10 litres of heptane cooled to 0/-5°C, and 14.3 kg of tri-n- butylphosphine (TBP) at a temperature below 25°C, in the presence of 4.22 kg of 99% acetic acid at a temperature below 7°C. The mixture is cooled to θ/5°C before adding thereto 14.5 kg of diisopropyl azodicarboxylate (DIAD) at a temperature below 5°C. The mixture is then reheated to a temperature of approximately 20°C and maintained at this temperature for 2 hours 45 min. The phosphine oxide and the DIAD derivative obtained alongside the acetate in the desired configuration are removed by liquid-liquid extraction (2 extractions with 5 volumes of a methanol/water mixture (85:15), then 2 counter-extractions with 5 volumes of heptane, and then 1 extraction with 5 volumes of methanol/water (85:15).

The trans-esterification of the R acetate is carried out in the presence of sodium carbonate (27.1 kg) and methanol (155 litres), heating the mixture at 40°C for 7 h 15. After the addition of a heptane/water mixture (50:50), the reaction mixture is again heated to 60/65°C in order to remove the methanol by distillation.

After separation of the organic and aqueous phases, the crystallization takes place by cooling the organic layer obtained until crystallization occurs and then maintaining it at a temperature below -5°C for 30 minutes. After filtration and then drying for approximately 11 hours at a maximum temperature of 30°C, the R(-) enantiomer of 1- (5, 6, 7, 8-tetrahydro- 5,5,8, 8-tetramethylnaphthalen-2-yl)prop-2-yn-l-ol (18.4 kg) is obtained.

The overall chemical yield for obtaining this enantiomerically pure alcohol from the formula racemic mixture is 60% and the chiral purity of the compound is 99%. The S- (+) -2-hydroxy-4- [3-hydroxy-3- (5,6, 7,8- tetrahydro-5 , 5 , 8 , 8-tetramethylnaphthalen-2 -yl) - 1- propynyl] benzoic acid below:

OH

is obtained after coupling of the R- (-) -1- (5, 6, 7, 8- tetrahydro-5, 5,8, 8-tetramethylnaphthalen-2-yl)prop-2- yn-l-ol with methyl iodo salicylate in triethylamine in the presence of Pd(PPh₃)₂Cl₂ and copper iodide, then saponification, in THF, of the ester obtained in the presence of lithium hydroxide, and then acidification with HC1.

Claims

1. Use of the enantiomerically pure alcohol of formula (I) below:

2. Use according to Claim 1, characterized in that the dermatological complaints are preferentially forms of acne.

3. Pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable carrier, at least 2-hydroxy- 4- [3-hydroxy-3- (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl- 2-naphthyl) -1-propynyl] benzoic acid in the S(+) configuration of formula (I) below:

(I) or one of its salts.

4. Composition according to Claim 3 , characterized in that it is administered orally and in that the concentration of 2-hydroxy-4- [3-hydroxy-3- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-naphthyl) -1- propynyl] benzoic acid in the S(+) configuration is between 0.01 mg/kg and 100 mg/kg of body weight, taken in 1 to 3 doses.

5. Composition according to Claim 4, characterized in that the concentration of 2-hydroxy-4- [3-hydroxy-3- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2- naphthyl) -1-propynyl] benzoic acid in the S(+) configuration is between 0.05 mg/kg and 20 mg/kg of body weight .

6. Composition according to Claim 3, characterized in that it is applied topically and in that the concentration of 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1- propynyl] benzoic acid in the S(+) configuration is between 0.00001% and 10% by weight relative to the total weight of the composition.

7. Composition according to Claim 6, characterized in that the concentration of 2-hydroxy-4- [3-hydroxy-3- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2- naphthyl) -1-propynyl] benzoic acid in the S(+) configuration is between 0.001% and 2% by weight relative to the total weight of the composition.

8. Composition according to Claim 7, characterized in that the concentration of 2-hydroxy-4- [3-hydroxy-3- (5,6,7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2- naphthyl) -1-propynyl] benzoic acid in the S(+) configuration is 0.1% relative to the total weight of the composition.

9. Composition according to one of Claims 3 to 8, characterized in that it is intended for the treatment of dermatological complaints.

10. Composition according to Claim 9, characterized in that the dermatological complaints are forms of acne.