NOVEL BIAROMATIC PROPYNYL COMPOUNDS, PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING SAME, AND USES THEREOF

Abstract

The invention relates to new compounds of the general formula (I):

##STR00001##

as well as the use thereof in pharmaceutical compositions intended for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmological disorders, in particular), or in the use of cosmetic compositions.

Claims

1.-17. (canceled)

18. A method of treating a keratinization disorder, a dermatological condition linked to a keratinization disorder pertaining to cellular differentiation and proliferation, or a dermatological condition associated with a keratinization disorder with an inflammatory or immunoallergenic component, the method comprising: administering to a human subject in need thereof a pharmaceutical composition comprising: (a) an effective amount of a compound having the structure of formula (I) below: ##STR00006## wherein: Ar is a radical selected from the group of radicals of formula (α) or (b) below: ##STR00007## ##STR00008## wherein R.sub.5 is OH; R.sub.1 is: (i) a hydrogen atom, (ii) a —CH.sub.3 radical, (iii) a —CH.sub.2—O—R.sub.6 radical, (iv) an —O—R.sub.6 radical, (v) a —CO—R.sub.7 radical, or (vi) an —S(O).sub.tR.sub.9 radical; R.sub.2 and R.sub.3, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring optionally substituted by methyl groups and includes only carbon atoms; R.sub.4 is a halogen atom or an —OR.sub.6 radical; R.sub.6 is a hydrogen atom, a lower alkyl radical, a linear or branched alkyl radical having 1 to 20 carbon atoms, or a —CO—R.sub.9 radical; R.sub.7 is a hydrogen atom, a lower alkyl radical, a radical of formula: ##STR00009## or an —OR.sub.8 radical; R.sub.8 is a hydrogen atom, a linear or branched alkyl radical having 1 to 20 carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical, a sugar residue, an amino acid, or a peptide residue; R.sub.9 represents a lower alkyl radical, or a linear or branched alkyl radical having 1 to 20 carbon atoms; each of R′ and R″ is a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical, an amino acid, a peptide residue, or a sugar residue; or R′ and R″, together with the nitrogen atom to which they are attached, form a heterocycle; and t is 0, 1 or 2, or a salt, or an optical or geometric isomer thereof; and (b) a pharmaceutically acceptable carrier.

19. The method of claim 18, wherein the compound is an alkali metal or alkaline earth metal salt, a zinc salt, or an organic amine salt.

20. The method of claim 18, wherein the lower alkyl radicals are selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl, and hexyl radicals.

21. The method of claim 18, wherein the linear or branched alkyl radicals having 1 to 20 carbon atoms are selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl radicals.

22. The method of claim 18, wherein the monohydroxyalkyl radicals are selected from the group consisting of 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl radicals.

23. The method of claim 18, wherein the polyhydroxyalkyl radicals are selected from the group consisting of 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl radicals, and a pentaerythritol residue.

24. The method of claim 18, wherein the aryl radical is a phenyl radical optionally substituted with at least one halogen atom, hydroxyl, or nitro.

25. The method of claim 18, wherein the aralkyl radicals are selected from the group consisting of benzyl or phenethyl radicals optionally substituted by at least one halogen atom, hydroxyl, or nitro.

26. The method of claim 18, wherein the alkenyl radicals are selected from the group consisting of radicals containing 2 to 5 carbon atoms and having one or more double bonds.

27. The method of claim 18, wherein the sugar residues are selected from the group consisting of glucose, galactose, mannose, and glucuronic acid residues.

28. The method of claim 18, wherein the amino acid residues are selected from the group consisting of residues deriving from lysine, glycine, and aspartic acid.

29. The method of claim 18, wherein the peptide residues are selected from the group consisting of dipeptide and tripeptide residues.

30. The method of claim 18, wherein the heterocyclic radicals are selected from the group consisting of piperidino, morpholino, pyrrolidino, and piperazino radicals, optionally substituted in position 4 by a C1-C6 alkyl or mono- or polyhydroxyalkyl radical.

31. The method of claim 18, wherein the compound is an alkali metal salt, an alkaline earth metal salt, a zinc salt, or an organic amine salt of compound 1 or 2: ##STR00010##

32. The method of claim 18, wherein the administering comprises enteral, parenteral, topical, or ocular administration.

33. The method of claim 18, wherein the keratinization disorder is selected from the group consisting of: ichthyosis; ichthyosiform states; Darier's disease; palmoplantar keratoderma; leukoplakia and leukoplakiform conditions; and cutaneous or mucosal (buccal) lichen.

34. The method of claim 18, wherein the dermatological condition linked to a keratinization disorder is selected from the group consisting of: acne vulgaris; comedonic or polymorphic acne; rosacea; nodulocystic acne; acne conglobate; senile acne; solar acne; drug-induced acne; and occupational acne.

35. The method of claim 18, wherein the dermatological condition associated with a keratinization disorder with an inflammatory or immunoallergenic component is selected from the group consisting of: psoriasis; psoriatic arthritis; eczema; respiratory atopy; and gingival hypertrophy.

36. The method of claim 18, wherein the administering is performed using a daily dosage of the compound having the structure of formula (I) of approximately 0.01 mg/kg to 100 mg/kg of bodyweight in 1 to 3 doses.

37. The method of claim 18, wherein the administering comprises ocular administration and the pharmaceutical composition comprises the compound having the structure of formula (I) at a concentration of between 0.001% and 5% by weight, relative to the total weight of the composition.

Description

EXAMPLE 1: TRANSACTIVATION TEST

a) Test Principle:

[0076] Activation of receptors by an agonist (activator) in HeLa cells leads to the expression of a reporter gene, luciferase, which generates light in the presence of a substrate. Therefore the activation of receptors can be measured by quantifying the luminescence produced after incubation of the cells in the presence of a reference antagonist. The activator products displace the antagonist from its site, thus permitting the receptor to be activated. The activity is measured by quantifying the increase in light produced. This measurement determines the activating activity of the useful compound in the invention.

[0077] In this study, a constant is determined that represents the affinity of the molecule for the receptor. This value can fluctuate according to the basal activity and expression of the receptor; it is designated apparent Kd (KdApp).

[0078] To determine this constant, cross curves are created of the product to be tested (4′-(3-hydroxy-propyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-biphenyl-4-carboxylic acid and 4′-(2,3-dihydroxy-propyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphtalen-2-yl)-biphenyl-4-carboxylic) acid versus a reference antagonist also called reference ligand, 4-(5,5-dimethyl-8-p-tolyl-5,6-dihydro-naphthalen-2-ylethynyl)-benzoc acid. The product to be tested is used at 10 concentrations and the reference antagonist at 7 concentrations. In each well (of a 96-well plate), the cells are in contact with one concentration of the product to be tested and one concentration of the reference antagonist.

[0079] Full agonist controls, also called 100% controls, (4-[2-(5,5,8,8 tetramethyl-5,6,7,8 tetrahydronaphthalene-2-yl)-propenyl]-benzoic acid) and inverse agonist controls, also called 0% controls, (4-{(E)-3-[4-(4-tert-butyl-phenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-oxo-propenyl}-benzoic acid) are also measured.

[0080] These cross curves allow determining the AC50 (concentration at which 50% activation of the receptor is observed) of the reference ligand at different concentrations of the product to be tested. These AC50s are used to calculate the Schild regression by plotting a line conforming to the Schild equation (“Quantitation in receptor pharmacology” Terry P. Kenakin, Receptors and Channels, 2001, 7, 371-385).

[0081] In the case of an agonist, the AC50 is calculated by plotting the curve of the product at the concentration of the reference ligand giving 80% activation. The percentage of activation that corresponds to the maximum level of activity obtained is also measured.

b) Materials and Method:

[0082] The HeLa cell lines used are stable transfectants containing the plasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and RAR (α, β, γ) ER-DBD-puro. These cells are inoculated onto 96-well plates in an amount of 10,000 cells per well in 100 μl DMEM medium with no phenol red and supplemented with 10% delipidated fetal bovine serum. The plates are then incubated at 37° C., 7% CO.sub.2 for 4 hours.

[0083] The different dilutions of the product to be tested, the reference ligand (4-(5,5-di methyl-8-p-tolyl-5,6-dihydro-naphthalen-2-ylethynyl)-benzoic acid), the 100% control (100 nM 4-[2-(5,5,8,8 tetramethyl-5,6,7,8 tetrahydronaphthalene-2-yl)propenyl]-benzoic acid) and the 0% control (500 nM 4-{(E)-3-[4-(4-tert-butyl-phenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-oxo-propenyl}-benzoic acid) are added in an amount of 5 μl per well. The plates are then incubated 18 hours at 37° C., 7% CO.sub.2.

[0084] The culture medium is removed by turning over and 100 μl of a 1:1 PBS (phosphate buffer solution)/luciferin mixture is added to each well. After 5 minutes, the plates are read by the luminescence reader.

c) Results:

[0085] The apparent Kd constant values are indicated in the table below. These values are compared to those of the compounds of patent WO 99/10308 presenting the best activities

TABLE-US-00001 RAR RAR RAR alpha beta gamma Kdapp Kdapp Kdapp (nM) (nM) (nM) Compound 1 120 4 4 Compound 2  30 2 4

EXAMPLE 2

[0086] In this example, various concrete formulations based on the compound according to the invention are illustrated.

A—Oral Administration

[0087] (a) 0.2 g tablet

TABLE-US-00002 Compound prepared in Example 7 0.001 g Starch 0.114 g Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 g Magnesium stearate 0.005 g [0088] (b) Oral suspension in 5-ml ampoules

TABLE-US-00003 Compound prepared in Example 3 0.001 g Glycerin 0.500 g 70% sorbitol 0.500 g Sodium saccharin 0.010 g Methyl parahydroxybenzoate 0.040 g Flavor qs Purified water qs    5 ml [0089] (c) 0.8 g tablet

TABLE-US-00004 Compound of Example 6 0.500 g Pregelatinized starch 0.100 g Microcrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate 0.010 g [0090] (d) Oral suspension in 10-ml ampoules

TABLE-US-00005 Compound of Example 2 0.200 g Glycerin 1.000 g 70% sorbitol 1.000 g Sodium saccharin 0.010 g Methyl parahydroxybenzoate 0.080 g Flavor qs Purified water qs    10 ml

B—Topical Administration

[0091] (a) Ointment

TABLE-US-00006 Compound of Example 9  0.020 g Isopropyl myristate 81.700 g Liquid Vaseline oil  9.100 g Silica (“Aerosil 200”  9.180 g sold by DEGUSSA) [0092] (b) Ointment

TABLE-US-00007 Compound of Example 10 0.300 g Codex white Vaseline   100 g [0093] (c) Nonionic water-in-oil cream

TABLE-US-00008 2-hydroxy-4-[3-  0.100 g hydroxy-3-(3-tert-butyl- 4-hydroxyphenyl)]- 1-propynylbenzoic acid Mixture of emulsive lanolin 39.900 g alcohols, waxes and oils (anhydrous Eucerin) sold by BDF) Methyl parahydroxybenzoate  0.075 g Propyl parahydroxybenzoate  0.075 g Sterile demineralized water: qs   100 g [0094] (d) Lotion

TABLE-US-00009 Compound of Example 8  0.100 g Polyethylene glycol (PEG 400) 69.900 g Ethanol (95%) 30.000 g [0095] (e) Hydrophobic ointment

TABLE-US-00010 Compound of Example 7  0.300 g Isopropyl myristate 36.400 g Silicone oil (“Rhodorsil 47 V 300” 36.400 g sold by RHONE-POULENC) Beeswax 13.600 g Silicone oil (“Abil 300.000 cst”   100 g sold by GOLDSCHMIDT) [0096] (f) Nonionic oil-in-water cream

TABLE-US-00011 Compound of Example 3 1.000 g Cetyl alcohol 4.000 g Glycerol monostearate 2.500 g PEG 50 stearate 2.500 g Shea butter 9.200 g Propylene glycol 2.000 g Methyl parahydroxybenzoate 0.075 g Propyl parahydroxybenzoate 0.075 g Sterile demineralized water:   100 g