Patent Application
20050208001
1. Technical Field of the Invention
The present invention relates to the administration of polycyclic aromatic compounds or cosmetic/pharmaceutical compositions comprised thereof, for treating skin disorders/afflictions such as rosacea, intrinsic (or chronological) aging, pigmentation disorders, seborrhoeic function disorders, barrier function disorders and more particularly epidermal lipid secretion disorders, wound healing disorders, corticosteroid-induced cutaneous atrophies, or ulcers; immune system disorders; cardiovascular system conditions, and/or lipid metabolism disorders.
The present invention also relates to a cosmetic/pharmaceutical regime or regimen for restoring the barrier function of the skin and more particularly for regulating and/or restoring the metabolism of cutaneous lipids, comprising topically applying onto the skin at least one compound of formula (I) below, and more particularly as a PPAR-type receptor activator, or composition comprised thereof.
It has now surprisingly and unexpectedly been determined that certain polycyclic aromatic compounds, notably those described in EP-220,118, U.S. Pat. No. 5,023,363 and FR-2,600,064 exhibit an antiproliferative action and elicit marked activity on the transactivation of PPAR-type receptors.
The present invention thus features administration of an effective amount of at least one polycyclic aromatic compound, and more particularly as PPAR-type receptor activators, or compositions comprised thereof, for treating skin disorders/afflictions such as rosacea, intrinsic (or chronological) aging, pigmentation disorders, seborrhoeic function disorders, barrier function disorders and more particularly epidermal lipid secretion disorders, wound healing disorders, corticosteroid-induced cutaneous atrophies, or ulcers; immune system disorders; cardiovascular system conditions, and/or lipid metabolism disorders.
This invention also features a cosmetic regime/regimen for restoring the barrier function of the skin and more particularly for regulating and/or restoring the metabolism of cutaneous lipids, comprising topically applying onto the skin at least one compound of formula (I), and more particularly as a PPAR-type receptor activator.
The subject compounds have the structural formula (I):
in which R is a hydrogen atom or an —OR3 radical, wherein R3 is as defined below; X is a ═C═O radical or a ═C═N—OH radical; R1 and R2, which may be identical or different, are each a hydrogen atom, a linear or branched alkyl radical having from 1 to 12 carbon atoms, an —OR4 radical, an —S(O)nR4 radical, an —OCOR4 radical, or an —NHCOR4 radical, n and R4 are as defined below, with the proviso that R1 and R2 may together form with the adjacent aromatic ring a 5- or 6-membered saturated or unsaturated ring optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulfur atom, a sulfone radical or a sulfoxide radical, said ring preferably being saturated, and with the further proviso that, when X is a ═C═O radical, then R1 and R2 do not form with the adjacent aromatic ring a 5-membered ring substituted with methyl groups; R3 is a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, or a mono- or polyhydroxyalkyl radical; n is 0, 1 or 2; R4 is a hydrogen atom, a lower alkyl radical, or a phenyl radical; and include the salts and/or chiral analogs thereof. Such salts include those of an alkali or alkaline earth metal, or of zinc, or of an organic amine.
More particularly according to the present invention, by the expression “lower alkyl radical” is intended a radical having from 1 to 6 carbon atoms, preferably methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
And exemplary linear or branched alkyl radicals having from 1 to 12 carbon atoms are methyl, ethyl, propyl, 2-ethylhexyl, octyl and dodecyl radicals.
Among the linear or branched alkyl radicals having from 1 to 20 carbon atoms, exemplary are methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
By the expression “monohydroxyalkyl radical” is intended a radical having 1 to 6 carbon atoms and preferably having from 2 to 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
By the expression “polyhydroxyalkyl radical” is intended a radical having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl radicals, or the pentaerythritol residue.
Particularly exemplary compounds of formula (I) are the following:
According to the present invention, the compound of formula (I) which is more particularly preferred is Compound 3: 6-(4-tert-butylbenzoyl)naphthalene-2-carboxylic acid.
The compounds of formula (I) can be prepared, in particular, by the methods of preparation described in EP-220,118, U.S. Pat. No. 5,023,363 and FR-2,600,064.
The compounds of the invention exhibit PPAR-type receptor activation properties. The PPAR-type receptors are receptors which belong to the family of nuclear steroid receptors.
By the expression “PPAR-type receptor activator” according to the invention is intended any compound which exhibits, in a transactivation test, as described in Kliewer et al., Nature, 358, 771-774 (1992), an AC50 of less than or equal to 10 μm. Preferably, the PPAR-type receptor activator exhibits an AC50 of less than or equal to 2 μm and advantageously of less than or equal to 1 μm.
An AC50 is the concentration of “activator” compound necessary to exhibit 50% of the activity of a reference molecule. This activity is determined with the aid of a reporter enzyme (luciferase) for activation due to the compound via one of the PPAR receptors.
The activity of the PPAR-type receptors has been the subject of numerous studies and publications. Exemplary is the publication entitled “Differential Expression of Peroxisome Proliferator-Activated Receptor Subtypes During the Differentiation of Human Keratinocytes”, Michel Rivier et al., J. Invest. Dermatol., 111, p 1116-1121 (1998), in which a large number of bibliographical references relating to the PPAR-type receptors are listed.
The use of PPAR-α-type receptor activators for restoring the barrier function and more particularly epidermal lipid secretion disorders, for promoting differentiation and for inhibiting epidermal proliferation has been described in WO 98/32444.
Furthermore, the administration of PPAR-α- and/or PPAR-γ-type receptor activators for treating cutaneous disorders related to abnormality in the differentiation of epidermal cells has been described in the publication by Michel Rivier et al., J. Invest. Dermatol., 111, p 1116-1121 (1998).
It has also been described in WO 96/33724 that compounds selective for PPARγ-receptors, such as prostaglandin-J2 or -D2, are potential active agents for the treatment of obesity and diabetes.
Pharmaceutical compositions comprising at least one compound of formula (I) are thus well suited for the treatment of rosacea, pigmentation disorders, seborrhoeic function disorders, barrier function disorders and more particularly epidermal lipid secretion disorders, wound healing disorders, corticosteroid-induced cutaneous atrophies, or ulcers; immune system disorders; cardiovascular system conditions, and/or lipid metabolism disorders.
By the expression “pigmentation disorders” are intended, in particular, hyperpigmentation, melasma, hypopigmentation or vilitigo. Preferably, the pigmentation disorders are not associated with the harmful effects of the sun (the damaging effects of solar radiation).
Exemplary seborrhoeic function disorders are, in particular, hyperseborrhoeic or seborrhoeic dermatitis.
Particularly exemplary barrier function disorders of the skin and more particularly the epidermal lipid secretion disorders are skin disorders in premature children born before 33 weeks, lip fissures, chapped lips or blisters resulting from mechanical friction.
Exemplary wound healing disorders are, in particular, keloids or hypertrophic scars.
Exemplary ulcers are, ulcers and erosions due to chemical or heat burns, bullous disorders, or vascular disorders or ischaemia, including venous, arterial, embolic or diabetic ulcers.
Exemplary immune system disorders are, in particular, autoimmune diseases (such as, but without limitation, type 1 diabetes mellitus, multiple sclerosis, lupus and lupus-type conditions, glomerulonephritis, and the like), or selective immune system dysfunctions (for example AIDS).
Exemplary cardiovascular system conditions include atherosclerosis or hypertension.
And exemplary lipid metabolism conditions include obesity, hyperlipidaemia or non-insulin-dependent diabetes.
The compositions according to the invention can be administered via the enteral, parenteral or topical or ocular route, for such period of time as required to elicit the desired response. The pharmaceutical compositions are preferably packaged in a form suitable for application by the topical route.
The subject compositions, more particularly the pharmaceutical compositions, can be provided, for the enteral route, in the form of tablets, including sugar-coated tablets, hard gelatin capsules, syrups, suspensions, solutions, powders, granules, emulsions or lipid or polymeric microspheres or nanospheres or vesicles which permit controlled release. The subject compositions can be provided, for the parenteral route, in the form of solutions or suspensions for infusion or for injection.
The subject compounds according to the invention are generally administered at a daily dose of approximately 0.001 mg/kg to 100 mg/kg of body weight, taken on 1 to 3 occasions.
The pharmaceutical compositions according to the invention, for the topical route, are more preferably for the treatment of the skin and mucous membranes and can be provided in the form of salves, creams, emulsions, milks, ointments, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. Same can also be provided in the form of lipid or polymeric microspheres or nanospheres or vesicles or of polymeric patches and hydrogels which permit controlled release. The compositions for topical application can be provided either in anhydrous form or in aqueous form.
The subject compounds are administered via the topical route at a concentration generally ranging from 0.001% to 10% by weight, preferably from 0.01 to 1 % by weight, with respect to the total weight of the composition.
The compounds of formula (I) according to the invention also find application in the cosmetics field, in particular in body and hair hygiene and more particularly for restoring the barrier function of the skin and more particularly for regulating and/or restoring the metabolism of cutaneous lipids. In comparison with the products known previously, these compounds of formula (I) present the advantage of additionally exhibiting other advantageous properties, in particular anti-inflammatory or soothing properties, which makes them less irritating and therefore better tolerated compounds.
The cosmetic compositions according to the invention, comprising, in a cosmetically acceptable vehicle, diluent or carrier, at least one compound of formula (I), one of its optical or geometrical isomers or one of its salts, can be provided, in particular, in the form of a cream, milk, lotion, emulsion, gel, lipid or polymeric microspheres or nanospheres or vesicles, soap or shampoo.
The concentration of compound of formula (I) in the cosmetic compositions advantageously ranges from 0.001% to 3% by weight.
The compositions according to the present invention can, of course, additionally comprise inert or even pharmacodynamically active additives or adjuvants, or combinations of these additives and adjuvants, and in particular: wetting agents; depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents, such as glycerol, PEG 400, thiamorpholinone and derivatives thereof, or urea; antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or derivatives thereof, or benzoyl peroxide; antifungal agents, such as ketoconazole or 4,5- polymethylene-3-isothiazolidones; antibacterials; carotenoids and in particular β-carotene; antipsoriatic agents, such as anthralin and derivatives thereof; eicosa-5,8,11,14- tetraynoic and eicosa-5,8,11-triynoic acids, their esters and amides, and also the retinoids. The subject compounds of formula (I) can also be formulated with vitamins D or derivatives thereof, with corticosteroids, with agents for combating free radicals, with α-hydroxy or α-keto acids or derivatives thereof, or with ion channel blockers.
These compositions can also comprise flavor-improving agents, preservatives, such as esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, agents for modifying osmotic pressure, emulsifying agents, UV-A and UV-B screening agents, or antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxy-toluene.
One skilled in this art will of course take care to select the optional compound or compounds to be added to these compositions such that the advantageous properties intrinsically associated with the present invention are not, or not substantially, detrimentally affected by the envisaged addition.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.
In said examples to follow, all parts and percentages are given by weight, unless otherwise indicated.
In this example, various results of biological tests have been illustrated which evidence the PPAR receptor transactivation properties of the compounds of the invention.
The comparative examples correspond to compounds which are described in EP-220,118 (comparative examples 1 and 2), or U.S. Pat. No. 5,023,363 (comparative examples 3 to 7), but which do not correspond to the conditions for the compounds of formula (I).
The biological tests carried out correspond to those described above. The method used to determine the AC50 values was that described in Kliewer et al., Nature, 358, 771-774 (1992). Thus, the activating power via PPAR-α, PPAR-γ or PPAR-δ of molecules may be evaluated with a transactivation test in which HeLa cells were cotransfected with an expression vector encoding these receptors and a reporter plasmid containing a PPRE response element cloned upstream of part of an SV40 virus promoter and of the luciferase gene. The cotransfected cells were treated for 24 hours with the molecules to be tested and the luciferase activity was determined by luminescence.
Reference 1, reference molecule for PPAR-α was [4-chloro-6-(2,3-dimethylphenylamnino)pyrimidin-2-ylsulphanyl]acetic acid;
Reference 2, reference molecule for PPAR-δ and PPAR-γ was 5-{4[2-(methylpyridin-2-ylamino)ethoxy]benzyl}thiazolidine-2,4-dione;
Comparative example 1 was 6-[butoxy(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]naphthalene -2-carboxylic acid;
Comparative example 2 was C-(6-carboxynaphthalen-2-yl)-C-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methylammonium;
Comparative example 3 was 6-(2,4-diisopropylbenzoyl)napthalene-2-carboxylic acid;
Comparative example 4 was 6-(6-methoxybiphenyl-3-carbonyl)napthalene-2-carboxylic acid;
Comparative example 5 was 6-(4-adamantan-1-yl-3-methoxybenzoyl)naphthalene-2-carboxylic acid;
Comparative example 6 was 4-[(3-adamantan-1-yl-4-methoxyphenyl)hydroxymethyl]benzoic acid;
Comparative example 7 was 4-(3-adamantan-1-yl-4-methoxybenzoyl)benzoic acid.
The results obtained in the PPAR-type receptor transactivation tests are grouped together in the following table:
n.a. connotes “not active”
*% activation
( )**AC50 in μM
These results evidence the activation for the compounds of the invention for the various subtypes of PPAR-type receptors: PPAR-α, PPAR-β and PPAR-γ.
In this example, various specific compositions according to the invention were formulated:
A—Oral Administration:
B—Topical Administration:
While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 99/16269 | Dec 1999 | FR | national |
This application claims priority under 35 U.S.C. §119 of FR-99/16269, filed Dec. 22, 1999, and is a continuation of PCT/FR00/03645, filed Dec. 21, 2000 and designating the United States (published in the French language on Jun. 28, 2001 as WO 01/45663 A2; the title and abstract were also published in English), both hereby expressly incorporated by reference. Copending application Serial No. _____________[Attorney Docket No. 016800-451], filed concurrently herewith and assigned to the assignee hereof.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10224449 | Aug 2002 | US |
| Child | 11121124 | May 2005 | US |
| Parent | 09933835 | Aug 2001 | US |
| Child | 10224449 | Aug 2002 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/FR00/03645 | Dec 2000 | US |
| Child | 09933835 | Aug 2001 | US |
