Patent Application
20150004110
The invention relates to novel anti-ageing and depigmenting cosmetic compositions. They contain 1-aryl-2-aryloxyethanes, representing a family of compounds with useful biological properties.
In 1989, Moinet et al. described the synthesis of a family of novel 1-aryl-2-aryloxyethanes (Lipha, FR2653119) with diuretic, antihypertensive, anti-platelet and anti-lipoxygenase properties. In particular, 2-[2-(4-fluoro-phenoxy)-ethyl]-phenol is a diuretic and antihypertensive agent in its sulphated form (R. P. Garay, J. P. Labaune, D. Mésangeau, C. Nazaret, T. Imbert, G. Moinet, J. Pharm. Exp. Therapeutics, 1990, 255, 415-422).
Other compounds such as derivatives of pyrocatechin-carboxylic acid (Hoffmann Laroche, EP0310126) for treating cardiovascular and bronchopulmonary diseases, and such as derivatives containing a heterocycle (Pfizer, U.S. Pat. No. 5,248,685), for treating asthma, were also described in the 1990s.
In 2006, Bayer described the use of certain derivatives for their anti-parasitic properties (WO119876).
Certain 1-aryl-2-aryloxyethanes are reaction intermediates in the preparation of phenoxypropanolamines, compounds that are antagonists of the β1 and β2 forms of adrenaline (S. N. Louis, T. L. Nero, D. Iakovidis, F. M. Colagrande, G. P. Jackman, W. J. Louis, Eur. J. Med. Chem., 1999, 34, 919-937).
It therefore appears that these compounds and their numerous sub-families on the one hand have useful biological properties, and on the other hand have not been investigated so far in the topical field.
One purpose of the invention is to use 1-aryl-2-aryloxyethanes or derivatives thereof in cosmetic compositions.
Another purpose of the invention is to use 1-aryl-2-aryloxyethanes or derivatives thereof in cosmetic compositions intended for anti-ageing and/or depigmenting care.
Another purpose of the invention is to provide a process for preparing novel 1-aryl-2-aryloxyethanes.
According to a general aspect, the invention relates to the use of the compounds of Formula I
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1 and R2, which may be identical or different, represent
group derived from ethylene glycol of formula
in which
δ varies from 1 to 12,
Ra represents a hydrogen, a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
group derived from propylene glycol of formula,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
group derived from a glycoside compound that may be α- or β-furanose or α- or β-pyranose, siloxy group of formula —OSi(Ra)3 in which Ra has the meanings stated above,
—OSitBdPh group of formula
or —OSitBdM group of formula,
in which
δ varies from 1 to 12,
Ra represents a hydrogen or a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
said R1 and R2 optionally forming a ring comprising 3 carbon atoms, said ring having the following formula
in which
R1a, R1b, R2a and R2b, which may be identical or different, represent
R3 and R4, which may be identical or different, represent
in which
x is equal to 0 or 1, y varies from 0 to 4,
Rb is a hydrogen or an acetyl —C(O)—CH3,
in which
δ varies from 1 to 12,
Ra represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
R5 represents
in which
x is equal to 0 or 1, y varies from 0 to 4,
Rb is a hydrogen or an acetyl —C(O)—CH3,
in which
δ varies from 1 to 12,
Ra represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
X− representing a halide ion,
provided that R3 and R4 do not represent simultaneously —OH groups or groups comprising an oxygen atom bound to the phenyl,
said compounds of Formula I being used in racemic form or as a single enantiomer for preparing cosmetic compositions having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
According to a particular aspect, said compounds of Formula I are used in racemic form or as a single enantiomer for preparing cosmetic compositions intended for anti-ageing and/or depigmenting care.
The compounds of Formula I belong to a family of compounds called “1-aryl-2-aryloxyethanes”.
“Aryl” denotes an aromatic group comprising 6 carbon atoms, optionally substituted with the R3 and R4 groups, and attached to the ethane chain by carbon 1.
R3 and R4 have the meanings designated above and in particular represent H, —OH, —OCH3, —F, —Br, —OC(O)CH3.
With the proviso “ . . . R3 and R4 do not represent simultaneously —OH groups or groups comprising an oxygen atom bound to the phenyl”, the aryl group derived from benzene-1,2-diol is excluded, in particular pyrocatechol is excluded, as well as its derivatives in which the —OH group would be in another form, in particular a protected form such as the ester form. “Aryloxy” denotes an aryl group attached to carbon 2 of the ethane chain by an oxygen atom. It is optionally monosubstituted with an R5 group represented in general formula I and having the meanings designated above.
R1 and R2 have the meanings designated above and in particular represent hydrogen atoms or —OH groups.
In the general formula, “n” and “m” are equal to 0 or 1. Their sum is always equal to 1.
A particular aspect of the invention relates to the use of the compounds of Formula II
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R3 and R4 have the meanings designated above,
—NR5aR5b represents a group comprising a nitrogen atom fixed to the ring, optionally in the form of its salt, this group being selected from
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position.
In particular, compounds belonging to the family of the 1-aryl-2-aryloxyethanes and comprising a nitrogen-containing group as substituent of the aryloxy group, have been prepared.
“Group comprising a nitrogen atom fixed to the ring” denotes a nitro function, primary, secondary or tertiary amine or salts thereof, an amide or carbamate function.
This nitrogen-containing group may occupy the ortho, meta or para positions.
Another particular aspect of the invention relates to the use of the compounds of Formula III
in which
R4 and R5 have the meanings designated above,
R1a, R1b, R2a and R2b, which may be identical or different, represent
These cyclopropyls have an —OH on the aromatic group in the α position of the carbon bearing the cyclopropyl group.
This cyclopropyl group may itself be substituted with the R1a, R1b, R2a and R2b groups, which may be identical or different, the meanings of which are given above. R1a, R1b, R2a and R2b are in particular four hydrogen atoms.
Another particular aspect of the invention relates to the use of the compounds of Formula 1V
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R4 and R5 have the meanings designated above.
Compounds IV are characterized by a hydroxy group specifically in the ortho position on the phenyl.
According to an advantageous embodiment of the invention, the compounds of Formula 1VA are used
in which R5 has the meaning designated above.
Compounds IVA are characterized by a hydroxy group specifically in the ortho position on the phenyl in which the R1, R2 and R4 groups are three hydrogen atoms.
R5 may occupy the ortho, meta or para positions.
Another particular aspect of the invention relates to the use of the compounds of Formula 1
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R3, R4 and R5 have the meanings designated above,
provided that R3 and R4 are both different from —OH or are of any form in which —OH is protected.
The compounds derived from catechol, already described, are excluded.
Another particular aspect of the invention relates to the use of the compounds of Formula V
in which
R1, R2, R3, R4 and R5 have the meanings designated above,
provided that R3 and R4 are both different from —OH or are of any form in which —OH is protected.
The ketones bearing a group derived from catechol are excluded.
R4 and R5 may occupy the ortho, meta or para positions.
Another particular aspect of the invention relates to the use of the compounds of Formula VI
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R3 and R4 have the meanings designated above,
R5c is a halogen atom selected from fluorine, chlorine or bromine
The compounds of Formula VI have a halogen fixed on the —OAr group described in the following general formula:
R4 and R5c may occupy the ortho,
meta or para positions.
According to an advantageous embodiment of the invention, compounds of Formula VII are used
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R3 and R4 have the meanings designated above.
Among the compounds having a halogen fixed on the —OAr group of the formula
the compounds of Formula VII are characterized by a fluorine atom in the para position.
R4 may occupy the ortho, meta or para positions.
Another particular aspect of the invention relates to the use of the compounds of Formula VIII
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R3 and R4 have the meanings designated above,
—O—R5d is a group selected from
in which
x is equal to 0 or 1, y varies from 0 to 4,
Rb is a hydrogen or an acetyl —C(O)—CH3,
in which
δ varies from 1 to 12,
Ra represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
This oxygen-containing group has the meanings stated above. It in particular represents a hydroxy group, —OCH3, —O—CH2Ph.
Another particular aspect of the invention relates to the use of the compounds of Formula 1X
in which R3, R4 and R5 have the meanings designated above.
According to general formula I, n=1 and m=0, carbon 1 of the formula
is in this case a carbonyl group: the compounds of Formula III are 1-aryl-2-aryloxyketones.
According to an advantageous embodiment of the invention, compounds of Formula 1XA are used
in which R4 and R5 have the meanings designated above.
These ketones comprise an —OH in the ortho position on the aromatic group in α of the carbonyl.
R4 may occupy the meta, para positions or the other ortho position of the ring; R5 may occupy the ortho, meta or para positions of the ring.
According to a particular aspect of the invention, compounds of Formula X are used
in which R1, R2, R3, R4 and R5 have the meanings designated above.
The carbon 1 of the formula
is in this case a methylene group: the compounds of Formula X are 1-aryl-2-aryloxyethanes, optionally substituted with the R1 and R2 groups, the meanings of which are designated above, R1 and R2 in particular being equal to hydrogen atoms, the ketones thus being excluded here.
R4 and R5 may occupy the ortho, meta or para positions.
According to an advantageous embodiment of the invention, compounds of Formula XA are used
in which R1, R2, R4 and R5 have the meanings designated above.
These compounds, not belonging to the family of the ketones, comprise an —OH in the ortho position on the —Ar group situated in a of carbon 1 of the formula
R4 may occupy the meta, para positions or the other ortho position of the ring; R5 may occupy the ortho, meta or para positions of the ring.
According to another particular aspect of the invention, compounds of Formula XI are used
in which R2, R3, R4 and R5 have the meanings designated above.
Compounds XI are alcohols obtained from the ketones of Formula 1X
The R3 group represents in particular a hydrogen atom, an alkyl group, an alkoxy group, a halogen selected from fluorine, chlorine, bromine or iodine, and is in particular a hydrogen atom.
According to an advantageous embodiment of the invention, compounds of Formula XIA are used
in which R2, R4 and R5 have the meanings designated above.
These alcohols comprise an —OH in the ortho position on the —Ar group situated in α of carbon 1 of the formula
R4 may occupy the meta, para positions or the other ortho position of the ring; R5 may occupy the ortho, meta or para positions of the ring.
According to a particular aspect of the invention, compounds of Formulae XIIA, XIIB and XIIC are used
in which
R1, R2, R3, R4 and R5 have the meanings designated above,
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1.
The compounds of Formulae XIIA, XIIB and XIIC belong to the family of the 1-aryl-2-aryloxyethanes in which the aryl group in position 1 on the ethane chain of the following formula
is monosubstituted.
According to another particular aspect of the invention, compounds of Formula 1 are used in which
R1, R2, R3, R4 and R5 have the meanings designated above, provided that R3 and R4 are both different from H,
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1.
These compounds belong to the family of the 1-aryl-2-aryloxyethanes in which the aryl group in position 1 on the ethane chain of the formula
is disubstituted with the R3 and R4 groups, the meanings of which are defined above.
R3 is in the ortho position on the ring. R4 may occupy the meta, para position or the second ortho position of the ring. R3 and R4 are different from the hydrogen atom.
According to another particular aspect of the invention, compounds of Formulae XIIIA, XIIIB and XIIIC are used
in which
R1, R2, R3, R4 and R5 have the meanings designated above,
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1.
The compounds of Formulae XIIIA, XIIIB and XIIIC belong to the family of the 1-aryl-2-aryloxyethanes in which the —OAr group in position 2 on the ethane chain of the formula
is substituted with the R5 group, the meanings of which are defined above.
R5 represents in particular a hydrogen atom, a halogen atom selected from fluorine, chlorine, bromine or iodine, —OH, an alkoxy group, an alkyl group optionally substituted with halogens, a nitrogen-containing group, and is in particular a hydrogen atom, a fluorine or bromine atom, —OH, —OCH3, —O—CH2—C6H5, —CH3, —NO2, —NH2, —NH—C(O)—CH3.
R5 may occupy all the positions on the ring:
According to a particular aspect of the invention, compounds of Formulae XIID, XIIE and XIIF are used
in which R3, R4 and R5 have the meanings designated above.
In the compounds of Formulae XIID, XIIE and XIIF, the R5 group is fixed in the para position.
The position of the group borne by the other aromatic ring, R3 or R4, is variable, all the positions being possible.
The invention also relates to the use of the compounds of the following formulae:
The compounds shown above are used as active ingredients for preparing cosmetic compositions having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
The invention relates to the use of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, or 130 mentioned above for preparing cosmetic compositions having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
The invention also relates to the use of the compounds 131, 132, 133, 134, 135, 136, or 137 mentioned above for preparing cosmetic compositions having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
According to a particular aspect of the invention, one or more compounds of Formula 1 are used for preparing cosmetic compositions in which the anti-ageing properties belong to the group constituted by reinforcement of the dermis, proliferation of dermal fibroblasts, production of collagen, inhibition of expression of the “matrix metallopeptidase” gene MMP9 and of the protein “heat shock protein beta-1” HSPB1.
“Matrix metallopeptidase 9” (MMP-9) is an enzyme encoded by the MMP-9 gene. It is involved in the degradation of extracellular proteins. It is involved in the remodelling of the extracellular matrix and, in particular, in the degradation of collagens of types IV and V.
The “extracellular matrix” denotes all the extracellular macromolecules of connective tissue.
The protein “heat shock protein beta-1 HSPB1” plays a role in the regulation of cellular development, in the inhibition of apoptosis and, in particular, in cellular differentiation.
According to another particular aspect of the invention, one or more compounds of Formula 1 are used for preparing cosmetic compositions in which the anti-inflammatory properties belong to the group constituted by inhibition of leukocyte elastase or inhibition of secretion of prostaglandins E2.
The elastases are a sub-family of the serine proteases responsible for the degradation of elastin. The numerous natural substrates of this enzyme include, in addition to elastin, the proteoglycans of cartilage, fibronectin and the collagens of type I, II, III and IV. With respect to the skin, inhibition of elastase makes it possible to combat the effects of ageing, photo-induced or not, and limit the appearance of wrinkles and stretch marks.
The prostaglandins E2 (PGE2) play a role in inflammatory processes.
According to another particular aspect of the invention, one or more compounds of Formula 1 are used for preparing cosmetic compositions in which the wound-healing properties belong to the group constituted by the proliferation and migration of keratinocytes for covering a wound.
The phases of migration and proliferation of the cells are major phases of wound healing that occur after the inflammation phase. They are necessary for the recolonization of the wound. An increase in migration and proliferation of the cells allows wound healing to be improved.
The wound healing effect is evaluated:
In the study of the proliferation and/or migration of fibroblasts, the biological model is constituted by normal human dermal fibroblasts (NHDF), for which the culture conditions are 37° C. and 5% CO2 in DMEM.
A control is carried out (NHDF in test medium DMEM 0% FCS) (n=6)) and a reference is used (FCS, Foetal Calf Serum at 10% (n=2)). For the compounds tested, n=2.
Incubation is for 72 hours.
The test consists of seeding normal human fibroblasts in 96-well plates suitable for migration studies. In these plates, the supports are pretreated with a solution of collagen and a mask is placed at the centre of each well, preventing adhesion of the cells in this zone and thus forming an artificial wound. After labelling the cells with calcein, the masks are removed and then the cells are treated with the compounds or the reference.
The migration of the cells is monitored microscopically for 72 hours, taking photographs at 0 h, 24 h, 48 h and 72 h. The results, expressed in percentage coverage, are compared with the untreated control.
In the study of the proliferation and/or migration of keratinocytes, the biological model is constituted by normal human epidermal keratinocytes (NHEK), for which the culture conditions are 37° C. and 5% CO2 in a medium of keratinocytes-SFM-PE-EGF (keratinocyte culture medium—serum free medium (SFM) without pituitary extract (PE) and without Epidermal Growth Factor (EGF), control (n=6), reference: EGF (Epidermal Growth Factor) at 10 ng/ml (n=2), compounds tested (n=2).
Incubation is for 72 hours.
The test consists of seeding normal human keratinocytes in 96-well plates suitable for migration studies. In these plates, the supports are pretreated with a solution of collagen and a mask is placed at the centre of each well, preventing adhesion of the cells in this zone and thus forming an artificial wound. After labelling of the cells with calcein, the masks are removed and then the cells are treated with the compounds or the reference.
The migration of the cells is monitored microscopically for 72 hours, taking photographs at 0 h, 24 h, 48 h and 72 h. The results, expressed in percentage coverage, are compared with the untreated control.
According to another particular aspect of the invention, one or more compounds of Formula 1 are used for preparing cosmetic compositions in which the depigmenting properties belong to the group constituted by anti-tyrosinase activity and anti-melanogenesis activity.
“Anti-melanogenesis activity” makes it possible to decrease the production of melanin, the main pigment responsible for the colour of the skin.
As tyrosine is involved in the production of melanin, “anti-tyrosinase activity” allows inhibition of the production of melanin and, consequently, a depigmenting action.
The depigmenting effect was evaluated on a line of type B16 melanocytes stimulated with NDP-MSH, (natural hormone stimulating melanogenesis; Melanocyte Stimulating Hormone, [Nle, DPhe]-α-MSH). Melanin synthesis was evaluated.
The study was carried out for compounds in solution in DMSO. The effects of the following 3 compounds, at concentrations of 30 μmol·L−1 (30 μM) and 100 μmol·L−1 (100 μM), were thus compared:
The results obtained showed that the compounds of Formula 1 had a clear inhibitory effect. Moreover, a comparative study of the effects of the compounds of Formula 1 with the effects of the other two compounds mentioned above shows that the compounds of Formula 1 are more effective with respect to depigmentation than the other two compounds.
The invention relates to cosmetic compositions containing as active ingredient one or more compounds of Formula 1
in which
R1 and R2, which may be identical or different, represent
group derived from ethylene glycol of formula
in which
δ varies from 1 to 12,
Ra represents a hydrogen or a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
group derived from propylene glycol of formula,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
group derived from a glycoside compound that may be α- or β-furanose or α- or β-pyranose, siloxy group of formula —OSi(Ra)3 in which Ra has the meanings stated above, —OSitBdPh group of formula
—OSitBdM group of formula,
in which
δ varies from 1 to 12,
Ra represents a hydrogen or a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
said R1 and R2 optionally forming a ring comprising 3 carbon atoms, said ring having the following formula
in which
R1a, R1b, R2a and R2b, which may be identical or different, represent
R3 and R4, which may be identical or different, represent
in which
x is equal to 0 or 1, y varies from 0 to 4,
Rb is a hydrogen or an acetyl —C(O)—CH3,
in which
δ varies from 1 to 12,
Ra represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
R5 represents
in which
x is equal to 0 or 1, y varies from 0 to 4,
Rb is a hydrogen or an acetyl —C(O)—CH3,
in which
δ varies from 1 to 12,
Ra represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms,
Rc represents a linear or branched alkyl group with 1 to 10 carbon atoms,
in which
δ′ varies from 1 to 5,
Ra and Rc have the meanings stated above,
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
X− representing a halide ion,
provided that R3 and R4 do not represent simultaneously —OH groups or groups comprising an oxygen atom bound to the phenyl,
said active ingredient being combined with a cosmetically acceptable vehicle.
According to a particular aspect, the invention relates to a cosmetic composition containing as active ingredient one or more compounds of Formula 1
in which:
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1 and R2 have the meanings given above
R3 and R4, which may be identical or different, represent:
and R5 represents:
On account of their cosmetic properties, the compounds according to the invention are used therapeutically as skin depigmenting agents, anti-ageing, wound-healing, and anti-inflammatory agents.
For these purposes, they will be used in the form of cosmetic compositions containing as active ingredient at least one of the compounds of general formulae I in combination with or mixed with an excipient or an inert, non-toxic, cosmetically acceptable vehicle.
Excipients that are suitable for such administrations are oils, water and alcohol as well as surfactants, and additives such as preservatives, antioxidants, colorants, and perfumes.
The invention relates to cosmetic compositions constituted by a mixture comprising at least one compound of Formula 1 as active ingredient in combination with one or more compounds having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties, in particular in combination with fatty acids such as linoleic acid or azelaic acid, and/or with antioxidants such as vitamin C and/or with tocopherol derivatives, and/or with desquamation additives such as retinoic acid or glycolic acid,
said composition having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
The cosmetic compositions will be able to contain a mixture of compound of Formula 1 combined, in variable proportions, with one or more other compounds already known for their anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory and/or antioxidant properties.
The cosmetic compositions will thus optionally be able to contain another agent known for its depigmenting properties such as:
According to a particular aspect of the invention, the cosmetic compositions have a content of compounds of Formula 1 from 0.001 to 10 wt %.
The dosage may vary depending on the form. If a mixture of compounds I is used, the proportions of compounds of Formula 1 in this mixture may vary, in such a way that the overall percentage by weight is from 0.001% to 10%.
According to a particular aspect of the invention, the cosmetic compositions are in the form of cream, ointment, gel, unguent, lotion, patch, oil, serum, milk, spray, balsam, emulsion, microemulsion.
The cosmetic compositions will be presented in one of the cosmetic forms suitable for cutaneous administration. In this respect, creams, ointments, gels, oils, serums, milks, sprays, emulsions, encapsulations may be mentioned.
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more compounds of Formula II
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1, R2, R3 and R4 have the meanings designated above,
—NR5aR5b represents a group comprising a nitrogen atom fixed to the ring, optionally in the form of its salt, this group being selected from
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
in combination with a cosmetically acceptable vehicle.
These are compounds comprising a nitrogen-containing group, in particular nitro, amino, amido, borne by the —OAr group of the following general formula
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more compounds of Formula III
in which
R4 and R5 have the meanings designated above,
R1a, R1b, R2a and R2b, which may be identical or different, represent
These compounds are characterized in that they contain a cyclopropyl.
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more compounds of Formula 1V
in which
R1, R2, R4 and R5 have the meanings designated above,
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
in combination with a cosmetically acceptable vehicle.
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more compounds of Formula 1VA
in which
R5 has the meaning designated above,
in combination with a cosmetically acceptable vehicle.
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more compounds of Formula V
in which
R3, R4 and R5 have the meanings designated above,
provided that R3 and R4 are both different from —OH or are of any form in which —OH is protected,
in combination with a cosmetically acceptable vehicle.
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more of the compounds of Formulae 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, or 130 mentioned above, in combination with a cosmetically acceptable vehicle.
According to a particular aspect of the invention, the cosmetic compositions contain as active ingredient one or more of the compounds of formulae 131, 132, 133, 134, 135, 136, or 137 mentioned above, in combination with a cosmetically acceptable vehicle.
According to a particular aspect of the invention, the cosmetic compositions contain a mixture comprising one or more compounds belonging to the list of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, or 130 mentioned above as active ingredient, in combination with one or more compounds having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties, in particular in combination with fatty acids such as linoleic acid or azelaic acid, and/or with antioxidants such as vitamin C and/or with tocopherol derivatives, and/or with desquamation additives such as retinoic acid or glycolic acid, said composition having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
According to a particular aspect of the invention, the cosmetic compositions contain a mixture comprising one or more compounds belonging to the list of compounds 131, 132, 133, 134, 135, 136, or 137 mentioned above as active ingredient, in combination with one or more compounds having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties, in particular in combination with fatty acids such as linoleic acid or azelaic acid, and/or with antioxidants such as vitamin C and/or with tocopherol derivatives, and/or with desquamation additives such as retinoic acid or glycolic acid, said composition having anti-ageing and/or depigmenting and/or wound-healing and/or anti-inflammatory properties.
The invention also relates to the compounds of Formula 1
in which:
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1 and R2 have the meanings given above
R3 and R4, which may be identical or different, represent:
and R5 represents:
The invention also relates to a compound of Formula X
in which
n is equal to 0, and m is equal to 1,
R1 and R2 have the meanings given above,
R3 and R4, which may be identical or different, represent:
and R5 represents:
The invention relates to the compounds of Formula II
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R3 and R4 have the meanings designated above,
—NR5aR5b represents a group comprising a nitrogen atom fixed to the ring, optionally in the form of its salt, this group being selected from
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position.
These are compounds comprising a nitrogen-containing group, in particular nitro, amino, amido, borne by the —OAr group of the following general formula
According to a particular aspect, the invention relates to compounds of Formula II
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1 and R2 have the meanings designated above,
R3 and R4 have the meanings designated above, with the exception of the hydrogen atoms,
—NR5aR5b represents a group comprising a nitrogen atom fixed to the ring, optionally in the form of its salt, this group being selected from
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position.
These are compounds comprising a nitrogen-containing group, in particular nitro, amino, amido, borne by the —OAr group of the following general formula
According to another particular aspect, the invention relates to compounds of Formula II
in which
n is equal to 0 or 1, m is equal to 0 or 1, provided that n+m=1,
R1 and R2 have the meanings designated above,
R3 represents a hydroxyl group and R4 has the meanings designated above,
—NR5aR5b represents a group comprising a nitrogen atom fixed to the ring, optionally in the form of its salt, this group being selected from
Rd, Re representing linear or branched alkyl groups comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or carbon chains interrupted by oxygen or sulphur atoms, benzyl groups optionally substituted with a halogen atom, a hydroxy group, an alkoxy group comprising from 1 to 8 carbon atoms,
Rf represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, a phthalimido group (in this case NH is replaced with N), a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position,
Rg represents a linear or branched alkyl group comprising from 1 to 4 carbon atoms, optionally substituted with one or more halogen atoms, or a carbon chain interrupted by oxygen or sulphur atoms, a phenyl group, a benzyl group optionally substituted with a halogen atom, a hydroxy group, an alkoxy group and in particular substituted with the methoxy group in the para position.
These are compounds comprising a nitrogen-containing group, in particular nitro, amino, amido, borne by the —OAr group of the following general formula
The invention relates to the compounds of Formula III
in which
R4 and R5 have the meanings designated above,
R1a, R1b, R2a and R2b, which may be identical or different, represent
These compounds are characterized in that they contain a cyclopropyl.
The invention relates to the compounds of formulae
3, 7, 8, 9, 10, 11, 12, 13, 14, 18, 19, 20, 21, 22, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 124, 125, 126, 127, 128, 129, or 130 mentioned above.
The invention also relates to the compounds of formulae 131, 132, 133, 134, 135, 136, or 137 mentioned above.
According to a particular aspect, the invention relates more particularly to the compounds of formula:
The invention relates to a process for preparing the compounds of Formula XA
in which
R1, R2, R4 and R5 have the meanings designated above,
comprising a step of reaction of a phenolic alcohol
with mesyl chloride
in order to obtain the protected compound XV
R1, R2, R4 having the meanings designated above,
comprising a step of reaction of compound XV of the above formula with a phenol derivative
R5 having the meanings stated above,
in order to obtain the protected compound XVII,
R1, R2, R4 and R5 having the meanings designated above,
comprising a step of deprotection of the phenolic function of compound XVII of the above formula
in order to obtain the compound of formula
R1, R2, R4 and R5 having the meanings designated above,
and in particular R1 and R2 are both hydrogen atoms.
This process is applied for preparing compounds having an —OH group in the ortho position on the —Ar group of the following general formula
The synthesis, comprising 3 steps, is represented in the following diagram:
In the first step, the phenolic alcohol XIV reacts with mesyl chloride to give the dimesylated compound. This step constitutes a means of protecting the phenolic —OH on the one hand and of activating the —OH borne by the ethane chain on the other hand. The first step thus supplies the dimesyl compound XV which, in the second step, undergoes a substitution by reaction with the phenol XVI to give the compound XVII, belonging to the family of the 1-aryl-2-aryloxyethanes. Basic hydrolysis constitutes the last step and makes it possible to release the phenolic —OH from compound XA.
The invention also relates to a process for preparing the compounds of Formula V
in which
R1, R2, R3, R4 and R5 have the meanings designated above,
provided that R3 and R4 are both different from —OH or are of any form in which —OH is protected,
comprising a reaction of the Mitsunobu type carried out on an aryl alcohol of formula
and a phenol XVI of formula
in order to obtain the compounds of Formula V,
R1, R2, R3, R4 and R5 have the meanings designated above,
and in particular R1 and R2 are both hydrogen atoms.
In contrast to the process described previously, this process is applied in order to prepare compounds that do not have an —OH group in the ortho position on the —Ar group of the following general formula
The synthesis, consisting of carrying out a Mitsunobu reaction, is represented in the following diagram:
Compound XVIII reacts with the phenol XVI in the presence of triphenylphosphine and then diethyl azodicarboxylate to give a compound of the family of the 1-aryl-2-aryloxyethanes, R3 being different from —OH or from any protected form of —OH.
The invention also relates to a process for preparing the compounds of Formula III
R4 and R5 having the meanings designated above,
R1a, R1b, R2a and R2b, which may be identical or different, representing
said process comprising a step of reaction of the Mitsunobu type on an alcohol of formula
R4, R1a, R1b, R2a et R2b having the meanings designated above,
in order to obtain compound XX
R5 having the meanings designated above,
said process comprising a reaction of deprotection of the phenolic —OH of compound XX shown above,
in order to obtain compound III
R1a, R1b, R2a, R2b, R4 and R5 having the meanings designated above, and in particular R1a, R1b, R2a and R2b being four hydrogen atoms.
In this process, the Mitsunobu reaction is carried out on the cyclopropanoic alcohol XIX and is followed by deprotection of the phenolic —OH, as shown in the following diagram:
When R1a═R1b═R2a═R2b═R4═H, compound XIX is commercially available.
When R1a═R1b═R2a═R2b═H and R4 and R5 have the meanings designated above, the derivatives may be obtained by formation of the cyclopropyl by the techniques known to a person skilled in the art (Cy C et al., Eur. J. Med. Chem 1991 26(2) p 125-128; Kirmse W et al., Chem. Ber. 1986 119(2) p 3694-3703; Qiao J et al., Bioorg. Med. Chem. Lett 2009 19(2) p 462-468): for example dibromoethane under basic conditions (Muthusamy S et al., Tet. Lett. 2005 46(4) p 635-638).
The conditions for deprotection make use of the knowledge of a person skilled in the art and of conventional techniques such as the use of boron tribromide.
The invention also relates to a process for preparing the compounds of Formula IIA
in which R1, R2 and R4 have the meanings designated above,
comprising a step of reaction of a phenolic alcohol
with mesyl chloride
in order to obtain the protected compound XV
R1, R2 and R4 having the meanings designated above,
comprising a step of reaction of compound XV of the above formula with a phenol derivative
in order to obtain the protected compound XVIIA
R1, R2 and R4 having the meanings designated above,
comprising a step of deprotection of the phenolic function of compound XVIIA of the above formula
in order to obtain the compound of formula
R1, R2 and R4 having the meanings designated above,
and in particular R1 and R2 being two hydrogen atoms.
The invention also relates to a process for preparing the compounds of Formula IIB
R1, R2 and R4 having the meanings designated above,
comprising a reduction of the nitro compound IIA of formula
by reduction under pressure of hydrogen in the presence of a catalyst
in order to obtain compound IIB shown above.
The invention relates to a process for preparing the compounds of Formula IIC
in which
R1, R2, R4 and Rf have the meanings designated above,
comprising a step of reaction of a phenolic alcohol
with mesyl chloride
in order to obtain the protected compound XV
R1, R2, R4 having the meanings designated above,
comprising a step of reaction of compound XV of the above formula with a phenol derivative
in order to obtain the protected compound XVIIA,
R1, R2, R4 and Rf having the meanings designated above,
comprising a step of deprotection of the phenolic function of compound XVIIA of the above formula
in order to obtain the compound of Formula IIC,
R1, R2, R4 and Rf having the meanings designated above,
and in particular R1 and R2 are both hydrogen atoms.
This route makes it possible to obtain the compounds bearing an amide function.
The acetamidophenol of Formula XVIA with Rf═—CH3 is commercially available. The molecules of Formula XVIA may be obtained by direct amidation of aminophenol with an anhydride or chloride acid derivative, as described by Fiez-David in Helv. Chim. Acta 1939, 22 p 89, Palm K et al., J. Med. Chem. 1998, 41(27), 5382-5392, Deng W et al., Bioorg. Med. Chem. Lett. 2006, 16(2), 469-472.
The invention relates to a process for preparing the compounds of Formula 1
in which
n, m, R1, R2, R4 and R5 have the meanings designated above,
R3 is an —OH group coupled to a glycoside compound, which may be an α- or β-furanose or an α- or β-pyranose,
said process comprising a coupling reaction between compound IV of formula
and a sugar, which may be an α- or β-furanose or an α- or β-pyranose, the —OH being protected, in particular in the form of acetates, and the anomeric position being activated beforehand in the form of bromine or of trichoroacetimidate,
in order to give a sugar derivative of Formula 1 shown above.
This is a modification of the Kœnigs-Knorr type. The phenol function of the compound of general formula I reacts with a glycoside unit, which may be an α- or β-furanose or an α- or β-pyranose, protected and previously activated in the form of brominated derivative, which may be commercially available, or in the form of trichloroacetimidate derivative. The preparation of the latter is described in the literature (Thisbe K. Lindhorst, Essentials of Carbohydrate Chemistry and Biochemistry, WILEY-VCH 2000). This coupling may or may not be followed by deprotection of the acetates, for example in a basic medium.
TEA: triethylamine
DMSO: dimethylsulphoxide
NDP-MSH: [Nle, DPhe]-α-MSH
DMEM: Dulbecco/Vogt modified Eagle's minimal essential medium (medium for cell culture developed by Harry Eagle; it is used for maintaining the cells of a tissue culture).
The analytical techniques are as follows:
The NMR spectra were recorded at 300 MHz (Brucker spectrometer) for the proton. The chemical shifts are expressed in ppm, the residual chloroform being taken as internal reference (singlet at 7.28 ppm), or the residual dimethylsulphoxide being taken as internal reference (multiplet at 2.50 ppm). The multiplicity of the signals is denoted by the following letters: s singlet, d doublet, dd doublet of doublets, t triplet, q quadruplet and m multiplet.
LC/MS analysis corresponds to coupling of HPLC analysis and analysis by mass spectrometry. It is carried out on an Alliance Waters 2695-ZQ2000 instrument.
Detector: DAD detector (Waters, ref.: 2996, λ=190 nm to 800 nm):
Mass detector (Waters, ref. ZQ2000): 100-1500 dalton; negative and positive ion
Temperature of HPLC furnace: 40° C.
Flow rate: 1 mL/min
The methods used for HPLC are shown below. The method and the retention time are stated for the analytical results.
XTerra method
Column: XTerra® MS C18: 4.6 mm×150 mm, 5 nm (Waters, ref. 186000490)
Eluent A: Water (HCOOH-0.02%); Eluent B=CH3CN) with elution gradient
Elution conditions: gradient
Column: XBridge™ C18: 4.6 mm×150 mm, 5 nm (Waters, ref. 186003116)
Eluent A: Water (HCOOH-0.02%); Eluent B=CH3CN) with elution gradient
Elution conditions: gradient
R1, R2, R4 and R5 having the meanings designated above,
by a multi-step synthesis represented in the following diagram:
In a dry 250 mL three-necked flask, under a nitrogen stream and with magnetic stiffing, the diol XIV (1 equivalent) is diluted in dichloromethane (5 volumes) and then TEA (2.2 equivalents) is added. The reaction medium is cooled to 5° C. Using a dropping funnel, methanesulphonyl chloride (2.2 equivalents), diluted in dichloromethane (5 volumes) is added while controlling the temperature. The reaction medium is then stirred at ambient temperature overnight. The reaction medium is poured into an ice water/HCl mixture. After extracting with dichloromethane three times, the organic phases are washed with saturated NaCl solution. After drying over MgSO4 and filtering on a frit, the filtrate is concentrated under vacuum. The residue is purified by trituration in pentane. The products obtained are oils or solids depending on the nature of R1, R2 and R4.
In a dry 100 mL three-necked flask, under a nitrogen stream and with magnetic stirring, the dimesylate compound XV (1 equivalent) is dissolved in acetonitrile (10 volumes). A phenol of Formula XVI (1.2 equivalents) is added, as well as K2CO3 (1.2 equivalents). The reaction mixture is heated under reflux for 4 h. At ambient temperature, the reaction medium is filtered to remove the salts and the filtrate is concentrated under vacuum. The residue is taken up in dichloromethane and an aqueous solution of NaHCO3. After extracting with dichloromethane three times, the organic phases are washed with saturated NaCl solution. After drying over MgSO4, the organic phase is filtered and concentrated under vacuum. The products obtained are monomesylates of Formula XII, oils or solids depending on the nature of R1, R2, R4 and R5, purified in particular by silica chromatography or by trituration in isopropyl ether/pentane mixtures of variable composition.
In a 50 mL three-necked flask equipped with a condenser, with magnetic stiffing, the monomesylate of Formula XII (1 equivalent) is dissolved in ethanol (12 volumes). A soda solution at 2 mol·L−1 (2 equivalents) is added and the mixture is heated with stiffing under reflux for 4 h. The reaction medium is concentrated under vacuum at ambient temperature. The residue is taken up in water and then the solution is acidified. It is extracted with dichloromethane and the organic phases are washed with saturated NaCl solution. After drying over MgSO4, the organic phase is filtered and concentrated under vacuum. The compounds XA are obtained, oils or solids, purified in particular by silica gel chromatography.
This is prepared by the multi-step synthesis represented in the following diagram:
Step 1 is carried out according to the procedure described in Example 1 starting from compound XIVA. After filtration and drying under vacuum, compound XVA is isolated. It is a white solid obtained with 92% yield. It is used in the next step.
Step 2 is carried out according to the procedure described in Example 1 using 4-fluorophenol. The residue is purified on a silica gel column eluted with a heptane—ethyl acetate gradient. The monomesylate XIIA is obtained. This is a yellow oil, obtained with 55-65% yield. It is used in the next step.
Step 3 is carried out according to the procedure described in Example 1. The residue is purified on a silica gel column eluted with a heptane—ethyl acetate gradient. Compound 1 is a colourless oil obtained with 60-70% yield.
1H NMR (300 MHz, CDCl3): δ (ppm) 3.14 (t, 2H, CH2—C6H5); 4.24 (t, 2H, CH2—O); 6.81 (s, 1H, —OH); 6.85-7.22 (m, 8H, H aromatic).
HPLC: XTerra tr=12.25 min
ES− mass: [M−H]−=231.2.
The synthesis is represented in the following diagram:
R1, R2, R3, R4 and R5 having the meanings designated above.
General procedure: In a 25 mL three-necked flask, under a nitrogen stream and with magnetic stirring, the alcohol compound XVIII (1 equivalent) is diluted in tetrahydrofuran (16 volumes) and then a phenol derivative (1 equivalent) and triphenylphosphine (1.3 equivalents) are added. The reaction medium is stirred at ambient temperature. Then diethyl azodicarboxylate (1.3 equivalents) is added dropwise. The reaction medium is stirred at ambient temperature overnight. The reaction medium is concentrated. The residue is taken up in distilled water and ethyl acetate. After extraction with ethyl acetate three times, the organic phases are washed with saturated NaCl solution. After drying over MgSO4 and filtering on a frit, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography eluted with a heptane/ethyl acetate gradient.
The phenol derivative may in particular be 4-fluorophenol.
The synthesis with 4-fluorophenol is represented in the following diagram:
Procedure: in the case where R4 is a methyl in the para position
In a 25 mL three-necked flask, under a nitrogen stream and with magnetic stiffing, compound XVIII (1 equivalent) is diluted in tetrahydrofuran (15 volumes) and then 4-fluorophenol (1 equivalent) and triphenylphosphine (1.3 equivalents) are added. The reaction medium is stirred at ambient temperature. Then diethyl azodicarboxylate (1.3 equivalents) is added dropwise. The reaction mixture is stirred at ambient temperature overnight. The reaction medium is concentrated. The residue is taken up in distilled water and ethyl acetate. After extraction with ethyl acetate three times, the organic phases are washed with saturated NaCl solution. After drying over MgSO4 and filtering on a frit, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography eluted with a heptane/ethyl acetate gradient. The fraction containing the desired product is concentrated: a colourless oil is obtained with 54% yield.
1H NMR (300 MHz, CDCl3): δ (ppm): 2.34 (s, 3H, —CH3); 3.09 (t, 2H, CH2—C6H5); 4.15 (t, 2H, CH2—O); 6.85-7.29 (m, 8H, aromatic H).
HPLC: XTerra tr=13.56 min
ES+ mass: [M+Na]+=253.3.
The synthesis is represented in the following diagram:
R1, R2, R3 and R4 having the meanings designated above.
General procedure for the step of reduction of the nitro function: in a flask equipped with a three-way cock, compound IIA (1 equivalent) is diluted in ethyl acetate (20 volumes) and then the reaction medium is purged by alternation of vacuum/nitrogen atmosphere. The 10% palladium on charcoal catalyst is added and the reaction medium is purged by alternation of nitrogen atmosphere and hydrogen atmosphere. The reaction medium is stirred at ambient temperature under atmospheric pressure of hydrogen for 7 h. After filtration on Celite cake, the filtrate is concentrated under vacuum and then the residue is purified by silica chromatography or by crystallization.
The derivative XVIII may in particular be 2-hydroxyphenylethanol.
The Synthesis is in this Case:
This reduction step is carried out according to the procedure described in Example 5 starting from compound 19, itself obtained according to the general procedure described in Example 1.
Compound 21 is obtained, after crystallization from dichloromethane, in the form of a beige solid, at 60% yield.
1H NMR (300 MHz, DMSO-d6): δ (ppm) 2.90 (t, 2H, CH2—C6H5); 3.96 (t, 2H, CH2—O); 4.58 (bs, 2H, —NH2); 6.46-7.14 (m, 8H, aromatic H); 9.42 (bs, 1H, —OH).
HPLC: XTerra tr=7.63 min
ES+ mass: [M+H]+=230.3.
The general synthesis is represented in the following diagram:
R1, R2, R4 and R5 have the meanings designated above.
In a 50 mL three-necked flask, under a nitrogen stream and with magnetic stirring, the phenol derivative of Formula V (1 equivalent) is dissolved in dichloromethane (7 volumes), then the activated glycoside derivative in the form of trichloroacetimidate (1.3 equivalents) is introduced, dissolved beforehand in 8 volumes of dichloromethane. At 0° C., in the presence of beads of molecular sieve, a solution of BF3.Et2O (2 equivalents) is added. The reaction medium is stirred for 2 h at ambient temperature. It is then poured into a saturated solution of NaHCO3. After extraction with dichloromethane, the organic phases are washed with saturated NaCl solution. After drying over MgSO4 and filtering on a frit, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography eluted with a heptane/dichloromethane gradient. The fraction containing the desired product is concentrated.
In a 20 mL flask, under inert atmosphere, the preceding derivative (1 equivalent) is dissolved in methanol (10 volumes). At ambient temperature, a 1M solution of sodium methanolate is added and the reaction medium is stirred for 2.5 h. After adding acid resin, the medium is filtered and concentrated under vacuum. The residue obtained is purified by chromatography or by trituration in carefully selected solvents.
The general synthesis is represented in the following diagram:
This Step 1 is carried out according to the procedure described in Example 7 starting from compound 1. After purification by silica gel chromatography, compound 30 is isolated. It is a white solid obtained with 85% yield.
1H NMR (300 MHz, DMSO-d6): δ (ppm) 2.05 (s, 12H, —CO—CH3); 3.08 (t, 2H, CH2—C6H5); 3.90 (m, 1H, anomeric H); 4.02-4.33 (m, 4H, glucose H); 5.10-5.23 (m, 2H, glucose H); 5.35 (t, 2H, CH2—O); 6.80-7.29 (m, 8H, aromatic H).
HPLC: XBridge tr=13.16 min
ES− mass: [M+H2O—H]−=580.2.
Step 2 is carried out according to the procedure described in Example 7 starting from compound 30. After purification by trituration in a pentane/isopropyl ether mixture, compound 29 is isolated. It is a white solid obtained with 80% yield.
1H NMR (300 MHz, DMSO-d6): δ (ppm) 3.04 (m, 2H); 3.12 (m, 1H); 3.28 (t, 2H, CH2—C6H5); 3.46 (m, 1H); 3.83 (m, 1H); 4.16 (t, 2H, CH2—O); 4.59 (m, 1H, —OH); 4.83 (d, 1H); 5.04-5.32 (m, 3H, —OH); 6.93-7.25 (m, 8H, aromatic H).
HPLC: XBridge tr=10.10 min
ES− mass: [M−H]−=393.4.
A multi-step synthesis, represented in the following diagram, is carried out:
In a dry 250 mL three-necked flask, under a nitrogen stream and with magnetic stirring, the compound 2-(2-hydroxy-ethyl)-phenol (1 equivalent) is diluted in dichloromethane (5 volumes) and then TEA (2.2 equivalents) is added. The reaction medium is cooled to 5° C. Using a dropping funnel, methanesulphonyl chloride (2.2 equivalents), diluted in dichloromethane (5 volumes) is added while controlling the temperature. The reaction medium is then stirred at ambient temperature overnight. The reaction medium is poured into an ice water/HCl mixture. After extracting with dichloromethane three times, the organic phases are washed with saturated NaCl solution. After drying over MgSO4 and filtering on a frit, the filtrate is concentrated under vacuum. The residue is purified by trituration in pentane. The products obtained are oils or solids depending on the nature of R.
In a dry 100 mL three-necked flask, under a nitrogen stream and with magnetic stiffing, compound XVA (1 equivalent) is dissolved in acetonitrile (10 volumes).
Phenol derivatives (1.2 equivalents) are added, as well as K2CO3 (1.2 equivalents).
Said phenol derivatives are as follows:
The reaction medium is heated under reflux for 4 h. At the end of the reaction, the reaction medium is hydrolysed with 25 volumes of distilled water. After extracting with dichloromethane twice, the organic phases are washed with a saturated solution of NH4Cl, dried over MgSO4, filtered and concentrated under vacuum.
The residue obtained is purified by silica gel chromatography eluted with a heptane/chloroform or heptane/isopropyl ether or heptane/isopropanol gradient, depending on the polarity of the compounds.
The colourless liquids, obtained with 20-60% yield, are each used in the next step of deprotection.
In a 50 mL three-necked flask equipped with a condenser, with magnetic stiffing, the monomesylate of formula
(1 equivalent) is dissolved in ethanol (12 volumes). A soda solution at 2 mol·L−1 (2 equivalents) is added and the mixture is heated with stiffing under reflux for 4 h.
Once the reaction has ended after 20 h, the solvent ethanol is removed under vacuum and the residue is taken up in a mixture of distilled water and dichloromethane. After extracting repeatedly, the organic phases are dried over MgSO4, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography eluted with a heptane/ethyl acetate gradient.
The yield of the reaction is 45-70%.
The compounds obtained are characterized as follows:
Compound 35: colourless oil
1H NMR (300 MHz, CDCl3): δ (ppm) 1.22 (t, 3H, CH3); 2.60 (q, 2H, CH2—CH3); 3.13 (t, 2H, CH2-Ph); 4.26 (t, 2H, CH2—O); 6.84-6.96 (m, 4H, aromatic H); 7.10-7.21 (m, 4H, aromatic H)
HPLC: XBridge tr=13.2 min
ES+ mass: [M+H]+=243.1
Compound 39: colourless oil
1H NMR (300 MHz, CDCl3): δ (ppm) 1.22 (s, 6H, CH3); 2.87 (heptuplet, 1H, CH—); 3.13 (t, 2H, CH2-Ph); 4.26 (t, 2H, CH2—O); 6.85-6.95 (m, 4H, aromatic H); 7.13-7.21 (m, 4H, aromatic H)
HPLC: XBridge tr=13.5 min
ES+ mass: [M+H]+=255.2
Compound 43: colourless oil
1H NMR (300 MHz, CDCl3): δ (ppm) 0.66 (t, 3H, —CH2—CH3); 1.26 (s, 6H, —C—CH3); 1.62 (m, 2H, —C—CH2—); 3.13 (t, 2H, CH2-Ph); 4.27 (t, 2H, CH2—O); 6.85-7.26 (m, 8H, aromatic H)
HPLC: XBridge tr=13.9 min
ES− mass: [M−H]−=283.2
Compound 47: colourless oil
1H NMR (300 MHz, CDCl3): δ (ppm) 1.30 (t, 9H, —C—(CH3)3); 3.13 (t, 2H, CH2-Ph); 4.27 (t, 2H, CH2—O); 6.86-7.33 (m, 8H, aromatic H)
HPLC: XBridge tr=13.7 min
ES− mass: [M−H]−=269.2
Compound 51: colourless oil
1H NMR (300 MHz, CDCl3): δ (ppm) 0.46-1.67 (m, 19H, —(CH2)8—CH3); 3.13 (t, 2H, CH2-Ph); 4.27 (t, 2H, CH2—O); 6.84-6.96 (m, 4H, aromatic H); 7.13-7.24 (m, 4H, aromatic H)
HPLC: XBridge tr=12.6 min
ES− mass: [M−H]−=339.3
Compound 130: colourless oil
1H NMR (300 MHz, CDCl3): δ (ppm) 0.93 (t, 3H, —CH2—CH3); 1.60 (m, 2H, —CH2—CH3); 2.54 (t, 2H, —CH2—CH2—); 3.14 (t, 2H, CH2-Ph); 4.26 (t, 2H, CH2—O); 6.84-6.97 (m, 4H, aromatic H); 7.08-7.22 (m, 4H, aromatic H)
HPLC: XBridge tr=13.5 min
ES− mass: [M−H]−=255.2
1H NMR (CDCl3 or DMSO-d6)
1. Preparation of the explants
2. Application of the products
3. Taking samples
4. Histological treatment
5. Microscopic observations
6. Staining and immunolabelling
Immunolabelling will be carried out on sections with the appropriate antibody. The nuclei may be stained with propidium iodide.
Compound 1, of formula
and the reference compound, (+)-dehydroisoandrosterone (DHEA Acros ref. 154980100), were tested at a concentration of 2 μg/mL in DMSO, on abdominoplasties. After 9 days of survival, compound 1 displayed a very clear epidermal and dermal restructuring activity: the epidermal structure is clearly acanthotic (thicker) with a good morphology, and the papillary dermis is clearly denser. In contrast, the reference product, (+)-dehydroisoandrosterone, does not alter the epidermal structure or the papillary dermis at a concentration of 2 μg/mL.
A more detailed study using staining and immunolabelling of the sections from the aforementioned plasty procedures treated with compound 1 shows
Effects of Compound 1 on Expression of Markers by Keratinocytes
The expression of the specific markers was evaluated by RT-qPCR (reverse transcription quantitative polymerase chain reaction) on messenger RNAs extracted from the cell lawns from each treatment. The transcriptomic profile contains 64 genes selected for their importance in keratinocyte differentiation. The PCR reactions (polymerase chain reactions) were carried out by quantitative PCR with the “Light Cycler” system (Roche Molecular System Inc.) according to the procedures recommended by the supplier.
Normal human epidermal keratinocytes were incubated in the presence of compound 1 or a reference with calcium chloride. The expression of the specific markers was evaluated by RT-qPCR on the messenger RNAs extracted from the cell lawns from each treatment.
Under the experimental conditions of this study, compound 1 tested at 10 μM showed an effect that was less, but similar to calcium chloride at 1.5 mM in stimulating the expression of markers involved in lipid synthesis, antimicrobial defence, innate immunity and cell-cell interactions. Moreover, in parallel with this effect, inhibition of expression of the “matrix metallopeptidase” gene MMP9 involved in the degradation of the extracellular matrix and of the stress protein HSPB1, “heat shock protein beta-1”, was also observed.
Compound 1 therefore displayed a pro-differentiating effect.
Transglutaminase K, TGK, and filaggrin are two protein markers of epidermal differentiation involved in arrangement of the keratin filaments and formation of the envelope of the stratum corneum. In situ immunolabelling of TGK and filaggrin in normal human epidermal keratinocytes cultured in the presence of calcium chloride or of compound 1 showed concentration-dependent stimulation of protein expression of filaggrin and TGK by compound 1.
The effects of compound 1 were evaluated on two routes of inflammation, the “chemokine” route and the “prostaglandin” route, by measuring the release of interleukin-8 (IL-8) and of prostaglandin E2 (PGE2) by a human keratinocyte line NCTC-2544 stimulated by phorbol-myristate acetate (PMA).
Compound 1 displays a clear anti-inflammatory effect by concentration-dependent inhibition of the release of PGE2 without altering the release of IL-8.
The effects of this compound were evaluated on a monolayer of normal human dermal fibroblasts by measuring the neosynthesis of glycosaminoglycans designated as sulphated GAGs (incorporation of [35S]-sulphate). Compound 1 stimulated the neosynthesis of sulphated GAGs, in a non-concentration-dependent fashion. This might explain the effect of dermal reinforcement already observed on skin explants ex vivo.
Evaluation of the Depigmenting Effect on the B16 Melanocyte Line Stimulated by NDP-MSH
The anti-melanogenesis activity of the compounds in solution in DMSO was evaluated by measuring melanin synthesis in a model of B16 melanocytes stimulated with a stable derivative of α-MSH (natural melanogenesis stimulating hormone): NDP-MSH.
The melanocytes were seeded in a 96-well plate and were cultured for 24 h (37° C., 5% CO2, DMEM 1 g/L glucose without phenol red supplemented with glucose at 3 g/L, L-glutamine at 2 mM, penicillin at 50 U/mL, streptomycin at 50 μg/mL, foetal calf serum (FCS) at 10%). After incubation, the culture medium was then replaced with culture medium supplemented or not supplemented (unstimulated control) with a stable derivative of α-MSH and containing or not containing (controls) the test compounds or the reference (kojic acid at 25, 100, 400, 800 μg/mL). Each experiment was carried out with n=3, apart from the controls carried out with n=6, then the cells were incubated for 72 h. Wells without cells received in parallel the same quantities of medium supplemented or not supplemented with NDP-MSH and containing or not containing the test compounds or the reference in order to quantify the background noise associated with the presence of the compounds.
After incubation for 72 hours, the total melanin (intra- and extracellular) was quantified by measuring the absorption at 405 nm of each sample (direct reading of the culture plates) against a standard range of melanin (melanin concentrations tested from 0.78 to 100 μg/mL). The background noise, measured in the wells without cells, was subtracted from the measured values so as only to take into account the effect connected with melanin production, without taking into account the possible interference connected with the presence of the compounds. The results were expressed as percentage of melanin relative to the control as well as percentage inhibition.
At the end of the treatment, the cells were incubated in the presence of MTT (tetrazolium salt), the transformation of which to blue crystals of formazan is proportional to the activity of succinate dehydrogenase (mitochondrial enzyme). After dissociation of the cells, the formazan was dissolved in DMSO medium and the optical density (OD), representative of the number of living cells and of their metabolic reactivity, was measured with a microplate reader at 540 nm (VERSAmax, Molecular Devices).
The results obtained are presented in the following table:
The operating conditions are the same as in Example 12.
The effects of the following three molecules were compared:
The following table summarizes the results obtained:
Ref 1 [18979-61-8]
Ref 2 [869743-37-3]
Compound 1 therefore displays a clear inhibitory effect at the two concentrations tested and is slightly more effective than the two reference products used.
The affinity of compound 1 for the PPAR receptors (α and γ) was tested by in vitro binding assays (tests carried out by the company Cerep).
This is a nuclear receptor competitive binding assay, between a radiolabelled ligand and the test molecule (here compound 1).
The principle of the technique consists of measuring the displacement of the radioactive ligand bound to the receptor by the test molecule.
The specific binding of the ligand is defined by the difference between total binding and non-specific binding determined in the presence of an excess of unlabelled ligand.
The results are expressed as:
The values of IC50 (concentration at which the maximum control specific binding is inhibited by 50%), and the Hill coefficient (nH) are determined by non-linear regression analysis of the curves of competition with a mean replicated value using adjustment of Hill's equation
(Y=D+[(A−D)/(1+(C/C50)nH)]).
in which,
This analysis was carried out using software developed by the company Cerep (Hill Software) and was validated by comparison with the data generated by the software SigmaPlot® 4.0 for Windows (® 1997 by SPSS Inc).
The inhibition constant (Ki) was calculated using the Cheng-Prusoff equation
[Ki=IC50/(1+(L/KD)],
in which
At different concentrations of compounds, and with either the receptor PPARα or PPARγ, the percentage of inhibition is close to zero. Therefore there is no activity of compound 1 with respect to the PPAR receptors.
The 49% value indicates a slight to moderate effect.
The agonist or antagonist activity of compound 1 on the PPAR receptors was tested by fluorescence techniques.
The results are expressed as:
The EC50 values (concentration at which the maximum specific response is 50%) and the IC50 values (concentration at which the maximum control specific agonist response is inhibited by 50%) are determined by non-linear regression analysis of the concentration-response curves with a mean replicated value using adjustment of Hill's equation
(Y=D+[(A−D)/(1+(C/C50)nH)]
in which,
This analysis was carried out using software developed by the company Cerep (Hill Software) and validated by comparison with the data generated by the software SigmaPlot® 4.0 for Windows (® 1997 by SPSS Inc).
For the antagonists, the apparent dissociation constants (KB) were calculated using the modified Cheng-Prusoff equation
K
B
=IC
50/(1+(A/EC50A)),
in which
As the percentage of response is low (−1 to 4), compound 1 is therefore not an agonist.
As the percentage inhibition is low (−5 to 4), compound 1 is therefore not an antagonist.
These various tests therefore prove that compound 1 is not a PPAR activator.
| Number | Date | Country | Kind |
|---|---|---|---|
| 11/62289 | Dec 2011 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2012/052964 | 12/18/2012 | WO | 00 |
