Skin Care Compositions Comprising Phenoxyalkyl Amines
Abstract:
Skin care compositions comprising certain phenoxyalkylamines, which are particularly beneficial for skin lightening and achieving evenness of color, especially for face and underarm skin.
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Notices, Deadlines & Correspondence
CONOPCO INC. D/B/A UNILEVER, 40 MERRITT BOULEVARD, TRUMBULL, CONNECTICUT 06611, UNITED STATES OF AMERICA
2. HARICHIAN BIJAN
CONOPCO INC. D/B/A UNILEVER, 40 MERRITT BOULEVARD, TRUMBULL, CONNECTICUT 06611, UNITED STATES OF AMERICA
3. BAJOR JOHN STEVEN
CONOPCO INC. D/B/A UNILEVER, 40 MERRITT BOULEVARD, TRUMBULL, CONNECTICUT 06611, UNITED STATES OF AMERICA
4. BOSKO CAROL ANNETTE
CONOPCO INC. D/B/A UNILEVER, 40 MERRITT BOULEVARD, TRUMBULL, CONNECTICUT 06611, UNITED STATES OF AMERICA
5. DRENNAN DIANA JEAN
CONOPCO INC. D/B/A UNILEVER, 40 MERRITT BOULEVARD, TRUMBULL, CONNECTICUT 06611, UNITED STATES OF AMERICA
6. NIP JOHN CHUN-SING
UNILEVER HOME & PERSONAL CARE USA, 40 MERRITT BOULEVARD, TRUMBULL, CONNECTICUT 06611, UNITED STATES OF AMERICA
Specification
FORM - 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
SKIN CARE COMPOSITIONS COMPRISING PHENOXYALKYL AMINES
HINDUSTAN UNILEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 and having its registered office at Hindustan Unilever Limited, Unilever House, B.D.Sawant Marg, Chakala, Andheri (East) Mumbai -400 099, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed
SKIN CARE COMPOSITIONS COMPRISING PHENOXYALKYL AMINES
TECHNICAL FIELD
The present invention relates to compositions for face and body skin.
BACKGROUND OF THE INVENTION
The desire to look young and healthy is universal. The primary attributes of the young and healthy-looking skin are evenness of the skin color and texture. Age spots and other skin hyperpigmentation are undesirable. In many parts of the world, consumers also want to lighten the background skin color. Accordingly, there is a need for commercially feasible, effective skin care compositions, especially skin lightening products.
Various compositions comprising some phenoxyalkyl amines or related structures have been described, for example in WO0063157 (Shrseido Co.); Sandberg et al., US 4,073,917; Biadatti et al., US2007021473; Labroo et al., US 5,416,098; WO 95/11238 (Smithkiine Beecham Pharmaceuticals); JP 01-261383 (Nippon Chemiphar Co. Ltd.); Anselmi et al., "Molecular mechanics conformational analysis of structurally related UV-filters: conformation-antibacterial activity relationships," Acta Technologiae et: Legis Medicametni (1998), 9(1), 49-67; Anselmi et al., "Sunscreen agents as multiactive ingredients," Active Ingredients, Conference Proceedings, Paris, Nov. 13-14, 1996 (1996), 55-62 Publisher: Verlag fuer Chemische Industrie H. Ziolkowsky, Augsburg, Germany; Anselmi et al., "Comparative conformational and dynamical study of some N-quatemized UV filters: structure-activity relationships" Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1996), (7), 1517-1524; Anselmi etal., "Synthesis, Crystal Structure and properties of N, N-Dimethyl-N-[6-(benzoyl-4-phenoxy) hexamthylenJ'N-n-dodecyl-ammonium Bromide: A New Substantive UV Filter," Acta Technolgiae et Legis Medicamenti, Vol. VIII, N. 2, 1997, 85-93.
Some documents also described various phenoxyalkyl amines (different from those included in the present application) for topical application, e.g. hair tonic for promoting hair growth (WO0063157 (Shiseido Co.) and local anesthetic (Sandberg etal., US 4,073,917).
SUMMARY OF THE INVENTION
The present invention is based at least in part on the finding that among hundreds of compounds described as "phenoxyalkyl amines," a sub-group (Structure I below) with critical structural elements, is effective at inhibiting melanin production.
The invention includes skin care compositions, preferably skin lightening compositions, comprising phenoxyalkylamines of Structure I. The invention also includes methods of using such compositions for skin care, especially face and underarms, most especially for skin lightening.
DETAILED DESCRIPTION OF THE INVENTION
Except in the examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or conditions of reaction, physical properties of materials and/or use are to be understood as modified by the word "about." All amounts are by weight of the final composition, unless otherwise specified.
It should be noted that in specifying any range of concentration or amount, any particular upper concentration can be associated with any particular lower concentration or amount.
For the avoidance of doubt, the word "comprising" is intended to mean "including" but not necessarily "consisting of or "composed of." In other words, the listed steps or options need not be exhaustive.
The disclosure of the invention as found herein is to be considered to cover all embodiments as found in the claims as being multiply dependent upon each other irrespective of the fact that claims may be found without multiple dependency or redundancy.
"Skin Care Composition" as used herein, is meant to include a composition for topical application to skin of mammals, especially humans. Such a composition may be generally classified as leave-on or rinse off, and includes any product applied to a human body for improving appearance, cleansing, odor control or general aesthetics. The composition of the present invention can be in the form of a liquid, lotion, cream, foam, scrub, gel, soap bar or toner, or applied with an implement or via a face mask, pad or patch. Non-limiting examples of skin care compositions include leave-on skin lotions and creams, shampoos, conditioners, shower gels, toilet bars, antiperspirants, deodorants, dental products, shave creams, depilatories, lipsticks, foundations, mascara, sunless tanners and sunscreen lotions. "Skin" as used herein is meant to include skin on the face and body (e.g., neck, chest, back, arms, underarms, hands, legs, buttocks and scalp).
The inventive compositions are especially useful for application to skin areas with the highest incidence of hyperpigmentation - face and underarms, most preferably the inventive compositions are skin lightening compositions, deodorants and anti-perspirants. "Lightening" as used herein, means the lightening of skin color as well as the lightening of spots (hyperpigmentation) on the skin, like age spots and freckles.
PHENOXYALKYL AMINES
The inventive compositions include phenoxyalkyl amines of Structure I:
wherein R1 is selected from the group consisting of hydrogen, linear, branched or cyclic C1-C6 alkyl, phenyl, and fused benzene, preferably from the group consisting of methyl, ethyl, and fused benzene. Preferably, R1 is a linear or branched alkyl, more preferably methyl or ethyl, and most preferably methyl; short chain (C1-C6, preferably C1 or C2) alkyl are preferred due to ease of commercially-scaled synthesis and also to render the molecule surface-active, making it more desirable for commercial products -easier to incorporate and contributing tactile and lather benefits in addition to its skin lightening properties. R1 is preferably at an ortho or meta position, more preferably ortho;
n is an integer from 4 to 6, preferably 5 or 6, most preferably 6. It has been found as part of the present invention that inhibition of melanin production is not achieved when n is below 4, and that the inhibition is best when n is 5 or 6, especially 6;
R2 and R3 are independently selected from the group consisting of hydrogen, linear, branched or cyclic C1-C6 alkyl, CH2CH2OH, or are fused to generate a ring which may include a heteroatom, with the proviso that R2 and R3 are not hydrogen at the same time. More preferably R2 and R3 are independently selected from hydrogen, C1-C6 alkyl and CH2CH20H, due to ease of synthesis. It has been found as part of the present invention that when R2 and R3 are simultaneously hydrogen (NH2), this detracts from melanin production inhibition.
It will be understood that Structure I also encompasses amine salts (e.g., halogen salts, tosylates, mesylates, carboxylates, and hydroxides).
Quaternary ammonium compounds, i.e. containing a permanently charged nitrogen, are not included within the scope of the invention, as it is difficult to achieve effective skin penetration for the quaternary ammonium compounds.
Phenoxyalkylamines included in the present invention contain a single ether linkage for greater ease of synthesis.
Amounts of the phenoxyalkyl amine may range from 0.001 % to 20%, preferably from 0.01 to 10%, more preferably from 0.1 to about 10%, optimally from 0.1 to about 5% by weight of the composition.
PROCESS OF MAKING PHENOXYALKYL AMINES Reagents & Analytical Methods
All reagents and solvents were obtained from commercial sources (Sigma-Aldrich, EMD Chemicals) and used without further purification unless otherwise indicated. 6-Aminohexanol (97%) was obtained from Aldrich and used without further purification. Parallel reactions and parallel solvent removal were performed using a Buchi Syncore reactor {Buchi Corporation, New Castle, DE). Microwave reactions were performed using a CEM Explorer reactor (CEM Corporation, Matthews, NC). Reaction monitoring was performed using either thin layer chromatography (TLC) or gas chromatography (GC). TLC was performed using silica gel 60 F254 plates (EMD Chemicals) and visualizing by UV (254nm), 4% phosphomolybdic acid (PMA) in ethanol (EtOH), 4% ninhydrin in ethanol and/or using an iodine chamber. GC was performed on a Hewlett Packard 5890 Series II Plus Gas Chromatograph equipped with a HP-1 crosslinked methyl silicone gum (25m X 0.2mm X 0.33mm film thickness) column operated by GC Chemstation (HP, version A.06.01 [403], Hewlett Packard) software and the following parameters and gradient applied; injector temp 250°C, oven temp: 70°C (2min), ramp at 25°C/min up to 250°C, held at 250°C (11min). High performance liquid chromatography (HPLC) was performed using a Waters 2695 Separations Module equipped with a Waters 2996 Photodiode Array Detector and operated with Empower Pro software (Waters Corp.). Separations were carried out at 1ml/min on a Restek Pinnacle DB C18 column (5um, 4.6 X 150mm) maintained at 30°C. Samples for HPLC were prepared by dissolving 1mg of sample in 1ml mobile phase A:B (1:1) and injecting 5uL onto the column. The mobile phase consisted of A = 0.1% trifluoroacetic acid (TFA) in water and B = 0.1% TFA in acetonitrile (ACN) operated using gradient elution from 95:5 A:B to 5:95 A:B (gradient, 25min) followed by 100% B (isocratic, 5min). Liquid chromatography/mass spectrometry (LC-MS) was performed using a Finnigan Mat LCQ Mass Spectrometer via direct infusion of
samples (50ppm) in methanol and the total ion count monitored using eiectrospray ionization in the (+) mode (ESI+). 1H and 13C Nuclear magnetic resonance (NMR) spectroscopy was performed using a Eft-60 NMR Spectrometer (Anasazi instruments, Inc.) and processed using WinNuts software (Acorn NMR, Inc.). Melting points were determined using a Meltemp apparatus (Laboratory Devices). Purity was determined by HPLC-UV/Vis or GC.
General Procedure I: Synthesis of Phenoxyalkyl Bromides Intermediates (3)
Structure ID Chemical Name Ri* n
3a 1 -(6-b ram oh exyloxy) benzene H 6
3b 1-(6-bromohexyloxy)-2-methylbenzene ortho-methyl 6
3c 1-(6-bromohexyloxy)-3-methylbenzene meta-methyi 6
3d 1-(6-bromohexyloxy)-4-methyi benzene para-methyi 6
3e 1-(6-bromohexyloxy)-2~ethylbenzene ortho-ethyl 6
3f 1-(6-bromohexyloxy)-2-isopropylbenzene ortho-(iso-propyl) 6
3g 1-(6-bromohexyloxy)-2-tert-butyl benzene ortho-(tert-butyl) 6
3h 1-(6-bromohexyloxy)-2-phenylbenzene ortho-phenyt 6
3i 1 -(6-bromohexyloxy)naphthalene -C4H4- 6
3j 1-(5-bromopentyloxy)-2-methylbenzene ortho-methyl 5
3k 1 -(4-bromobutoxy)-2-methylbenzene ortho-methyl 4
31 1-(3-bromopropoxy)-2-methy!benzene ortho-methyl 3
3m 1-(2-bromoethoxy)-2-methylbenzene ortho-methyl 2
* The -C4H4- substituent is fused at positions 2,3 of the phenyl group to generate an 1-naphthyl group
Tetrahydrofuran (THF) (1ml) was added to mixtures of the phenolic derivatives 1 (1.0g, 1.0 equivalents), dibromo-alkanes 2 (2.5 equivalents), and 1M potassium hydroxide (KOH) in methanol (MeOH) (1.05 equivalents) and the resulting homogeneous solutions microwaved at 90°C for 10min (200W). Reactions were monitored by TLC using 80% hexanes in chloroform and PMA staining until complete disappearance of phenols. Reaction mixtures were diluted with ethyl ethensaturated sodium chloride (NaCI) (20ml:20ml) and the layers separated. The organic layer was washed with saturated NaCI (20ml), dried with sodium sulfate (Na2S04)and the solvents removed in parallel under reduced pressure at 45°C. The crude products were purified by flash chromatography using the following ratios of hexane:chloroform (H:C): 3a-3c and 3f-3m (80:20); 3d
(83:17); 3e (60:40) followed by 100% chloroform. The purified products were used directly for aminations without further characterization.
General Procedure II: Synthesis of Phenoxyalkyl Amines (5)
Structure ID Chemical Name R, R2 R3 n Purity
(%) LC-MS {% Relative Abundance)
5a 2-(6-phenoxyhexylamino)ethanol H H hydroxyethyl 6 99.5 238.1 (100)
5b 2-[[6-(2-
rnethylphenoxy)hexyl]amino]-
ethanol ortho-methyl H hydroxyethyl 6 99.4 252.2(100)
5c 6-(o-tolyloxy)-N-(2-methoxyethyl)hexan-1 -amine ortho-methyl H methoxyethyl 6 99.5 266.2(100)
5d 2-(5-
Documents
Application Documents
#
Name
Date
1
1149-MUMNP-2012-FORM 3(10-12-2013).pdf
2013-12-10
2
1149-MUMNP-2012-FORM 3(10-11-2014).pdf
2014-11-10
3
1149-MUMNP-2012-FORM 3-(25-04-2015).pdf
2015-04-25
4
1148-MUMNP-2012-FORM 3-(25-04-2015).pdf
2015-04-25
5
Other Document [13-06-2017(online)].pdf
2017-06-13
6
Form 26 [13-06-2017(online)].pdf
2017-06-13
7
Form 13 [13-06-2017(online)].pdf
2017-06-13
8
1149-MUMNP-2012-ORIGINAL UNDER RULE 6 (1A)-19-06-2017.pdf