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IE62691B1 - Retinoides for the treatment of photodamaged skin - Google Patents

Retinoides for the treatment of photodamaged skin

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Publication number
IE62691B1
IE62691B1 IE252388A IE252388A IE62691B1 IE 62691 B1 IE62691 B1 IE 62691B1 IE 252388 A IE252388 A IE 252388A IE 252388 A IE252388 A IE 252388A IE 62691 B1 IE62691 B1 IE 62691B1
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IE
Ireland
Prior art keywords
formula
skin
compounds
alkyl
signifies
Prior art date
Application number
IE252388A
Other versions
IE882523L (en
Inventor
Graeme Findlay Bryce
Stanley Seymour Shapiro
Original Assignee
Hoffmann La Roche
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Publication of IE882523L publication Critical patent/IE882523L/en
Publication of IE62691B1 publication Critical patent/IE62691B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/004—Aftersun preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Organic Chemistry (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of the formula <IMAGE> in which Z and n have the meanings defined in the description, can be used as active ingredients in products for topical treatment of skin damaged by light.

Description

Description The skin, particularly in humans, contains an elaborate network of elastin fibres which are responsible for maintaining its elastic properties. With excessive exposure to sunlight the elastic fibre system becomes hyperplastic, disorganized and ultimately disrupted.
This phenomenon is known as actinic elastosis and is the principal cause of wrinkling, discoloration and laxity of the skin in the exposed areas of the body. The skin can repair itself to some extent, but it is nevertheless desirable to have an agent which can accelerate the repair of this prematurely aged skin.
It has been found that the UV-B irradiated hairless mouse is a convenient model for actinic elas^sis in the skin (Kligman et al. J. Invest. Dermatol. 78. 181 [1982]). It has been shown by Johnston et al. in J. Invest. Dermatol. 82. 587 (1984) that UV-B irradiation, which has been adjusted such that it simulates solar radiation, leads to a significant increase in skin elastin which can be measured by demosine content. The amount of this amino acid, which can be isolated by the acidic hydrolysis of elastin, is proportional to the elastin present in the skin (Uitto et al., Lab. Invest. 49. 1216 [1973]). It has been shown that the topical treatment of irradiated mice with retinoic acid normalizes the histological features of the skin in which the previously elastotic dermis has the appearance of unirradiated tissue (Kligman el al., Conn. Tissue Res. 12. 139 (1984), Kligman U. S. Patent No. 4, 603, 146). Therefore, this model can be used to determine the efficacy of compounds in the repair of photodamaged skin.
In accordance with the invention it has been found that compounds of the formula wherein n signifies Ί or 2; Z signifies mercapto or a residue -S(O)mR; m signifies 0, Ί or 2; R signifies lower-alkyl, lower-alkenyl, lower-alkynyl, lower alkoxy-lower alkyl, lower alkanoyMower-alkyl, hydroxv-lower-alkyl, halolower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is Ί or 2, R also represents lower-alkoxy, hydroxy, mono-loweralkvlamino or di-lower-alkylamino, and pharmaceutically acceptable salts of sulphonic acids and sulphinic acids of formula I, except ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulphone, when applied topically to the skin of a patient reverse the conditions associated with photodamage. Accordingly, by the topical application of compounds of formula I to the skin of patients which has been damaged by sunlight, the effects of wrinkling, elastosis and premature ageing can be reversed, which leads to an improvement in the appearance of the skin.
By the topical administration of compounds of the formula I, the repair of skin damage is accelerated, whereby the skin takes on a smoother and younger appearance.
The term lower as used herein denotes groups which contain 1-4 C atoms. Alkyl groups can be straight-chain or branched. Preferred lower-alkyl groups are methyl, ethyl and isopropyl. Examples of lower-alkenyl groups are vinyl, allyl and methallvl. Examples of lower-alkanovl groups are acetyl, propionyl and butyryl. Alkynyl groups can be straight-chain or branched. Preferred lower-alkynyl groups are ethynyl and propvnvl. The term halogen embraces fluorine, chlorine, bromine and iodine, of which chlorine is preferred. Examples of lower-carbalkoxy-lower-alkyl groups are carbomethoxv- and carboethoxy-methyl and -ethyl. Examples of lower-alkoxv groups are methoxy and ethoxy. Examples of alkylamino groups are methylamino, ethylamino, isopropylamino, dimethylamino and diethylamino.
The present invention is accordingly concerned with the compounds of formula I and pharmaceutically acceptable salts thereof for the manufacture of preparations for the topical treatment of photodamaged skin.
Pharmaceutically usable salts of compounds of formula I are all salts which are permissible having regard to the chemistry of the compounds of formula I and which can be administered to human patients in pharmaceutical preparations. Any conventional pharmaceutically usable salt of a sulphonic or sulphinic acid of the compound of formula I can be used.
Examples of such salts are alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, and ammonium or alkylammonium salts. Furthermore, conventional acid addition salts such as acetates may be used for compounds of formula I in which R is monolower-alkvlamino or di-lower-alkvlamino.
Of the compounds of formula I in which Z represents -S(O)mR there are preferred those compounds in which R represents lower-alkvl, lower-alkenvl, hvdroxy-lower-alkyl, or, when m is 1 or 2, lower-alkoxv, hydroxy, mono-lower-alkvlamino or di-lower-alkylamino.
Furthermore, there are preferred compounds of formula I in which m = 2 and those in which R is lower-alkvl, except ethyl. Further preferred compounds of formula I are those in which n is 2.
Especially preferred is methyl p-[2-(5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulphone.
Other interesting compounds of formula I are: Ethyl p-[2-( 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2~ naphthyl)propenyl]phenvlsulphonate; ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8~tetramethyl-2naphthvl)propenyl]phenylsulphoxide; ethyl p"[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl"2naphthyl)propenyl]phenvlsulphide; and isopropyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)propenyl]phenvlsulphone.
The compounds of formula I can be prepared as described in U.S. Patent Mo. 4,396,553.
As mentioned earlier, the compounds of the formula I upon topical application to the skin reverse the conditions associated with photodamage and thus moderate and retard the damage caused by sun. This damage is more pronounced with increasing age of the patient. By the topical application of the compounds of formula I to the skin in an amount effective to reverse the symptoms associated with elastosis, the acceleration of skin repair is accomplished and the skin takes on a smoother and younger appearance. The compounds of formula I should be applied to that area of the skin which is affected by elastosis or at which treatment is desired. The use of the compounds of formula I in accordance with this invention counteracts the ageing and wrinkling of the skin and enhances the repair of sundamaged skin.
The compounds of formula I or a combination thereof can be applied in accordance with this invention to human skin in conventional topical compositions. These compositions can be used to apply compounds of formula I to the skin of the body especially to the face, legs, arms and hands. In order to produce the best results, the treatment should start where a patient is between 30 and 55 years of age, when elastosis begins to appear and becomes more pronounced. Thereafter, the preparations can be applied continuously in order to reduce the age-related effects associated with elastosis. Generally, it is preferred to begin the treatment when the patient reaches approximately 30 years of age and to continue the treatment for life in order to reduce the effects of elastosis and to prevent any relapse.
The compounds of formula I can be administered in accordance with this invention in any conventional suitable topical form of administration, i.e. in combination with any conventional carrier which is suitable for topical administration. Accordingly compounds of formula I can be administered in accordance with this invention in any suitable topical composition such as a cream, ointment, soap, solution, lotion, emulsion or shampoo. Generally, for best results these topical preparations contain about 0.001% to about 1% by weight of a compound of formula I based on the total composition, with amounts of about 0.01 to 1 weight percent being especially preferred. If desired, higher concentrations may be used depending upon the nature and extent of elastosis.
In the production of these compositions any conventional non-toxic, dermatologically usable carriers in which the compounds of formula I are stable can be used. Preferred for the purpose in accordance with the invention are conventional cosmetic preparations which contain a further cosmetically active ingredient which confers a cosmetic effect to human skin. Such substances are moisturisers, surfactants, emollients, colorants, conditioners, bacteriocides, astringents and detergents.
Topical preparations in accordance with the invention can, if desired, contain suitable sunscreen filters. Any conventional sunscreen agent can be used in accordance with the invention. These topical preparations which contain compounds of formula I can contain conventional excipients and additives usually used in the production of topical preparations. Examples of such substances are preservatives, thickeners and perfumes. In addition, conventional antioxidants such as butylated hydroxyanisole, ascorbyl palmitate, propyl gallate, citric acid, butylated hydroxytoluene, or ethoxyquin can be incorporated into these preparations. Furthermore, the topical preparations can contain carriers which are generally used in such preparations. The preparations can contain usual thickeners, emulsifiers agents and viscosity stabilizers as well as flavorants, colorants, and perfume. The topical preparations containing compounds of formula I are preferably applied to the skin at least once a day or at least two to three times a week. In order to elastosis and to impart to the skin a smooth and younger appearance, the topical preparations should preferably be applied for a period of at least 5 months. Thereafter, the preparation should be applied on a continuing basis to maintain the effect of younger and smoother skin. The preparations can be applied according to the needs of the patient as determined by the physician. In any event, the particular application regimen for the preparations will depend on the age, weight and skin condition of the particular patient.
The following Examples illustrate the invention in more detail.
Example 1 Repair of UV-B induced skin damage in the hairless mouse Hairless mice (HRS/J strain, Jackson Labs, 5-7 weeks old at the start of the experiments) were irradiated three times per week with a bank of 8 Westinhouse Sunlamps (FS40) placed about 20 cm above the animals. The radiation dose was controlled by a commercial phototherapeutic control device. The UV-B dosage was chosen such that the doses, seldom exceeding 0.0SJ/cm2, caused minimal erythema but no burning or scarring. There was significant elastosis, detected by histology, after a total dose of about 3.5J/cm2; this was confirmed by measuring elastin in whole skin by means of a radioimmunoassay for desmosine. The demosine content increased by about two- to three-fold after 3.5J/cm2 of UV-B irradiation. In order to repair the skin damage, the UV-B irradiation was discontinued and groups of animals were treated separately three times per week with various dosages of different concentrations of the compounds of formula I dissolved in acetone. The solutions were made up freshly every week such that the dosage to be administered was contained in Ί 00 μϊ of acetone and applied topically to an area of about 10 cm2 on the back of the animal. A control group was treated with acetone alone.
After Ί0 weeks of treatment the animals were killed, skin preparations were made up and the extent of repair was measured quantitatively by Luna staining of the elastin. In this test model, the repair of the skin was defined by the appearance of a normal dermis extending from the epidermis down to the layer of compressed elastin. The extent of repair was reflected by the width of this zone. The area of the zone on a standard length of histological section was measured and the results were expressed as the total area in mm2 per 20 microscopic fields.
The results are compiled in Table I.
TableJ Repair zone, mnU Control 0.005±0.00l 0.2 μ0 of compound A 0.013±0.002* 0.6 91 0.019±0.005* 2 (1 0.02S±0.008* 6 II 0.007±0.002 20 11 0.010±0.003 Control 0.005±0.001 0.1 gg of compound B 0.017±0.007 0.5 11 0.021+0.005* 2 If 0.027±0.005'Λ Ί0 11 0.028±0.003*** 50 11 0.014±0.005 * P < 0.05, ** P < 0.01, *** p < 0.001 vs control Control 0.005±0.001 0.1 μ9 of compound C 0.022±0.007 * II 0.5 It II 0.033±0.007 *** 0.023±0.004 *** 0.033+0.005 *** * P < 0.05, *** P < 0.001 vs control Compound A: Methyl p-[2~(5,6,7,8tetrahydro-5,5,8,8tetramethvl^-naphthyO-propenyljphenylsulphone; Compound B: Methyl p-[2-(5,6,7,8-tetrahvdro-5,5,8,8tetramethyl-2-naphthyl)-propenyl]phenylsulphoxide; Compound C: Ethyl p-[2 (5,6,7,8-tetrahvdro-5,5,8,8tetramethyl-2-naphthyl)propenvl]phenylsulphide.
Examole 2 Effect on wrinkles in hairless mice caused bv UV-B irradiation It was found that dosages of UV-B irradiation which induced skin damage in hairless mice caused the appearance of wrinkles on the skin exposed to the irradiation. Skin impressions were taken of the irradiated areas with the aid of a liquid used in dentistry in order to permit a visual evaluation of the skin surface. Wrinkles appeared in these impressions as ridges which cast a shadow when illuminated with low angle light. A characteristic of the wrinkling pattern was the occurrence of ridges in a regularly-spaced array about 2 mm apart. The extent of this wrinkling was assessed visually, with a wrinkle Index of 0 to 4 being assigned. It was observed that the compounds of formula I caused a dosage-dependent effacement of the wrinkles, ED50 lying in the μο range. The results are compiled in Table II hereinafter.
Table II Wrinkle Index Control 0.2 μο of compound A 1.6±0.3 0.7±0.3* «I It II Control 0.Ί pg of compound b 0.5 2 10 * P < 0.o5, ** P < 0.0 Q.S±0.3:' 0.5 ±0. ΊΟ. 2 ± 0.11.6±0.3 0.6±0.2* 0.3±0.1** 0.7±0.4 0.2±0.Ί7'· 0.4±0.1 ** *** p < q qqi vs Control Creams and gels containing ingredients in the proportions set forth in Examples 3-7 can be produced in the usual manner. «. « , £xama!e_3 Cream Wt.% Compound of formula 1 0.00001-Ί.3 Cetyl alcohol 1.5 Stearyl alcohol 2.5 Span 60 (sorbitan stearate) 2.0 Mineral oil 2.0 Arlacel 165 (glyceryl/PEG Ί00 stearate) 4.0 Tween 60 (polvsorbate 80) 1.0 Miglvol 8Ί8 (caprylic/capric/linoleic triglyceride) 5.0 Sorbitol solution 4.0 Disodium edetate 0.1 BHA (butylated hvdroxvanisole) 0.05 Methylparaben 0.18 Propylparaben 0.05 Water q.s. 100.00 Example 4 Cream Wt.% Compound of formula 1 0.00001-1.0 Cetyl alcohol 5.25-8.75 Arlacel 165 (glvcervl/PEG 100 stearate) 3.75-6.25 Miglyol 818 (caprylic/capric/linoleic triglyceride) 11.25-18.75 Sorbitol solution 3.75-6.25 Disodium edetate .075-0.125 Carbopol 934P® (carbomer 934P) 0.15-0.25 BHA (butvlated hydroxyanisole) 0.0375-0.0625 Methvlparaben 0.135-0.225 Propylparaben 0.0375-0.0625 Sodium hydroxide (10% solution) 0.15-0.25 Distilled water, q.s 100.00 Example 5 Cream Wt.% Compound of formula 1 0.00001-1.0 Cutina MD (glyceryl stearate) 4.5-7.5 Ceteareth-1 2 3.0-5.0 Cetyl alcohol 3.0-5.0 General 122E-10 (ethoxylated soya sterol) 2.25-3.75 Cetiol LC (oleic acid decyl ester) 7.5-12.5 BHA (butvlated hvdroxyanisole) 0.0375-0.0625 Sorbitol solution 3.75-6.25 Disodium edetate 0.075-0.125 Methvlparaben 0.135-0.225 Propylparaben 0.0375-0.0625 Distilled water, q.s. 100.00 Example 6 fif&am Wl% Compound of formula 1 0.00001-1.0 Arlatone 983 (PEG 30/glyceryl stearate) 7.0 Cetyl alcohol 1.0 Stearic acid 4.0 Neobee oil (medium chain-length triglyceride) 17.0 Propylene glycol 5.0 2-phenoxyethanol 0.5 Distilled water, q.s. 100.00 Example 7 fie! Wt.% Compound of formula 1 0.00001-1.0 Pluronic L 101 (poloxamer 331) 10.00 Aerosil 200® (silica) 8.00 PCL Liquid (fatty acid esters) 15.00 Cetiol V (decyl oleate) 20.00 Neobee Oil (medium chain length triglyceride) 15.00 Euhanol G (octyldodecanol), q.s. 100.00 The physical properties of the preparations can be altered by varying the ratio between the excipients in Examples 3-7.

Claims (4)

Claims
1. The use of compounds of the formula wherein n signifies 1 or 2; Z signifies mercapto or a residue -S(O) m R; m signifies 0, 1 or 2; R signifies lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkoxy-lower alkyl, lower-alkanoyl-lower-alkyl, hydroxv-lower-alkyl, halolower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R also represents lower-alkoxv, hydroxy, mono-lower alkylamino or di-lower-alkylamino, whereby lower denotes groups with 1-4 C atoms, and pharmaceutically acceptable salts of sulphonic acids and sulphinic acids of formula I, except ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulphone 8 for the manufacture of preparations for the topical treatment of photodamaged skin.
2. The use according to claim 1 of compounds in accordance with claim 1 in which n = 2, m = 2 and R is loweralkyl, except ethyl.
3. The use of methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-raaphthyl)-propenyl]phenylsulphone according to claim 1.
4. Use according .to Claim 1 t , substantially as hereinbefore described.
IE252388A 1987-08-19 1988-08-18 Retinoides for the treatment of photodamaged skin IE62691B1 (en)

Applications Claiming Priority (1)

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US8699287A 1987-08-19 1987-08-19

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IE882523L IE882523L (en) 1989-02-19
IE62691B1 true IE62691B1 (en) 1995-02-22

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JP (1) JPH0627063B2 (en)
KR (1) KR890003369A (en)
AT (1) ATE89723T1 (en)
AU (1) AU610632B2 (en)
CA (1) CA1329553C (en)
DE (1) DE3881299D1 (en)
HU (1) HU203195B (en)
IE (1) IE62691B1 (en)
IL (1) IL87488A0 (en)
PH (1) PH24867A (en)
ZA (1) ZA885192B (en)

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IL87488A0 (en) 1989-01-31
IE882523L (en) 1989-02-19
EP0303915A3 (en) 1990-08-08
EP0303915B1 (en) 1993-05-26
JPS6470457A (en) 1989-03-15
PH24867A (en) 1990-12-26
KR890003369A (en) 1989-04-14
HUT48116A (en) 1989-05-29
JPH0627063B2 (en) 1994-04-13
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AU2118488A (en) 1989-02-23
HU203195B (en) 1991-06-28

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