CA1329553C - Pharmaceutical preparations - Google Patents
Pharmaceutical preparationsInfo
- Publication number
- CA1329553C CA1329553C CA000574958A CA574958A CA1329553C CA 1329553 C CA1329553 C CA 1329553C CA 000574958 A CA000574958 A CA 000574958A CA 574958 A CA574958 A CA 574958A CA 1329553 C CA1329553 C CA 1329553C
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- CA
- Canada
- Prior art keywords
- alkyl
- formula
- compound
- compounds
- skin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
Abstract
ABSTRACT
Compounds of formula I for use in topical agents to combat the disorders of the skin produced by photodamage which disorders include: wrinkling, elastosis and premature aging.
I
wherein n represents 1 or 2, Z represents -S(O)mR, wherein m represents 0, 1 or 2: R
represents lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino and pharmaceutically acceptable salts thereof.
Compounds of formula I for use in topical agents to combat the disorders of the skin produced by photodamage which disorders include: wrinkling, elastosis and premature aging.
I
wherein n represents 1 or 2, Z represents -S(O)mR, wherein m represents 0, 1 or 2: R
represents lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino and pharmaceutically acceptable salts thereof.
Description
" -- 1329~3 The skin, particularly in humans, contalns an elaborate network of elastin fibers which are responsible for maintaining its elastic properties. With excessive exposure to sunlight the elastic fiber system becomes hyperplastic, disorganized and ultimately disruQted. This is known as 10 actinic elastosis and is the principal cause of wrinkling, discoloeation and laxity of the skin in the exposed areas of the body. The skin can repair itself to some extent but it is nevertheless de~irable to have an agent which can accelerate the repair of this prematurely aged skin.
The UVB icradiated hairless mouse has been found to be a convenient model for actinic elastosis in the skin. tKligman et al. J. Inve6t. Dermatol. 78:181 ~1982). It has been shown by Johnston et al. in J. Invest. Dermatol. 82:587 (1984) that irradiation with low levels of W B which simulate realistic solar exposure leads ~o a significant increase in skin elastin as mea~ured by demosine content. The amount of thi-s amino acid, which is isolated fro~ acid hydrolysis of elastin, is ~roportional to the elastin present in the skin.
(Uitto et al., Lab. Inve t. 49:1216 (1973). Treatment of irradiated mice with topical retinoic acid has been shown to normalize the histological features of the skin in which the previously elastotic dermis has the appearance of unirradiated ~issue ~Klig~an et al., Con~. Tissue Res. 12:139 (1984), Kligman U.S. Patent ~o. 4,603,146 July 1986).
Therefore this model can be used to determine the efficacy of ~ompounds in the repair of sum damaged skin.
Gen/21.6.88 .
' , .. ~ . .... ..
The UVB icradiated hairless mouse has been found to be a convenient model for actinic elastosis in the skin. tKligman et al. J. Inve6t. Dermatol. 78:181 ~1982). It has been shown by Johnston et al. in J. Invest. Dermatol. 82:587 (1984) that irradiation with low levels of W B which simulate realistic solar exposure leads ~o a significant increase in skin elastin as mea~ured by demosine content. The amount of thi-s amino acid, which is isolated fro~ acid hydrolysis of elastin, is ~roportional to the elastin present in the skin.
(Uitto et al., Lab. Inve t. 49:1216 (1973). Treatment of irradiated mice with topical retinoic acid has been shown to normalize the histological features of the skin in which the previously elastotic dermis has the appearance of unirradiated ~issue ~Klig~an et al., Con~. Tissue Res. 12:139 (1984), Kligman U.S. Patent ~o. 4,603,146 July 1986).
Therefore this model can be used to determine the efficacy of ~ompounds in the repair of sum damaged skin.
Gen/21.6.88 .
' , .. ~ . .... ..
2 ~3295~3 In accordance with this inYention, it has been found that compounds of formula ~ Z :~
(C~
X
,~' wherein n represents l or 2; Z represents -S(O~ R, wherein m represen~s 0, l or 2; R
represents lower-alkyl, lower-alkenyl, lower alkynyl lower-alkoxy-lowe~-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lowe~-alkyl, halo-lower-alkyl, lower-carbal~oxy-lower-alkyl or, when m is l or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino, and pharmaceutically acceptable salts thereof when applied topically to the skin of a patient reverse the : conditions a6sociated with photodamage. Hence, by the topical application of comeounds of formula I to the skin of patien~s which has been da~aged through sun exposure, the ef~ects of wrinkling, elasto~is and premature aging can be re~ersed leading to an improvement in the appearance of the skin.
Through the topical ad~inistration of the compounds of the formula I, the acceleration o~ repair of dermal damage is ~ :
accomplished so as to provide the skin with a smoother and younger appearance.
:. ' ' ' :
` --`` 1329~53 The term "lower" as used herein denotes groups which preferably contain 1-4 carbon atoms. Alkyl groups can be straight-chain or branched-chain. Preferred lower-alkyl groups are methyl, ethyl and isopropyl. ~xamples of lower-alkenyl groups are vinyl, allyl and methallylO
Examples of lower-alkanoyl groups are acetyl, propionyl, and butyryl. Alkynyl groups can be s~raight-chain or branched-chain. Preferred lower alkynyl groups are ethynyl and propynyl. The term "halogen" embraces fluorine, chlorine, bromine and iodine, of which chlorine is preferred. ~xamples of lower-caLbalkoxy-lower-alkyl groups are carbomethoxy- and carboethoxy-methyl and -e~hyl.
Examples of lower-alkoxy 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 or pharmaceutically acceptable salts therof for use in the topical treatment of conditions associated with photodamaged skin and for the manufacture of pharmaceutical preparations for topical application intended for the treatment of such conditions. The invention is also concerned with a method of treatment of the conditions associated with photodamaged skin by topically administering a compound of the formula I or a pharmaceutically acceptable salt thereof to an area of the skin of a patient in need of said treatment.
A ~harmaceutically acceptable salt of compounds of focmula I, which compounds belong to the class of retinoids, includes any salt che~ically permissible in the art for compounds of formula I and applicable to human patients in a pharmaceutically acceptable preparation. Among such phàrmaceutically acceptable salts of compounds of formula I
there are especially included salts of sulfonic acids and sulfinic acids of compounds of formula I. Any conventional pharmaceutically acceptable base salt of sulfonic or - , . ~: :
- 4 - 1329~3 sulfinic acids of compounds of formula I can be utilized.
Among the conventional base salts which ca~ be utilized there are included, ~or example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or alkyl ammonium salts.
Furthermoce, conventional acid addition salts, such as acetates, may be utilized for compounds of formula I wherein R is mono- lower-alkylamino or di-lower-alkyl-amino.
In a par~icular aspect, this in~ention relates to the compounds of formula I and their salts except the compound ethyl p- E2- ~5,6,7,8-tetrahydro-5,5,8,8-tetrame~hyl -2-naphthyl)propenyl]phenylsulfo~e.
Gf the compounds of formula I wherein Z represents -S(O)mR, there are preferred those compounds in which R is lower-alkyl, lower-alkenyl, hydroxy-lower-alkyl, or, when m is l or 2, lower-alkoxy, hydroxy, mono-lower-alkylamino or di-lower-alkylamino.
Furthermore, there are especially preferred compounds of formula I in which m i~ 2 as well as those in which R is lower-alkyl except ethyl. Further preferred compounds of formula I are those in which n of formula I is 2.
Especially preferred i6 methyl e- ~ 2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone.
Other i~teresting compounds of Formula I are ethyl p-~2-(5,6,7,8-tetrahydro-5,5,~,8-tetramethyl -2-naphthyl~propenyl]phenylsulfonate:
ethyl p-C2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl~propenyl]phenylsulfone;
ethyl p-[2 (5,6,7,8-tetrahydro-5,5,8,8-teteamethyl -2-naphthyl)propenyl]phenylsulfoxide;
- 5 - 1329~3 ethyl p-[2-(5~6~7~8-tetrahydro-5~5~8~8-tetrameth -2-naphthyl)propenyl]phenylsulfide;
isopropyl p-[2-(5,6,7,8-tetrahydro~5,5,8,8-tetramethyl -2-naphthyl)propenyl]phenylsulfone.
Processes for preearing compounds of Formula I are set forth in U.S. Paten~ No. 4,396,553.
The compounds of the formula I when applied topically to the skin, reverse the conditions assoclated with photodamage so as to moderate and retard the damage to the skin caused by sun exposure. The damage caused by sun exposure may include premature aging, elastosis and wrinkling. This damage is more pronounced in older patients. By applying the compounds f formula I topically to the skin in an amount e~fective to reverse the conditions associated with photodamage, the acceleration of skin repair is accomplished to enhance the skin with a smoother and younger appearance. The compounds of formula I should be applied to that portion or area of the skin which is affected by photodamage or in which treatment is desired. The use of the compounds o~ formula I in accordance with thi invention can ærovide the effects of anti-aging and anti-wrin~ling, as well as enhance the repai~
of ~un damaged skin.
A compound of formula I, or a combination of compounds of formula I can be applied in accordanee with this invention to human ~kin in conventional topical compositions. These compositions can be u~ilized to apply compounds of formula I
to the skin of the body, particula~ly the face, legs, arms and hands. The preferred method of a~plication of compounds of formula I topically to produce the best effects should ~tart where a patient is between 30 and 55 years o~ age, when elastosis begins to appear and b~co~es more pronounced.
Thereafter, this compo~ition can be continuously applied to patients to reduce ~he effects and injury associated with sun . :
. :. - ~ , , ; : . , . . ~ .
- 6 ~ 132~3 exposure. GenerallY, it is preferred to begin the treatment when the patient reaches approximately 30 years of age and to continue the treatment throughout his life, in order that the effects of elastosis be reduced and to pcevent any further progression of photodamage.
The compounds of formula I can be administered in accordance with this invention in any conventional suitable topical preparation, i.e. in combination with any suitable conventional carrier useful for topical administration.
Therefore, compounds of formula I can be administered in accordance with this invention in any suitable ~opical composition such as a cream, ointment, 80ap, solution, lotion, emulsion, shampoo, etc. Generally, for most efficaciou6 results, these topical compositions contain from about 0.0000~% to about l.OS by weight of the total compoition of a compound oP ~ormula I, with amounts of from about O.OOOl~ to about 0.1% by weight of the composition being especially preferred. If desired, higher concentrations may be utilized depending upon the nature and extent of elastosis.
In formuIating these compositions, any conventional non-toxic, dermatologically acceptable base or carrier in which a compound of formula I is stable can be utilized. The preferred compositions for use in this invention are the conventionally cosmetic compositions which can contain a cosmetically active ingredient which i8 topically administered to human skin to provide a cosmetic effec~.
A~ong the conventional cosmetically active materials which can be utilized in this compo~i~ion are included: sunscreens, pene~ration enhancers, moisturizers, surfactants, emollients, colorants, conditioners, bacteriocides, astringents, detergents, etc.
_ 7 _ 1329~3 The topical compositions of this inve~tion can, if desired contain suitable sunscreen agents. Any conventional sunscreen agent can be utilized in formu:Lating the formulations containing compounds of formula I which can be utilized in accordance with this invention.
These topical compositions which conl;ain compounds of ~ormula I can contain any of the conventional excipients and additives commonly used in preparinq topical compositions.
Among the conventional additives or excipients, which can be utilized in ereparing these cosmetic compositions in accordance with this inventi~on are prese~vatives, thickener~, perfumes and the like. In addition, the conventional antioxidants, such a6 butylated hydroxyanisoles (B~A), a corbyl pal~itate, propyl gallate, citric acid butylated hydroxy toluene (BHT~, ethoxyquin, tocopherol, and the like can be incorporated into these compositions. Thes~ topical composition6 can contain conventional acceptable carriers for topical applications which are generally ueilized in these compo6itions. These compositions may contain thickening agants, humectants, emulsifying agents and viscosity stabilizers, ~uch as those generally utilized. In addition, these compo~itions can con~ain flavoring agent~, colorants, and perfume which are conventional in preparing cosmetic compositiOns.
The topical compositions containing compounds o~ formula I can be applied to ~he skin and should be preferably applied to the skin at least once a day for at least 2 or 3 times a 30 week. Fo~ obtaininq the rever~al of the elastosis ~o as to impart to the skin a smooth and younger appearance the topical compositions should be preferably applied for a period of at least five month~. After that compo6i~ions which contain compounds of formula I should be applied continually to maintain the efect of younger and smoother skin. The6e preparation~ can be applied according to the need of the pa~ient as determined by the pre~cribing . : , -; . :
. .
: '- ' ~ ' .
- 8 - ~329~3 physician. In any event, the particular regiment or ap~lication of this composition to a patient will ~ypically depend on the age, weight and skin condition of the individual.
The invention is further illustrated in the following examples. These examples are for illustration and are not li~itative of the claimed invention.
Example l RePair of WB-Induced Dermal Damaqe in the Hairless Mouse bY
Co~Pounds of Formula I
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 Westinghouse Sunlamps (FS40) placed about 20cm above the animal6. The radiation dose was controlled by an International Light Model IL8~4A
20 Phototherapy Exposure Control and a detector. The WB dosing schedule ~as such that individual dose~, seldom exceeding 0.06J/cm , caused minimal erythema but QO burning or scarring. There was sig~ificant elastosis, detected by histology, after a to~al dose of about 3.5J/cm : this was confirmed in ~easurement6 of elastin in whole skin by means o~ a radioimmunoas6ay for desmo~ine. Demosine is found in elastin hydrolysates and is derived from crosslinks in th~
elastin molecule: it is a reliable index of total elastin.
Typically, desmosine increased by about 2-3 Pold after 3.5J/cm2 of UV~ irradiation. To e~fect repair of the dermal damage, the WB irradiation was discontinued and animals we~e treated three time~ pe~ week with various concentrations o~ ~he compounds of ~ormula I dis~olved in acetone. Solutions were made up freshly every week at concentrations such that the dose was delivered in 100~1 acetone and applied topically ~o an area of about 10 cm on the back of the animal with a plastic pipette: a control 9 132~3 g~oup treated with acetone alone was also included.
After lO weeks of treatment the animals were sacrificed, skin samples were taken and processed by standard methods. A
six micron section from each animal was stained for elastin with Luna~s 6tain and the degree of repair measured quantitatively. In this model. repair is defined by the appearance of a normalized dermis extending from the epidermis down to the layer of co~pressed elastin. The extent of repair was reflected by the width of this zone. In these studies, the area of the zone on a s~andard length of histological section was measured by a~ image analyzer and the results are given as total area in mm per twenty microscopic fields. Data was analyzed by Student's t-test.
15 The results are given in Table I. In Table I, and Table II
each group dosed at a particular concentration of com~ound of focmula I contained six to ten animals.
.
- lo- 132~3 Table_I
Grou~ -ePair Zone, mm2 Control 0.005 +/- O.OOl 0.2~g of Compound A 0.013 +/- 0.002*
0.6 " 0 Ol9 +/- 0 005*
2 1' 0 02g ~/- 0 00~*
6 1l o . 007 +/- O . 002 Z " O. 010 +/- O. 003 Group Con~rol 0.003 ~/- O.OOl O.l~g of Compound B O.Oll +/- 0.003 0-3 " 0.014 +/- 0.003*
l " 0.021 +/- 0.005*
3 " 0.022 +/- 0.004*
lO " O.Oll +/- 0.005 * P < 0.005, ~ P < O.Ol, **~ P < O.OOl vs Control GrouD RePair Zone, mm2 Control 0.005 +/- O.OOl O.l~g o~ Compound C 0.017 +/- 0.007 " 0.021 ~/- 0.0~5*
2 " 0.027 +/- 0.005~*
lO " 0.028 +/- 0.003~*
50 " 0.014 +/- 0.005 * P < 0.05, *~ P ~ 0.0l, *** P < O.OOl v6 Control Group Re~ir Zone mm2 Control 0.005 +/- O.OOl o.l~g of Compoun~ D 0.022 +/- 0.007 *
0.5 " 00033 +/- 0.007 ~**
2 " 0.023 +/- 0.004 ***
lO 1' 0.033 +/- 0.005 ***
* P < 0.05, *** P < O.OOl vs Control Throughout the 6pecification, Compound A is methyl p-~2-(5,6,7,8-tetrahydro 3~ -5,5,8,8-~etramethyl-2-naphthyl~-propenyl]phenylsulfone: :
.
~ ~ , ' ' ll 1329~
Compound B is ethyl p-~2-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthyl~-propenyl]phenylsulfone:
Compound C is methyl p-[2-(5,6,7,8-tetrahydro -5,5,~,8-tetramethyl-2-naphthyl)-propenyl]phenylsulfoxide; and Compound D is ethyl p-~2-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfid~.
Exam~le 2 10 Effect of Com~ounds sf Formula I on the Wrinkles Produced in Hairless Mice bv WB-lrradiation Doses of WB-irradiation sufficient to induce dermal damage in hairles~ mice were found to cause the appearance of wrinkles on the exposed skin. One skin replica for each animal was taken of these areas u~ing a liquid dental impression material (SILFLO - Flexico Developments Ltd., England). 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 the ridges in a regularly-spaced ar~ay about 2-mm apar~. The extent of wrinkling was visually asses6ed using this line pattern and a~signed a value (Wrinkle Index) of zero to 4 with zero representing complete effacement of wrinkling and 4 epresenting the maximum degree of wrinkling. It was observed that compounds of formula I caused a dose-dependent effacement of the wrinkles with ED50 value~ in the microgram range. The results are shown in the following Table.
I " ~
. .
, 1329~5~
- lZ -Table II
GrouP Wrinkle_Index Control l.6 +/- 0.3 0.2~g of Compound A 0.7 ~/- 0.3*
2 " 0.6 +/- 0.3~
6 " 0.5 +/- O.l~*
" 0.2 +/- O.l~
Group Control l.3 +/- O.Z
O.l~g of Compound B l.3 ~/- 0.3 0.3 It 0.7 +/- 0.2~
l " 0.3 +/- O.l~**
3 It 0.2 +/- O.l~
* P < 0.05, *~ P < O.Ol, *** P < O.OOl vs Control Group Wrinkle Index Control l.6 +/- 0.3 ~' O.l~g o~ Compound C 0.6 +/- 0.2*
0.5 1- 0.3 ~/- O.l**
2 " 0.7 ~/- 0.4 lO " 0.2 ~/- O.l*~ :
50 " 0.4 +/- O.l~
* P < 0.05, ** P ~ O.Ol, *** P ~ O.OOl vs Control Creams and gels containing iQgredients within the : proportions set forth in Examples 3 through 7 below can be ~ormulated by conventional meanfi.
.
. . .
.
13295~3 EXAMPLE 3.
CREAM
% w/~
A compound of formula I 0.00001-1.3 Cetyl Alcohol 1.5 10 Stearyl Alcohol 2.5 Span 60 ~Sorbitan 6tearate) 2.0 Mineral Oil 2.0 Arlacel 165 (Glyceryl/PEG 109 Stearate) 4.0 Tween 60 ~Poly~orbate 80) 1.0 *
Miglyol 818 (Caprylic/Capric/Linoleic 5.0 triglyceride) Sorbitol Solution g.0 Disodiu~ Edetate 0.1 BHA (Butylated Hydroxyani~ole) 0.05 20 Methylparaben 0.18 Propylparaben 0.05 Water q.s. 100.00 3~ :
*Trade Marks ..
r `: ~
13295~3 EXAMPLE 4.
CREAM
w/w A Compound o~ Formula I 0.00001-1.0 Cetyl Alcohol 5.25-8.75 Arlacel 165 (Glyceryl/PEG 100 Seearate~ 3.75-6.Z5 1O Miglyol R18 (Caprylic/Capeic/Linoleic ll.Z5 18.75 triglyceride) Socbitol Solutio~ 3.75-6.25 Disodium Edetate .075-0.125 Ca!bopol 934P (Carbomer 93gP) 0.15-0.25 BHA (Butylated ~ydroxyanisole)0.0375-0.0625 Metbylparaben 0.135-0.225 Peopylparaben 0.0375-0.0625 Sodium Hydeoxide (10% 801ution)0.15-0. Z5 Distilled Water, q.s. 100.00 ,. .
*Trade Mark ~' .
- 15 - i32~3 EXAMPLE 5.
CP~
~ w/w A Compound of Focmula I 0.00001-1.0 Cutina MD (Glyceryl Steara~e) 4.5-7.5 Ceteareth-12 3.0-s.o 10 Cetyl Alcohol 3.0-5.0 ~enerol 122E-10 ~Ethoxylated Soya Sterol) 2.25-3.75 *
Cetiol LC (Oleic Acid Decyl Ester) 7.5-12.5 BHA (Butylated Hydroxyanisole) 0.0375-0.0625 Sorbitol Solution 3.75-6.25 15 Disodium Edetate 0.075-0.125 Methylparaben 0.}35-0.225 Propylparaben 0.0375-0.0625 Distilled Water, q.s. 100.00 .~
' :
~ .
~Trade Mark -- 'D
~' ' ' : ' ' '. ' :' - 16 - 1329~3 EXAMPLE 6.
CREAM
~ w/w compound of formula I O.OOOOl-l.O
Arlatone 9a3 (PEG 30/Glyceryl Stearate) 7.0 Cetyl Alcohol 1.0 10 SteariC Acid Neobee Oil (Medium chain-length 17.0 triglyceride) Propylene Glycol S.O
2-phenoxyethanol 0.5 15 Distilled Water, q.s 100.00 EXAMPLE 7.
GEL
,% w/w A compound of formula I o.OOOOl-l.O
Pluronic L 101 tPoloxa~er 331) lo.Qo 26 Aero6il 200 (Silica) 8.00 PCL Liquid (Fatty Acid Eseer6) 1~.00 Cetiol V (Decyl Oleate) ZO.OO
Neobee Oil (Medium chain-length 15.00 triglyceride~
30 Euhanol G (Oct~ldodecanol~, q.6.100.00 Crea~ of ~xample 3, wherein Compound I i8 present in ~
weight/weight of 0.0001, O.oOl. 0.03, O.Ql, 0.1 and 0.3 ~ere 3S made and a~e preferred.
*Trade Marks A~
:
~ . . . .
- ~ .
~ 329~53 A cream of Example 6 and a gel of Example 7 were made wherein Compound I is present in % weight/weight of 0.5.
It is understood that the proportions of excipients in creams of Examples 3 and 6, and the gels of Example 7 can be varied, if desired. to change the physical properties of the resulting creams and gel .
: ,' ' ~ ' ' ~ ', , ~ , ,: ' . . , i~ :
(C~
X
,~' wherein n represents l or 2; Z represents -S(O~ R, wherein m represen~s 0, l or 2; R
represents lower-alkyl, lower-alkenyl, lower alkynyl lower-alkoxy-lowe~-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lowe~-alkyl, halo-lower-alkyl, lower-carbal~oxy-lower-alkyl or, when m is l or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino, and pharmaceutically acceptable salts thereof when applied topically to the skin of a patient reverse the : conditions a6sociated with photodamage. Hence, by the topical application of comeounds of formula I to the skin of patien~s which has been da~aged through sun exposure, the ef~ects of wrinkling, elasto~is and premature aging can be re~ersed leading to an improvement in the appearance of the skin.
Through the topical ad~inistration of the compounds of the formula I, the acceleration o~ repair of dermal damage is ~ :
accomplished so as to provide the skin with a smoother and younger appearance.
:. ' ' ' :
` --`` 1329~53 The term "lower" as used herein denotes groups which preferably contain 1-4 carbon atoms. Alkyl groups can be straight-chain or branched-chain. Preferred lower-alkyl groups are methyl, ethyl and isopropyl. ~xamples of lower-alkenyl groups are vinyl, allyl and methallylO
Examples of lower-alkanoyl groups are acetyl, propionyl, and butyryl. Alkynyl groups can be s~raight-chain or branched-chain. Preferred lower alkynyl groups are ethynyl and propynyl. The term "halogen" embraces fluorine, chlorine, bromine and iodine, of which chlorine is preferred. ~xamples of lower-caLbalkoxy-lower-alkyl groups are carbomethoxy- and carboethoxy-methyl and -e~hyl.
Examples of lower-alkoxy 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 or pharmaceutically acceptable salts therof for use in the topical treatment of conditions associated with photodamaged skin and for the manufacture of pharmaceutical preparations for topical application intended for the treatment of such conditions. The invention is also concerned with a method of treatment of the conditions associated with photodamaged skin by topically administering a compound of the formula I or a pharmaceutically acceptable salt thereof to an area of the skin of a patient in need of said treatment.
A ~harmaceutically acceptable salt of compounds of focmula I, which compounds belong to the class of retinoids, includes any salt che~ically permissible in the art for compounds of formula I and applicable to human patients in a pharmaceutically acceptable preparation. Among such phàrmaceutically acceptable salts of compounds of formula I
there are especially included salts of sulfonic acids and sulfinic acids of compounds of formula I. Any conventional pharmaceutically acceptable base salt of sulfonic or - , . ~: :
- 4 - 1329~3 sulfinic acids of compounds of formula I can be utilized.
Among the conventional base salts which ca~ be utilized there are included, ~or example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or alkyl ammonium salts.
Furthermoce, conventional acid addition salts, such as acetates, may be utilized for compounds of formula I wherein R is mono- lower-alkylamino or di-lower-alkyl-amino.
In a par~icular aspect, this in~ention relates to the compounds of formula I and their salts except the compound ethyl p- E2- ~5,6,7,8-tetrahydro-5,5,8,8-tetrame~hyl -2-naphthyl)propenyl]phenylsulfo~e.
Gf the compounds of formula I wherein Z represents -S(O)mR, there are preferred those compounds in which R is lower-alkyl, lower-alkenyl, hydroxy-lower-alkyl, or, when m is l or 2, lower-alkoxy, hydroxy, mono-lower-alkylamino or di-lower-alkylamino.
Furthermore, there are especially preferred compounds of formula I in which m i~ 2 as well as those in which R is lower-alkyl except ethyl. Further preferred compounds of formula I are those in which n of formula I is 2.
Especially preferred i6 methyl e- ~ 2-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfone.
Other i~teresting compounds of Formula I are ethyl p-~2-(5,6,7,8-tetrahydro-5,5,~,8-tetramethyl -2-naphthyl~propenyl]phenylsulfonate:
ethyl p-C2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl~propenyl]phenylsulfone;
ethyl p-[2 (5,6,7,8-tetrahydro-5,5,8,8-teteamethyl -2-naphthyl)propenyl]phenylsulfoxide;
- 5 - 1329~3 ethyl p-[2-(5~6~7~8-tetrahydro-5~5~8~8-tetrameth -2-naphthyl)propenyl]phenylsulfide;
isopropyl p-[2-(5,6,7,8-tetrahydro~5,5,8,8-tetramethyl -2-naphthyl)propenyl]phenylsulfone.
Processes for preearing compounds of Formula I are set forth in U.S. Paten~ No. 4,396,553.
The compounds of the formula I when applied topically to the skin, reverse the conditions assoclated with photodamage so as to moderate and retard the damage to the skin caused by sun exposure. The damage caused by sun exposure may include premature aging, elastosis and wrinkling. This damage is more pronounced in older patients. By applying the compounds f formula I topically to the skin in an amount e~fective to reverse the conditions associated with photodamage, the acceleration of skin repair is accomplished to enhance the skin with a smoother and younger appearance. The compounds of formula I should be applied to that portion or area of the skin which is affected by photodamage or in which treatment is desired. The use of the compounds o~ formula I in accordance with thi invention can ærovide the effects of anti-aging and anti-wrin~ling, as well as enhance the repai~
of ~un damaged skin.
A compound of formula I, or a combination of compounds of formula I can be applied in accordanee with this invention to human ~kin in conventional topical compositions. These compositions can be u~ilized to apply compounds of formula I
to the skin of the body, particula~ly the face, legs, arms and hands. The preferred method of a~plication of compounds of formula I topically to produce the best effects should ~tart where a patient is between 30 and 55 years o~ age, when elastosis begins to appear and b~co~es more pronounced.
Thereafter, this compo~ition can be continuously applied to patients to reduce ~he effects and injury associated with sun . :
. :. - ~ , , ; : . , . . ~ .
- 6 ~ 132~3 exposure. GenerallY, it is preferred to begin the treatment when the patient reaches approximately 30 years of age and to continue the treatment throughout his life, in order that the effects of elastosis be reduced and to pcevent any further progression of photodamage.
The compounds of formula I can be administered in accordance with this invention in any conventional suitable topical preparation, i.e. in combination with any suitable conventional carrier useful for topical administration.
Therefore, compounds of formula I can be administered in accordance with this invention in any suitable ~opical composition such as a cream, ointment, 80ap, solution, lotion, emulsion, shampoo, etc. Generally, for most efficaciou6 results, these topical compositions contain from about 0.0000~% to about l.OS by weight of the total compoition of a compound oP ~ormula I, with amounts of from about O.OOOl~ to about 0.1% by weight of the composition being especially preferred. If desired, higher concentrations may be utilized depending upon the nature and extent of elastosis.
In formuIating these compositions, any conventional non-toxic, dermatologically acceptable base or carrier in which a compound of formula I is stable can be utilized. The preferred compositions for use in this invention are the conventionally cosmetic compositions which can contain a cosmetically active ingredient which i8 topically administered to human skin to provide a cosmetic effec~.
A~ong the conventional cosmetically active materials which can be utilized in this compo~i~ion are included: sunscreens, pene~ration enhancers, moisturizers, surfactants, emollients, colorants, conditioners, bacteriocides, astringents, detergents, etc.
_ 7 _ 1329~3 The topical compositions of this inve~tion can, if desired contain suitable sunscreen agents. Any conventional sunscreen agent can be utilized in formu:Lating the formulations containing compounds of formula I which can be utilized in accordance with this invention.
These topical compositions which conl;ain compounds of ~ormula I can contain any of the conventional excipients and additives commonly used in preparinq topical compositions.
Among the conventional additives or excipients, which can be utilized in ereparing these cosmetic compositions in accordance with this inventi~on are prese~vatives, thickener~, perfumes and the like. In addition, the conventional antioxidants, such a6 butylated hydroxyanisoles (B~A), a corbyl pal~itate, propyl gallate, citric acid butylated hydroxy toluene (BHT~, ethoxyquin, tocopherol, and the like can be incorporated into these compositions. Thes~ topical composition6 can contain conventional acceptable carriers for topical applications which are generally ueilized in these compo6itions. These compositions may contain thickening agants, humectants, emulsifying agents and viscosity stabilizers, ~uch as those generally utilized. In addition, these compo~itions can con~ain flavoring agent~, colorants, and perfume which are conventional in preparing cosmetic compositiOns.
The topical compositions containing compounds o~ formula I can be applied to ~he skin and should be preferably applied to the skin at least once a day for at least 2 or 3 times a 30 week. Fo~ obtaininq the rever~al of the elastosis ~o as to impart to the skin a smooth and younger appearance the topical compositions should be preferably applied for a period of at least five month~. After that compo6i~ions which contain compounds of formula I should be applied continually to maintain the efect of younger and smoother skin. The6e preparation~ can be applied according to the need of the pa~ient as determined by the pre~cribing . : , -; . :
. .
: '- ' ~ ' .
- 8 - ~329~3 physician. In any event, the particular regiment or ap~lication of this composition to a patient will ~ypically depend on the age, weight and skin condition of the individual.
The invention is further illustrated in the following examples. These examples are for illustration and are not li~itative of the claimed invention.
Example l RePair of WB-Induced Dermal Damaqe in the Hairless Mouse bY
Co~Pounds of Formula I
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 Westinghouse Sunlamps (FS40) placed about 20cm above the animal6. The radiation dose was controlled by an International Light Model IL8~4A
20 Phototherapy Exposure Control and a detector. The WB dosing schedule ~as such that individual dose~, seldom exceeding 0.06J/cm , caused minimal erythema but QO burning or scarring. There was sig~ificant elastosis, detected by histology, after a to~al dose of about 3.5J/cm : this was confirmed in ~easurement6 of elastin in whole skin by means o~ a radioimmunoas6ay for desmo~ine. Demosine is found in elastin hydrolysates and is derived from crosslinks in th~
elastin molecule: it is a reliable index of total elastin.
Typically, desmosine increased by about 2-3 Pold after 3.5J/cm2 of UV~ irradiation. To e~fect repair of the dermal damage, the WB irradiation was discontinued and animals we~e treated three time~ pe~ week with various concentrations o~ ~he compounds of ~ormula I dis~olved in acetone. Solutions were made up freshly every week at concentrations such that the dose was delivered in 100~1 acetone and applied topically ~o an area of about 10 cm on the back of the animal with a plastic pipette: a control 9 132~3 g~oup treated with acetone alone was also included.
After lO weeks of treatment the animals were sacrificed, skin samples were taken and processed by standard methods. A
six micron section from each animal was stained for elastin with Luna~s 6tain and the degree of repair measured quantitatively. In this model. repair is defined by the appearance of a normalized dermis extending from the epidermis down to the layer of co~pressed elastin. The extent of repair was reflected by the width of this zone. In these studies, the area of the zone on a s~andard length of histological section was measured by a~ image analyzer and the results are given as total area in mm per twenty microscopic fields. Data was analyzed by Student's t-test.
15 The results are given in Table I. In Table I, and Table II
each group dosed at a particular concentration of com~ound of focmula I contained six to ten animals.
.
- lo- 132~3 Table_I
Grou~ -ePair Zone, mm2 Control 0.005 +/- O.OOl 0.2~g of Compound A 0.013 +/- 0.002*
0.6 " 0 Ol9 +/- 0 005*
2 1' 0 02g ~/- 0 00~*
6 1l o . 007 +/- O . 002 Z " O. 010 +/- O. 003 Group Con~rol 0.003 ~/- O.OOl O.l~g of Compound B O.Oll +/- 0.003 0-3 " 0.014 +/- 0.003*
l " 0.021 +/- 0.005*
3 " 0.022 +/- 0.004*
lO " O.Oll +/- 0.005 * P < 0.005, ~ P < O.Ol, **~ P < O.OOl vs Control GrouD RePair Zone, mm2 Control 0.005 +/- O.OOl O.l~g o~ Compound C 0.017 +/- 0.007 " 0.021 ~/- 0.0~5*
2 " 0.027 +/- 0.005~*
lO " 0.028 +/- 0.003~*
50 " 0.014 +/- 0.005 * P < 0.05, *~ P ~ 0.0l, *** P < O.OOl v6 Control Group Re~ir Zone mm2 Control 0.005 +/- O.OOl o.l~g of Compoun~ D 0.022 +/- 0.007 *
0.5 " 00033 +/- 0.007 ~**
2 " 0.023 +/- 0.004 ***
lO 1' 0.033 +/- 0.005 ***
* P < 0.05, *** P < O.OOl vs Control Throughout the 6pecification, Compound A is methyl p-~2-(5,6,7,8-tetrahydro 3~ -5,5,8,8-~etramethyl-2-naphthyl~-propenyl]phenylsulfone: :
.
~ ~ , ' ' ll 1329~
Compound B is ethyl p-~2-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthyl~-propenyl]phenylsulfone:
Compound C is methyl p-[2-(5,6,7,8-tetrahydro -5,5,~,8-tetramethyl-2-naphthyl)-propenyl]phenylsulfoxide; and Compound D is ethyl p-~2-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylsulfid~.
Exam~le 2 10 Effect of Com~ounds sf Formula I on the Wrinkles Produced in Hairless Mice bv WB-lrradiation Doses of WB-irradiation sufficient to induce dermal damage in hairles~ mice were found to cause the appearance of wrinkles on the exposed skin. One skin replica for each animal was taken of these areas u~ing a liquid dental impression material (SILFLO - Flexico Developments Ltd., England). 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 the ridges in a regularly-spaced ar~ay about 2-mm apar~. The extent of wrinkling was visually asses6ed using this line pattern and a~signed a value (Wrinkle Index) of zero to 4 with zero representing complete effacement of wrinkling and 4 epresenting the maximum degree of wrinkling. It was observed that compounds of formula I caused a dose-dependent effacement of the wrinkles with ED50 value~ in the microgram range. The results are shown in the following Table.
I " ~
. .
, 1329~5~
- lZ -Table II
GrouP Wrinkle_Index Control l.6 +/- 0.3 0.2~g of Compound A 0.7 ~/- 0.3*
2 " 0.6 +/- 0.3~
6 " 0.5 +/- O.l~*
" 0.2 +/- O.l~
Group Control l.3 +/- O.Z
O.l~g of Compound B l.3 ~/- 0.3 0.3 It 0.7 +/- 0.2~
l " 0.3 +/- O.l~**
3 It 0.2 +/- O.l~
* P < 0.05, *~ P < O.Ol, *** P < O.OOl vs Control Group Wrinkle Index Control l.6 +/- 0.3 ~' O.l~g o~ Compound C 0.6 +/- 0.2*
0.5 1- 0.3 ~/- O.l**
2 " 0.7 ~/- 0.4 lO " 0.2 ~/- O.l*~ :
50 " 0.4 +/- O.l~
* P < 0.05, ** P ~ O.Ol, *** P ~ O.OOl vs Control Creams and gels containing iQgredients within the : proportions set forth in Examples 3 through 7 below can be ~ormulated by conventional meanfi.
.
. . .
.
13295~3 EXAMPLE 3.
CREAM
% w/~
A compound of formula I 0.00001-1.3 Cetyl Alcohol 1.5 10 Stearyl Alcohol 2.5 Span 60 ~Sorbitan 6tearate) 2.0 Mineral Oil 2.0 Arlacel 165 (Glyceryl/PEG 109 Stearate) 4.0 Tween 60 ~Poly~orbate 80) 1.0 *
Miglyol 818 (Caprylic/Capric/Linoleic 5.0 triglyceride) Sorbitol Solution g.0 Disodiu~ Edetate 0.1 BHA (Butylated Hydroxyani~ole) 0.05 20 Methylparaben 0.18 Propylparaben 0.05 Water q.s. 100.00 3~ :
*Trade Marks ..
r `: ~
13295~3 EXAMPLE 4.
CREAM
w/w A Compound o~ Formula I 0.00001-1.0 Cetyl Alcohol 5.25-8.75 Arlacel 165 (Glyceryl/PEG 100 Seearate~ 3.75-6.Z5 1O Miglyol R18 (Caprylic/Capeic/Linoleic ll.Z5 18.75 triglyceride) Socbitol Solutio~ 3.75-6.25 Disodium Edetate .075-0.125 Ca!bopol 934P (Carbomer 93gP) 0.15-0.25 BHA (Butylated ~ydroxyanisole)0.0375-0.0625 Metbylparaben 0.135-0.225 Peopylparaben 0.0375-0.0625 Sodium Hydeoxide (10% 801ution)0.15-0. Z5 Distilled Water, q.s. 100.00 ,. .
*Trade Mark ~' .
- 15 - i32~3 EXAMPLE 5.
CP~
~ w/w A Compound of Focmula I 0.00001-1.0 Cutina MD (Glyceryl Steara~e) 4.5-7.5 Ceteareth-12 3.0-s.o 10 Cetyl Alcohol 3.0-5.0 ~enerol 122E-10 ~Ethoxylated Soya Sterol) 2.25-3.75 *
Cetiol LC (Oleic Acid Decyl Ester) 7.5-12.5 BHA (Butylated Hydroxyanisole) 0.0375-0.0625 Sorbitol Solution 3.75-6.25 15 Disodium Edetate 0.075-0.125 Methylparaben 0.}35-0.225 Propylparaben 0.0375-0.0625 Distilled Water, q.s. 100.00 .~
' :
~ .
~Trade Mark -- 'D
~' ' ' : ' ' '. ' :' - 16 - 1329~3 EXAMPLE 6.
CREAM
~ w/w compound of formula I O.OOOOl-l.O
Arlatone 9a3 (PEG 30/Glyceryl Stearate) 7.0 Cetyl Alcohol 1.0 10 SteariC Acid Neobee Oil (Medium chain-length 17.0 triglyceride) Propylene Glycol S.O
2-phenoxyethanol 0.5 15 Distilled Water, q.s 100.00 EXAMPLE 7.
GEL
,% w/w A compound of formula I o.OOOOl-l.O
Pluronic L 101 tPoloxa~er 331) lo.Qo 26 Aero6il 200 (Silica) 8.00 PCL Liquid (Fatty Acid Eseer6) 1~.00 Cetiol V (Decyl Oleate) ZO.OO
Neobee Oil (Medium chain-length 15.00 triglyceride~
30 Euhanol G (Oct~ldodecanol~, q.6.100.00 Crea~ of ~xample 3, wherein Compound I i8 present in ~
weight/weight of 0.0001, O.oOl. 0.03, O.Ql, 0.1 and 0.3 ~ere 3S made and a~e preferred.
*Trade Marks A~
:
~ . . . .
- ~ .
~ 329~53 A cream of Example 6 and a gel of Example 7 were made wherein Compound I is present in % weight/weight of 0.5.
It is understood that the proportions of excipients in creams of Examples 3 and 6, and the gels of Example 7 can be varied, if desired. to change the physical properties of the resulting creams and gel .
: ,' ' ~ ' ' ~ ', , ~ , ,: ' . . , i~ :
Claims (16)
1. Compounds of the formula I
wherein n represents 1 or 2; Z represents -S(O)mR, wherein m represents 0, 1 or 2; R
represents lower-alkyl, lower-alkenyl, lower-alkynyl lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino, or a pharmaceutically acceptable salt thereof for use in the manufacture of medicaments for the topical treatment of the conditions associated with photodamegad skin.
wherein n represents 1 or 2; Z represents -S(O)mR, wherein m represents 0, 1 or 2; R
represents lower-alkyl, lower-alkenyl, lower-alkynyl lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino, or a pharmaceutically acceptable salt thereof for use in the manufacture of medicaments for the topical treatment of the conditions associated with photodamegad skin.
2. Comeounds as in claim 1 exept the compound ethyl p-[2-(5,6,7,8-tetrahyro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenylsulfone for use according to claim 1.
3. Compounds as in claim 1 wherein n is 2, m is 2 and R
is lower alkyl, except ethyl, for use according to claim 1.
is lower alkyl, except ethyl, for use according to claim 1.
4. Methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl)propenyl]phenylsulfone for use according to claim 1.
5. Compounds as in claim 1 for use according to claim 1 wherein said topical compositions contains a compound of formula I in an amount of from about 0.00001% to about 1.0%
by weight of the composition.
by weight of the composition.
6. Compounds as in claim 1 for use according to claim 1 wherein said topical composition contains a compound of formula I in amount of from about 0.0001 to about 0.1% by weight of the composition.
7. Compounds of formula I given in claim 1 or pharmaceutically acceptable salts thereof for use in the topical treatment of the conditions associated with photodamaged skin.
8. Compounds of formula I given in claim 1 or pharmaceutically acceptable salt thereof except the compound ethyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl)propenyl]phenylsulfone, for use according to claim 7.
9. Compounds of formula I given in claim 1 wherein n is 2, m is 2 and R is lower alkyl except ethyl, for use according to claim 7.
10. Methyl p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl)propenyl]phenylsulfone for use according to claim 7.
11. The use of a compound of the formula I
wherein n represents 1 or 2; Z represents -S(O)mR, wherein m represents 0, 1 or 2; R
represents lower-alkyl, lower-alkenyl, lower-alkynyl lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino, or a pharmaceutically acceptable salt thereof;
for topical treatment of conditions associated with photodamaged skin, said compound being applied to said area in an amount effective to reverse the effects of photodamage in said area;
or for preparing a medicament therefor.
wherein n represents 1 or 2; Z represents -S(O)mR, wherein m represents 0, 1 or 2; R
represents lower-alkyl, lower-alkenyl, lower-alkynyl lower-alkoxy-lower-alkyl, lower-alkanoyl-lower-alkyl, hydroxy-lower-alkyl, halo-lower-alkyl, lower-carbalkoxy-lower-alkyl or, when m is 1 or 2, R represents also lower-alkoxy, hydroxy, mono-lower-alkyl amino or di-lower-alkylamino, or a pharmaceutically acceptable salt thereof;
for topical treatment of conditions associated with photodamaged skin, said compound being applied to said area in an amount effective to reverse the effects of photodamage in said area;
or for preparing a medicament therefor.
12. A use in accordance with claim 11 wherein in the compound of formula I, n is 2, m is 2 and R is lower alkyl, except ethyl.
13. The use in accordance with claim 11 wherein the compound of formula I is methyl p-[22-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--naphthyl)propenyl]phenylsulfone.
14. The use in accordance with any one of claims 11, 12 or 13 wherein the compound of formula I is administered in a topical composition containing at least 0.0001% by weight of said compound of formula I and an inert dermatologically acceptable carrier.
15. A use in accordance with any one of claims 11, 12 or 13, wherein said topical composition contains a compound of formula I in an amount of from about 0.00001%
to about 1.0% by weight of the composition.
to about 1.0% by weight of the composition.
16. The use in accordance with any one of claims 11, 12 or 13 wherein said topical composition contains a compound of formula I in amount of from about 0.0001% to about 0.1% by weight of the composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8699287A | 1987-08-19 | 1987-08-19 | |
| US086,992 | 1987-08-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1329553C true CA1329553C (en) | 1994-05-17 |
Family
ID=22202176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000574958A Expired - Fee Related CA1329553C (en) | 1987-08-19 | 1988-08-17 | Pharmaceutical preparations |
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| Country | Link |
|---|---|
| EP (1) | EP0303915B1 (en) |
| 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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| US5264578A (en) | 1987-03-20 | 1993-11-23 | Allergan, Inc. | Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity |
| US5602130A (en) * | 1987-03-20 | 1997-02-11 | Allergan | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
| US5272156A (en) * | 1989-09-19 | 1993-12-21 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
| US5183827A (en) * | 1989-09-19 | 1993-02-02 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
| US5264456A (en) * | 1989-12-29 | 1993-11-23 | Allergan, Inc. | Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity |
| US5324840A (en) * | 1992-06-11 | 1994-06-28 | Allergan, Inc. | Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects |
| CH686285A5 (en) * | 1992-08-06 | 1996-02-29 | Beiersdorf Ag | Cosmetic or pharmaceutical preparation used to delay the aging of human skin. |
| US5455265A (en) * | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
| US6172115B1 (en) | 1993-02-11 | 2001-01-09 | Allergan Sales, Inc. | Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid |
| US5475022A (en) * | 1993-10-18 | 1995-12-12 | Allergan, Inc. | Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compounds having retinoid like biological activity |
| US5426118A (en) * | 1993-12-30 | 1995-06-20 | Allergan, Inc. | [4-(1,2-epoxycyclohexanyl)but-3-en-1-ynyl]aromatic and heteroaromatic acids and derivatives having retinoid-like biological activity |
| US5498755A (en) * | 1994-08-23 | 1996-03-12 | Chandraratna; Roshantha A. | Disubstituted aryl and heteroaryl imines having retinoid-like biological activity |
| US5618943A (en) * | 1994-12-29 | 1997-04-08 | Allergan | Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
| US5618931A (en) * | 1994-12-29 | 1997-04-08 | Allergan | Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
| US5648514A (en) | 1994-12-29 | 1997-07-15 | Allergan | Substituted acetylenes having retinoid-like biological activity |
| US5543534A (en) * | 1994-12-29 | 1996-08-06 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
| US5599967A (en) * | 1994-12-29 | 1997-02-04 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity |
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS235526B2 (en) * | 1981-02-13 | 1985-05-15 | Hoffmann La Roche | Method of tetrahydronaphtalene and indane new derivatives production |
| CA1162200A (en) * | 1981-02-13 | 1984-02-14 | Michael Klaus | Process for the manufacture of indanyl (or tetrahydronaphthyl)propenyl phenyl derivatives |
| US4603146A (en) * | 1984-05-16 | 1986-07-29 | Kligman Albert M | Methods for retarding the effects of aging of the skin |
| AU599135B2 (en) * | 1986-07-16 | 1990-07-12 | Albert M. Kligman | Methods for treatment of sundamaged human skin with retinoids |
| US4889847A (en) * | 1986-11-03 | 1989-12-26 | Ortho Pharmaceutical Corporation | Prevention of glucocorticoid-induced skin atrophy |
-
1988
- 1988-07-18 ZA ZA885192A patent/ZA885192B/en unknown
- 1988-08-05 DE DE8888112801T patent/DE3881299D1/en not_active Expired - Fee Related
- 1988-08-05 AT AT88112801T patent/ATE89723T1/en not_active IP Right Cessation
- 1988-08-05 EP EP88112801A patent/EP0303915B1/en not_active Expired - Lifetime
- 1988-08-17 KR KR1019880010430A patent/KR890003369A/en not_active Application Discontinuation
- 1988-08-17 HU HU884372A patent/HU203195B/en not_active IP Right Cessation
- 1988-08-17 CA CA000574958A patent/CA1329553C/en not_active Expired - Fee Related
- 1988-08-18 IE IE252388A patent/IE62691B1/en not_active IP Right Cessation
- 1988-08-18 JP JP63203952A patent/JPH0627063B2/en not_active Expired - Lifetime
- 1988-08-18 PH PH37425A patent/PH24867A/en unknown
- 1988-08-18 IL IL87488A patent/IL87488A0/en not_active IP Right Cessation
- 1988-08-19 AU AU21184/88A patent/AU610632B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU2118488A (en) | 1989-02-23 |
| EP0303915B1 (en) | 1993-05-26 |
| AU610632B2 (en) | 1991-05-23 |
| ATE89723T1 (en) | 1993-06-15 |
| ZA885192B (en) | 1989-04-26 |
| HUT48116A (en) | 1989-05-29 |
| KR890003369A (en) | 1989-04-14 |
| HU203195B (en) | 1991-06-28 |
| IE62691B1 (en) | 1995-02-22 |
| EP0303915A3 (en) | 1990-08-08 |
| DE3881299D1 (en) | 1993-07-01 |
| EP0303915A2 (en) | 1989-02-22 |
| JPS6470457A (en) | 1989-03-15 |
| JPH0627063B2 (en) | 1994-04-13 |
| PH24867A (en) | 1990-12-26 |
| IE882523L (en) | 1989-02-19 |
| IL87488A0 (en) | 1989-01-31 |
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| Date | Code | Title | Description |
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| MKLA | Lapsed |