CA2037150C - Retinoids - Google Patents
RetinoidsInfo
- Publication number
- CA2037150C CA2037150C CA002037150A CA2037150A CA2037150C CA 2037150 C CA2037150 C CA 2037150C CA 002037150 A CA002037150 A CA 002037150A CA 2037150 A CA2037150 A CA 2037150A CA 2037150 C CA2037150 C CA 2037150C
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- Prior art keywords
- compound
- compounds
- formula
- active substance
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Abstract
Retinoids of the formula R1-OCH(R2)OC(O)R3 wherein R1 signifies 13-cis-retinoyl, R2 signifies hydrogen or lower-alkyl and R3 signifies straight-chain lower-alkyl can be used as medicaments in the case of dermatological disorders.
Description
The present invention is concerned with novel retinoids, their manufacture and use for the manufacture of medicaments, as well as medicaments which contain these compounds as active substances.
The retinoids in accordance with th.e invention can be represented by the general formula Rl-OCI-i(R~~)OC(O)R3 I
wherein Rl signifies 13-cis-retinoyl; R2 signifies hydrogen or lower-alkyl;
and R3 signifies straight-chain lo~~er-alkyl.
Lower-alkyl groups can contain 1-6 C atoms. Methyl, ethyl, propyl, to isopropyl, n-butyl, sec-butyl and tert-but~,~l are examples of lower-alkyl groups R2. Methyl, ethyl, propyl and n-butyl, preferably methyl, are examples of lower-alkyl groups R3. Hydrogen and methyl are preferred residues R2.
The compounds of formula I can be obtained by reacting 13-cis-retinoic acid or a salt thereof with a compound o~f the formula XCH(R2)OC(O)R3 II;
or by reacting a compound of the formula RlOCHf(R2)X
with a salt of an acid of the formula R3COOH, whereby in the above formulae X is halogen and Rl, R2 and R3 have the significance given above.
Examples of halogens represented by X are especially chlorine or iodine.
Examples of salts of 13-cis-retinoic acid a:re alkali salts such as the sodium salt or the potassium salt; or trialkylammon:ium salts, e.g. the triethylammonium salt; or, preferably, salts with 1,8-diazacyclo[5.4.0]undec-7-ene.
Grn/ 16.1.91 _2:_ The reacrion is conveniently carried out in an inert organic solvent, e.g.
in acetonitrile, dimethylformamide or acetone. The reaction temperature is not critical. The reaction can be performed at room temperature or while heating, e.g. to the reflux temperature of the solvent which is used.
The compounds of formulae II and III are known or can be prepared in a manner known per se. For example, the compounds II can be prepared by reacting an acid chloride with an aldehyde in the presence of zinc chloride (J.
Am. Chem. Soc. 43 (1921), 660. The chloromethyl ester of 13-cis-retinoic and can be prepared e.g. by reacting a salt of 13-cis-retinoic acid with bromochloro-1o methane.
The compounds of formula I are therapeutically active. They can be used, for example, for the treatment of dermatological disorders, especially in the case of acne and those which are accompanied by cornification disorders of the skin such as e.g. psoriasis, ichthyosis and. Darier's disease and in the case of dis-orders of fibroblast activities such as e.g. keloidosis and localized sclerodermia;
as well as in the case of precanceroses of the skin.
The compounds of formula I can also be used in the treatment of aging skin.
The novel compounds are especially suitable for topical use. They exhibit a good skin tolerance, good penetration capability and cause no or only a slight systemic retinoid effect.
The efficacy of the compounds can be determined in mice in which papillomas of the skin have been produced by treatment with dimethylbenz-anthracene and croton oil. By the topical. administration of compounds of formula I there is observed a regression of the papillomas, which represents a measurement for the therapeutic efficacy of the compounds, e.g. for the treatment of psoriasis. The test methodology for the production of the papillomas is described in Europ. J. Cancer, Vol. 10, 731-737 (1974). The papillomas were treated topically for 3 weeks with different concentrated 3o solutions of the test compounds. Only 3 papillomas of each animal were treated with the test compounds. The remaining papillomas were treated only with the vehicle. An influence on these papillomas which were not treated topically with the test compounds is due to the systemic effect of the topically-admirustered test preparation. The result obtained with compounds of formula I in this test model are given in Table I.
Table 1 Compound Concentration of Change in the the applied solution [%] papillomas (%a]*
Treated Untreated Vehicle (acetone) - +25 0 I, R2=H 0.124 0 0 R3 = ~3 I.24 -;33 0 3.1 -:i0 0 I, R2 = CH3 O.I29 0 0 R3 = CH3 1.24 :'0 0 3.2 -~E3 0 * -Median value: average value .in respect of which the same number of higher and lower test values exist A model for testing the efficacy in the treatment of acne is the change in size of the sebaceous glands in the ear of Syrian golden hampsfers after topical application of the test substance. In this test, one ear is treated with active substance solution, the other ear is treated. with vehicle. The change in the size of the sebaceous glands is measured on tissue sections by digital planimetry.
An influence on the sebaceous glands of the ear treated only with vehicle is 1o due to a systemic effect. The results obtained with the compound I with R2 and R3 = methyl are compiled in Table II.
H
Table Il Compound Dosage Reduction in sebaceous [N,g/~y] gland diameter (%]
Activ<~ substance Vehicle I, R1- CH3 10 R3 = CH3 100 -4.5 -16*
statistically insignificant For topical use the active substances are conveniently used in the form of salves, tinctures, creams, solutions, lotions, sprays, suspensions and the like.
Salves and creams as well as solutions are preferred. These preparations specified for topical use can be manufactured by mixing the process products as active ingredients with non-toxic, inert, solid or liquid carriers which are suitable for topical treatment and which are customary in such preparations.
Convenient for topical use are about 0.005-2%, preferably O.OI-1 %, solutions, lotions, salves or creams.
An antioxidant, e.g. tocopherol, N-methyl-~ tocopheramine as well as butylated hydroxyanisole or butylated hydr~oxytoluene, can be admixed with the preparations if desired. Furthermore, the preparations can contain other active substances, especially radiation-protection agents such as silicates, talc, titanium dioxide, zinc oxide or cinamic acid derivatives such as <Parsol>'~
The following Examples illustrate the invention further. The temperatures are given in degrees Celsius.
Example 1 45 g of 3,7-dimethyl-9-(2,6,6-trimethyl-'.t-cyclohexen-1-yl)-2-(Z),4,6,8(E)-2o nonatetraenoic acid are suspended in 750 ml of dry acetonitrile and treated with 22.8 g of 1,8-diazabicyclo- (5,4,0)undec-7-ene. After stirring at room temperature under argon and with the exclusion of light for T hour 30.8 g of iodomethyl acetate in 30 ml of acetonitrile acre added thereto. The reaction mixture is stirred at 80~ for 3 hours and at room temperature overnight. Then, the solvent is removed on a rotary evaporavtor in a vacuum and the residue is taken up in 500 ml of methylene chloride. T'he organic phase is extracted once ~x * Trademark with 250 ml of a dilute hydrochloric acid solution and twice with in each case 250 ml of a saturated sodium chloride solution. The methylene chloride phase is separated, dried over sodium sulphates and filtered over a column containing 150 g of neutral aluminium oxide. The adsorption agent is rinsed with 300 ml of methylene chloride and the eluate is concentrated on a rotary evaporator in a vacuum. Crystallization of the oily residue from ethanol gives yellow crystals. The mother liquor of the crystallization is concentrated in a vacuum and the residual oil is purified by chromatography over 300 g of silica gel with methylene chloride-petroleum ether-tert.butyl methyl ether 62:130:8.
1o There thereby separates a further fraction of the desired product which is combined with the solid from the first crystallization. After renewed crystallization from ethanol there are obtained 18.3 g of methylene acetate 3,7-dimethyl-9-(2,6,6-trimethyl-I-cyclohexen-1-yl)-2-(Z),4,6,8(E)-nonatetraenoate with a melting point of 56-58~. Rf (silica gel/methylene chloride-petroleum ether-tert.butyl methyl ether 62:130:8) 0.44.
Examx~le 2 Ethylidene acetate 3,7-dimethyl-9-(2.,6,6-trimethyl-1-cyclohexen-1-yl)-2-(Z),4,6,8(E)-nonatetraenoate is manufactured analogously to Example 1 from 45 g of 3,7-dimethyl-9-(2,6,6-trimethyl-I-cyclohexen-1-yl)-2-(Z),4,68(E)-2o nonatetraenoic acid, 22.8 g of 1.8-diazabiryclo(5,4,0)undec-7-ene, 20.4 g of 1-chloroethyl acetate and 10 g of NaI. Crysvtallization from ethanol gives a first fraction of the desired product. After evaporation of the mother liquor [the residue] is chromatographed over 350 g of silica gel with methylene chloride-petroleum ether-tert.butyl methyl ether 25:71:4 as the elution agent, whereby a further fraction of the product is obtained. Crystallization of the two fractions leads to 23.5 g of yellow crystals with a melting point of 84-86~. Rf (silica gel/methylene chloride-petroleum ether-tert.butyl methyl ether 62:130:8) 0.42.
Example 3 -T-A hydrogel can have the following composition:
Active substance 0.2 g Hydroxypropylcellulose ~0 g Ethanol ~_0 g Propylene glycol 20.0 g Butylated hydroxytoluene 0.05 g D,L-a-Tocopherol 0.15 g Water ad 100.0 g Production:
The active substance, the antioxidant and the preserving agent are dissolved in ethanol. After admixture of the propylene glyool~water solution the mixture is left until the gel former has ;swollen clear.
Example 4 A lipogel can have the following composition:
Active substance 0.1 g D,L-a-Tocopherol 0.15 g Aerosil 200 8.0 g Triglyceride, medium-chain ad 100.0 g l0 Production:
The active substance and the antioxidant are dissolved in the triglycedride. The gel-former is then incorporated while stirring.
* Trademark B:
. 2037150 _7_ Example 5 A solution can have the following rnmposition:
Active substance 0.~ g Butylated hydroxytoluene 0.05 g Ethanol 50.0 g Polyethylene glycol 400 ad 100.0 g Production The active substance and the preserving agent are dissolved in ethanol.
The polyethylene glyrnl is added to this solution.
Example 6 An oil-in-water cream can have the following rnmposition:
Active substance 0.2 g Butylated hydroxytoluene 0.05 g Polyoxyethylene-sorbitan monostearate ~ 6.5 g Cetyl alcohol 10.0 g Vaseline* white ~.0 g Glycerine 10.0 g Benzoic and 0.2 g Water ad 100.0 g 1o Production:
The active substance is incorporated into the molten fatty phase at 70-75~.
Glycerine, the emulisifier and benzoic acid a.re added to the water. The two * Trademark _8_ phases are homogenized at 70~ and left to cool to room temperature while homogenizing.
Exa~de 7 A salve can have the following composition:
Active substance 0.2 g Hydroxylated butyltoluene 0.05 g D,L-a-Tocopherol 0.15 g Paraffin, viscous 40.0 g Vaseline, white 45.0 g Castor oil, hardened ad 100.0 g Production:
The active substance is incorporated. into the 80~ hot fatty phase and the mixture is left to cool to room temperature while stirring.
The retinoids in accordance with th.e invention can be represented by the general formula Rl-OCI-i(R~~)OC(O)R3 I
wherein Rl signifies 13-cis-retinoyl; R2 signifies hydrogen or lower-alkyl;
and R3 signifies straight-chain lo~~er-alkyl.
Lower-alkyl groups can contain 1-6 C atoms. Methyl, ethyl, propyl, to isopropyl, n-butyl, sec-butyl and tert-but~,~l are examples of lower-alkyl groups R2. Methyl, ethyl, propyl and n-butyl, preferably methyl, are examples of lower-alkyl groups R3. Hydrogen and methyl are preferred residues R2.
The compounds of formula I can be obtained by reacting 13-cis-retinoic acid or a salt thereof with a compound o~f the formula XCH(R2)OC(O)R3 II;
or by reacting a compound of the formula RlOCHf(R2)X
with a salt of an acid of the formula R3COOH, whereby in the above formulae X is halogen and Rl, R2 and R3 have the significance given above.
Examples of halogens represented by X are especially chlorine or iodine.
Examples of salts of 13-cis-retinoic acid a:re alkali salts such as the sodium salt or the potassium salt; or trialkylammon:ium salts, e.g. the triethylammonium salt; or, preferably, salts with 1,8-diazacyclo[5.4.0]undec-7-ene.
Grn/ 16.1.91 _2:_ The reacrion is conveniently carried out in an inert organic solvent, e.g.
in acetonitrile, dimethylformamide or acetone. The reaction temperature is not critical. The reaction can be performed at room temperature or while heating, e.g. to the reflux temperature of the solvent which is used.
The compounds of formulae II and III are known or can be prepared in a manner known per se. For example, the compounds II can be prepared by reacting an acid chloride with an aldehyde in the presence of zinc chloride (J.
Am. Chem. Soc. 43 (1921), 660. The chloromethyl ester of 13-cis-retinoic and can be prepared e.g. by reacting a salt of 13-cis-retinoic acid with bromochloro-1o methane.
The compounds of formula I are therapeutically active. They can be used, for example, for the treatment of dermatological disorders, especially in the case of acne and those which are accompanied by cornification disorders of the skin such as e.g. psoriasis, ichthyosis and. Darier's disease and in the case of dis-orders of fibroblast activities such as e.g. keloidosis and localized sclerodermia;
as well as in the case of precanceroses of the skin.
The compounds of formula I can also be used in the treatment of aging skin.
The novel compounds are especially suitable for topical use. They exhibit a good skin tolerance, good penetration capability and cause no or only a slight systemic retinoid effect.
The efficacy of the compounds can be determined in mice in which papillomas of the skin have been produced by treatment with dimethylbenz-anthracene and croton oil. By the topical. administration of compounds of formula I there is observed a regression of the papillomas, which represents a measurement for the therapeutic efficacy of the compounds, e.g. for the treatment of psoriasis. The test methodology for the production of the papillomas is described in Europ. J. Cancer, Vol. 10, 731-737 (1974). The papillomas were treated topically for 3 weeks with different concentrated 3o solutions of the test compounds. Only 3 papillomas of each animal were treated with the test compounds. The remaining papillomas were treated only with the vehicle. An influence on these papillomas which were not treated topically with the test compounds is due to the systemic effect of the topically-admirustered test preparation. The result obtained with compounds of formula I in this test model are given in Table I.
Table 1 Compound Concentration of Change in the the applied solution [%] papillomas (%a]*
Treated Untreated Vehicle (acetone) - +25 0 I, R2=H 0.124 0 0 R3 = ~3 I.24 -;33 0 3.1 -:i0 0 I, R2 = CH3 O.I29 0 0 R3 = CH3 1.24 :'0 0 3.2 -~E3 0 * -Median value: average value .in respect of which the same number of higher and lower test values exist A model for testing the efficacy in the treatment of acne is the change in size of the sebaceous glands in the ear of Syrian golden hampsfers after topical application of the test substance. In this test, one ear is treated with active substance solution, the other ear is treated. with vehicle. The change in the size of the sebaceous glands is measured on tissue sections by digital planimetry.
An influence on the sebaceous glands of the ear treated only with vehicle is 1o due to a systemic effect. The results obtained with the compound I with R2 and R3 = methyl are compiled in Table II.
H
Table Il Compound Dosage Reduction in sebaceous [N,g/~y] gland diameter (%]
Activ<~ substance Vehicle I, R1- CH3 10 R3 = CH3 100 -4.5 -16*
statistically insignificant For topical use the active substances are conveniently used in the form of salves, tinctures, creams, solutions, lotions, sprays, suspensions and the like.
Salves and creams as well as solutions are preferred. These preparations specified for topical use can be manufactured by mixing the process products as active ingredients with non-toxic, inert, solid or liquid carriers which are suitable for topical treatment and which are customary in such preparations.
Convenient for topical use are about 0.005-2%, preferably O.OI-1 %, solutions, lotions, salves or creams.
An antioxidant, e.g. tocopherol, N-methyl-~ tocopheramine as well as butylated hydroxyanisole or butylated hydr~oxytoluene, can be admixed with the preparations if desired. Furthermore, the preparations can contain other active substances, especially radiation-protection agents such as silicates, talc, titanium dioxide, zinc oxide or cinamic acid derivatives such as <Parsol>'~
The following Examples illustrate the invention further. The temperatures are given in degrees Celsius.
Example 1 45 g of 3,7-dimethyl-9-(2,6,6-trimethyl-'.t-cyclohexen-1-yl)-2-(Z),4,6,8(E)-2o nonatetraenoic acid are suspended in 750 ml of dry acetonitrile and treated with 22.8 g of 1,8-diazabicyclo- (5,4,0)undec-7-ene. After stirring at room temperature under argon and with the exclusion of light for T hour 30.8 g of iodomethyl acetate in 30 ml of acetonitrile acre added thereto. The reaction mixture is stirred at 80~ for 3 hours and at room temperature overnight. Then, the solvent is removed on a rotary evaporavtor in a vacuum and the residue is taken up in 500 ml of methylene chloride. T'he organic phase is extracted once ~x * Trademark with 250 ml of a dilute hydrochloric acid solution and twice with in each case 250 ml of a saturated sodium chloride solution. The methylene chloride phase is separated, dried over sodium sulphates and filtered over a column containing 150 g of neutral aluminium oxide. The adsorption agent is rinsed with 300 ml of methylene chloride and the eluate is concentrated on a rotary evaporator in a vacuum. Crystallization of the oily residue from ethanol gives yellow crystals. The mother liquor of the crystallization is concentrated in a vacuum and the residual oil is purified by chromatography over 300 g of silica gel with methylene chloride-petroleum ether-tert.butyl methyl ether 62:130:8.
1o There thereby separates a further fraction of the desired product which is combined with the solid from the first crystallization. After renewed crystallization from ethanol there are obtained 18.3 g of methylene acetate 3,7-dimethyl-9-(2,6,6-trimethyl-I-cyclohexen-1-yl)-2-(Z),4,6,8(E)-nonatetraenoate with a melting point of 56-58~. Rf (silica gel/methylene chloride-petroleum ether-tert.butyl methyl ether 62:130:8) 0.44.
Examx~le 2 Ethylidene acetate 3,7-dimethyl-9-(2.,6,6-trimethyl-1-cyclohexen-1-yl)-2-(Z),4,6,8(E)-nonatetraenoate is manufactured analogously to Example 1 from 45 g of 3,7-dimethyl-9-(2,6,6-trimethyl-I-cyclohexen-1-yl)-2-(Z),4,68(E)-2o nonatetraenoic acid, 22.8 g of 1.8-diazabiryclo(5,4,0)undec-7-ene, 20.4 g of 1-chloroethyl acetate and 10 g of NaI. Crysvtallization from ethanol gives a first fraction of the desired product. After evaporation of the mother liquor [the residue] is chromatographed over 350 g of silica gel with methylene chloride-petroleum ether-tert.butyl methyl ether 25:71:4 as the elution agent, whereby a further fraction of the product is obtained. Crystallization of the two fractions leads to 23.5 g of yellow crystals with a melting point of 84-86~. Rf (silica gel/methylene chloride-petroleum ether-tert.butyl methyl ether 62:130:8) 0.42.
Example 3 -T-A hydrogel can have the following composition:
Active substance 0.2 g Hydroxypropylcellulose ~0 g Ethanol ~_0 g Propylene glycol 20.0 g Butylated hydroxytoluene 0.05 g D,L-a-Tocopherol 0.15 g Water ad 100.0 g Production:
The active substance, the antioxidant and the preserving agent are dissolved in ethanol. After admixture of the propylene glyool~water solution the mixture is left until the gel former has ;swollen clear.
Example 4 A lipogel can have the following composition:
Active substance 0.1 g D,L-a-Tocopherol 0.15 g Aerosil 200 8.0 g Triglyceride, medium-chain ad 100.0 g l0 Production:
The active substance and the antioxidant are dissolved in the triglycedride. The gel-former is then incorporated while stirring.
* Trademark B:
. 2037150 _7_ Example 5 A solution can have the following rnmposition:
Active substance 0.~ g Butylated hydroxytoluene 0.05 g Ethanol 50.0 g Polyethylene glycol 400 ad 100.0 g Production The active substance and the preserving agent are dissolved in ethanol.
The polyethylene glyrnl is added to this solution.
Example 6 An oil-in-water cream can have the following rnmposition:
Active substance 0.2 g Butylated hydroxytoluene 0.05 g Polyoxyethylene-sorbitan monostearate ~ 6.5 g Cetyl alcohol 10.0 g Vaseline* white ~.0 g Glycerine 10.0 g Benzoic and 0.2 g Water ad 100.0 g 1o Production:
The active substance is incorporated into the molten fatty phase at 70-75~.
Glycerine, the emulisifier and benzoic acid a.re added to the water. The two * Trademark _8_ phases are homogenized at 70~ and left to cool to room temperature while homogenizing.
Exa~de 7 A salve can have the following composition:
Active substance 0.2 g Hydroxylated butyltoluene 0.05 g D,L-a-Tocopherol 0.15 g Paraffin, viscous 40.0 g Vaseline, white 45.0 g Castor oil, hardened ad 100.0 g Production:
The active substance is incorporated. into the 80~ hot fatty phase and the mixture is left to cool to room temperature while stirring.
Claims (5)
1. Ethylidene acetate 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-
2(Z),4,6,8(E)-nonatetraenoate.
2. The compound of Claim 1 for use as medicament.
2. The compound of Claim 1 for use as medicament.
3. A process for the manufacture of the compound of Claim 1, which process comprises reacting 13-cis-retinoic acid or a salt thereof with a compound of the formula XCH(CH3)OC(O)CH3 whereby in the above formulae X is halogen.
4. Pharmaceutical or cosmetical compositions containing the compound of Claim 1 and pharmaceutical or cosmetical carriier.
5. The use of the compound of Claim 1 as active substances in the manufacture of medicaments for the topical treatment of dermatological disorders and in cosmetic agents for the treatment of aging skin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH100890 | 1990-03-27 | ||
| CH1008/90 | 1990-03-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2037150A1 CA2037150A1 (en) | 1991-09-28 |
| CA2037150C true CA2037150C (en) | 1999-12-28 |
Family
ID=4200298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002037150A Expired - Lifetime CA2037150C (en) | 1990-03-27 | 1991-02-26 | Retinoids |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5158773A (en) |
| EP (1) | EP0449099B1 (en) |
| JP (1) | JPH0798797B2 (en) |
| KR (1) | KR960008666B1 (en) |
| AT (1) | ATE130848T1 (en) |
| AU (1) | AU646439B2 (en) |
| CA (1) | CA2037150C (en) |
| DE (1) | DE59106962D1 (en) |
| DK (1) | DK0449099T3 (en) |
| ES (1) | ES2080848T3 (en) |
| FI (1) | FI96201C (en) |
| GR (1) | GR3019014T3 (en) |
| HR (1) | HRP930344B1 (en) |
| HU (1) | HU207980B (en) |
| IE (1) | IE71178B1 (en) |
| IL (1) | IL97607A (en) |
| MC (1) | MC2222A1 (en) |
| NO (1) | NO174801B (en) |
| NZ (1) | NZ237513A (en) |
| PT (1) | PT97148B (en) |
| SA (1) | SA91110302B1 (en) |
| YU (1) | YU48480B (en) |
| ZA (1) | ZA912075B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5710176A (en) * | 1994-09-16 | 1998-01-20 | Bar-Ilan University | Retinoyloxy (substituted) methyl butyrates useful for the treatment of cancer and other proliferative diseases |
| US6040342A (en) * | 1994-09-16 | 2000-03-21 | Bar-Ilan University | Retinoyloxy (alkyl-substituted) methyl butyrates useful for the treatment of cancer and other proliferative diseases |
| US6071923A (en) * | 1994-09-16 | 2000-06-06 | Bar-Ilan University | Retinoyloxy aryl-substituted alkylene butyrates useful for the treatment of cancer and other proliferative diseases |
| US5534261A (en) * | 1995-01-17 | 1996-07-09 | University Of Southern California | Retinoid-based compositions and method for preventing adhesion formation using the same |
| EP0927033A1 (en) * | 1996-07-02 | 1999-07-07 | Bar-Ilan University | Retinoyloxy(substituted)alkylene butyrates useful for the treatment of cancer and other proliferative diseases |
| US6130248A (en) * | 1996-12-30 | 2000-10-10 | Bar-Ilan University | Tricarboxylic acid-containing oxyalkyl esters and uses thereof |
| US6124495A (en) * | 1997-03-11 | 2000-09-26 | Beacon Laboratories, Inc. | Unsaturated oxyalkylene esters and uses thereof |
| US6110970A (en) * | 1997-03-11 | 2000-08-29 | Beacon Laboratories, Inc. | Nitrogen-containing oxyalkylene esters and uses thereof |
| US6030961A (en) * | 1997-03-11 | 2000-02-29 | Bar-Ilan Research & Development Co., Ltd. | Oxyalkylene phosphate compounds and uses thereof |
| US6110955A (en) * | 1997-03-11 | 2000-08-29 | Beacon Laboratories, Inc. | Metabolically stabilized oxyalkylene esters and uses thereof |
| US5939455A (en) * | 1997-03-11 | 1999-08-17 | Beacon Laboratories, Inc. | Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives |
| US6043389A (en) * | 1997-03-11 | 2000-03-28 | Mor Research Applications, Ltd. | Hydroxy and ether-containing oxyalkylene esters and uses thereof |
| US6720445B2 (en) * | 2000-12-21 | 2004-04-13 | Beacon Laboratories, Inc. | Acetyloxymethyl esters and methods for using the same |
| KR102406880B1 (en) | 2015-10-30 | 2022-06-08 | 팀버 파마슈티칼스 엘엘씨 | Isotretinoin formulations and uses and methods of use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4476056A (en) * | 1982-11-05 | 1984-10-09 | Hoffmann-La Roche Inc. | Trifluoromethoxy analogs of aromatic retinoids |
| US4677120A (en) * | 1985-07-31 | 1987-06-30 | Molecular Design International | Topical prodrugs for treatment of acne and skin diseases |
| JP2622955B2 (en) * | 1986-07-29 | 1997-06-25 | エイボン プロダクツ インコ−ポレイテツド | Anhydrous cosmetics |
| ZA877325B (en) * | 1986-10-06 | 1988-04-07 | F. Hoffmann-La Roche & Co. Aktiengesellschaft | Novel retinoids |
| DK498487A (en) * | 1986-10-06 | 1988-04-07 | Hoffmann La Roche | UNKNOWN RETINOIDS |
-
1991
- 1991-02-26 CA CA002037150A patent/CA2037150C/en not_active Expired - Lifetime
- 1991-03-04 US US07/663,356 patent/US5158773A/en not_active Expired - Lifetime
- 1991-03-12 FI FI911207A patent/FI96201C/en not_active IP Right Cessation
- 1991-03-14 YU YU45591A patent/YU48480B/en unknown
- 1991-03-20 NZ NZ237513A patent/NZ237513A/en unknown
- 1991-03-20 AT AT91104375T patent/ATE130848T1/en not_active IP Right Cessation
- 1991-03-20 DK DK91104375.0T patent/DK0449099T3/en active
- 1991-03-20 ES ES91104375T patent/ES2080848T3/en not_active Expired - Lifetime
- 1991-03-20 IL IL9760791A patent/IL97607A/en not_active IP Right Cessation
- 1991-03-20 EP EP91104375A patent/EP0449099B1/en not_active Expired - Lifetime
- 1991-03-20 DE DE59106962T patent/DE59106962D1/en not_active Expired - Fee Related
- 1991-03-20 ZA ZA912075A patent/ZA912075B/en unknown
- 1991-03-21 MC MC912176A patent/MC2222A1/en unknown
- 1991-03-22 HU HU91968A patent/HU207980B/en not_active IP Right Cessation
- 1991-03-22 JP JP3081208A patent/JPH0798797B2/en not_active Expired - Fee Related
- 1991-03-25 KR KR91004702A patent/KR960008666B1/en not_active IP Right Cessation
- 1991-03-26 IE IE100591A patent/IE71178B1/en not_active IP Right Cessation
- 1991-03-26 AU AU73831/91A patent/AU646439B2/en not_active Ceased
- 1991-03-26 PT PT97148A patent/PT97148B/en not_active IP Right Cessation
- 1991-03-26 NO NO911233A patent/NO174801B/en not_active IP Right Cessation
- 1991-04-09 SA SA91110302A patent/SA91110302B1/en unknown
-
1993
- 1993-03-12 HR HRP-455/91A patent/HRP930344B1/en not_active IP Right Cessation
-
1996
- 1996-02-19 GR GR960400415T patent/GR3019014T3/en unknown
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKEC | Expiry (correction) |
Effective date: 20121202 |