WO1993006086A1 - Retinoids and their use in treating skin diseases and leukemia - Google Patents
Retinoids and their use in treating skin diseases and leukemia Download PDFInfo
- Publication number
- WO1993006086A1 WO1993006086A1 PCT/US1992/006485 US9206485W WO9306086A1 WO 1993006086 A1 WO1993006086 A1 WO 1993006086A1 US 9206485 W US9206485 W US 9206485W WO 9306086 A1 WO9306086 A1 WO 9306086A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- formula
- compound
- acid
- skin
- Prior art date
Links
- 0 CC(CCC1)NCC1(*)C1(C)CCCCC1 Chemical compound CC(CCC1)NCC1(*)C1(C)CCCCC1 0.000 description 10
- FJZNSGQHDXVONJ-UHFFFAOYSA-N Oc(cc1)cc(C2(CC(C3)C4)CC4CC3C2)c1O Chemical compound Oc(cc1)cc(C2(CC(C3)C4)CC4CC3C2)c1O FJZNSGQHDXVONJ-UHFFFAOYSA-N 0.000 description 3
- UZHCJGSIRIFQTO-UHFFFAOYSA-N CC(C)(CCC(C)(C)c1c2)c1ccc2O Chemical compound CC(C)(CCC(C)(C)c1c2)c1ccc2O UZHCJGSIRIFQTO-UHFFFAOYSA-N 0.000 description 2
- XQQBUAPQHNYYRS-UHFFFAOYSA-N Cc1ccc[s]1 Chemical compound Cc1ccc[s]1 XQQBUAPQHNYYRS-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/80—Phthalic acid esters
- C07C69/82—Terephthalic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/86—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl groups
Definitions
- the present invention relates to novel retinoids, methods for their preparation, pharmaceutical compositions comprising such compounds and the use of the compounds in treating the skin and in treating leukemia.
- vitamin A acid for the treatment of acne as set forth in U.S. Patent No. 3,729,568.
- Other known uses of vitamin A acid which were reviewed by Thomas and Doyle in the Journal of American Academy of Dermatology, 4, 505-513 (1981), include, in addition to acne treatment, treatment of senile comedones, nervus comedonicus, linear verrucous nevus, plantar warts, pseudofolliculitis, keratoacanthoma, solar keratosis of extremities, callosities, keratosis palmaris et plantaris, Darier's disease, ichthyosis, psoriasis, acanthosis nigricians, lichen planus, molluscum contagiosum, reactive perforating collagenosis, melasma, corneal epithelial healing, geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids or hypertrophic scars
- Vitamin A acid derivatives are known to have prophylactic and therapeutic effects on a great variety of tumors and are being increasingly used as anti-tumor drugs.
- the use of oral retinoic acid in treating leukemia has been reported by R. P. Warrell, Jr. et al., New England Journal of Medicine, 324, 1385-1393 (1991).
- the present invention relates to a compound of the formula:
- R 1 is C 1 to C 8 alkyl and Q is selected from
- Preferred prodrugs of the present invention are compounds wherein Z is selected from groups of the formula:
- Y is selected from groups of the formula:
- R 2 is C 1 to C 8 alkyl, phenyl-C 1 to C 8 alkyl or substituted phenyl-C 1 to C 8 alkyl wherein the substituted phenyl may be substituted with one or two substituents selected from C 1 to C 4 alkyl and halogen (i.e. fluoro, chloro, bromo or iodo).
- halogen i.e. fluoro, chloro, bromo or iodo
- Other prodrugs include compounds wherein R 2 is or -CH 2 - wherein R 3 is H, CH 3 ,
- esters of alpha-amino penicillins having such R 2 groups are disclosed in United States Patent 3,873,521, the disclosure of which is hereby incorporated herein by reference.
- the present invention also relates to the use of an amount of a compound of the formula I or II, including a pharmaceutically acceptable salt or prodrug thereof, effective in moderating or retarding the effects of aging of the skin and generally improving the quality of the skin or in treating conditions of the skin selected from the group consisting of psoriasis, acne and related disorders of keratinization and epithelial differentiation, and skin tumors.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of a compound of the formula I or II, including a pharmaceutically acceptable salt or prodrug thereof, effective in moderating or retarding the effects of aging of the skin and generally improving the quality of the skin or in treating conditions of the skin selected from the group consisting of psoriasis, acne and related disorders of keratinization and epithelial differentiation, and skin tumors.
- the present invention also relates to a pharmaceutical composition useful for treating leukemia comprising a pharmaceutically acceptable carrier and an amount of a compound of the formula I or II, including a pharmaceutically acceptable salt or prodrug thereof, effective in halting or ameliorating the symptoms of leukemia.
- the composition is preferably administered as an oral dosage form.
- the present invention also relates to a method for treating leukemia, which comprises administering to a patient in need of such treatment an amount of a compound of the formula I or II, including a pharmaceutically acceptable salt or prodrug thereof, effective in halting or ameliorating the symptoms of leukemia.
- the present invention also relates to a compound of the formula:
- R 2 is C 1 to C 8 alkyl, phenyl-C 1 to C 8 alkyl or substituted phenyl-C 1 to C 8 alkyl wherein the substituted phenyl may be substituted with one or two substituents selected from C 1 to C 4 alkyl and halogen, or
- R 3 is H, CH 3 , or C 2 H 5 and R 4 is C 1 to C 4 alkyl, which is useful in preparing compounds of the formulae I and II wherein Q is wherein R 2
- R 2 is C 1 to C 6 alkyl.
- the active compounds of the present invention may be prepared as follows:
- Amides are prepared by converting a dicarboxylic acid monoester derivative of the formula HO 2 C-K-CO 2 R 2 wherein K is heteroarylene and R 2 is as defined above to its acid chloride and reacting the acid chloride with an amine of the formula:
- R 1 is C 1 to C 8 alkyl, or by reacting an amino acid ester of the formula H 2 N-K-CO 2 R 2 wherein K is heteroarylene and R 2 is as defined above with an acid chloride of the formula:
- R 1 is C 1 to C 8 alkyl, in an inert solvent such as tetrahydrofuran and in the presence of a tertiary amine base, such as triethylamine, at a temperature of from about -20°C to reflux, preferably at about 0°C to room temperature, to yield compounds of the formulae:
- Suitable solvents include tetrahydrofuran, diethylether, dimethylformamide or toluene.
- the preferred solvent is tetrahydrofuran.
- These intermediate compounds may then be saponified to the corresponding carboxylic acids by treatment with a base such as aqueous sodium hydroxide in a solvent such as tetrahydrofuran or ethanol to give a base such as aqueous sodium hydroxide in a solvent such as tetrahydrofuran or ethanol to
- Esters of the formulae I or II are prepared by converting a dicarboxylic acid mono-benzylester of the formula HO 2 C-M-CO 2 CH 2 -phenyl wherein M is phenylene or heteroarylene to its acid chloride and reacting it with a hydroxy compound of the formula:
- Suitable solvents include tetrahydrofuran, diethylether, dimethylformamide, methylene chloride or toluene.
- the preferred solvent is tetrahydrofuran.
- the intermediate compounds (which also can be considered prodrugs) can then be hydrogenated, using a suitable catalyst such as palladium on carbon in an inert solvent, such as ethyl acetate, at temperatures between about 0° and about 50°C and at a pressure between about 14 and about 50 psi to provide the final esters of formulae I
- -O-C-R 4 or -CH 2 -NHC-OR 4 may be prepared from compounds of
- the compounds of the formulae I and II are carboxylic acids and form salts with bases.
- these salts are the salts with alkali metals such as sodium and potassium; or alkaline earth metals such as calcium, and magnesium; the salts with ammonia; and the salts with organic bases such as methylamine, ethylamine, diethylamine, trimethylamine, triethylamine, pyridine, picoline, arginine, lysine, triethanolamine, and meglumine.
- the salts are prepared by reacting a compound of the formulae I or II with 1 equivalent of base in a suitable inert solvent.
- the active compounds of the present invention are useful in moderating and retarding the effects of aging of the skin and generally improving the quality of the skin, particularly human facial skin, resulting in a more youthful appearance.
- the compounds may be administered by topical application beginning in middle age when aging changes first become evident clinically. Certain of the anatomic alterations may be corrected and at least partially reversed, accompanied by improvement in the appearance of the skin. More specifically, the compounds of the present invention have the following advantages inter alia: Clinical
- the active compounds of the present invention suppress the hyperkeratinization of human tissue cells and are useful in the systemic and topical treatment of dermatological ailments linked to a keratinization disorder (differentiation proliferation) or epithelial differentiation. They are also useful in treating dermatologic ailments with inflammatory and/or immunoallergic components (e.g., psoriasis and acne) and also have anti-tumoral activity. These compounds can also be employed in the treatment of cutaneous atrophy. These compounds are also usefully employed in the field of ophthalmology and principally in the treatment of corneopathy. Unless otherwise indicated, treatment can be systemic or topical. Treatment of leukemia is generally systemic.
- the effectiveness of the active compounds of the present invention in retarding the effects of aging of the skin and generally improving the quality of the skin may be evaluated in the rhino mouse model described below.
- mice Three groups of mice, each having five mice are used. One group receives test agent, one group receives vehicle, and the third group is untreated.
- the mice used are female rhino (age about 7 weeks).
- the dorsal surface of each animal is treated with 100 ⁇ l of topical agents, once a day, 5 times a week for 4 weeks. At the end of the treatment period, animals are clinically assessed for effacement of skin folds and wrinkles. Representative animals are photographed with untreated controls.
- dorsal skin biopsies strips about 1 cm long
- Sections are evaluated on an ordinal scale for normalization of the epidermis and utriculi (abnormal hair follicles).
- the active compounds of this invention may be tested according to the following procedure which shows the differentiation of malignant cells, whereby the differentiation of human acute promyelocytic leukemia cells (HL-60) and their conversion to mature granulocytes (myelocytes) can be assayed by an observation of the morphological changes of nuclei and further by the measurement of the degree of reduction of nitro-blue tetrazolium (NBT) which is induced by a test compound [Proc. Natl. Acad. Sci. U.S.A., 77, 2936-2940 (1980)].
- HL-60 human acute promyelocytic leukemia cells
- NBT nitro-blue tetrazolium
- the HL-60 cells are cultured in plastic flasks in RPMI- 1640 medium supplemented with 5% heat inactivated fetal calf serum and antibiotics (penicillin G and streptomycin).
- the cells (3x10 4 /ml) are then cultured with a compound of the present invention for 4 days. Growth inhibition of the cells by the test compounds is then determined by counting the number of cells by microscope and relative ratio was examined by taking the number of cells by control (without test compound) as 100%.
- the cells are fixed and stained with Wright-Giemsa stain to examine the morphological changes of the nuclei.
- the cells treated with the present compounds are differentiated to mature granulocytes . (myelocytes, metamyelocytes and neutrophils), just as the cells treated with retinoic acid.
- the biochemical activity of cells treated with the compound is measured as follows:
- the cells after 5 days incubation are centrifuged and diluted with RPMI-1640 medium supplemented with 5% fetal calf serum, to provide a definite number of the cells.
- To the diluted cell suspension are then added 200 mg/ml of 12- O-tetradodecanoylphorbol-13-acetate (TPA) and the resulting culture medium is then incubated for 20 minutes at 37°C in the presence of 0.1% of NBT.
- TPA 12- O-tetradodecanoylphorbol-13-acetate
- the active compounds of the present invention can be used for determining the type of leukemia a patient may have by incubating a sample of a patient's blood in vitro in the presence of a compound of the present invention in an analogous manner as described in the morphological assay for the HL-60 cells: Only promyelocytic leukemia cells, but no lymphocytic leukemia cells, differentiate to mature granulocytes, which can be clearly determined by observation with a microscope [Sabo in Cells, 14. 533 (1982)]. When the incubation is performed in a soft agar, promyelocytic leukemia cells do not form a colony, since the differentiated cells do not proliferate further. Thus, these compounds are very useful in the determination of promyelocytic leukemia, which enables one to select the appropriate therapeutic method.
- the antileukemic activity of the active compounds of the present invention may be demonstrated by testing for their ability to treat HL-60 (human derived leukemia cells) nude mice by the following procedure:
- test compound is suspended in 10% (v/v) Tween 80 (trademark) in a concentration of 10 mg/ml.
- Cells (5x10 7 ) of test compound is suspended in 10% (v/v) Tween 80 (trademark) in a concentration of 10 mg/ml.
- HL-60 are transplanted subcutaneously to a nude mouse
- compositions containing the active compounds of the present invention as the main component are formulated in a conventional manner, using conventional carriers for formulation, including excipients.
- the medicaments may be administered orally as tablets, pills, capsules, granules, etc., or may be administered parenterally as injections such as intravenous injections, intramuscular injections, etc., in the form of ointments, creams and the like for external application in particular for the treatment of dermatological disorders. They may be used as aerosols, suppositories, etc.
- the doses of the medicaments are properly determined according to each case on considering the symptom, the age of patient, sex, etc., but are usually about 1 to about 300 mg per day for an adult in case of oral administration and about 1 to about 100 mg per day for an adult in case of parenteral administration, the daily amount usually being administered in 2 or 3 separate dosages.
- the active compounds of the present invention retard the effects of normal aging of the skin due to impairment of the differentiation of epidermal epithelial cells and due to loss of collagen fibers, abnormal changes in the elastic fibers and deterioration of small blood vessels of the dermis of the skin.
- the compounds are applied topically to the epidermis of the skin in a program of maintenance therapy, whereby epithelial growths are substantially reduced and prevented and the skin substantially regains and maintains its firmness, turgor and elasticity during the therapy.
- the maintenance therapy is begun in middle age when epithelial growths and other aging changes begin to appear clinically.
- the active compounds of the present invention may be applied to the skin in any suitable non-toxic, dermatologically acceptable vehicle (preferably a non-volatile, emollient or lubricating vehicle, such as an oleaginous substance, which helps hydrate the skin) in an amount and at a frequency which are insufficient to cause excessive irritation of the skin.
- a suitable non-toxic, dermatologically acceptable vehicle preferably a non-volatile, emollient or lubricating vehicle, such as an oleaginous substance, which helps hydrate the skin
- concentrations in the range of about 0.0005 to about 0.05% and preferably about 0.005% to about 0.025% by weight of the vehicle are preferred.
- ointment bases are petrolatum, petrolatum plus volatile silicones, and lanolin.
- emulsion (cream) bases which are mixtures of oils and water are preferred.
- suitable cream bases are Eucerin (trademark, Beiersdorf), cold cream (USP), Purpose Cream (trademark, Johnson & Johnson) and hydrophilic ointment (USP).
- the treatment according to the present invention relating to aging of the skin is intended to continue indefinitely; otherwise, the effects of aging may reappear after treatment is terminated. That is, the treatment of the present invention may be considered to be intervention therapy in decelerating the aging process. If the intervention is stopped, there may be regression to the original state.
- the particular program of maintenance therapy according to the present invention will vary depending upon the individual being treated. Generally, depending upon the age and state of the skin when treatments begin, once a day applications for up to 6 months may be necessary to reduce and control the effects of aging which have already occurred. Once a stabilized skin control has been obtained, the frequency of application of an active compound of the present invention may be reduced, for example, to two or three times a week, and in some cases only once a week for the rest of the person's life. That is, once the aging process has been controlled, a maintenance dose on the order of two applications per week may be sufficient to maintain that state.
- a 250 ml three-neck round-bottom flask equipped with a stirrer, condenser and a nitrogen inlet tube was charged with a solution of 2.11 g (0.00925 mole) of benzyl 4- hydroxybenzoate in 50 ml of dry tetrahydrofuran, cooled to 0°C in an ice-bath, at which point 1.3 ml (0.934 g; 0.00925 mole) of triethylamine and then the acid chloride prepared above (slurried in 50 ml of tetrahydrofuran) were added. The mixture was heated under stirring to 60°C for 5 hours and then kept at room temperature overnight.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP92917698A EP0642499A1 (en) | 1991-09-24 | 1992-08-10 | Retinoids and their use in treating skin diseases and leukemia |
JP5506024A JPH06507178A (en) | 1991-09-24 | 1992-08-10 | Retinoids and their use in the treatment of skin diseases and leukemia |
FI941345A FI941345A (en) | 1991-09-24 | 1994-03-23 | Retinoids and their use in the treatment of skin diseases and leukemia |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76457891A | 1991-09-24 | 1991-09-24 | |
US764,578 | 1991-09-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993006086A1 true WO1993006086A1 (en) | 1993-04-01 |
Family
ID=25071126
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/006485 WO1993006086A1 (en) | 1991-09-24 | 1992-08-10 | Retinoids and their use in treating skin diseases and leukemia |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0642499A1 (en) |
JP (1) | JPH06507178A (en) |
CA (1) | CA2119571A1 (en) |
FI (1) | FI941345A (en) |
PT (1) | PT100878A (en) |
WO (1) | WO1993006086A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0637297A1 (en) * | 1992-04-22 | 1995-02-08 | Ligand Pharmaceuticals, Inc. | Compounds having selectivity for retinoid x receptors |
US5420145A (en) * | 1993-03-22 | 1995-05-30 | Koichi Shudo | Carboxylic acid derivative |
WO1996006070A1 (en) * | 1994-08-23 | 1996-02-29 | Allergan | Disubstituted aryl and heteroaryl imines having retinoid-like biological activity |
US5523457A (en) * | 1994-01-03 | 1996-06-04 | Bristol-Myers Squibb Company | Retinoid-like compounds |
US5559248A (en) * | 1995-04-05 | 1996-09-24 | Bristol-Myers Squibb Co. | Retinoid-like heterocycles |
US5618839A (en) * | 1994-01-03 | 1997-04-08 | Bristol-Myers Squibb Company | Retinoid-like compounds |
WO1997016422A1 (en) * | 1995-11-01 | 1997-05-09 | Allergan | Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity |
WO1997018192A1 (en) * | 1995-11-16 | 1997-05-22 | F. Hoffmann-La Roche Ag | Aromatic carboxylic acid esters, the production of same and use of same as medicaments |
US5780676A (en) * | 1992-04-22 | 1998-07-14 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors |
US5962731A (en) * | 1992-04-22 | 1999-10-05 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
WO2000063196A1 (en) * | 1999-04-20 | 2000-10-26 | Novo Nordisk A/S | New compounds, their preparation and use |
WO2022140467A1 (en) * | 2020-12-21 | 2022-06-30 | Samson Pharma, Llc | Topical compositions and methods of treating skin diseases and conditions with such compositions |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3729568A (en) * | 1969-09-23 | 1973-04-24 | Johnson & Johnson | Acne treatment |
US4141977A (en) * | 1975-08-04 | 1979-02-27 | Yu Ruey J | Treatment of psoriasis with 6-substituted nicotinamides, 2-substituted pyrazinamides and closely related compounds |
EP0435222A2 (en) * | 1989-12-27 | 1991-07-03 | Hoechst-Roussel Pharmaceuticals Incorporated | Aminopyridinylmethanols and aminomethylpyridinamines and related compounds, a process for their preparation and their use as medicaments |
-
1992
- 1992-08-10 JP JP5506024A patent/JPH06507178A/en active Pending
- 1992-08-10 CA CA002119571A patent/CA2119571A1/en not_active Abandoned
- 1992-08-10 WO PCT/US1992/006485 patent/WO1993006086A1/en not_active Application Discontinuation
- 1992-08-10 EP EP92917698A patent/EP0642499A1/en not_active Withdrawn
- 1992-09-18 PT PT100878A patent/PT100878A/en not_active Application Discontinuation
-
1994
- 1994-03-23 FI FI941345A patent/FI941345A/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3729568A (en) * | 1969-09-23 | 1973-04-24 | Johnson & Johnson | Acne treatment |
US4141977A (en) * | 1975-08-04 | 1979-02-27 | Yu Ruey J | Treatment of psoriasis with 6-substituted nicotinamides, 2-substituted pyrazinamides and closely related compounds |
EP0435222A2 (en) * | 1989-12-27 | 1991-07-03 | Hoechst-Roussel Pharmaceuticals Incorporated | Aminopyridinylmethanols and aminomethylpyridinamines and related compounds, a process for their preparation and their use as medicaments |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5962731A (en) * | 1992-04-22 | 1999-10-05 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
EP0637297A4 (en) * | 1992-04-22 | 1995-09-20 | Ligand Pharm Inc | Compounds having selectivity for retinoid x receptors. |
EP0637297A1 (en) * | 1992-04-22 | 1995-02-08 | Ligand Pharmaceuticals, Inc. | Compounds having selectivity for retinoid x receptors |
EP0983991A3 (en) * | 1992-04-22 | 2001-01-17 | Ligand Pharmaceuticals, Inc. | Compounds having selectivity for retinoid x receptors |
US6043279A (en) * | 1992-04-22 | 2000-03-28 | Ligand Pharmaceuticals, Incorporated | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
EP0983991A2 (en) * | 1992-04-22 | 2000-03-08 | Ligand Pharmaceuticals, Inc. | Compounds having selectivity for retinoid x receptors |
US5780676A (en) * | 1992-04-22 | 1998-07-14 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors |
US5420145A (en) * | 1993-03-22 | 1995-05-30 | Koichi Shudo | Carboxylic acid derivative |
US5523457A (en) * | 1994-01-03 | 1996-06-04 | Bristol-Myers Squibb Company | Retinoid-like compounds |
US5618839A (en) * | 1994-01-03 | 1997-04-08 | Bristol-Myers Squibb Company | Retinoid-like compounds |
US5648385A (en) * | 1994-01-03 | 1997-07-15 | Bristol-Myers Squibb Co. | Retinoid-like compounds |
WO1996006070A1 (en) * | 1994-08-23 | 1996-02-29 | Allergan | Disubstituted aryl and heteroaryl imines having retinoid-like biological activity |
US5559248A (en) * | 1995-04-05 | 1996-09-24 | Bristol-Myers Squibb Co. | Retinoid-like heterocycles |
US5849923A (en) * | 1995-04-05 | 1998-12-15 | Bristol-Myers Squibb Company | Heterocyclic-substituted naphthalenyl retinobenzoic acid derivatives |
WO1997016422A1 (en) * | 1995-11-01 | 1997-05-09 | Allergan | Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity |
US5958956A (en) * | 1995-11-16 | 1999-09-28 | Hoffmann-La Roche Inc. | Aromatic carboxylic acid esters |
US5726191A (en) * | 1995-11-16 | 1998-03-10 | Hoffmann-La Roche Inc. | Aromatic carboxylic acid esters |
WO1997018192A1 (en) * | 1995-11-16 | 1997-05-22 | F. Hoffmann-La Roche Ag | Aromatic carboxylic acid esters, the production of same and use of same as medicaments |
KR100286190B1 (en) * | 1995-11-16 | 2001-04-16 | 프리돌린 클라우스너, 롤란드 비. 보레르 | Aromatic carboxylic acid esters, the production of same and use of same as medicaments |
WO2000063196A1 (en) * | 1999-04-20 | 2000-10-26 | Novo Nordisk A/S | New compounds, their preparation and use |
WO2022140467A1 (en) * | 2020-12-21 | 2022-06-30 | Samson Pharma, Llc | Topical compositions and methods of treating skin diseases and conditions with such compositions |
Also Published As
Publication number | Publication date |
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JPH06507178A (en) | 1994-08-11 |
EP0642499A1 (en) | 1995-03-15 |
FI941345A0 (en) | 1994-03-23 |
PT100878A (en) | 1993-10-29 |
FI941345A (en) | 1994-03-23 |
CA2119571A1 (en) | 1993-04-01 |
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