RETINOIDS AND THEIR USE IN TREATING SKIN DISEASES AND LEUKEMIA

Abstract: Compounds of formula (I) or (II) and pharmaceutically acceptable salts and prodrugs thereof, wherein R<1> is C1 to C8 alkyl and Q is selected from (a), (b), (c), (d), (e) and (f), wherein Y is selected from (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) and Z is selected from groups of formula (XI), with the pharmaceutically acceptable salts and prodrugs of the aforesaid formula I or II final products being derived from the hereinbefore described Y and Z acid groups. These compounds are useful in treating aging skin, and also skin conditions such as psoriasis, acne and related disorder of keratinization and epithelial differentiation, as well as skin tumors.

Description: RETINOIDS AND THEIR USE IN TREATING SKIN DISEASES AND LEUKEMIA Technical Field 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. Background Art Caucasians who have had a good deal of sun exposure in childhood will show the following gross cutaneous alterations in adult life: wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling (hyperpigmentation) and various premalignant growths (often subclinical) . These changes are most prominent in light skinned persons who burn easily and tan poorly. The baleful effects of sunlight are cumulative, increasing with time. Although the anatomic degradation of the skin is most advanced in the elderly, the destructive effects of excessive sun exposure are already evident by the second decade. Serious microscopic alterations of the epidermis and dermis occur decades before these become clinically visible. Wrinkling, yellowing, leatheriness, and loss of elasticity are very late changes. It is known to use 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. _, 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 (retinoids) 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) . Disclosure of the Invention The present invention relates to a compound of the formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is C, ^ to C 8 alkyl and Q is selected from 0 H H 0 II I I II C N — Y — N — C 0 0 II II — C — 0 — Y — 0 — C — Y 0 II — C — 0 — Z and — 0 — C — Z wherein Y is selected from and Z is selected from groups of the formula: with the pharmaceutically acceptable salt and prodrug of the formula I or II compound being derived from the aforesaid Y and Z acid groups. These compounds are hereinafter also referred to as the active compounds of the present invention. Preferred prodrugs of the present invention are compounds wherein Z is selected from groups of the formula: and Y is selected from groups of the formula: OOR cooR, 0R- wherein R 2 is C t to C 8 alkyl, phenyl-Ci to alkyl or substituted phenyl-Cj to C 8 alkyl wherein the substituted phenyl may be substituted with one or two substituents selected from C x to C 4 alkyl and halogen (i.e. fluoro, chloro, bromo or iodo) . Other prodrugs include compounds 0 0 wherei •n R 2 2 i ■s -CH-O-C'I-R4 4 or -CH 2 -NHCI'-OR4 4 wherein R 3 is H, CH 3 , _> or C 2 H 5 and R 4 is C- to C 4 alkyl. 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 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 following are preferred compounds of the present invention: 4- (5, 6, 7, 8-tetrahydro-5 ,5,8, 8-tetramethyl-2- naphthoyloxy)-benzoic acid; 4-(5 , 6, 7 , 8-tetrahydro-5,5,8, 8-tetramethyl-2- naphthyloxy-carbonyl)-benzoic acid; 6- (5 , 6 , 7 , 8-tetrahydro-5 ,5,8,8, -tetramethyl-2- naphthoylamino) -nicotinic acid; and 6-[3-(l-adamantyl) -4-methoxybenzoylamino] -nicotinic acid. Other specific compounds of the present invention are the following: 3- ( 5 , 6 , 7 , 8-tetrahydro-5 ,5,8, 8-tetra ethy 1-2 - naphthoyloxy) -benzoic acid; 2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethy 1-2- naphthoyloxy) -benzoic acid; 6-(5,6,7,8-tetrahydro-5,5,8, 8 -tetr amethy 1-2- naphthoyloxy) -nicotinic acid; 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyloxy-carbonyl) -benzoic acid; 2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethy 1-2- naphthyloxy-carbonyl) -benzoic acid; 6-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethy 1-2 - naphthyloxy-carbonyl) -nicotinic acid; 5- (5 , 6 , 7 , 8-tetrahydro-5 ,5,8, 8 -tetr amethy 1-2- naphthoylamino)-thiophene-2-carboxylic acid; 5- (5 , 6 , 7 , 8-tetrahydro-5 , 5,8, 8 -tetr amethy 1-2 - naphthoylamino) -nicotinic acid; 6-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethy 1-2 - naphthoylamino) -pyrazine-3-carboxylic acid; 2-(5,6,7,8-tetrahydro-5,5,8, 8 -tetr amethy 1-2 - napthoylamino) -pyrimidine-5-carboxylic acid; 5- [3- (1-adamantyl) -4-methoxybenzoylamino] -thiophene-2- carboxylic acid; 5- [3- (1-adamantyl) -4-methoxybenzoylamino] -nicotinic acid; 6- [3- (1-adamantyl) -4-methoxybenzoylamino] -pyrazine-3- carboxylic acid; and 2- [ 3- ( 1-adamantyl) -4-methoxybenzoylamino] -pyrimidine-5- carboxylic acid. The present invention also relates to a compound of the formula : wherein R 2 is C, to C g alkyl, phenyl-C. to C g alkyl or substituted phenyl-C ! to C g alkyl wherein the substituted phenyl may be substituted with one or two substituents O II 4 selected from C x to C 4 alkyl and halogen, -CH-O-C-R 4 or R 3 O -CH 2 -NHC-OR 4 wherein R 3 is H, CH 3 , or C-.H 5 and R 4 is C, to C 4 alkyl, which is useful in preparing compounds of the 0 H r*^-*s*-r—C00R 2 formulae I and II wherein Q is c \ \ <{ ~ wherein R 2 is as defined above. Preferably R 2 is C to C 6 alkyl. Detailed Description 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 H0 2 C-K-C0 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: wherein R 1 is C x to C g alkyl, or by reacting an amino acid ester of the formula H 2 N-K-C0 2 R 2 wherein K is heteroarylene and R 2 is as defined above with an acid chloride of the formula: wherein R 1 is C, to C g 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 amides of the formulae I and II wherein Q is -C-NH-Y O or -NH-C II-Y wherein Y is defined as above. Esters of the formulae I or II are prepared by converting a dicarboxylic acid mono-benzylester of the formula H0 2 C-M-C0 2 CH 2 -phenyl wherein M is phenylene or heteroarylene to its acid chloride and reacting it with a hydroxy compound of the formula: or by reacting a hydroxy-acid benzyl ester of the formula HO-__-C0 2 CH 2 -phenyl wherein M is phenylene or heteroarylene with an acid chloride of the formula: 1 in either case in an inert solvent in the presence of a tertiary amine base, such as triethylamine, at a temperature between about -20°C to reflux, preferably at room temperature, to yield intermediates of the formulae: ϋxr f . l— C0-.Crl 2 --ph en yl , 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 and II wherein Q is -C00Y, -OC-Y, -C-O-Z or -O-C-Z, where Y and Z are as defined above. Other prodrugs wherein R 2 is O O -CH-O-C "-R4* or -CH 2 -NHCH-OR4 4 may be prepared from compounds of R 3 formulae I and II as outlined in U. S. Patent No. 3,873,521. The compounds of the formulae I and II are carboxylic acids and form salts with bases. Examples of 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 Effacement of fine wrinkles Smoother surface Lighten pigmented blotches Skin has more turgor Large pores less noticeable Skin feels livelier and tighter Histologic Thicker epidermis Normalizes atypia and pre-malignant changes Atrophy and dysplasia corrected Stimulate blood flow; new vessels formed Stimulate fibroblasts with collagen formation Increase ground substance Melanin with keratinocytes is decreased 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 immuno- allergic 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. 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 μl 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. For histologic evaluation, dorsal skin biopsies (strips about 1 cm long) are processed for light microscopy. Sections are evaluated on an ordinal scale for normalization of the epidermis and utriculi (abnormal hair follicles) . For the split skin assessment, a 2 cm 2 portion of dorsal skin is excised. Epidermis is separated from the dermis with 0.5% acetic acid and processed for light microscopy and microphotography. Utriculi are measured from the photographs for numerical data (mean + S.D.). 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 fProc. Natl. Acad. Sci. U.S.A.. 77, 2936-2940 (1980)]. 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 (3xl0 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. Thus, the mature differentiated cells containing blue-black formazan are counted by microscopy, so that the ratio of the cells having the ability to reduce NBT, to total cells, can be calculated. 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: A test compound is suspended in 10% (v/v) Tween 80 (trademark) in a concentration of 10 mg/ml. Cells (5xl0 7 ) of HL-60 are transplanted subcutaneously to a nude mouse (BALB/c, nu/nu female Nihon Clea) . At the end of days 9, 14 and 17 after the transplantation, 0.1 ml of the suspension per 10 g of body weight of mouse are administered per os two times at intervals of 7 hours (200 mg/kg/day) . Tumor volumes are measured after 4, 6, 8 and 11 days after the first administration. Compounds effective against HL-60 cells are also expected to be effective against neuroblastoma, squamous cells carcinoma, and melanoma. The pharmaceutical 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 g 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. Generally, the maintenance therapy is begun in middle age when epithelial growths and other aging changes begin to appear clinically. For topical application, 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. Generally, 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. Various non-toxic, dermatologically acceptablevehicles or carriers will be evident to those of ordinary skill in the art. Volatile vehicles which dry or otherwise harm the skin, such as alcohol and acetone, should be avoided. An ointment base (without water) is preferred in the winter and in subjects with very dry skin. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, and lanolin. In warm weather and often for younger persons, emulsion (cream) bases, which are mixtures of oils and water are preferred. Examples of 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. Usually, there is little point in beginning the treatments of the present invention relating to aging until middle age when the effects of aging begin to appear. 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. EXAMPLE 1 4-(5.6.7.8-Tetrahydro-5.5.8.8-tetramethyl-2-naphthoyl¬ oxy)-benzoic acid A 500 ml three-neck round-bottom flask equipped with a stirrer and a condenser was charged with 5.0 g (0.0217 mole) of 2-acetyl-5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl- naphthalene and 261.1 ml of a 3% NaOCl solution [149.1 ml of 5.25% NaOCl (Clorox) (trademark)], and combined with 112 ml water and 4.7 ml of a 45% aqueous KOH solution. The mixture was heated with an oil bath to reflux under stirring for 2 hours, allowed to cool to room temperature and extracted with ethyl acetate. The aqueous layer was acidified with IN HC1 and the precipitated product was extracted with ethyl acetate. This organic layer was then washed with water and with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give, after trituration with petroleum ether, 4.0 g (79%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethy1-2-naphthoic acid, mp 174-6°C; MS: m/e, 232; NMR (CDC1 3 ) consistent with product. Anal.: Calcd. for C 15 H 20 O 2 : C, 75.55; H, 8.68; Found: C, 76.01; H, 8.40. A 50 ml three-neck round-bottom flask equipped with a stirrer, a condenser and a nitrogen inlet tube was charged with 2.15 g (0.00927 mole) of 5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthoic acid (prepared as described above) , 5 ml (8 g; 0.067 mole) of thionyl chloride and a catalytic amount of pyridine. The resulting orange solution was heated at reflux for 2.5 hours, cooled and evaporated in vacuo to give the acid chloride as an orange-brown oil. 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. After evaporation of the solvent in vacuo, the residue was taken up in ethyl acetate/water, the organic layer was washed with water, dried over anhydrous sodium sulfate and then evaporated in vacuo to a yellow solid. This solid was dissolved in 30 ml of tetrahydrofuran, 10% Pd/C was added and the mixture was hydrogenated at 10 psi on a Parr shaker for 2.5 hours, and then hydrogenated with fresh catalyst for another hour when TLC (thin layer chromatography) analysis (ethyl acetate) indicated the reaction to be complete. The catalyst was removed by filtration over diato aceous earth [Celite(trademark) ] and washed with ethyl acetate, the filtrate was evaporated in vacuo and the residual white solid (2.6 g) recrystallized from absolute ethanol to give 1.39 g (43%) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthoyloxy)-benzoic acid as white crystals, mp > 230°C; MS: m/e, 352; NMR (DMS0-d 6 ) consistent with product. Anal. Calcd. for C^H^O,,: C, 74.98; H, 6.86. Found: C, 75.14; H, 6.69. EXAMPLE 2 4-(5 1 6,7 r 8-Tetrahγdro-5,5,8,8-tetramethγl-2-naphthyl- oxy-carbonyl)-benzoic acid A 50 ml three-neck round bottom flask equipped with a stirrer, a condenser and a nitrogen inlet tube was charged with 0.4 g (0.00156 mole) of terephthalic acid mono-benzyl ester [prepared according to G. J. Atwell and B. F. Cain, in J. Med. Chem.. 10, 706 (1967)], 1.15 ml (1.86 g; 0.0156 mole) of thionyl chloride and a catalytic amount of pyridine. The mixture was heated at reflux for 2 hours. The solution was then kept at 65°C overnight, cooled and evaporated in vacuo to give the acid chloride as a yellow semi-solid. A 50 ml three-neck round-bottom flask equipped with a stirrer, condenser and a nitrogen inlet tube was charged with a slurry of 0.305g (0.0015 mole) of 5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthol [prepared according to H.A. Bruson and J.W. Kroeger, J. Am. Chem. Soc.. 62, 36 (1940)] in 25 ml of dry tetrahydrofuran, 0.207 ml (0.15 g; 0.0015 mole) of triethylamine and 0.410 g (0.0015 mole) of the acid chloride prepared above. The mixture was heated under stirring to reflux for 2 hours and then kept at 50°C overnight, at which point TLC analysis (hexane/ethyl acetate 1:1) indicated that the reaction was complete. After evaporation of the solvent j_n vacuo. the residue was taken up in ethyl acetate/water, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give, after trituration with hexane, 230 mg (35%) of a white solid; MS: m/e, 442; NMR (DMSO-d 6 ) consistent with product. This solid was dissolved in 30 ml of ethyl acetate, 10% Pd/C was added and the mixture was hydrogenated at 40 psi on a Parr shaker for 4 hours when TLC analysis (hexane/ethyl acetate 1:1) indicated that the reaction was complete. The catalyst was removed by filtration over diatomaceous earth [Celite (trademark) ] and washed with ethyl acetate, the filtrate was evaporated in vacuo and the residual white solid triturated with hexane to give 85 mg (46%) of the title compound as white crystals, mp > 220°C; MS: m/e, 352; NMR (DMSO-d 6 ) consistent with product; Anal. Calcd. for C^H^O-,: C, 74.98; H, 6.86. Found: C, 74.50; H, 6.59. EXAMPLE 3 6-(5,6 ,7,8-Tetrahydro-5,5,8,8-tetramethy1-2-naphthoyl¬ amino)-nicotinic acid A 500 ml three-neck round-bottom flask equipped with a stirrer and a condenser was charged with 11.81 g (0.085 mole) of 6-aminonicotinic acid and 60 ml of thionyl chloride; 5 ml of pyridine were then added and the mixture was refluxed under stirring for 1 hour. After evaporation in vacuo, the residual orange-brown oil was cooled to 0°C and carefully treated with 50 ml of methanol. After the slight exotherm subsided, the yellow solution was evaporated in vacuo and the residue was taken up in ethyl acetate/water. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give, after crystallization of the residue from chloroform/hexane, 8.71 g (65%) of methyl 6-aminonicotinate, mp 153-155°C; MS: m/e, 152; NMR (CDC1 3 ) consistent with product. A 500 ml three-neck round-bottom flask equipped with a stirrer and a condenser was charged with 7.67 g (0.049 mole) of methyl 6-aminonicotinate (prepared as described above) and 150 ml of tetrahydrofuran; 6.81 ml (4.96 g; 0.049 mole) of triethylamine and 12.29 g (0.049 mole) of 5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthoylchloride(prepared as described in Example l) were then added and the mixture stirred at room temperature overnight. After evaporation in vacuo. the residue was partitioned between water and ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica, using hexane/ethyl acetate as the eluant. The major LP spot was collected to give a tan solid [NMR (CDC1 3 ) consistent with the methyl ester of the desired product] . This material was dissolved in 50 ml of tetrahydrofuran, 50 ml of 2N NaOH was added and the mixture was stirred at room temperature overnight. After partial evaporation in vacuo to remove the organic solvent, the aqueous solution was acidified to pH 4 with 6N HCl to give a cream-colored precipitate, which was filtered and recrystallized from ethanol to afford 6.32 g (37%) of the title compound as white crystals, mp > 240°C; MS: m/e, 352; NMR (DMSO-d 6 ) consistent with product. Anal. Calcd. for C 2 -H 2 N 2 O 3 : C, 71.56; H, 6.86; N, 7.95. Found: C, 71.24; H, 7.11; N, 7.87. EXAMPLE 4 6-f3-(1-Adamantyl)-4-methoxy-benzoylamino1-nicotinic acid A 150 mL three-neck round-bottom flask equipped with a stirrer and a condenser was charged with 250 mg (0.0016 mole) of methyl 6-aminonicotinate (prepared as described in Example 3) and 15 L of tetrahydrofuran; 0.23 mL (0.16 g; 0.0016 mole) of triethylamine and 0.5 g (0.0016 mole) of 3- (1-adamantyl)-4-methoxybenzoyl chloride (prepared according to the method of B. Shroot et al., as described in U.S. Patent No. 4,927,928) were then added and the mixture stirred at room temperature overnight. After evaporation in vacuo, the residue was partitioned between water and ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous and evaporated in vacuo. The residue was purified by column chromatography on silica, using hexane/ethyl acetate as the eluant. The major arid less lipophilic spot was collected to give a tan solid [NMR (CDC1 3 ) consistent with methyl ester of the desired product] . This material was dissolved in 5 mL of tetrahydrofuran, 3 mL of 2N aqueous NaOH were added and the mixture was stirred at room temperature overnight. After partial evaporation in vacuo to remove the organic solvent, the aqueous solution was acidified to pH 4 with 6N HCl to give a white precipitate, which was filtered and recrystallized from ethanol to afford 203 mg (31%) of the title compound as white crystals, mp >250°C; MS: m/e, 406; NMR (DMSO-d 6 ) consistent with product. Anal. Calcd. for C 24 H 26 N 2 0 4 »H 2 0: C, 67.91; H, 6.65; N, 6.60. Found: C, 67.81; H, 6.82; N, 6.43. EXAMPLE 5 The compounds of Examples 1-3 were tested in the rhino mouse model hereinbefore described at a concentration of 0.1%. All of the compounds improved the appearance of the skin.

Claims: CLAIMS 1. A compound of the formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is C, to C 8 alkyl and Q is selected from O H H O II I I II — C— N— Y — — C— Y 0 0 II — C— 0— Y -0-C— Y 0 0 — C— 0— Z and 0— C— Z wherein Y is selected from r cooH and Z is selected from groups of the formula: COOH with the pharmaceutically acceptable salt and prodrug of the formula I or II compound being derived from the aforesaid Y and Z acid groups. 2. A compound according to claim 1, wherein said prodrugs are compounds wherein Y is selected from and Z is selected from groups of the formula: wherein R 2 is C x to C g alkyl, phenyl-C, to C 8 alkyl or substituted phenyl-C r to C g alkyl wherein the substituted phenyl may be substituted with one or two substituents selected from C t to C 4 alkyl and halogen. 3. A compound according to claim 1, said compound being selected from the group consisting of: 4-(5, 6, 7, 8-tetrahydro-5,5,8, 8-tetramethy1-2- naphthoyloxy)-benzoic acid; 4-(5, 6, 7 , 8-tetrahydro-5,5,8, 8-tetramethy1-2- naphthyloxy-carbonyl)-benzoic acid; 6-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthoy¬ lamino)-nicotinic acid; and 6-[3-(1-adamantyl)-4-methoxybenzoylamino]-nicotinic acid. 4. A pharmaceutical composition useful for treating the skin comprising a pharmaceutically acceptable carrier and an amount of a compound according to claim 1 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. 5. A method for treating the disorders of aging skin in an afflicted subject, which comprises administering to said patient in need of such treatment an amount of a compound according to claim 1 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. 6. A pharmaceutical composition useful for treating leukemia comprising a pharmaceutically acceptable carrier and an amount of a compound according to claim 1 effective in halting or ameliorating the symptoms of leukemia. 7. A composition according to claim 6, adapted to be administered as an oral dosage form. 8. A method for treating leukemia, which comprises administering to a patient in need of such treatment an amount of a compound according to claim 1 effective in halting or ameliorating the symptoms of leukemia. 9. A compound of the formula: wherein R 2 is C j to C 8 alkyl, phenyl-C- to C 8 alkyl or substituted phenyl-Cj to C 8 alkyl wherein the substituted phenyl may be substituted with one or two substituents o selected from C- to C 4 alkyl and halogen, -CH-O-C 11 -R4 4 or R 3 O -CH 2 -NHC 'I-OR4 4 wherein R 3 is H, CH 3 or C 2 H 5 and R 4 is C- to C 4 alkyl . 10. A compound according to claim 9 wherein R 2 is Cj to C 6 alkyl. 11. A process for preparing a compound of the formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is C x to C 8 alkyl and Q is selected from O H H O II I I ll — C— N— Y — N— C— Y 0 0 II II — C— 0— Y — 0— C— Y 0 0 II C — 0— Z and — 0— — Z wherein Y is selected from and Z is selected from groups of the formula: _^ f6kC00H > with the pharmaceutically acceptable salt and prodrug of the formula I or II compound being derived from the aforesaid Y and Z acid groups; (a) characterized in that the amides are prepared by reacting an acid chloride of the formula ClCO-K-Cθ 2 R 2 , wherein K is heteroarylene derived from decarboxylated Y and R 2 is C x to C 8 alkyl, phenyl-Cj to C 8 alkyl having up to two substituents on the phenyl moiety selected from C- to C 4 alkyl and halogen, with an amine of the formula: wherein R 1 is Ci to C 8 alkyl, or by reacting an amino acid ester of the formula H 2 N-K-C0 2 R 2 wherein K is heteroarylene as previously defined and R 2 is as defined above with an acid chloride of the formula: wherein R 1 is C, to C 8 alkyl, in the presence of a base to yield a prodrug compound of the formulae: followed by hydrolysis of the aforesaid prodrug intermediate compound to yield the corresponding amido carboxylic acid final product of the structural formulae I and II wherein Q is -C-NHY or -NHC-Y; and (b) characterized in that the esters are prepared by reacting an acid chloride of the formula C1C0-M-C0 2 CH 2 - phenyl, wherein M is phenylene or heteroarylene as previously defined, with a hydroxy compound of the formula: or by reacting an hydroxy-acid benzyl ester of the formula HO-M-C0 2 CH 2 -phenyl wherein M is phenylene or heteroarylene with an acid chloride of the formula: wherein R 1 is as previously defined, in the presence of a base to yield a prodrug intermediate compound of the formulae: followed by hydrogenolysis of the aforesaid prodrug intermediate compound to yield the corresponding half-acid ester final product of the structural formulae I and II O O O O wherein Q is -C II-OY, -OCII-Y, -CII-OZ or -O-CI!-Z, wherein Y and Z are each as defined above; and thereafter, . (c) when required, converting a free carboxylic acid final product of structural formula I or II, as originally defined, into a pharmaceutically acceptable base salt of said acid or into a prodrug of same by using conventional means. 12. A process as claimed in parts (a) and (b) of claim 11, characterized by the fact that the acylation reaction is carried out in a reaction-inert organic solvent under substantially anhydrous conditions in the presence of a tertiary amine as the base. 13. A process as claimed in parts (a) and (b) of claim 11, characterized by the fact that the acylation reaction is conducted at a temperature ranging from about -20°C up to about the reflux temperature of the reaction mixture. 14. A process as claimed in claim 12, characterized by the fact that the acylation reaction is carried out in tetrahydrofuran in the presence of triethylamine and at a temperature ranging from about 0°C up to room temperature. 15. A process as claimed in part (a) of claim 11, characterized by the fact that the hydrolysis of the amido ester prodrug intermediate compound to the corresponding amido carboxylic acid final product of structural formulae I and II is effected under alkaline conditions. 16. A process as claimed in part (b) of claim 11, characterized by the fact that the hydrogenolysis of the diester prodrug intermediate compound to the corresponding half-acid ester final product of structural formulae I and II is effected by means of catalytic hydrogenation via a palladium-on-carbon catalyst. 17. The process as claimed in part (a) of claim 11 wherein the compound prepared is 6-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthoylamino)-nicotinic acid. 18. The process as claimed in part (a) of claim 11 wherein the compound prepared is 6-[3-(1-adamantyl)-4- methoxybenzoylamino)-nicotinic acid. 19. The process as claimed in part (b) of claim 11, wherein the compound prepared is 4-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthoyloxy)-benzoic acid. 20. The process as claimed in part (b) of claim 11 wherein the compound prepared is 4-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyloxycarbonyl)-benzoic acid.

Inventors: SARGES REINHARD, SARGES, REINHARD
Applicants: PFIZER, PFIZER INC.
Application year: 1992
Main classification: C07C69
IPC codes: A61K31, A61P17, A61P35, C07C69, C07D213, C07D239, C07D241, C07D333