EP0155940A1 - Analogues des acides benzonorbornenyle, benzopyranyle et benzothiopyranyle retinoiques - Google Patents

Analogues des acides benzonorbornenyle, benzopyranyle et benzothiopyranyle retinoiques

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Publication number
EP0155940A1
EP0155940A1 EP19840901274 EP84901274A EP0155940A1 EP 0155940 A1 EP0155940 A1 EP 0155940A1 EP 19840901274 EP19840901274 EP 19840901274 EP 84901274 A EP84901274 A EP 84901274A EP 0155940 A1 EP0155940 A1 EP 0155940A1
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European Patent Office
Prior art keywords
compound
tumor promotion
animal
combined
acceptable carrier
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19840901274
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German (de)
English (en)
Inventor
Marcia Ilton Dawson
Rebecca Leung-Shun Chan
Peter D. Hobbs
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SRI International Inc
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SRI International Inc
Stanford Research Institute
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Publication of EP0155940A1 publication Critical patent/EP0155940A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/546—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/782—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic
    • C07C49/792—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic containing rings other than six-membered aromatic rings

Definitions

  • the invention is in the fields of retinoid chemistry and chemotherapy. More particularly the invention relates to certain benzonorbornenyl, dihydrobenzopyranyl and dihydrobenzothiopyranyl retinoic acid analogues.
  • Retinoic acid and some of its analogues have been investigated as "chemopreventive" agents, that is, agents that interfere with tumor promotion in epithelial cells.
  • the first Dawson, M.I., et al, article describes the synthesis of ethyl (E)-3,7-dimethyl-9-(exobicyclo[2.2.1]hept-2-en-2-yl)-2,4,6,8-nonatetraenoate.
  • This compound is highly labile but exhibited activity in the ornithine decarboxylase (ODC) assay, which assay is described by Verma, A.K. and Boutwell, R.K., Cancer Res (1977) 37:2196-2201.
  • ODC ornithine decarboxylase
  • aromatic retinoic acid analogues also exhibited biological activity in the ornithine decarboxylase (ODC) assay.
  • ODC ornithine decarboxylase
  • Other reported aromatic retinoic acid analogues with biological activity are 4-[(E)-2-(1,2,3,4tetrahydro-1,1,4,4-tetramethyl-6-napthyl)-1-propen-1yl]benzoic acid and ethyl 4-[(E)-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-1-propen-1yl]benzoate.
  • a principal object of this invention is to provide retinoic acid analogues which are biologically active and which may exhibit lesser toxicity than other retinoic acid analogues.
  • retinoic acid analogues of the invention are compounds of the formula:
  • A is the substituent system of a fused ring selected from:
  • R 1 , R 2 , R 3 and R 4 are hydrogen or methyl, X is hydrogen or fluorine and Q is:
  • X 1 is hydrogen, hydroxy, methoxy or fluorine
  • R is hydroxy, alkoxy with 0 or 1 hydroxy substituent, aroxy or NR 5 R 6 , where R 5 is hydrogen, alkyl with 0 or 1 hydroxy substituent or aryl and R 6 is alkyl with 0 or 1 hydroxy substituent or aryl, with the provisos that X is fluorine only when R 2 is methyl, when R 3 or R 4 is methyl, the other R 3 or R 4 is also methyl, and when Q is (i) Q may be in either the cis or trans position.
  • retinoids When used as pharmaceuticals, eg, as a chemopreventive agent or for treating skin disorders such as proliferative skin diseases or acne, one or more of these retinoids is combined with a suitable pharmaceutically acceptable carrier and an effective dose thereof is administered to the patient.
  • a suitable pharmaceutically acceptable carrier When used as pharmaceuticals, eg, as a chemopreventive agent or for treating skin disorders such as proliferative skin diseases or acne, one or more of these retinoids is combined with a suitable pharmaceutically acceptable carrier and an effective dose thereof is administered to the patient.
  • the alkoxy groups represented by R will usually contain 1 to about 10 carbon atoms and have 0 or 1 hydroxy substituent. They will preferably contain 1 to 4 carbon atoms, and have 0 or 1 hydroxy substituent..
  • the alkoxy groups represented by R may be straight chain or branched chain. Examples of such alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, n-hexoxy, 2-methylpentoxy, n-heptoxy, 2-hydroxyethoxy, 3-methylhexoxy, n-octoxy, and n-decoxy.
  • the aroxy groups represented by R will usually be mononuclear and contain 6 to 15 carbon atoms, more usually 6 to 10 carbon atoms and have 0 or 1 hydroxy or C 1 -C 4 alkoxy substituent.
  • Preferred aroxy groups are phenoxy and hydroxy- or C 1 -C 4 alkoxy-monosubstituted phenoxy.
  • Examples of aroxy groups are phenoxy, o- , m-, or p-hydroxyphenoxy, o-, m-, or p-methoxyphenoxy, toloxy, cumoxy, xyloxy, and naphth ⁇ xy.
  • the alkyl groups represented by R 1 and R 2 may be straight chain or branched chain.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, n -butyl, s-butyl, n -amyl, n-hexyl, 2-methylamyl, n-heptyl, 3-methylhexyl, n-octyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydfoxyhexyl, and the like.
  • the corresponding aryl groups represented by R 1 and R 2 may be substituted or unsubstituted mononuclear or polynuclear moieties.
  • the substituents will usually be lower (ie, 1 to 4 carbon atoms) alkyl, monohydroxyalkyl, lower alkoxy, monohydroxyalkoxy or hydroxy. When substituted, the group will usually be mono-substituted. Examples of such groups are phenyl, o- , m-, or p-hydroxyphenyl, o-, m-, or p-methoxyphenyl, ethylbenzyl, cumyl, and the like. These aryl groups will usually contain 6 to about 15 carbon atoms, more usually 6 to 10 carbon atoms. Phenyl, 4hydroxyphenyl, and 4-methoxyphenyl are preferred aryl groups.
  • esters and esters of the other aromatics may be made by starting with the desired phosphonate of the appropriate aromatic carboxyl ester.
  • the carboxamides may be made from the acids by conversion to acid chlorides or activated esters followed by reaction with an appropriate amine.
  • the dihydrobenzothiopyranyl retinoids of formula 1 may be made by the following schemes:
  • dihydrobenzopyrans are made analogously from the oxygen analog of 2,3-dihydro-4,4-dimethyl-1benzothiopyran (compound 5 in the above scheme):
  • esters and esters of other aromatics of the benzopyran and benzothiopyran compounds may be made by varying the phosphonate reactant.
  • Cyclopentadiene (bp 39-40oC) was prepared by heating the dimer and distilling twice through a 10-cm Vigreaux column packed with glass helices. It was stored at -78oC before use.
  • 1,4-Methano-1,2,3,4-tetrahydronaphthalene To 16.0 g (0.113 mol) of the purified 1,4-methano-1,4-dihydronaphthalene in 150 mL of absolute EtOH was added 1.0 g of 5% Pd/C. This mixture was hydrogenated at room temperature and atmospheric pressure. After about 20 h, TLC indicated that no starting material remained.
  • 6-Acetyl-1,4-methano-1,2,3,4-tetrahydronaphthalene A mixture of 6.9 g (47.9 mmol) of 1,4-methano-1,2,3,4tetrahydronaphthalene and 4.14 g (52.7 mmol) of AcCl was added dropwise over a period of 20 min to a stirred suspension of 7.34 g (55 mmol) of AlCl 3 in 50 mL of ClCH 2 CH 2 Cl, which was cooled in a water bath at 20oC . When the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was quenched with 100 mL of ice-water and extracted with Et 2 O (2 x 150 mL).
  • This oil was partially purified on 150 g of silica gel (7% Et 2 O/hexane) to give 3.0 g of the unrea ⁇ ted starting material, 6-acetyl-1,4-methano-1,2,3,4-tetrahydronaphthalene, and 7.0 g (70% yield from the amount of ketone consumed) of an approximately 2:1 mixture of Z and E isomers, (Z)-1-(4-carbethoxyphenyl)-2-(1,4methano-1,2,3,4-tetrahydro-6-naphthyl)-1-propene and (E)-1-(4-carbethoxyphenyl)-2-(1,4-methano-1,2,3,4tetrahydro-6-naphthyl)-1- ⁇ ropene, respectively.
  • Phenyl 3,3-Dimethylthiolacrylate To a degassed (argon) suspension of -NaH, which was obtained from 3.2 g (80 mmol) of 60% NaH/mineral oil dispersion, which had been washed with hexane (3 x 15 mL) under argon, in 30 mL of THF, was added over a period of 5 min with stirring and cooling in ice a solution of 8.8 g (80 mmol) of thiophenol in 80 mL of THF.
  • the suspension was stirred for a further 15 min and then treated with a solution of 10.1 g (85 mmol) of 3,3dimethylacryloyl chloride in 40 mL of THF over a period of 10 min and then allowed to warm to room temperature over a 2-h period.
  • the suspension was poured into 200 mL of water containing 2 mL of HOAc and stirred for 15 min and then extracted with 200 mL of Et 2 O.
  • the extract was washed with dilute brine (3 x 100 mL), dried (Na 2 SO 4 ), and concentrated to give a yellow oil.
  • Method B To a solution of 22.9 g (88 mmol) of SnCl 4 in 200 mL of CH 2 Cl 1 , cooled in ice, was added a solution of 7.83 g (44 mmol) of 3-methyl-2-buten-1-yl phenyl sulfide in 40 mL of CH 2 Cl 2 . The solution was stirred at 0-5oC for 20 min and then at room temperature for 20 h. The red solution was poured onto 500 g of ice/brine,' and the organic extract was washed successively with 250-mL volumes of brine, aqueous
  • the suspension was stirred for 40 min before a solution of 9.3 g (62.4 mmol) of 3,3-dimethylallyl bromide in 25 mL of THF was added over a 10-min period, while the reaction mixture was maintained at ice-bath temperature. The reaction mixture was stirred for a further 45 min and then allowed to warm to room temperature over a 1.25-h period.
  • the white suspension was poured into 300 mL of water. The organic phase was washed with 150 mL of 1 N NaOH solution and twice with 150 mL of dilute brine and dried (Na 2 SO 4 , overnight).
  • 6-Acetyl-2,3-dihydro-4,4-dimethyl-1-benzothiopyran A solution of 1.3 g (16.6 mmol) of acetyl chloride and 2.85 g (16.0 mmol) of 2,3-dihydro-4, 4-dimethyl-1benzothiopyran in 50 mL of CS 2 was added dropwise over a 15-min period to 3.2 g (24.0 mmol) of AlCl 3 with stirring and cooling in ice. The additon funnel was rinsed with 10 mL of CS 2 . The reaction mixture was stirred at room temperature for 2.25 h, before the resultant orange suspension was treated with 50 mL of ice/brine.
  • the mixture was again degassed (twice) and then heated at reflux in a 100-110oC oil bath for 40 min.
  • the ester dissolved within 15 min to give a pale-yellow solution.
  • the reaction mixture was cooled to room temperature, quenched with a solution of 2 mL of HOAc in 10 mL of water, and then diluted with 10 mL of brine. Because the white, solid carboxylic acid failed to dissolve in Et 2 O, it was extracted out with EtOAc (100 mL, then 50 mL).
  • the very pale-yellow extract was washed with dilute brine (2 x 25 mL) and water (25 mL), dried (Na 2 SO 4 ), and concentrated.
  • Method B as shown on page 17 employed an intramolecular Friedel-Crafts alkylation (Milstien, S., et al, supra) of phenyl 3,3-dimethylacrylate to give the lactone, 2,3-dihydro-4,4-dimethyl-2-oxo-1-benzopyran, which was reduced to the diol (compound 18 on page 17, Borchardt, R.T., et al, supra), and the primary alcohol group of which was selectively esterified as the mesylate. Intramolecular displacement of the mesylate by phenoxide ion gave 2,3-dihydro-4,4dimethyl-1-benzopyran in 71% overall yield from phenol.
  • the olefin (E)-1-(4-carbethoxy ⁇ henyl)-2-(4,4-dimethyl2,3-dihydro-1-benzopyran-6-yl)-1-propene was prepared from 6-acetyl-2,3-dihydro-4,4-dimethyl-1-benzopyran by Horner-Emmons reaction using diethyl 4-carbethoxybenzyl phosphonate in the presence of 15Crown-5 at room temperature. Surprisingly, the reaction was not completely stereoselective. (6) The major, E-isomer was easily isolated in 57% yield by crystallization from hexane.
  • Method B To a degassed (3 times, argon) suspension of NaH, obtained from 2.15 g (54 mmol NaH) of 60% NaH/mineral oil, which had been washed with hexane (3 x 10 mL), in 20 mL of THF was added over a 5-min period with stirring and cooling in ice a solution of 5.0 g (53 mmol) of phenol in 55 mL of THF. The suspension was stirred for a further 10 min, treated with a solution of 7.0 g (59 mmol) of 3,3-dimethylacryloyl chloride in 27 mL of THF over a 5-min period, and then allowed to warm to room temperature over a 3h period.
  • the suspension was poured into 150 mL of water containing 1 mL of HOAc. The mixture was stirred for 15 min and extracted with 150 mL of Et 2 O. The extract was washed with dilute brine (2 x 100 mL) and water (100 mL), dried (Na 2 SO 4 ), and concentrated to give a pale yellow liquid.
  • This purified ester (9.0 g, 51.1 mmol) in 50 mL of CH 2 Cl 2 was added to a stirred, ice-cooled suspension of 12.0 g (90 mmol) of AlCl 3 in 200 mL of CH 2 Cl 2 .
  • This suspension was stirred at room temperature for 63 h to give a dark brown solution, which was poured onto 500 mL of ice/brine and then extracted with 150 mL of CH 2 Cl 2 .
  • the brown extract which contained some suspended solid and aqueous emulsion, was filtered to separate out a dark-red organic phase.
  • the suspension was stirred at room temperature for 16 h to give a red gum and a red solution.
  • the reaction mixture was treated with 200 mL of brine containing 1 mL of HOAc and extracted with Et 2 O (2 x 150 mL). The extract was washed with water (150 mL), dried (Na 2 SO 4 ), and concentrated. The yellow oil was eluted through a 4.5 x 35-cm silica gel column with 7%
  • the cold white suspen- sion was diluted with 5 mL of 50% HOAc and 50 mL of brine.
  • the product was extracted into 500 mL of 50% Et 2 O/THF.
  • the extract was washed with dilute brine (2 x 100 mL), dried (MgSO 4 ), and concentrated.
  • the white solid was dissolved in 250 mL of 50% EtOAc/C 6 H 6 at reflux.
  • 1,2,3,4-Tetrahydro-1,4-methano-6-naphthoic Acid To a solution of 60 g (1.5 mol) of NaOH in 300 mL of H 2 O cooled to -5°C was added 25.6 mL (0.5 mol) of Br 2 over a period of 5 min. The resulting solution of NaOBr was kept below 0°C, while a solution of 18.6 g (0.1 mol) of 1,2,3,4-tetrahydro-6-acetyl-1,4-methanonaphthalene in 10 mL of dioxane was added. The temperature of the reaction mixture was gradually raised to 60-65°C with a hot-water bath and was maintained there for 0.5 h.
  • reaction mixture was then cooled to room temperature, before a solution of 50 g (0.48 mol) of NaHSO 3 in 200 mL of H 2 O was added.
  • the yellow reaction mixture turned colorless.
  • the mixture was acidified with about 120 mL of concentrated HCl; and the white, precipitated acid was extracted into 800 mL of Et 2 O.
  • the ethereal solution was dried (Na 2 SO 4 ) and concentrated.
  • the naphthoic acid prepared as described above (9.4 g, 0.05 mol) was added slowly to a stirred suspension of 1.0 g (26.4 mmol) of LiAlH 4 in 100 mL of THF. Another 0.6-g (15.8 mmol) portion of LiAlH 4 was then added. This mixture was stirred at room temperature for 2 h, when TLC (25% EtOAc/hexane) indicated that no starting material remained. To the reaction mixture was slowly added 1.6 mL of H 2 O, 4.8 mL of 15% aqueous NaOH, and 1.6 mL of H 2 O. The mixture was filtered through Celite (100-mL Et 2 O wash).
  • the retinoids of formula (1) may be used topically or systemically as chemopreventive agents and in the treatment, amelioration, or prevention of the skin, rheumatic and other disorders for which retinoic acid and other retinoids are useful.
  • they may be used for therapy in animals, including humans, of premalignant epithelial cell lesions, as a prophylaxis against tumor promotion in epithelial cells and treatment for dermatoses such as icthyoses, follicular disorders, benign epithelial disorders, and other proliferative skin diseases (nonmalignant conditions of the skin that are characterized by epidermal cell proliferation or incomplete cell differentiation) such as acne, psoriasis, eczema, atopic dermatitis, nonspecific dermatitis and the like.
  • a pharmaceutically acceptable carrier is a material that is nontoxic and generally inert and does not affect the functionality of the active ingredients adversely. Such materials are well known and include those materials sometimesreferred to as diluents or vehicles in the pharmaceutical formulation art.
  • the carrier may be organic or inorganic in nature.
  • Examples of pharmaceutically acceptable carriers that may be used to formulate the retinoids are water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, sorbitol, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers.
  • the formulation may contain minor amounts of additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
  • the retinoids are conveniently provided in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions, and the like.
  • the amount of retinoid in such topical formulations will normally be in the range of about 0.01 to about 1% by weight.
  • enteral (oral or rectal) administration the retinoids will typically be formulated as tablets, capsules, dragees, syrups, solutions, or suppositories.
  • parenteral administration the retinoids will be formulated as injectable solutions or suspensions.
  • the dosages and dosage regimen in which the retinoids are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. They will, of course, be administered in chemopreventive (tumor promotion inhibiting) amounts or therapeutically effective amounts. For adult humans such chemopreventive amounts will usually be about 0.01 mg to 10.0 mg daily given in one or more doses. Oral doses will generally be more than topical doses and doses for treating skin disorders will typically be less than doses administered for cancer chemoprevention. The dose for treating skin disorders will be on the order of, but normally less than, the dose of retinoic acid prescribed for the disorder. The usefulness of the invention compounds was demonstrated by testing the compounds of the
  • ODC ornithine decarboxylase
  • the ODC assay is carried out as follows. Female Charles River CD-I mice from Charles River
  • TPA 12-O-tetradecanoylphorbol-13-acetate
  • the epidermis is obtained from the sacrificed animals. To obtain sufficient material, the dorsal skins from 2 to 3 mice in each treatment group are pooled. The depilatory agent Nudit® (Helena Rubinstein, New York) is applied to the shaved area of the skin; after 5 minutes, it is washed off thoroughly with cold tap water. Then the skin is excised and plunged immediately into ice-cold water; it is then placed in a 55°C water bath for 30 seconds and reimmersed in ice-cold water for at least another 30 seconds. The skin is placed epidermis side up on a cold plate, and the epidermis is scraped off with a razor blade.
  • Nudit® Helena Rubinstein, New York
  • the pooled epidermal sheets are homogenized (Polytron PT-10 homogenizer) at 0° to 4°C for 1520 seconds in 50 mM sodium phosphate and 0.1 mM ethylenediaminetetraacetic acid (EDTA), at a volume of 1 mL/skin.
  • Polytron PT-10 homogenizer Polytron PT-10 homogenizer
  • EDTA ethylenediaminetetraacetic acid
  • the supernatant fraction remaining after centrifugation of the homogenate at 10,000 x g for 30 seconds at 0°C is used for the enzyme assay. Enzyme activity is determined using the microassay for ODC as described by Verma and Boutwell to measure the release of 14 CO 2 from DL-[1- 14 C]-ornithine (58 mCi/mmol) after incubation with the 10,000 x g supernatant. The incubations are carried out by decanting, with a Pasteur pipette, 100 ⁇ L of the supernatant containing 100 to 120 ⁇ g of protein into two or three 15-mL Corex tubes in a shaking water bath at 37°C.
  • the assay mixture in the tubes consists of 50 ⁇ L of 100 ⁇ M sodium phosphate buffer (pH 7.2), 10 ⁇ L of 4 ⁇ M pyridoxal phosphate, 40 ⁇ L of 25 mM dithiothreitol, and 1 ⁇ L of 0.1 M EDTA.
  • the center wells in the tubes are filled with 200 ⁇ L of a 2:1 solution (v/v) of ethanolamine:2methoxyethanol.
  • the reaction is started by adding 50 ⁇ L of substrate (0.5 ⁇ Ci of DL-[1- 14 C]-ornithine in 2 mM cold ornithine) at 1-minute intervals by injection to each of the stoppered tubes. Incubations are routinely carried out at 37oC for 30 to 60 minutes.
  • the reaction is stopped by addition of 0.5 ml of 2 M citric acid, and incubation is continued for an additional hour without heating to ensure complete absorption of 14 CO 2 .
  • Radioactivity is measured using a toluenebased scintillant (4 g of PPO and 50 mg of POPOP/L of toluene) in a Beckman LS-250 liquid scintillation counter.
  • Enzyme activity is determined in triplicate and expressed as nanomoles of CO 2 released in 30 minutes per milligram of protein. Enzyme activity is linear for the protein concentration used.
  • the protein concentrations of the epidermal extracts are determined by the Lowry procedure, using bovine serum albumin as the standard.
  • the tracheal organ culture assay is carried out as follows. Tracheas are taken from hamsters that are in very early stages of vitamin A deficiency and placed in organ culture. At the time of culture, the animals are still gaining weight; the tracheal epithelium is generally low columnar or cuboidal, with only occasional patches of squamous metaplasia.
  • Each trachea is opened from the larynx to the carina along the membranous dorsal wall and cultured in a serumfree medium (CMRL-1066; with crystalline bovine insulin, 0.1 ⁇ g/ml; hydrocortisone hemisuccinate, 0.1 ⁇ g/ml; glutamine, 2 mM; penicillin, 100 units/ml; and streptomycin, 100 ⁇ g/ml, added).
  • Cultures are gassed with 50% oxygen, 45% nitrogen, and 5% CO 2 .
  • the culture dishes are rocked at 35.5-36.0 degrees to allow the tracheas contact with both gas and medium. All tracheas are grown in medium containing no retinoid for the first 3 days.
  • tracheas are harvested; almost all of these tracheas have significant squamous metaplasia, and approximately 60% have keratinized lesions.
  • the remaining tracheas are then divided into different groups which are treated with either: 1) retinoid dissolved in dimethylsulfoxide (final concentration of DMSO in culture medium is never greater than 0.1%) or 2) an equivalent amount of DMSO alone.
  • Culture medium is changed three times a week, and all of the remaining tracheas are harvested at the end of 10 days in culture. Tracheas are fixed in 10% buffered formalin and embedded in paraffin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formules (I), (II) et (III), où R1, R2, R3 et R4 représentent un hydrogène ou un méthyle, X représente un hydrogène ou un fluor et Q représente (IV), (V), (VI), (VII), (VIII) ou (IX) et X1 représente un hydrogène, un hydroxy, un méthoxy ou un fluor, R représente un hydroxy, un alkoxy avec 0 ou 1 substituant hydroxy, un aroxy ou NR5R6, où R5 représente un hydrogène, un alcoyle avec 0 ou 1 substituant hydroxy ou un aryle, et R6 représente un alcoyle avec 0 ou 1 substituant hydroxy ou un aryle, à condition que X ne représente un fluor que lorsque R2 est un méthyle, lorsque R3 ou R4 est un méthyle, l'autre R3 ou R4 étant également un méthyle et lorsque Q est un groupe thiényle, Q pouvant être en position cis ou trans. Ces composés sont utiles comme agents chimiopréventifs pour inhiber l'activation tumorale dans des cellules épithéliales et pour traiter des affections cutanées non malignes.
EP19840901274 1983-08-08 1984-02-24 Analogues des acides benzonorbornenyle, benzopyranyle et benzothiopyranyle retinoiques Withdrawn EP0155940A1 (fr)

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