USRE33533E - Polycyclic heterocyclic compounds, a process for their preparation and their use in human and veterinary medicine - Google Patents

Polycyclic heterocyclic compounds, a process for their preparation and their use in human and veterinary medicine Download PDF

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USRE33533E
USRE33533E US07/513,970 US51397090A USRE33533E US RE33533 E USRE33533 E US RE33533E US 51397090 A US51397090 A US 51397090A US RE33533 E USRE33533 E US RE33533E
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tetramethyl
tetrahydro
benzoic acid
compound
naphth
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Braham Shroot
Jacques Eustache
Jean-Michel Bernardon
Philippe Nedoncelle
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Galderma Research and Development SNC
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Centre International de Recherches Dermatologiques Galderma
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/008—Preparations for oily hair
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/06—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/25—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups bound to carbon atoms of six-membered aromatic rings being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/60—Naphthoxazoles; Hydrogenated naphthoxazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/74—Naphthothiophenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/008—Preparations for oily skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to polycyclic heterocyclic derivatives, to processes for their preparation and their use in human and veterinary medicine and in cosmetic compositions.
  • heterocyclic derivatives find use in the topical and systemic treatment of dermatologic diseases linked to a keratinization disorder (differentiation-proliferation) and dermatologic disorders, or others, having inflammatory and/or immunoallergic components and in the treatment of conjunctive tissue degeneration illnesses. These derivatives also exhibit antitumoral activity. Moreover, these derivatives can be employed in the treatment of atrophy, be it cutaneous or respiratory and in the treatment of rheumatoid psoriasis.
  • the polycyclic heterocyclic derivatives in accordance with the present invention can be represented by the formula ##STR4## wherein n is 1 or 2, R 1 represents (i) lower alkyl, (ii) --CH 2 OH or (iii) ##STR5## R 2 represents (a) hydrogen, (b) ##STR6## or (c) --OR 3 wherein R 3 represents hydrogen, alkyl having 1-20 carbon atoms, mono or polyhydroxyalkyl, aryl or aralkyl optionally substituted or the residue of a sugar or ##STR7## wherein p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl, monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted, amino acid residue, aminated sugar residue or, taken together, form a heterocycle,
  • X represents oxygen, sulfur, SO, SO 2 or --NR 4 ,
  • Y represents CR 4 or a nitrogen atom
  • R 4 represents hydrogen or lower alkyl, and the salts of said polycyclic heterocyclic derivatives of formula I.
  • alkyl having 1-20 carbon atoms is meant, principally, methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl.
  • lower alkyl is meant a radical having 1-4 carbon atoms and principally methyl, ethyl, isopropyl, butyl and tert.butyl.
  • monohydroxyalkyl is meant a radical having 2-4 carbon atoms and principally 2-hydroxyethyl, 2-hydroxypropyl and 2'-hydroxy-2-ethoxy ethyl.
  • polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and 2-5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the residue of pentaerythritol.
  • residue of a sugar is meant a residue derived, for example, from glucose, mannose, erythrose or galactose.
  • aminated sugar residues include those derived from glucosamine, galactosamine or mannosamine.
  • aryl is meant phenyl optionally substituted by halogen, hydroxy, a nitro function or lower alkyl.
  • Representative preferred aralkyls include, preferably, benzyl as well as phenethyl.
  • the heterocycle can be piperidino, piperazino, morpholino, pyrrolidino or 4-(2'-hydroxyethyl) piperazino.
  • the compounds of the present invention can be salts of an alkali or alkaline earth metal or even of zinc, or of an organic amine when they have at least one free acid function, or salts of a mineral or organic acid, principally, hydrochlorides, hydrobromides or citrates when they have at least one amine function.
  • Representative compounds of formula I include, principally, the following:
  • R 3 represents hydrogen or lower alkyl
  • X represents oxygen, sulfur or NR 4 ,
  • Y represents CR 4 or a nitrogen atom
  • R 4 represents hydrogen or methyl.
  • the present invention also relates to a process for the preparation of the compounds of formula I.
  • This method comprises reacting an aromatic carboxylic acid derivative of formula (1) with an aromatic diamino, hydroxyamino or thioamino derivative of formula (2). ##STR9##
  • This intermediate compound (3') is then cyclized by acid treatment to give compounds of formula (3).
  • a sulfonic acid such as p-toluene sulfonic acid in an inert solvent such as toluene or xylene.
  • the cyclization reaction temperature is preferably close to the reflux temperature of the solvent employed.
  • the cyclization reaction that is, the conversion of the derivative (7) having a phosphonium or phosphinyl group to compound (8) is effected in accordance with the Wittig or Wittig-Horner reaction conditions, that is, in the presence of a base which can be a hydroxide or carbonate of an alkali metal, for example, lithium hydroxide or potassium carbonate, an alkali metal hydride, for example, sodium hydride, an alkali metal alcoholate, for example, sodium methylate or potassium tert.butoxide, a tertiary amine, for example, triethylamine, di-isopropylethylamine or diazabicycloundecene (DBU) or even an alkali amide, for example, sodium amide or lithium di-isopropylamide.
  • a base which can be a hydroxide or carbonate of an alkali metal, for example, lithium hydroxide or potassium carbonate, an alkali metal hydride
  • the reaction temperature is between -78° C. and +150° C. and there can be employed, as a dipolar aprotic solvent (dimethylsulfoxide or dimethylformamide), an alcohol, or an ether (dioxane or tetrahydrofuran).
  • a dipolar aprotic solvent dimethylsulfoxide or dimethylformamide
  • an alcohol or an ether (dioxane or tetrahydrofuran).
  • ether dioxane or tetrahydrofuran
  • the bromination reaction i.e., the production of the compound of the formula (6) is carried out in the presence of N-bromosuccinimide in previously dried benzene or carbon tetrachloride, the temperature preferably being between 70° C. and 90° C., the radical initiator being, preferably, benzoyl peroxide.
  • the acylation reaction i.e., the production of the compound of formula (5) is carried out in a conventional manner.
  • X represents NH
  • the reaction is advantageously effected using the compound of formula (1) in the form of an acid chloride (Q ⁇ Cl) in the presence of a tertiary amine.
  • esters give the corresponding acids which can then be transformed into acid chlorides which are then easily converted into amides.
  • amides can also be obtained by the direct reaction of amines with previously obtained esters.
  • Reduction of esters, aldehyde or amide by an appropriate reducing agent for example, lithium aluminum hydride
  • the present invention also relates to, as novel industrial products, synthesis intermediates having the formula ##STR11## wherein
  • n 1 or 2
  • X represents oxygen, sulfur or NR 4 .
  • R 4 represents hydrogen or lower alkyl.
  • Representative intermediate compounds of formula III include particularly the following:
  • the compounds of the present invention exhibit excellent activity in the inhibition test of ornithine decarboxylase in nude rats, after induction, by "tape stripping," M. Bouclier et al., Dermatologica, 169, No. 4, 1984. This test is recognized as a measure of the activity of retinoides or cellular proliferation phenomena.
  • These compounds are particularly appropriate for treating dermatologic ailments linked to a keratinization disorder (differentiation-proliferation) as well as dermatologic diseases having an inflammatory and/or immunoallergic component, principally:
  • acne vulgaris comedons or polymorphs
  • solar senile acne and medicinal or professional acne
  • These compounds can also be employed to combat against ageing of the skin and in particular ageing due to the effects of the sun.
  • the present invention also relates to medicinal compositions containing at least one compound of formula I, such as defined above, or one of its salts.
  • the present invention thus relates to a new medicinal composition, intended principally for the treatment of the above-mentioned disorders, comprising in a pharmaceutically acceptable support, an effective amount of at least one compound of formula I or one of its salts.
  • the compounds according to the present invention are generally administered at a daily dosage of about 0.01 ⁇ g/kg to 1 mg/kg of body weight.
  • any conventional vehicle can be employed, the active component being found either in the dissolved state, or in the dispersed state, in said vehicle.
  • the administration of the compounds of the present invention can be effected enterally, parenterally, rectally, topically or ocularly.
  • the medicines When administered enterally, the medicines can be provided in the form of tablets, gelules, lozenges, syrups, suspensions, solutions, powders, granules or emulsions.
  • the medicinal compositions When administered parenterally, can be provided in the form of solutions or suspensions for perfusion or injection.
  • compositions When administered rectally, the compositions can be provided in the form of suppositories.
  • compositions When administered topically, the pharmaceutical compositions, based on the compounds according to the present invention, can be provided in the form of ointments, tinctures, creams, salves, powders, pads, impregnated tampons, solutions, lotions, gels, sprays or suspensions.
  • the compositions for topical administeration contain preferably from 0.000001 to about 0.01 percent by weight of the compound of formula I.
  • These compositions for topical administration can be provided under anhydrous form or in aqueous form according to clinical indications.
  • the composition When administered ocularly, the composition is provided principally in the form of an eyewash.
  • the compounds of formula I are also useful in the cosmetic field, and n particular in body and hair hygiene compositions and principally for the treatment of skin having acne tendencies, to improve the growth of the hair, i.e., to promote the growth of existing hair folicles, to combat hair loss, to combat against an oily appearance of the skin or hair, in the prevention or treatment of the harmful effects of the sun or in the treatment of physiologically dry skin.
  • the present invention thus relates to a cosmetic composition containing, in a cosmetically acceptable vehicle, an effective amount of at least one compound of formula I or one of its salts, this composition being provided principally in the form of a lotion, gel, soap or shampoo.
  • the concentration of the compound of formula I in these cosmetic compositions is between 0.00001 and 0.01 percent by weight based on the total weight of the composition.
  • the medicinal and cosmetic compositions according to the present invention can contain inert or even pharmacodynamic or cosmetically active additives and, principally: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrheic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, tioxolone or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, tetracyclines or 4-polymethylene-4-isothiazoline-3-ones; agents promoting the growth of hair such as "Minoxidil” (2,4-diamino-6-piperidino-3-pyrimidine oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin (5,5-diphenyl-2,4-imida
  • compositions according to the present invention can also include flavor improving agents, preservatives, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, anti-oxidants such as ⁇ -tocopherol, butylhydroxyanisole or butylhydroxytoluene.
  • reaction mixture is poured into water, extracted with ether and washed with a saturated solution of sodium bicarbonate.
  • the organic phase is decanted, dried on MgSO 4 and the solvent evaporated.
  • the residue is recrystallized in isooctane to give 9.5 g (81%) of the methyl ester of p-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) carbonyl benzoic acid which melts at 105°-106° C.
  • the solution is cooled to -10° C. and 40 ml of acetic acid are added. There is then added fuming nitric acid (8.7 ml - 210 mmoles) in solution in a mixture of acetic anhydride (40 ml) and acetic acid (40 ml). The reaction mixture is stirred for one hour at ambient temperature.
  • reaction mixture is then poured into water (1 liter) plus ice.
  • the precipitate that forms is filtered, washed with water, taken up in dichloromethane (3 ⁇ 200 ml).
  • the organic phase is washed with a saturated solution of sodium bicarbonate and then with water. It is dried on magnesium sulfate, filtered and the solvent evaporated.
  • the resulting solid is purified by chromatography on silica and eluted with a 50/50 mixture of dichloromethane and hexane.
  • the catalyst is filtered and the solvents are evaporated.
  • reaction mixture is stirred for 2 hours at ambient temperature and then poured into a mixtureof water (500 ml) and dichloromethane (300 ml).
  • aqueous phase is extracted with dichloromethane (2 ⁇ 300 ml) and the organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvent evaporated.
  • the resulting solid is purified by column chromatography and eluted with dichloromethane.
  • the methyl ester of p-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbamoyl] benzoic acid (23.25 g - 61 mmoles) is mixed with xylene (600 ml). There are added 11.6 g (61 mmoles) of p-toluene sulfonic acid and the mixture is heated at reflux, with stirring, for 3 hours. The xylene is evaporated and there are added water (500 ml) and some dichloromethane.
  • the organic phase is dried on magnesium sulfate, filtered and the solvents are evaporated.
  • the resulting solid is purified by column chromatography and eluted with a mixture of 80% dichloromehtane and 20 % hexane.
  • the methanol is evaporated and ethyl ether (300 ml) and 4N HCl (200 ml) are added.
  • the aqueous phase is extracted with ether (2 ⁇ 300 ml) and the organic phase is washed twice with water and once with a saturated solution of sodium chloride.
  • reaction mixture is heated at reflux for 5 hours, cooled to 0° C., then hydrolyzed by the slow addition of 30 ml of a solution of the double tartrate of sodium and potassium.
  • the product is purified by column chromatography and eluted with a mixture composed of 80% ether and 20% hexane. The solvents are evaporated and the resulting solid is taken up in hexane, filtered and dried. 920 mg (75%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -naphth[2,3-d]oxazolyl) benzoic aldehyde which melts at 179° C. are obtained.
  • the reaction mixture is stirred for 2 hours at ambient temperature.
  • the formed dicyclohexylamine hydrochloride is filtered and the dichloromethane is evaporated.
  • Ethylamine (216 mg-4.8 mmoles) is dissolved in dry tetrahydrofuran (25 ml). There are added successively triethylamine (485 mg-4.8 mmoles) and then slowly the acid chloride obtained in Example 12(a) (1.6 g - 4.4 mmoles) in solution in dry tetrahydrofuran (25 ml).
  • reaction mixture is stirred for 1 hour at ambient temperature and then poured into 2N HCl (200 ml).
  • the product is extracted with ether (3 ⁇ 100 ml), and then the organic phase is washed with water (3 times), then by a saturated solution of sodium chloride and dried on magnesium sulfate
  • Morpholine (417 mg - 4 8 mmoles) is dissolved in dry tetrahydrofuran (25 ml) There are successively added triethylamine (485 mg - 4.8 mmoles) and then slowly p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid chloride (1.6 g- 4.4 mmoles) in solution in dry tetrahydrofuran (25 ml).
  • reaction mixture is stirred for 2 hours at ambient temperature and then poured into 4N HCl (200 ml).
  • the product is extracted with ether (3 ⁇ 200 ml), the organic phase is washed with water (3 times) and then with a saturated solution of sodium chloride and finally dried on magnesium sulfate.
  • the solution is filtered and the solvents evaporated.
  • the product is purified by chromatography on silica, eluted with a mixture of 50% dichloromethane, 20% ether and 30% hexane.
  • Ethylene glycol (298 mg - 4.8 mmoles) is dissolved in dry dichloromethane (25 ml). There are successively added pyridine (380 mg - 4.8 mmoles) and then slowly p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid chloride (1.6 g - 4.4 mmoles) in solution in dry dichloromethane (25 ml).
  • reaction mixture is stirred for 2 hours at ambient temperature and then poured into 200 ml of 4N HCl.
  • the product is extracted with ether (3 ⁇ 200 ml).
  • the organic phase is washed with water (3 times) and then with a saturated solution of sodium chloride and finally dried on magnesium sulfate.
  • the solution is filtered and the solvents are evaporated.
  • the product is purified by chromatography on silica, eluted by a mixture of 70% dichloromethane and 30% ether.
  • reaction mixtures is stirred for 2 hours at ambient temperature and then poured over ice.
  • the product is extracted with ethyl ether (3 ⁇ 1 liter).
  • the organic phase is neutarlized by the addition of solid sodium bicarbonate (+300 ml of water), decanted and dried on magnesium sulfate.
  • 2,3-diamino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene (6.55 g - 30 mmoles) is mixed with methyl ether (170 ml); there are added to the mixture triethylamine (4.2 m-30 mmoles) and then, slowly, methyl p-chloroformyl benzoate (5.96 g - 30 mmoles) in solution in ether (70 ml).
  • reaction mixture is stirred for 2 hours at ambient temperature and it is then poured into a mixtureof water (400 ml) and dichloromethane (400 ml).
  • the resulting solid is purified by column chromatography, eluted with a system composed of 10% ethyl ether and 90% dichloromethane.
  • aqueous phase is extracted with dichloromethane (3+300 ml) and the organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvents evaporated.
  • the resulting solid is purified by column chromatography and eluted with a mixture composed of 95% dichloromethane and 5% ethyl ether
  • the product is extracted with ether (5 ⁇ 400 ml), and the organic phase is washed with water (2 ⁇ 500 ml) and then with a saturated solution of sodium chloride (2 ⁇ 300 ml).
  • the organic phase is dried on magnesium sulfate, filtered and the solvents are evaporated.
  • the resulting solid is taken up in 300 ml of hexane, filtered and oven dried.
  • reaction mixture is stirred for 1 hour and there are then added 300 ml of dichloromethane.
  • the aqueous phase is extracted with dichloromethane (2 ⁇ 300 ml) and the organic phase is washed with a saturated solution of sodium chloride
  • the organic phase is dried on magnesium sulfate, filtered and the solvents are evaporated.
  • the product is purified by column chromatography and eluted with a mixture of 10% ether and 90% dichloromethane.
  • the aqueous phase is extracted with dichlormethane.
  • the organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvents are evaporated.
  • the product is purified by column chromatography and eluted with a mixture of 10% ether and 90% hexane.
  • the active compound can be replaced by its methyl ester.
  • the capsule is made of gelatin, glycerine, titanium dioxide and water.
  • the above powder is packaged in a gelule composed of gelatin and TiO 2 .

Abstract

A polycyclic heterocyclic compound has the formula <IMAGE> (I) wherein n is 1 or 2, R1 l represents (i) lower alkyl, (ii) -CH2OH or (iii) <IMAGE> R2 represents (a) hydrogen, (b) <IMAGE> or (c)-OR3, R3 represents hydrogen, C1-C20 alkyl mono or polyhydroxyalkyl, aryl or aralkyl optionally substituted, the residue of a sugar or <IMAGE> wherein p is 1, 2, or 3, and r' and r'' represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl optionally substituted, amino acid residue, aminated sugar residue, or together form a heterocycle, X represents oxygen, sulfur, SO, SO2 or -NR4, Y represents CR4 or a nitrogen atom and R4 represents hydrogen or lower alkyl. This polycyclic heterocyclic compound can be used in human and veterinary medicine and especially in the topical or systemic treatment of determatologic diseases.

Description

BACKGROUND OF THE INVENTION
The present invention relates to polycyclic heterocyclic derivatives, to processes for their preparation and their use in human and veterinary medicine and in cosmetic compositions.
These heterocyclic derivatives find use in the topical and systemic treatment of dermatologic diseases linked to a keratinization disorder (differentiation-proliferation) and dermatologic disorders, or others, having inflammatory and/or immunoallergic components and in the treatment of conjunctive tissue degeneration illnesses. These derivatives also exhibit antitumoral activity. Moreover, these derivatives can be employed in the treatment of atrophy, be it cutaneous or respiratory and in the treatment of rheumatoid psoriasis.
Lastly, they find use in the ophthalmologic field, principally in the treatment of corneopathies.
The polycyclic heterocyclic derivatives in accordance with the present invention can be represented by the formula ##STR4## wherein n is 1 or 2, R1 represents (i) lower alkyl, (ii) --CH2 OH or (iii) ##STR5## R2 represents (a) hydrogen, (b) ##STR6## or (c) --OR3 wherein R3 represents hydrogen, alkyl having 1-20 carbon atoms, mono or polyhydroxyalkyl, aryl or aralkyl optionally substituted or the residue of a sugar or ##STR7## wherein p is 1, 2 or 3, r' and r" represent hydrogen, lower alkyl, monohydroxyalkyl, polyhydroxyalkyl, aryl optionally substituted, amino acid residue, aminated sugar residue or, taken together, form a heterocycle,
X represents oxygen, sulfur, SO, SO2 or --NR4,
Y represents CR4 or a nitrogen atom, and
R4 represents hydrogen or lower alkyl, and the salts of said polycyclic heterocyclic derivatives of formula I.
By alkyl having 1-20 carbon atoms is meant, principally, methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl.
By lower alkyl is meant a radical having 1-4 carbon atoms and principally methyl, ethyl, isopropyl, butyl and tert.butyl.
By monohydroxyalkyl is meant a radical having 2-4 carbon atoms and principally 2-hydroxyethyl, 2-hydroxypropyl and 2'-hydroxy-2-ethoxy ethyl.
By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and 2-5 hydroxyl groups such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the residue of pentaerythritol.
By residue of a sugar is meant a residue derived, for example, from glucose, mannose, erythrose or galactose.
Representative aminated sugar residues include those derived from glucosamine, galactosamine or mannosamine.
By aryl is meant phenyl optionally substituted by halogen, hydroxy, a nitro function or lower alkyl.
Representative preferred aralkyls include, preferably, benzyl as well as phenethyl.
When r' and r" taken together form a heterocycle, the heterocycle can be piperidino, piperazino, morpholino, pyrrolidino or 4-(2'-hydroxyethyl) piperazino.
When the compounds of the present invention are provided in the form of salts they can be salts of an alkali or alkaline earth metal or even of zinc, or of an organic amine when they have at least one free acid function, or salts of a mineral or organic acid, principally, hydrochlorides, hydrobromides or citrates when they have at least one amine function.
Representative compounds of formula I include, principally, the following:
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]furyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphtho[2,3-b]furyl) benzoic acid,
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid,
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid,
methyl ester of p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid,
p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid,
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzyl alcohol,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic aldehyde,
ethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic
morpholide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid,
2-hydroxyethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid,
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl) benzoic acid and
2-(4-methyl)phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth[2,3-d]imidazole.
Particularly preferred compounds of formula I in accordance with the present invention are those having the following formula: ##STR8## wherein
R3 represents hydrogen or lower alkyl,
X represents oxygen, sulfur or NR4,
Y represents CR4 or a nitrogen atom, and
R4 represents hydrogen or methyl.
Representative compounds corresponding to formula II include, principally:
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid and its methyl ester,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1H-benz[f]indolyl) benzoic acid and its methyl ester,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid and its methyl ester,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl)benzoic acid and its methyl ester, and
p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid and its methyl ester.
The present invention also relates to a process for the preparation of the compounds of formula I.
These compounds can be obtained in accordance with two synthesis methods:
(A) The First method (Scheme I)
This method is particularly preferred when, in the compounds of formula I, Y represents a nitrogen atom.
This method comprises reacting an aromatic carboxylic acid derivative of formula (1) with an aromatic diamino, hydroxyamino or thioamino derivative of formula (2). ##STR9##
The action of the acid chloride (1) (Q═Cl) on the aromatic amino compound (2) leads to the intermediate (3') which is isolated. In the same way, the coupling of the acid (1) (Q═OH) with the compound (2), in the presence of triphenylphosphine and dicyclohexylcarbodiimide, or diethylazodicarboxylate and triphenylphosphine, in a known manner, leads to intermediate compounds (3').
This intermediate compound (3') is then cyclized by acid treatment to give compounds of formula (3). There can be employed for this cyclization reaction a sulfonic acid such as p-toluene sulfonic acid in an inert solvent such as toluene or xylene. The cyclization reaction temperature is preferably close to the reflux temperature of the solvent employed.
In accordance with a variation of this process, it is possible to directly produce the compounds of formula (3) by direct heating of the acid of formula (1) (Q═OH) and the aromatic amino compound (2) in an inert solvent such as xylene in the presence of an acid catalyst; for example, p-toluene sulfonic acid at the reflux temperature of the solvent.
(B) Second method (Scheme II)
The method is quite particularly preferred when, in the compounds of formula I, Y represents CR4. ##STR10##
In accordance with this second method, the cyclization reaction, that is, the conversion of the derivative (7) having a phosphonium or phosphinyl group to compound (8) is effected in accordance with the Wittig or Wittig-Horner reaction conditions, that is, in the presence of a base which can be a hydroxide or carbonate of an alkali metal, for example, lithium hydroxide or potassium carbonate, an alkali metal hydride, for example, sodium hydride, an alkali metal alcoholate, for example, sodium methylate or potassium tert.butoxide, a tertiary amine, for example, triethylamine, di-isopropylethylamine or diazabicycloundecene (DBU) or even an alkali amide, for example, sodium amide or lithium di-isopropylamide. The reaction temperature is between -78° C. and +150° C. and there can be employed, as a dipolar aprotic solvent (dimethylsulfoxide or dimethylformamide), an alcohol, or an ether (dioxane or tetrahydrofuran). The reaction is advantageously carried out in tetrahydrofuran (THF) at a temperature between 0° C. and 80° C. using triethylamine or DBU as the base.
The bromination reaction, i.e., the production of the compound of the formula (6) is carried out in the presence of N-bromosuccinimide in previously dried benzene or carbon tetrachloride, the temperature preferably being between 70° C. and 90° C., the radical initiator being, preferably, benzoyl peroxide.
The acylation reaction, i.e., the production of the compound of formula (5) is carried out in a conventional manner. When X represents NH, the reaction is advantageously effected using the compound of formula (1) in the form of an acid chloride (Q═Cl) in the presence of a tertiary amine.
The compounds produced in accordance with the two methods described above can be converted in accordance with conventional procedures to provide compounds having any of the other meanings of R1 set forth above.
Thus, saponification of esters gives the corresponding acids which can then be transformed into acid chlorides which are then easily converted into amides. These amides can also be obtained by the direct reaction of amines with previously obtained esters. Reduction of esters, aldehyde or amide by an appropriate reducing agent (for example, lithium aluminum hydride) produces corresponding alcohols and amines.
The present invention also relates to, as novel industrial products, synthesis intermediates having the formula ##STR11## wherein
n is 1 or 2,
X represents oxygen, sulfur or NR4, and
R4 represents hydrogen or lower alkyl.
Representative intermediate compounds of formula III include particularly the following:
2,3-diamino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene and
3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol.
The compounds of the present invention exhibit excellent activity in the inhibition test of ornithine decarboxylase in nude rats, after induction, by "tape stripping," M. Bouclier et al., Dermatologica, 169, No. 4, 1984. This test is recognized as a measure of the activity of retinoides or cellular proliferation phenomena.
These compounds are particularly appropriate for treating dermatologic ailments linked to a keratinization disorder (differentiation-proliferation) as well as dermatologic diseases having an inflammatory and/or immunoallergic component, principally:
acne vulgaris, comedons or polymorphs, solar senile acne and medicinal or professional acne,
solar keratites,
extensive or severe forms of psoriasis, and other keratinization disorders and principally ichtysoses and ichtysosis like conditions,
Darier malady,
palmo-plantar keratodermies,
leucophasies and leucophasis-like states, lichen plane, and
all malignant or benign dermatologic proliferations, severe or extensive.
They are also active for certain rheumatoid disorders, in the treatment of tumors, of rheumatoid psoriasis, cutaneous or respiratory atrophies as well as in certain ophthalmoligic problems relating to corneopathies.
These compounds can also be employed to combat against ageing of the skin and in particular ageing due to the effects of the sun.
Thus the present invention also relates to medicinal compositions containing at least one compound of formula I, such as defined above, or one of its salts.
The present invention thus relates to a new medicinal composition, intended principally for the treatment of the above-mentioned disorders, comprising in a pharmaceutically acceptable support, an effective amount of at least one compound of formula I or one of its salts.
The compounds according to the present invention are generally administered at a daily dosage of about 0.01 μg/kg to 1 mg/kg of body weight.
As the vehicle or carrier for these compositions any conventional vehicle can be employed, the active component being found either in the dissolved state, or in the dispersed state, in said vehicle.
The administration of the compounds of the present invention can be effected enterally, parenterally, rectally, topically or ocularly.
When administered enterally, the medicines can be provided in the form of tablets, gelules, lozenges, syrups, suspensions, solutions, powders, granules or emulsions.
When administered parenterally, the medicinal compositions can be provided in the form of solutions or suspensions for perfusion or injection.
When administered rectally, the compositions can be provided in the form of suppositories.
When administered topically, the pharmaceutical compositions, based on the compounds according to the present invention, can be provided in the form of ointments, tinctures, creams, salves, powders, pads, impregnated tampons, solutions, lotions, gels, sprays or suspensions. The compositions for topical administeration contain preferably from 0.000001 to about 0.01 percent by weight of the compound of formula I. These compositions for topical administration can be provided under anhydrous form or in aqueous form according to clinical indications.
When administered ocularly, the composition is provided principally in the form of an eyewash.
The compounds of formula I, according to the present invention, are also useful in the cosmetic field, and n particular in body and hair hygiene compositions and principally for the treatment of skin having acne tendencies, to improve the growth of the hair, i.e., to promote the growth of existing hair folicles, to combat hair loss, to combat against an oily appearance of the skin or hair, in the prevention or treatment of the harmful effects of the sun or in the treatment of physiologically dry skin.
The present invention thus relates to a cosmetic composition containing, in a cosmetically acceptable vehicle, an effective amount of at least one compound of formula I or one of its salts, this composition being provided principally in the form of a lotion, gel, soap or shampoo.
The concentration of the compound of formula I in these cosmetic compositions is between 0.00001 and 0.01 percent by weight based on the total weight of the composition.
The medicinal and cosmetic compositions according to the present invention can contain inert or even pharmacodynamic or cosmetically active additives and, principally: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrheic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, tioxolone or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, tetracyclines or 4-polymethylene-4-isothiazoline-3-ones; agents promoting the growth of hair such as "Minoxidil" (2,4-diamino-6-piperidino-3-pyrimidine oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin (5,5-diphenyl-2,4-imidazolidine dione); steroidal and non-steroidal anti-inflammatory agents; carotenoids and, principally, β-carotene; anti-psoriasic agents such as anthralin and its derivatives and 5,8,11,14-eicosatetraynoic and 5,8,11-eicosatriynoic acids, and their esters and amides.
The compositions according to the present invention can also include flavor improving agents, preservatives, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, anti-oxidants such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene.
The following non-limiting examples illustrate the preparation of the active compounds of formula I according to the present invention as well as compositions containing these compounds.
Examples of Preparation EXAMPLE 1 Preparation of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]furanyl) benzoic acid (a) 3-methyl-5,6,7,8-tetrahydro-5,5,8,8p-(5,6,7,8-tetramethyl-2-naphthol
Into a round bottom flask there are introduced 10.8 g (100 mmoles) of ortho cresol, 100 ml of dichloromethane (CH2 Cl2) and 18.3 g (100 mmoles) of 2,4-dichloro-2,4-dimethylhexane. The reaction mixture is cooled to 5° C. and there are added, in small quantities, 6.6 g (50 mmoles) of aluminum chloride. The temperature is permitted to rise to 20° C. The reaction mixture is stirred for 2 hours and it is then poured into 200 ml of water. The organic phase is decanted, dried on magnesium sulfate (MgSO4) and the solvents are evaporated. The residue is recrystallized in 100 ml of hexane, yielding 20.3 g (93%) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol which melts at 122°-123° C.
(b) methyl ester of p-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy carbonyl) benzoic acid
In 100 ml of tetrahydrofuran (THF) there are disolved 8.7 g (40 mmoles) of the naphthol obtained in 1(a) above and 6.2 ml (44 mmoles) of triethylamine. A solution of p-(methoxycarbonyl) benzoyl chloride (8.8 g=44 mmoles) in THF (50 ml) is slowly added and the reaction mixture is stirred for 4 hours at ambient temperature. The reaction mixture is poured into 200 ml of water and extracted with 300 ml of CH2 Cl2. The organic phase is decanted, dried on MgSO4 and the solvents are evaporated. The residue is recrystallized in isooctane, yielding 11 g (72%) of the methyl ester of p-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy carbonyl) benzoic acid which melts at 111°-114° C.
(c) Methyl ester of p-(3-bromomethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy carbonyl) benzoic acid
A mixture of the ester obtained in 1(b) (10.60 g; 27.8 mmoles), benzoyl peroxide (50 mg) and carbon tetrachloride (CCl4), (150 ml) is brought to reflux. There are then added, in small quantities, 4.96 g (27.8 mmoles) of N-bromosuccinimide (NBS).
Reflux is maintained for 24 hours and the solvent is evaporated. The residue is purified by passage through a silica column (eluant: 1/1 mixture of hexane/CH2 Cl2). 12 g of a mixture containing 80% of the expected ester and 20% of the starting ester are recovered.
(d) Methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphtho[2,3-b]furanyl-2-yl) benzoic acid
In a round bottom flask, 11.8 g of the mixture obtained in 1(c), 100 ml of THF and 6.50 g (24.6 mmoles) of triphenylphosphine are introduced. The reaction mixture is heated at reflux for 4 hours and cooled to 10° C. There are then slowly added 3.70 ml (24.6 mmoles) of 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU). The reaction mixture is permitted to return to ambient temperature and it is stirred for 5 hours. The reaction mixture is then poured into water, extracted with ether, dried on MgSO4 and the solvents are evaporated.
The residue is purified by passage through a silica column (eluant: 1/1 mixture of hexane/CH2 Cl2). 4.20 g of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol[2,3,b]furanyl) benzoic acid which melts at 184°-185° C. are recovered.
EXAMPLE 2 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3,b]furanyl) benzoic acid
3.80 g (10.4 mmoles) of the ester obtained in 1(d) above are treated at reflux for 4 hours with 200 ml of 2N methanolic soda. The methanol is evaporated and the remainder is taken up in water and acidified with concentrated HCl. The reaction mixture is extracted with ether and the organic phase is decanted, dried on MgSO4 and the solvents are evaporated. The residue is recrystallized in a 2/1 mixture of diisopropyl ether and ethyl acetate. 3.50 g (97%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3,b]furanyl) benzoic acid which melts at 307°-312° C. are recovered.
EXAMPLE 3 Methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid (a) 2-N,N-dimethylthiocarbamoyloxy)-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene
In a round bottom flask there are introduced 1.7 g (57 mmoles) of sodium hydride (80% in oil) and 50 ml of dimethylformamide. There is slowly added a solution of 10.3 g (47 mmoles) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol in 100 ml of DMF and the reaction mixture is stirred until the cessation of gas evolvement. There are then added 8.1 g (66 mmoles) of dimethylthio-carbamoylchloride in 100 ml of DMF and the reaction mixture is stirred for 4 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethylether. The organic phase is decanted, washed with water, dried on MgSO4 and the solvent evaporated. The residue is purified by chromatography on a silica column (eluant: 20/80 mixture of CH2 Cl2 /hexane). 13.2 g (92%) of 2-(N,N-dimethylthiocarbamoyloxy)-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 102°-103° C. are recovered.
(b) 2-N,N-dimethylcarbamoylthio)-3-methyl-5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl naphthalene
13 g (42.5 mmoles) of the compound obtained in 3(a) above are heated under nitrogen at 280° C. After cooling, the residue is passed through a silica column (eluant: 70/30 mixture of hexane/CH2 Cl2).
10.2 g (79%) of 2-(N,N-dimethylcarbamoylthio-3-methyl-5,6,7,8-tetahydro-5,5,8,8-tetramethyl naphthalene which melts at 142°-143° C. are obtained.
(c) 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-thionaphthol
9.2 g (30 mmoles) of the product obtained in 3(b) above are treated at reflux with 200 ml of 2N methanolic soda for 2 hours. The solvents are evaporated and the remainder is taken up in water, acidified to pH 0 (concentrated HCl) and extracted with ether. The organic phase is decanted, dried on magnesium sulfate and the solvents are evaporated. 6.9 g (98%) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-thionaphthol which melts at 91°-92° C. are obtained.
(d) Methyl ester of p-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) carbonyl benzoic acid
In a round bottom flask there are introduced 5.9 g (33 mmoles) of the monomethyl ester of terephthalic acid and 50 ml of THF. There are then added, by small portions, 5.3 g (33 mmoles) of 1,1'-carbonyldiimidazole. The reaction mixture is stirred until the cessation of gaseous emissions. There are then added 7 g (30 mmoles) of the compound obtained in 3(c) above in 50 ml of THF and the mixture is stirred for 7 hours at ambient temperature.
The reaction mixture is poured into water, extracted with ether and washed with a saturated solution of sodium bicarbonate. The organic phase is decanted, dried on MgSO4 and the solvent evaporated. The residue is recrystallized in isooctane to give 9.5 g (81%) of the methyl ester of p-(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) carbonyl benzoic acid which melts at 105°-106° C.
(e) Methyl ester of p-(3-bromomethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio) carbonyl benzoic acid
9.26 g (23 mmoles) of the compound prepared in 3(d) above are heated at reflux in 150 ml of carbon tetrachloride containing 50 mg of benzoyl. peroxide. There are then added, in small amounts 4.16 g (23 mmoles) of N-bromosuccinimide and once the addition has ended, reflux is maintained for 12 hours. The solvent is evaporated and the residue is purified by chromatography on a silica column (eluant: 1/1 mixture of CH2 Cl2 /hexane). 10.8 g of a mixture of the expected monobromo derivative (85%) and nonbrominated and dibrominated (15%) are obtained. (Dosage effected by comparing the integration of signals in NMR of the proton of the methyl, bromomethyl and dibromomethyl groups in the compounds of the mixture). The mixture is used as such for the following synthesis.
(f) Methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid
In a round bottom flask, there are introduced 10.5 g of the preceding mixture, 6 g (23 mmoles) of triphenylphosphine and 100 ml of THF. The reaction mixture is heated at reflux for 4 hours and cooled to 10° C. 3.5 ml (23 mmoles) of DBU are added and the reaction mixture is stirred for 4 hours at ambient temperature, poured into water and extracted with ether. The organic phase is decanted, dried on MgSO4 and the solvent evaporated. The residue is purified by chromatograph on a silica column (eluant: 80/20 mixture of hexane/dichloromethane) 6.6 g of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid which melts at 186°-187° C. are obtained.
EXAMPLE 4 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid
5 g (13 mmoles) of the ester obtained in 3(f) are treated with 200 ml of 2N methanolic soda. The reaction mixture is heated at reflux for 2 hours, evaporated to dryness, taken up in water, acidified to pH=1 with concentrated HCl and extracted with ether. The organic phase is decanted, dried on MgSO4 and the solvent evaporated. The residue is recrystallized in a 2/1 mixture of isopropylether/ethyl acetate. 4.6 g (96%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho[2,3-b]thienyl) benzoic acid which melts at 291°-292° C. are obtained.
EXAMPLE 5 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid (a) 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthanlene
In a round bottom flask there are introduced 64 ml (600 mmoles) of toluene and 36.6 g (200 mmoles) of 2,5-dichloro-2,5dimethyl hexane. The reaction mixture is cooled to 0° C. and there are added, by small amounts, 4.1 g (30 mmoles) of aluminum chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into water and extracted with CH2 Cl2. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting oil is purified by distillation. 39.4 g (98%) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which boils at 68° C. (under 1 mm of mercury) are obtained.
(b) 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene
50 g (250 mmoles) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in 200 ml of acetic anhydride. The solution is cooled to 0° C. and there is slowly added a solution of 10.5 ml (250 mmoles) of nitric acid, 20 ml of acetic acid and 20 ml of acetic anhydride, while maintaining the temperature between 0° and 5° C. The reaction mixture is then stirred for 1 hour at ambient temperature, poured into ice water and filtered. The resulting solid is washed with water. The solid is dissolved in methylene chloride, washed with water and then with a saturated solution of sodium bicarbonate, dried on MgSO4 and evaporated. 45.8 g (74%) of 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 143°-144° C. are obtained.
(c) 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine
24.7 g (100 mmoles) of the nitro derivative obtained in 5(b) are dissolved in 400 ml of ethanol. To this solution there are added 33.6 g (600 mmoles) of powdered iron and then, slowly, 38 ml of concentrated HCl. The reaction mixture is heated at reflux for 1 hour and evaporated to dryness. The residue is taken up in water to which is added with caution an excess of sodium bicarbonate. The mixture is then extracted with ether, filtered and the filtrate is recovered, dried on MgSO4 and evaporated. 21.2 g (98%) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine which melts at 94°-95° C. are obtained.
(d) Methyl ester of p-[(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] benzoic acid
8.1 g (45 mmoles) of methyl monoterephthalate are dissolved in 100 ml of THF. To this solution there are added, by small quantities, 8 g (45 mmoles) of 1,1'-carbonyldiimidazole. The mixture is stirred until the gaseous emissions have ceased and then there is slowly added a solution of 9.8 g (45 mmoles) of the amine obtained in 5(c) above in 50 ml of THF. The reaction mixture is stirred for 2 hours at ambient temperature, poured into water and extracted with CH2 Cl2. The organic phase is decanted, dried on MgSO4 and evaporated.
The residue is recrystallized in isopropylether to give 14.6 g (86%) of the methyl ester of p-[(3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] benzoic acid which melts at 169°-170° C.
(e) Methyl ester of p-[(N-tert.butoxycarbonyl-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylcarbamoyl)] benzoic acid
In a round bottom flask there are introduced 1.2 g (40.5 mmoles) of sodium hydride (80% in oil), 20 ml of DMF and 30 ml of THF. There is slowly added a solution of 13.9 g (37 mmoles) of the ester obtained in 5(d) in 60 ml of THF. The reaction mixture is stirred until the gaseous emissions have ceased. There are then added 8.8 g (40.5 mmoles) of di-tert.butyl dicarbonate in 100 ml of THF and the mixture is stirred at ambient temperature for 4 hours. The reaction mixture is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on MgSO4 and evaporated. The residue is purified by chromatography on a silica column (eluant: 7/3 mixture of dichloromethane/hexane). 14.1 g (82%) of the methyl ester of p-[(N-tert.butoxy carbonyl-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthylcarbamoyl)] benzoic acid which melts at 176°-177° C. are obtained.
(f) Methyl ester of p-(3-bromomethyl-N-tert.butoxycarbonyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylcarbamoyl) benzoic acid
13.25 g (27.6 mmoles) of the ester obtained in 5(e) are placed in a round bottom flask. There are added 150 ml of carbon tetrachloride and 50 mg of benzoyl peroxide The mixture is heated at reflux and there are introduced, in small amounts, 4.9 g (27.6 mmoles) of N-bromosuccinimide. Reflux is maintained for 12 hours. The solvent is evaporated and the residue is purified by chromatography on silica, by eluting with a 1/1 mixture of dichloromethane and hexane. 14.2 g are obtained of a mixture containing about 85% of the expected monobromo derivative and 15% of a mixture of dibromonated product and starting product (these proportions being estimated by NMR, in a manner analogous to that of Example 3(e). The mixture is used as such in the following synthesis.
(g) Methyl ester of p-(N-tert.butoxycarbonyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f] indoly) benzoic acid
Into a round bottom flask there are introduced 13.9 g of the mixture obtained in 5(f), 6.7 g (25.5 mmmoles) of triphenyl phosphine and 100 ml of THF. The mixture is heated at reflux for 8 hours and then cooled to 5° C. There are then slowly added 3.8 ml (25.5 mmoles) of DBU. The reaction mixture is stirred at ambient temperature for 2 hours, poured into water and extracted with ether. The organic phase is decanted, dried on MgSO4 and evaporated. The residue is purified by chromatography on a silica column (eluant: 20/80 mixture of CH2 Cl2 /hexane). 6.7 g (69%) of the methyl ester of p-(N-tert.butoxycarbonyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid which melts at 145°-146° C. are obtained.
(h) p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid
6.4 g (14 mmoles) of the ester obtained in 5(g) are treated at reflux for 4 hours with 100 ml of 2N methanolic soda. The solvent is evaporated and the remainder is taken up in water, acidifying the aqueous phase to pH 5 with HCl and extracted with ethyl ether. The organic phase is decanted, dried on MgSO4 and evaporated. The residue is triturated in 100 ml of hexane. 4.3 g (40%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid which melts at 294°-296° C. are obtained.
EXAMPLE 6 Preparation of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid
2.3 g (6.6 mmoles) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid are introduced into a round bottom flask containing 150 ml of methanol. There are slowly added 2 ml of concentrated sulfuric acid and the reaction mixture is heated at reflux for 4 hours. The reaction mixture is then evaporated to dryness and the remainder is taken up in water, alkalinized with sodium bicarbonate and extracted with methylene chloride. The organic phase is decanted, dried on MgSO4 and evaporated. 2.3 g (96%) of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-1H-benz[f]indolyl) benzoic acid which melts at 212°-213° C. are obtained.
EXAMPLE 7 Preparation of the methyl ester of p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid
180 mg (5.1 mmoles) of sodium hydride (80% in oil are suspended in 20 ml of DMF. There are slowly added 1.8 g (5 mmoles) of the ester prepared in Example 6, dissolved in 5 ml of THF. The reaction mixture is stirred until the evolution of gas ceases. There are then added 0.4 ml (6.4 mmoles) of methyl iodide and the reaction mixture is stirred for 2 hours at ambient temperature. The reaction mixture is poured into water and extracted with CH2 Cl2. The organic phase is decanted dried on MgSO4 and evaporated. The residue is purified by chromatography on a silica column by eluting with a 4/1 mixture of dichloromethane and hexane. After evaporation of the solvents, 1.4 g (78%) of the methyl ester of p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid which melts at 147°-148° C. are obtained.
EXAMPLE 8 Preparation of p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-benz[f]indolyl) benzoic acid
1.2 g (3.2 mmoles) of the ester obtained in Example 7 are treated at reflux for 2 hours with 100 ml of 2N methanolic soda. The mixture is heated for 2 hours at reflux evaporated to dryness, taken up in water, the aqueous phase is acidified to pH 5 with HCl and extracted with ether. The organic phase is decanted, dried on MgSO4 and evaporated. The residue is pulverized in 100 ml of hexane and then filtered togive 1.13 g (97%) of p-(1-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-benz[f]indolyl) benzoic acid which melts at 288°-289° C.
EXAMPLE 9 Preparation of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (a) 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol.
54.9 g (300 mmoles) of 2,5-dichloro-2,5-dimethyl hexane are dissolved in dichloromethane (500 ml). There is then added phenol (28.2 g - 300 mmoles) and then aluminum chloride (8.0 g - 60 mmoles). The mixture is vigorously stirred for 16 hours. Water is then added (200 ml) and the mixture is extracted with dichloromethane (3×200 ml). The organic phase is washed with a saturated solution of sodium bicarbonate and then with a saturated solution of sodium chloride. It is then dried on magnesium sulfate, filtered and the solvents are evaporated.
The resulting solid is washed with a mixture composed of 80% hexane and 20% dichloromethane, (200 ml), yielding 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol: 43.5 g (71%), which melts at 142° C.
(b) 3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol
5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol (42.86 g-210 mmoles) is dissolved in acetic anhydride (420 ml).
The solution is cooled to -10° C. and 40 ml of acetic acid are added. There is then added fuming nitric acid (8.7 ml - 210 mmoles) in solution in a mixture of acetic anhydride (40 ml) and acetic acid (40 ml). The reaction mixture is stirred for one hour at ambient temperature.
The reaction mixture is then poured into water (1 liter) plus ice. The precipitate that forms is filtered, washed with water, taken up in dichloromethane (3×200 ml). The organic phase is washed with a saturated solution of sodium bicarbonate and then with water. It is dried on magnesium sulfate, filtered and the solvent evaporated.
The resulting solid is purified by chromatography on silica and eluted with a 50/50 mixture of dichloromethane and hexane.
19.6 g (37%) of 3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol which melts at 139° C. are obtained.
(c) 3-amino-5,6,7,8-tetramethyl-2-naphthol.
3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol (35.3 g - 14 mmoles) is mixed with methanol (1 liter).
To this mixture there are added about 2 spatulas full of Raney nickel washed with methanol and the mixture is hydrogenated until the end of absorption.
The precipitate that forms is dissolved by the addition of dichloromethane (1 liter).
The catalyst is filtered and the solvents are evaporated.
The resulting crystals are washed with hexane (2 liters) and then filtered. 30.9 g (99%) of 3-amino-5,5,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol which melts at 225° C. are obtained.
(d) Methyl ester of p-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl(carbamoyl] benzoic acid
17.5 g (80 mmoles) of 3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol are mixed with ethyl ether (400 ml). Triethylamine (11.1 ml - 80 mmoles) is added and then slowly 15.81 g (80 mmoles) of p-methoxy carbonyl benzoyl chloride in solution in ether (200 ml).
The reaction mixture is stirred for 2 hours at ambient temperature and then poured into a mixtureof water (500 ml) and dichloromethane (300 ml).
The aqueous phase is extracted with dichloromethane (2×300 ml) and the organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvent evaporated.
The resulting solid is purified by column chromatography and eluted with dichloromethane.
24.38 g (80%) of the methyl ester of p-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid which melts at 200°-210° C. are obtained.
(e) methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid
The methyl ester of p-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbamoyl] benzoic acid (23.25 g - 61 mmoles) is mixed with xylene (600 ml). There are added 11.6 g (61 mmoles) of p-toluene sulfonic acid and the mixture is heated at reflux, with stirring, for 3 hours. The xylene is evaporated and there are added water (500 ml) and some dichloromethane. There are then added to the aqueous phase about 300 ml of a saturated solution of sodium bicarbonate and the mixture is extracted with dichloromethane (3×300 ml). The organic phase is then washed with a saturated solution of sodium bicarbonate and then with water.
The organic phase is dried on magnesium sulfate, filtered and the solvents are evaporated.
The resulting solid is purified by column chromatography and eluted with a mixture of 80% dichloromehtane and 20 % hexane.
The methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (12.25 g - 54%) which melts at 174° C. is obtained.
EXAMPLE 10 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid
The methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (7.27 g - 20 mmoles) is mixed with methanol (400 ml). There is then added 5N soda (40 ml) and the mixture is heated at reflux for 1 hour.
The methanol is evaporated and ethyl ether (300 ml) and 4N HCl (200 ml) are added. The aqueous phase is extracted with ether (2×300 ml) and the organic phase is washed twice with water and once with a saturated solution of sodium chloride.
The organic phase is dried on magnesium sulfate, filtered and the solvent evaporated.
The resulting solid is taken up in hexane (300 ml), filtered and dried. 7.00 g (100%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtho [2,3-d]oxazolyl) benzoic acid which melts at 290° C. are obtained.
EXAMPLE 11 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzyl alcohol
The methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (2.64 g - 7.26 mmoles) is dissolved in dry tetrahydrofuran (50 ml). This solution is slowly (474 mg - 11.9 mmoles) in suspension in dry tetrahydrofuran (50 ml).
The reaction mixture is heated at reflux for 5 hours, cooled to 0° C., then hydrolyzed by the slow addition of 30 ml of a solution of the double tartrate of sodium and potassium.
The solvent is evaporated, 300 ml of water are added and the product is extracted with ether (6×200 ml). The organic phase is washed with a saturated solution of sodium chloride and then dried on magnesium sulfate. After evaporation of the solvent, the product is recrystallized in acetonitrile. 216 g (89%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzyl alcohol which melts at 200° C. are obtained.
EXAMPLE 12 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic aldehyde
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzyl alcohol (1.24 g - 3.7 mmoles) is dissolved in dichloromethane (30 ml). There is then added pyridinium chlorochromate (1.20 g - 5.54 mmoles) in solution in 8 ml of dichloromethane. The reaction mixture is stirred for 2 hours at ambient temperature and the solvent is then evaporated.
The product is purified by column chromatography and eluted with a mixture composed of 80% ether and 20% hexane. The solvents are evaporated and the resulting solid is taken up in hexane, filtered and dried. 920 mg (75%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -naphth[2,3-d]oxazolyl) benzoic aldehyde which melts at 179° C. are obtained.
EXAMPLE 13 Preparation of the ethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (a) p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid chloride
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (4.57 g - 13.1 mmoles) is suspended in dichloromethane (200 ml). There is then slowly added dicyclohexylamine (2.37 g - 13.1 mmoles) and the dichloromethane is then evaporated.
The resulting solid is taken up in ether (500 ml), filtered and then dried, yielding the dicyclohexylamine salt o p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (6.94 g - 100%).
The above salt is dissolved in dichloromethane (100 ml). The resulting solution is cooled to 0° C. and there is then slowly added thionychloride (1.55 g 13.1 mmoles).
The reaction mixture is stirred for 2 hours at ambient temperature. The formed dicyclohexylamine hydrochloride is filtered and the dichloromethane is evaporated.
The resulting crude acid chloride is used as such for the following synthesis.
(b) ethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid
Ethylamine (216 mg-4.8 mmoles) is dissolved in dry tetrahydrofuran (25 ml). There are added successively triethylamine (485 mg-4.8 mmoles) and then slowly the acid chloride obtained in Example 12(a) (1.6 g - 4.4 mmoles) in solution in dry tetrahydrofuran (25 ml).
The reaction mixture is stirred for 1 hour at ambient temperature and then poured into 2N HCl (200 ml). The product is extracted with ether (3×100 ml), and then the organic phase is washed with water (3 times), then by a saturated solution of sodium chloride and dried on magnesium sulfate
The solution is filtered and the solvents are evaporated The resulting solid is taken up in hexane (300 ml), filtered and dried. The ethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (1.07 g - 65%) which melts at 174° C. is obtained.
EXAMPLE 14 Preparation of the morpholide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid
Morpholine (417 mg - 4 8 mmoles) is dissolved in dry tetrahydrofuran (25 ml) There are successively added triethylamine (485 mg - 4.8 mmoles) and then slowly p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid chloride (1.6 g- 4.4 mmoles) in solution in dry tetrahydrofuran (25 ml).
The reaction mixture is stirred for 2 hours at ambient temperature and then poured into 4N HCl (200 ml).
The product is extracted with ether (3×200 ml), the organic phase is washed with water (3 times) and then with a saturated solution of sodium chloride and finally dried on magnesium sulfate.
The solution is filtered and the solvents evaporated. The product is purified by chromatography on silica, eluted with a mixture of 50% dichloromethane, 20% ether and 30% hexane.
The solvents are evaporated and the resulting solid is taken up in hexane (300 ml).
The morpholide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (1.13 g - 62%) which melts at 193° C. is obtained.
EXAMPLE 15 Preparation of the 2-hydroxyethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid
Ethylene glycol (298 mg - 4.8 mmoles) is dissolved in dry dichloromethane (25 ml). There are successively added pyridine (380 mg - 4.8 mmoles) and then slowly p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid chloride (1.6 g - 4.4 mmoles) in solution in dry dichloromethane (25 ml).
The reaction mixture is stirred for 2 hours at ambient temperature and then poured into 200 ml of 4N HCl.
The product is extracted with ether (3×200 ml). The organic phase is washed with water (3 times) and then with a saturated solution of sodium chloride and finally dried on magnesium sulfate.
The solution is filtered and the solvents are evaporated. The product is purified by chromatography on silica, eluted by a mixture of 70% dichloromethane and 30% ether.
875 mg (51%) of the 2-hydroxyethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth [2,3-d]oxazolyl) benzoic acid which melts at 144° C. are obtained.
EXAMPLE 16 Preparation of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl) benzoic acid (a) 2,3-dinitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene
91.5 g (490 mmoles) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in concentrated sulfuric acid (365 ml). The solution is cooled to 0° C. and there is added, with mechanical stirring, fum9ing nitric acid (365 ml).
The reaction mixtures is stirred for 2 hours at ambient temperature and then poured over ice.
The product is extracted with ethyl ether (3×1 liter). The organic phase is neutarlized by the addition of solid sodium bicarbonate (+300 ml of water), decanted and dried on magnesium sulfate.
The organic phase is filtered, the solvent is evaporated and the resulting solid is recrystralized in cyclohexane.
80.19 g (59%) of 2,3-dinitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene, which melts at 200° C. are obtained.
(b) 2,3-diamino-5,6,7,8-tetarhydro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene
36.12 g (130 mmoles) of 2,3-d(nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphalene are dissolved in 1 liter of methanol. There are added about 2 spatulas-full of Raney nickel and the mixture is washed with methanol and hydrogenated until the end of absorption The catalyst is filtered, the solvents are evaporated and the resulting solid is washed with about 300 ml of hexane.
14.49 g (51%) of 2,3-diamino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 185° C. are obtained.
(c) methyl ester of p-[(3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] benzoic acid
2,3-diamino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene (6.55 g - 30 mmoles) is mixed with methyl ether (170 ml); there are added to the mixture triethylamine (4.2 m-30 mmoles) and then, slowly, methyl p-chloroformyl benzoate (5.96 g - 30 mmoles) in solution in ether (70 ml).
The reaction mixture is stirred for 2 hours at ambient temperature and it is then poured into a mixtureof water (400 ml) and dichloromethane (400 ml).
The organic phase is washed with a saturated solution of sodium bicarbonate, then with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvents evaporated.
The resulting solid is purified by column chromatography, eluted with a system composed of 10% ethyl ether and 90% dichloromethane.
3.73 g of the methyl ester of p-[3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbamoyl] benzoic acid in the form of a white solid are obtained.
(d) methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl benzoic acid
3.65 g (9.6 mmoles of the methyl ester p-[(3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl(carbamoyl] benzoic acid are dissolved in xylene (200 ml) To the solution there is added p-toluene sulfonic acid monohydrate (1.82 g - 9.6 mmoles) and the mixture is heated at reflux, with stirring, for 1 hour. The xylene is evaporated and there are added 300 ml of water and 300 ml of a saturated solution of sodium bicarbonate. The aqueous phase is extracted with dichloromethane (3+300 ml) and the organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvents evaporated. The resulting solid is purified by column chromatography and eluted with a mixture composed of 95% dichloromethane and 5% ethyl ether
2.7 g (78%) of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth [2,3-d]imidazolyl) benzoic acid which melts at 270°-275° C. (decomposition) are obtained.
EXAMPLE 17 Preparation of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]imidazolyl) benzoic acid
1.52 g (4.2 mmoles) of the methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth [2,3-d]imidazolyl) benzoic acid are mixed with 300 ml of methanol. There is added to the mixture 5N soda solution (8.4 ml) and it is heated at reflux for 24 hours.
The methanol is evaporated and the pH is the adjusted too 5 by the addition 1N HCl.
The product is extracted with ether (5×400 ml), and the organic phase is washed with water (2×500 ml) and then with a saturated solution of sodium chloride (2×300 ml).
The organic phase is dried on magnesium sulfate, filtered and the solvents are evaporated. The resulting solid is taken up in 300 ml of hexane, filtered and oven dried.
920 mg (63%) of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3d]imidazolyl) benzoic acid, which melts at 250° C. (decomposition), are obtained.
EXAMPLE 18 Preparation of 2-(4-methyl)phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphth[2,3-d]imidazole (a) N-(3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-4-methylbenzamide
4 g (18 mmoles) of 2,3-diamino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are suspended in 100 ml of ether. There are added to the suspension triethylamine (2.55 ml - 18.3 mmoles) and then 2.83 g (18.3 mmoles) of 4-methyl benzoyl chloride in solution in 50 ml of ether.
The reaction mixture is stirred for 1 hour and there are then added 300 ml of dichloromethane. The aqueous phase is extracted with dichloromethane (2×300 ml) and the organic phase is washed with a saturated solution of sodium chloride
The organic phase is dried on magnesium sulfate, filtered and the solvents are evaporated.
The product is purified by column chromatography and eluted with a mixture of 10% ether and 90% dichloromethane.
2.75 g (45%) of N-(3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-4-methylbenzamide, which melts at 180° C. are obtained.
(b) 2-(4-methyl)phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth-[2,3-d]imidazole
2.72 g (8.1 mmoles) of N-(3-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthyl)-4-methylbenzamide are mixed with 150 ml of xylene. There are added to the mixture 1.54 g (8.1 mmoles) of p-toluene sulfonic acid and the mixture is heated at reflux for 2 hours. The xylene is evaporated and there are added 300 ml of water and 300 ml of dichloromethane.
The aqueous phase is extracted with dichlormethane. The organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and the solvents are evaporated.
The product is purified by column chromatography and eluted with a mixture of 10% ether and 90% hexane.
1.78 g (69%) of 2-(4-methyl)phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphth[2,3-d]imidazole are obtained.
EXAMPLES OF COMPOSITIONS A. Oral Compositions 
______________________________________                                    
Example I - 0.2 g tablet                                                  
______________________________________                                    
p-(5,6,7,8-tetrahydro-5,5,8,8-                                            
                       0.0001  g                                          
tetramethyl-2-naphtho [2,3-b]                                             
thienyl) benzoic acid                                                     
Dicalcium phosphate    0.020   g                                          
Silica                 0.020   g                                          
Lactose                0.030   g                                          
Talc                   0.040   g                                          
Magnesium stearate     0.005   g                                          
Starch, sufficient amount for                                             
                       0.200   g                                          
______________________________________
In this Example, the active compound can be replaced by its methyl ester.
______________________________________                                    
Example II - 0.4 g capsule                                                
______________________________________                                    
p-(5,6,7,8-tetrahydro-5,5,8,8-                                            
                       0.0002  g                                          
tetramethyl-naphtho[2,3-b]                                                
furan-2-yl benzoic acid                                                   
Glycerine              0.200   g                                          
Sucrose                0.0050  g                                          
Polyethylene glycol 400                                                   
                       0.050   g                                          
Purified water, sufficient                                                
                       0.400   g                                          
amount for                                                                
______________________________________
The capsule is made of gelatin, glycerine, titanium dioxide and water.
______________________________________                                    
Example III - 0.5 g gelule                                                
______________________________________                                    
Morpholide of p-(5,6,7,8-tetrahydro-                                      
                        0.0005  g                                         
5,5,8,8-tetramethyl-2-naphth                                              
[2,3-d]oxazolyl) benzoic acid                                             
Cornstarch              0.150   g                                         
Magnesium stearate      0.250   g                                         
Sucrose, sufficient amount for                                            
                        0.500   g                                         
______________________________________
The above powder is packaged in a gelule composed of gelatin and TiO2.
B. Topical Compositions 
______________________________________                                    
Example IV - Ointment                                                     
______________________________________                                    
p-(5,6,7,8-tetrahydro-5,5,8,8-                                            
                       0.0001  g                                          
tetramethyl-2-naphth[2,3-d]                                               
oxazoyl) benzoic acid                                                     
Stearyl alcohol        3.000   g                                          
Lanolin                5.000   g                                          
Petrolatum             15.000  g                                          
Distilled water, sufficient                                               
                       100.000 g                                          
amount for                                                                
______________________________________                                    

______________________________________                                    
Example V - Ointment                                                      
______________________________________                                    
p-(5,6,7,8-tetrahydro-5,5,8,8-                                            
                       0.0005  g                                          
tetramethyl-2-1H-benz[f]                                                  
indolyl)benzoic acid                                                      
Stearyl alcohol        3.000   g                                          
Lanolin                5.000   g                                          
Petrolatum             15.000  g                                          
Distilled water, sufficient                                               
                       100.000 g                                          
amount for                                                                
______________________________________                                    

______________________________________                                    
Example VI - Gel                                                          
______________________________________                                    
Methyl ester of p-(5,6,7,8-                                               
                        0.0005  g                                         
tetrahydro-5,5,8,8-tetramethyl-                                           
2-naphtho[2,3-b]furan-2-yl)                                               
benzoic acid                                                              
Hydroxypropyl cellulose, sold by                                          
                        2.000   g                                         
Hercules under the trade name                                             
"Klucel HF"                                                               
Water/ethanol, 50:50, sufficient                                          
                        100.000 g                                         
amount for                                                                
______________________________________

Claims (12)

What is claimed is:
1. A polycyclic heterocyclic compound having the formula ##STR12## wherein n is 1 or 2,
R1 represents (i) .[.hydrogen.]. .Iadd.lower alkyl.Iaddend.,(ii) --CH2 OH or (iii) ##STR13## R2 represents (a) hydrogen, (b) ##STR14## or (c) --OR3 wherein R3 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl, polyhydroxyalkyl, phenyl, phenyl substituted by halogen, hydroxy, nitro or lower alkyl, benzyl, phenethyl, a sugar radical selected from the group consisting of glucose, mannose, erythrose and galactose, or ##STR15## wherein p is 1, 2 or 3 and r' and r" represents hydrogen, lower alkyl, monohydroxyalkyl, polyhydroxyalkyl, phenyl, phenyl substituted by halogen, hydroxy, nitro or lower alkyl, aminated sugar radical selected from the group consisting of glucosamine, galactosamine and mannosamine, or r' and r" taken together form a heterocycle selected from the group consisting of piperidino, piperazino, morpholino, pyrrolidino and 4-(2'-hydroxyethyl) piperazino,
X represents oxygen,
Y represents a nitrogen atom, or a salt of said polycyclic heterocyclic compound of formula I.
2. A polycyclic heterocyclic compound having the formula ##STR16## wherein n is 1 or 2,
R1 represents (i) .[.hydrogen.]. .Iadd.lower alkyl.Iaddend., (ii) --CH2 OH or (iii) ##STR17## R2 represents (a) hydrogen, (b) ##STR18## or (c) --OR3 wherein R3 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl, polyhydroxyalkyl, phenyl, phenyl substituted by halogen, hydroxy, nitro or lower alkyl, benzyl, phenethyl, or ##STR19## wherein p is 1, 2 or 3 and r' and r" represent hydrogen, lower alkyl, monohydroxyalkyl, polyhydroxyalkyl, phenyl, phenyl substituted by halogen, hydroxy, nitro or lower alkyl, or r' and r" taken together form a heterocycle selected from the group consisting of piperidino, piperazino, morpholino, pyrrolidino and 4-(2'-hydroxyethyl( piperazino,
X represents oxygen,
Y represents a nitrogen atom, or
a salt of said polycyclic heterocyclic compound of formula I.
3. The compound of claim 1 wherein said lower alkyl has 1-4 carbon atoms.
4. The compound of claim 2 wherein said lower alkyl is methyl, ethyl, isopropyl, butyl or tert.butyl.
5. The compound of claim 1 wherein said monohydroxyalkyl has 2-4 carbon atoms.
6. The compound of claim 4 wherein said monohydroxyalkyl is 2-hydroxyethyl, 2-hydroxypropyl or 2'-hydroxy-2-ethoxyethyl.
7. The compound of claim 1 wherein said polyhydroxyalkyl has 3-6 carbon atoms and 2-5 hydroxyl groups.
8. The compound of claim 6 wherein said polyhydroxyalkyl is 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,2,3,4,5-tetrahydroxypentyl or the residue of pentacrythritol.
9. The compound of claim 1 having the formula ##STR20## wherein R3 represents hydrogen or lower alkyl,
X represents oxygen,
Y represents a nitrogen atom,
R4 represents hydrogen or methyl.
10. The compound of claim 2 selected from the group consisting of
methyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid,
p-(5,6,7,8-tetrahydro-b 5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzyl alcohol,
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic aldehyde,
ethylamide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3d]oxazolyl) benzoic acid,
morpholide of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid, and
2-hydroxyethyl ester of p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid.
11. A pharmaceutical composition for the treatment of a dermotologic, rheumatoidal, respiratory or opthalmologic disorder containing in a vehicle suitable for enteral, parenteral, rectal, topical or ocular administration an effective amount of a compound of formula I of claim 1.
12. The pharmaceutical composition of claim 11 in a vehicle for topical application, said composition containing said compound to 0.01 percent by weight based on the total weight of said composition.
US07/513,970 1987-04-30 1990-04-24 Polycyclic heterocyclic compounds, a process for their preparation and their use in human and veterinary medicine Expired - Lifetime USRE33533E (en)

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US5770383A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770382A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770378A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US6545049B1 (en) 1995-10-06 2003-04-08 Ligand Pharmaceuticals Incorporated Dimer-selective RXR modulators and methods for their use
US20050287115A1 (en) * 2004-06-25 2005-12-29 Minas Theodore Coroneo Treatment of ocular lesions
US20060204474A1 (en) * 2005-02-25 2006-09-14 Coroneo Minas T Treatment of epithelial layer lesions
US7259188B2 (en) 1998-06-12 2007-08-21 Llgand Pharmaceuticals Incorporated Methods and pharmaceutical compositions for treatment of anti-estrogen resistant breast cancer using RXR modulators
US11045441B2 (en) 2015-10-13 2021-06-29 Wisconsin Alumni Research Foundation Use of retinoic acid and analogs thereof to treat central neural apneas

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US5166170A (en) * 1989-07-03 1992-11-24 Hoechst-Roussel Pharmaceuticals Incorporated 2-(aminoaryl) indoles and indolines as topical antiinflammatory agents for the treatment of skin disorders
ATE151418T1 (en) * 1992-12-28 1997-04-15 Eisai Co Ltd HETEROCYCLIC CARBOXYLIC ACID DERIVATIVES THAT CAN BIND TO RARE RECEPTORS
FR2750426B1 (en) * 1996-06-28 1998-08-07 Cird Galderma NOVEL HETEROCYCLIC BIARYLATED COMPOUNDS AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS
US6566372B1 (en) * 1999-08-27 2003-05-20 Ligand Pharmaceuticals Incorporated Bicyclic androgen and progesterone receptor modulator compounds and methods
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AU6941200A (en) 1999-08-27 2001-03-26 Ligand Pharmaceuticals Incorporated 8-substituted-6-trifluoromethyl-9-pyrido(3,2-g)quinoline compounds as androgen receptor modulators
CA2383565A1 (en) 1999-09-14 2001-03-22 Ligand Pharmaceuticals Incorporated Rxr modulators with improved pharmacologic profile
FR2804323B1 (en) * 2000-01-31 2006-07-07 Galderma Res & Dev USE OF RETINOID-LIKE COMPOUNDS AS ANTI-BACTERIAL AGENTS
FR2910320B1 (en) 2006-12-21 2009-02-13 Galderma Res & Dev S N C Snc EMULSION COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE
FR2910321B1 (en) 2006-12-21 2009-07-10 Galderma Res & Dev S N C Snc CREAM GEL COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE
FR2931661B1 (en) 2008-05-30 2010-07-30 Galderma Res & Dev NOVEL DEPIGMENTING COMPOSITIONS IN THE FORM OF AN ANHYDROUS VASELIN - FREE AND ELASTOMER - FREE COMPOSITION COMPRISING A SOLUBILIZED PHENOLIC DERIVATIVE AND A RETINOID.

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
US5770383A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770382A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US5770378A (en) * 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US6545049B1 (en) 1995-10-06 2003-04-08 Ligand Pharmaceuticals Incorporated Dimer-selective RXR modulators and methods for their use
US7259188B2 (en) 1998-06-12 2007-08-21 Llgand Pharmaceuticals Incorporated Methods and pharmaceutical compositions for treatment of anti-estrogen resistant breast cancer using RXR modulators
US20090093546A1 (en) * 1998-06-12 2009-04-09 Lamph William W Method and Pharmaceutical Compositions for Treatment of Anti-Estrogen Resistant Breast Cancer Using RXR Modulators
US20050287115A1 (en) * 2004-06-25 2005-12-29 Minas Theodore Coroneo Treatment of ocular lesions
US9050310B2 (en) 2004-06-25 2015-06-09 Minas Theodore Coroneo Treatment of ocular lesions
US20060204474A1 (en) * 2005-02-25 2006-09-14 Coroneo Minas T Treatment of epithelial layer lesions
US11045441B2 (en) 2015-10-13 2021-06-29 Wisconsin Alumni Research Foundation Use of retinoic acid and analogs thereof to treat central neural apneas

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