EP1569648A1 - Prodrogues utilisees comme agents ophtalmiques - Google Patents

Prodrogues utilisees comme agents ophtalmiques

Info

Publication number
EP1569648A1
EP1569648A1 EP03796804A EP03796804A EP1569648A1 EP 1569648 A1 EP1569648 A1 EP 1569648A1 EP 03796804 A EP03796804 A EP 03796804A EP 03796804 A EP03796804 A EP 03796804A EP 1569648 A1 EP1569648 A1 EP 1569648A1
Authority
EP
European Patent Office
Prior art keywords
quinol
group
compounds
steroidal
prodrugs
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03796804A
Other languages
German (de)
English (en)
Other versions
EP1569648A4 (fr
Inventor
Laszlo Prokai
Katalin Prokai
James Simpkins
Neeraj Agarwal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Florida
University of North Texas
University of North Texas Health Science Center
Original Assignee
University of Florida
University of North Texas
University of North Texas Health Science Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/405,413 external-priority patent/US7026306B2/en
Application filed by University of Florida, University of North Texas, University of North Texas Health Science Center filed Critical University of Florida
Publication of EP1569648A1 publication Critical patent/EP1569648A1/fr
Publication of EP1569648A4 publication Critical patent/EP1569648A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group

Definitions

  • the present invention relates to prodrugs for use as ophthalmic agents, specifically for retinal protection.
  • the present invention relates to the use of steroidal quinols as prodrugs of phenolic A-ring steroid compounds to treat and/or prevent eye pathologies.
  • Estrogens have demonstrated an important role in the health maintenance of all mucous membranes in the body, including the maintenance of a healthy ocular surface. Additional studies have revealed that the biological activity of estrogen may be effective in the protection and treatment of the eye, including the lens and retina, against cataracts and the detrimental effects of glaucoma.
  • estrogens Unfortunately, many regions of the eye are relatively inaccessible to systemically administered estrogens. For example, orally administered estrogen passes through the liver before reaching estrogen sensitive tissues. Because the liver contains enzymes that can inactivate the estrogen, the estrogen that eventually reaches tissue targeted for treatment is virtually ineffective. Moreover, systemic administration of estrogen often produces undesirable side effects, i.e., feminizing side effects in men.
  • topical drug delivery remains the preferred route of administration to the eye.
  • factors that affect the absorption of drugs into the eye There are a variety of factors that affect the absorption of drugs into the eye.
  • GI gastrointestinal
  • the direct administration to an eye lens of estrogen having quinolines (i.e., 6-hydroxyquinoline) and fused quino lines that act as steroid receptor modulators to prevent or treat cataract disorders has been disclosed.
  • the administration of 17- 3-estradiol to the surface of the eye to alleviate dry-eye syndrome or keratoconjunctivitis sicca has been disclosed.
  • Glycosides of catechol estrogens have been formulated that demonstrate antioxidant activity to the same degree as to that of the parent catechol estrogens. Nonetheless, all of the previously disclosed compounds and methods for applying estrogens to the eye relate to compounds that lack efficient corneal penetration and/or are inapplicable to men because of their activity as a female hormone.
  • the major barrier to ocular drug penetration is the cornea.
  • the cornea is composed of three layers: a lipid-rich epithelium, a lipid-poor soma, and a lipid-rich endothelium. Therefore, an agent must possess both lipophilic-hydrophilic balance for adequate transcorneal penetration and, thus, ocular bioavailability (Akers HJ, "Ocular bioavailability of topically applied ophthalmic drugs," Am Pharm, NS23:33-36 (1983)).
  • ocular bioavailability is an issue for estrogens and their synthetic analogs, because estrogens are highly lipid soluble molecules that are usually not amenable to adequate transcorneal penetration.
  • Prodrugs are inactive compounds that are converted in vivo into biologically active agents by enzymatic and/or chemical transformations. Prodrugs are advantageous because they can be designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability, that may exist with the active form of a drug. Thus, there is a need to develop effective prodrugs of estrogen as a medical compound.
  • Estrogen quinols have been known for decades among organic chemists (Gold A.M., and Schwenk E., "Synthesis and reaction of steroidal quinols," J Am Chem Soc, 80:5683-5687 (1958)) though their metabolic formation has only been reported recently (Ohe T., et al, "Novel metabolic pathway of estrone and 17
  • the subject invention provides materials and methods wherein unique and advantageous steroidal quinols are used for a broad range of therapeutic purposes, including the treatment or prevention of ophthalmic disorders and/or conditions by modulating or activating estrogen receptors.
  • ophthalmic disorders and/or conditions include, but are not limited to, conjunctivitis, diabetic retinopathy, dry eye, glaucoma, and cataract.
  • a quinol i.e., the 10c ⁇ jS-hydroxyestra-l,4-diene-3-one structures
  • phenolic A-ring steroids has been found to confer significant reduced lipid solubility compared to the parent phenolic A-ring steroid compounds to provide improved transcorneal penetration.
  • these quinols can be converted to phenolic A-ring steroid structures by endogeneous NAD(P)H as a reducing agent.
  • an oxidoreductase catalyst converts subject steroidal quinols to phenolic A- ring steroids that possess pharmacological activity in the eye.
  • the present invention exploits the benefits of prodrugs (including but not exclusively based on the quinol structure as a novel pro-moiety) for phenolic A-ring steroid compounds to provide ocular bioavailability of the therapeutic agent in question.
  • Prodrugs are, by definition, inactive compounds that are converted to the biologically active agents by chemical or enzymatic transformation in vivo.
  • the subject invention provides a mechanism by which quinol derived phenolic
  • A-ring steroid compounds confer beneficial ophthalmic effects.
  • the subject compounds possess a lipophilic-hydrophilic balance for transcorneal penetration and are readily reduced into parent phenolic A-ring steroid compounds to provide protection or treatment against various ocular symptoms and disorders.
  • the compounds according to the subject invention appear to be highly advantageous as prodrugs to provide protection and/or treatment against ocular disorders. These prodrugs confer low lipid solubility and are readily converted by endogenous reducing agents into active phenolic A-ring steroid compounds. To the extent that these prodrugs have reduced feminizing effects and systemic toxicity, they would be expected to be quite advantageous for protecting or treating the eye against ocular disorders such as cataract or glaucoma.
  • the subject invention provides steroidal quinol compounds that are, themselves, inactive.
  • these quinol structures can act as prodrugs because they are converted to a therapeutically active phenolic A-ring steroid upon exposure to a reducing agent.
  • an active phenolic A-ring steroid compound arises after conversion by a reducing agent, a smaller concentration of the steroidal quinols is required as compared to direct administration of phenolic A-ring steroid, thus reducing the potential for systemic toxicity.
  • isomers of 10- hydroxyestra-l,4-diene-3-one quinol structure are converted to active, phenolic A-ring steroid compounds (i.e., estrone) when exposed to a reducing agent.
  • quinols are derived from estrogen analogues, i.e., 3,17- dihydroxyestra-l,3,5(10),9(l l)-tetraene (ZYC1).
  • steroidal quinols are provided as prodrugs that require at least one-step activation in vivo to yield pharmaceutically active estrogen compounds.
  • quinols derived from estrogen prodrugs that require two-step activation can include a polar functional group to enhance hydrophilicity at the 17-OH group or may have the 10-OH group esterified to decrease lipophilicity through phosphate, or N,N,N-trialkylammonium esters.
  • the 3,17-keto groups of quinols of the present invention can be functionalized as oxime and/or alkoximes. In doing so, preliminary compounds to the subject quinols are created (to form i.e. pro-prodrugs).
  • Such functionalized quinols can be functionalized as oxime and/or alkoximes.
  • 3-keto functionalized as an oxime can be used for a variety of therapeutic purposes, including use for ocular-specific delivery of phenolic A-ring steroids.
  • An object of the present invention is to provide compounds formulated for ophthalmic administration.
  • solutions or suspensions of these compounds may be formulated in the form of eye drops, or membranous ocular patch, which is applied directly to the surface of the eye.
  • FIG. 1 illustrates the viability of retinal ganglial cells in the presence of glutamate, estrogen analog 3,17-dihydroxyestra-l,3,5(10),9(ll)-tetraene (ZYC1), or combinations of glutamate and various concentrations of ZYC 1.
  • FIG. 2 illustrates retinal ganglial cell viability when treated with glutamate in the presence or absence of ZYCl or ZYCl incubated in the presence of various concentrations of estrogen receptor antagonist, ICII82,780 (ICI).
  • FIG. 3 illustrates a quinol acetate in accordance with the subject invention.
  • FIG. 4 illustrates an (alk)oxime of a quinol, in accordance with the subject invention.
  • FIG. 5 illustrates the viability of retinal ganglial cells in the presence of glutamate, phenolic A-ring steroid 2-(l-adamantyl)-3-hydroxyestra-l, 3, 5 (10)-trien-17- one (ZYC3), or combinations of glutamate and various concentrations of ZYC3.
  • the subject invention provides steroidal quinol compounds that produce phenolic A-ring steroids in vivo.
  • these compounds provide improved physicochemical properties including, but not limited to, favorable ocular bioavailability and facile transcorneal penetration.
  • estrogen derived quinol compounds demonstrate decreased lipophilicity as compared to lipophilic estrogens and estrogen analogues.
  • these compounds treat and/or protect against various ocular diseases.
  • Preferred compounds of the subject invention are effective in treating and/or preventing maladies associated with vision-threatening intraocular damage due to pathophysiological predispositions. Particularly preferred compounds are those which treat glaucoma and/or macular degeneration.
  • the subject invention provides steroidal quinol compounds that are, themselves, inactive.
  • these quinol structures can act as prodrugs because they are converted to a therapeutically active phenolic A-ring steroid upon exposure to a reducing agent.
  • an active phenolic A-ring steroid compound arises after conversion by a reducing agent, a smaller concentration of the steroidal quinols is required due to their improved ocular bioavailability as compared to direct administration of estrogen, thus reducing the potential for systemic toxicity.
  • steroidal quinols are provided as prodrugs that are converted into an active phenolic A-ring steroid via a one-step conversion by a reducing agent.
  • Suitable reducing agents include endogenous NAD(P)H or oxidoreductases.
  • a 10 ⁇ -hydroxyestra-l,4- diene-3-one quinol structure is converted to an active, phenolic A-ring estrogen compound (estrone) when exposed to a reducing agent.
  • quinols are derived from estrogen analogues, i.e., 3,17-dihydroxyestra-l,3,5(10),9(l l)- tetraene (ZYCl) or 2-(l-Adamantyl)estrone (ZYC3).
  • steroidal quinols are provided as prodrugs that require two (or more than two) step activation in vivo to yield pharmaceutically active estrogen compounds.
  • the liberation of a parent estrogen occurs through a two-step reaction: (1) enzymatic (phosphatase, esterase) cleavage of the ester group followed by
  • these compounds according to the present invention can include a polar functional group to enhance hydrophilicity at the 17-OH group or may have the 10-OH group esterified to decrease lipophilicity through phosphate or N,N,N- trialkylammonium esters.
  • the prodrugs according to the subject invention can be synthesized by attaching a polar functional group to enhance affinity to water and facilitate the transport of the prodrug of the subject invention through the lipid-poor middle stroma in the cornea.
  • the 17-OH group of a quinol according to the subject invention is the primary site to which a polar functional group is added.
  • the 10/3-OH of a steroidal quinol i.e., 17- hydroxyestra-l,4-diene-17-one
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (i.e., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by conventional methods including, for example, by classical separation techniques and by stereochemically controlled synthesis.
  • estradien refers to both naturally occurring and synthetic substances classed as estrogen on the basis of their therapeutic or biological action (see listing under 'Estrogens' in the 'Therapeutic Category and Biological Activity Index' of The Merck Index, 12th Edition, Merck Research Laboratories, NJ, 1996, page THER-22).
  • estrogens may be steroids (i.e., estradiol, ethinyl estradiol, colpormon, conjugated estrogenic hormones, equilenin, equilin, estriol, estrone, mestranol, moxestrol, mytatrienediol, quinestradiol and quinestrol) or non-steroids (i.e., diethylstilbestrol, dienestrol, benzestrol, broparoestrol, chlorotrianisene, dimestrol, fosfestrol, hexestrol, methallenestril, methestrol).
  • steroids i.e., estradiol, ethinyl estradiol, colpormon, conjugated estrogenic hormones, equilenin, equilin, estriol, estrone, mestranol, moxestrol, mytatrienediol, quinestradiol and quinestrol
  • non-steroids i
  • estrogenic that is, they interact with cellular estrogen receptors and mimic the effects of estrogens, include estrogenic substances that have been shown to be tissue selective in their estrogenic effects.
  • Diverse classes of molecules fall within this category, for example: quinolines and fused quinolines that act as steroid receptor modulators such as 3,9-dihydroxy-5H-benzofuro[3,2-c]quinoline-6-one and those disclosed in WO 96/19458; phytoestrogens which occur naturally in plants such as forage plants, soya beans, seeds, berries and nuts (Jordan et al, "Structure-activity relationships of estrogen," Env.
  • isoflavones such as genistein and genistein glycosides, equol, O-desmethyl-angolensin, biochanin A, daidzein and formononetin; flavones such as phloretin, 4'-6-dihydroxyflavone and tricin, and coumestans such as coumestrol, 4'-O-methyl coumestrol, medicagol and sativol, lignans such as matairesinol, enterodiol, enterolactone, guaiaretic acid, nordihydroguaiaretic acid and derivatives thereof, jS-sitosterol; mycoestrogens such as zeranol, zearalenol and zearalenone; estrogen receptor agonist/antagonists, such as tamoxifen, hydroxytamoxifen, zindoxifene and its metabolites,
  • estrogenic substances may exert their estrogenic effect(s) directly or they may require metabolic conversion to an active form after administration.
  • metabolic activation of some phytoestrogens involves demethylation to phenols (Jordan et al, "Structure-activity relationships of estrogen,” Env. Health Per., 61:97-110 (1985)).
  • estrogen derived quinols (i.e., 10 ⁇ 3-hydroxyestra-l,4-diene-3-one structure) as used herein, refers to quinols and quinol derivatives related to estrogens, as described above, andjc ⁇ ra-substituted phenols obtained by oxidation of the phenolic ring, as described below.
  • phenolic A-ring steroid used herein refers to compounds containing a 3-hydroxy-l,3,5(10)-triene moiety as the six-membered A-ring of a steroid, steroid analogue or steroid mimic, including compounds that manifest affinity to estrogen receptors (i.e., 3,17-dihydroxyestra-l,3,5(10),9(l l)-tetraene) as well as compounds that do not bind to such receptors (i.e., 2-(l-adamantyl)-3-hydroxyestra-l, 3, 5 (10)-trien-17- one).
  • steroidal quinol used herein refers to a steroid containing a lO / ⁇ - hydroxy-l,4-diene-3-one moiety as the six-membered A-ring of a steroid, steroid analogue or steroid mimic.
  • ophthalmic disorders refers to ophthalmic diseases, conditions, and/or disorders including, without limitation, those associated with the anterior chamber of the eye (i.e., hyphema, synechia); the choroid (i.e., choroidal detachment, choroidal melanoma, multifocal choroidopathy syndromes); the conjunctiva (i.e., conjunctivitis, cicatricial pemphigoid, filtering Bleb complications, conjunctival melanoma, Pharyngoconjunctival Fever, pterygium, conjunctival squamous cell carcinoma); connective tissue disorders (i.e., ankylosing spondylitis, pseudoxanthoma elasticum, corneal abrasion or edema, limbal dermoid, crystalline dystrophy keratits, keratoconjunctivitis, kera
  • connective tissue disorders i.e., ankylosing
  • patient describes an organism, including mammals, to which treatment with the compositions according to the present invention is provided.
  • Mammalian species that benefit from the disclosed methods of treatment include, and are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and domesticated animals (i.e., pets) such as dogs, cats, mice, rats, guinea pigs, and hamsters.
  • polar aprotic solvent refers to polar organic solvents lacking an easily removed proton, including, but not limited to, ethyl acetate, dimethylformamide (DMF), and acetonitrile.
  • pharmaceutically acceptable salts refers to those carboxylate salts, esters, and prodrugs of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts are well known in the art and refer to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention.
  • S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977) which is incorporated herein by reference.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclop entanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to a derivative of a biologically active compound (i.e., the steroidal quinols according to the present invention) that lacks pharmaceutical activity, but is converted (i.e., by NAD(P)H) to an active agent, which is a phenolic A-ring steroid such as estrogen hormone, estrogen analogue, substituted estrogen or estrogen-receptor agonist or antagonist) upon interaction with a biological or chemical system, for example catalyzed reduction by enzymes in the eye.
  • an active agent which is a phenolic A-ring steroid such as estrogen hormone, estrogen analogue, substituted estrogen or estrogen-receptor agonist or antagonist
  • a prodrug can be converted into an active compound with one or more steps.
  • substituted shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or severally.
  • alkyl refers to a straight or branched or cyclic alkyl moiety.
  • the alkyl moiety is C ⁇ - 20 alkyl, which refers to an alkyl moiety having from one to twenty carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and octyl, cycloalkyl including for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the alkyl group specifically includes fluorinated alkyls such as CF and other halogenated alkyls such as CH CF 2 , CF 2 CF 3 , the chloro analogs, and the like.
  • the alkyl group can be optionally substituted with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclic, carbocycle, alkoxy, heterocycloxy, heterocylalkoxy, aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, a ido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl,
  • alkenyl refers to a straight or branched alkyl moiety having one or more carbon double bonds, of either E or Z stereochemistry where applicable. This term includes for example, vinyl, 1-propenyl, 1- and 2- butenyl, and 2- methyl-2-propenyl, as well as “cycloalkenyl” groups such as cyclopentenyl and cyclohexenyl.
  • alkoxy refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above. The alkyl group can be optionally substituted as described above. Alkoxy groups can include OCF 3 , OCH 2 CF 3 , OCF 2 CF 3 , and the like.
  • alkynyl refers to a hydrocarbon with at least one triple bond, including for example, d to Cio groups including but not limited to ethynyl, 1-propynyl, 1- and 2- butynyl, 1- methyl-2-butynyl, and the like.
  • aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
  • the aryl group can be optionally substituted with one or more of the moieties selected from the group consisting of alkyl, heteroaryl, heterocyclic, carbocycle, alkoxy, aryloxy, aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl
  • adjacent groups on the aryl ring may combine to form a 5 to 7 membered carbocyclic, aryl, heteroaryl or heterocylic ring.
  • aralkoxy refers to an aryl group attached to an alkyl group that is attached to the molecule through an oxygen atom.
  • the aryl and alkyl groups can be optionally substituted as described above.
  • aralkyl refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above.
  • the aryl and alkyl portions can be optionally substituted as described above.
  • aryloxy refers to an aryl group bound to the molecule through an oxygen atom.
  • the aryl group can be optionally substituted as set out above for aryl groups.
  • heteroaryl and heteromatic refer to monocyclic or bicyclic aromatic ring systems of five to ten atoms of which at least one atom is selected from O, N, and S, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced with a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are replaced by nitrogen heteroatoms.
  • Heteroaryl thus includes aromatic and partially aromatic groups that contain one or more heteroatoms. Examples of this type include but are not limited to are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, imidazole, oxazole, benzoxazole, thiazole, benzthiazole, isothiazole, thiadiazole, triazole, benzotriazole,furazan, benzofurazan, thiafurazan, benzothiafurazan, tetrazole, oxadiazole, triazine, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indolizine, indole, isoindole, purine, quinoline, benzimidazole, pteridine, isoquinoline, cinnoline, quinazoline, and quinoxaline.
  • heteroarylkyl iso
  • heterocyclealkyl refers to a heterocyclic group bound to the molecule through an alkyl group.
  • the heterocyclic group and the alkyl group can be optionally substituted as described above.
  • heterocycloalkyl can also refer to a saturated heterocyclic moiety having from two to six carbon atoms and one or more heteroatom from the group N, O, and S (or oxidized versions thereof) which may be optionally benzofused at any available position. This includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, benzodioxolyl and the like.
  • heterocycloalkyl also refers to an alicyclic moiety having from three to six carbon atoms and one or more heteroatoms from the group N, O, and S and having in addition one double bond. Such moieties may also be referred to as “heterocycloalkenyl” and includes, for example, dihydropyranyl, and the like.
  • heterocyclic refers to a nonaromatic cyclic group that may be partially (contains at least one double bond) or fully saturated and wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
  • heteroaryl or heteroaromatic refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
  • heterocylics and heteroaromatics are pyrrolidinyl, tetrahydrofuryl, piperazinyl, piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl, pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, 1,4-dioxanyl, aziridinyl, furyl, furanyl, pyridyl, pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl, 1,3,5-triazinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofu
  • Suitable protecting groups can include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.
  • heteroaryloxy refers to a heteroaryl group bound to the molecule through an oxygen atom.
  • the heteroaryl group can be optionally substituted as set out above for aryl groups.
  • heterocyclearalkoxy refers to, a heterocyclic group attached to an aryl group attached to an alkyl-O- group.
  • the heterocyclic, aryl and alkyl groups can be optionally substituted as described above.
  • electrolyte refers to salts generally and specifically to ions.
  • An electrolyte refers to an ion that is electrically-charged, either negative or positive. Common electrolytes include chloride (0 " ), bromide (Br " ), bicarbonate (HCO “ ), sulfate (SO 4 2 ⁇ ), sodium (Na + ), potassium (K + ), calcium (Ca 2+ ), and magnesium (Mg 2+ ).
  • Abbreviations used in the examples are: DCC for 1,3-dicyclohexylcarbodiimide; DMAP for 4-dimethylamino-pyridine; LC/MS for liquid chromatography-mass spectrometer; m-CPBA for meta-chloroperoxybenzoic acid; and PhMe/EtOAC for toluene/ethyl acetate.
  • a quinol of Formula I is provided as follows
  • quinol of Formula I is derived from the following estrogen analogue (ZYCl)
  • ZYCl is an analogue of estrogen and has been demonstrated to have estrogen-like activity.
  • the physicochemical properties of ZYCl inhibit facile transcorneal penetration upon topical admimstration (i.e., eye-drops).
  • ZYCl is oxidized to produce an steroidal quinol, 10,17-dihydroxyestra-l,4,9(ll)-triene- 3-one ("ZYCl -quinol").
  • ZYCl-quinol as discussed in more detail below, has demonstrated improved physicochemical properties, including decreased lipophilicity, to facilitate transcorneal penetration.
  • a quinol of Formula II is provided as follows:
  • quinol of Formula II is derived from 3-hydroxyestra-l,3,5(10-triene-17-one (estrone).
  • a quinol of Formula III is provided as follows:
  • quinol of Formula III is derived from 3,17-dihydroxyestra-l,3,5(10)-triene (estradiol).
  • the compounds of Formulas I-HI can also be functionalized at the 3- or 17-keto group as an oxime or alkoxime. Such compounds are useful as preliminary compounds to the quinol, for use as pro-prodrug compounds. These compounds would be useful for a variety of therapeutic purposes including, for example, use as a ⁇ -blocker.
  • the compounds and processes of the invention will be better understood in connection with the Examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
  • Example 1 Physicochemical Properties of ZYCl Human retinal ganglial cells (RGC) were incubated with glutamate (5mM), the estrogen analogue 3,17-dihydroxyestra-l,3,5(10),9(l l)-tetraene (ZYCl) or combination of glutamate and various concentrations of ZYCl. As illustrated in Figure 1, glutamate killed about 70% of RGC while the compound of Formula ZYCl alone had no effect on RGC viability. In the presence of all three concentrations of ZYCl, glutamate killed significantly fewer cells.
  • estrone was used as a lead compound.
  • Table I indicates a very significant drop in lipophilicity of Formula I, Formula II, and Formula III, compared to the parent phenolic A-ring steroids, ZYCl, estrone, and estradiol.
  • the log of the /z-octanol/water partitioning coefficient (log P or log D 7 . 4 ) is the measure of attraction to lipid phase versus an aqueous phase.
  • Log P is a crucial factor governing passive membrane partitioning, influencing permeability opposite to its effect on solubility (i.e., increasing log P enhances permeability while reducing water solubility).
  • the log P values pertain to n-octanol/water partitioning were predicted by the method incorporated into CAChe WorkSystem Pro 5.0 (Fujitsu America, Inc., Beaverton, OR).
  • steroidal quinols according to the present invention may be synthesized using a "one-pot" phenol to quinol transformation.
  • the synthesis method utilizes m-CPBA as an oxidant, dibenzoyl peroxide [(PheCO) O ] as a radical initiator and visible-light irradiation that, in refluxing aprotic solvent, produces excellent yields of the quinols of the present invention.
  • estrome quinols of the present invention can be prepared using 2- (l-adamantyl)-3-hydroxyestra-l, 3, 5 (l ⁇ )-trien-l 7-one [2-(l-adamantyl)estrone], which can be made using methods previously described by Lunn, W.H. and E. Farkas, "The adamantly carbonium ion as a dehydrogenating agent, its reactions with estrone," Tetrahedron, 24:6773-6776 (1968). Estrone (270 mg, lmmol) and 1-adamantanol (170 mg, lmmol) were added to anhydrous w-pentane (6 mL) and the stirred mixture was cooled with an ice bath.
  • the pink crude powder (0.4 g) was purified by flash chromatography (silica gel, eluted with 20% ethyl acetate in hexanes to yield the pure product; 0.31 g, 76.7%).
  • the product was recrystalhzed from a mixture of chloroform and isopropyl alcohol and had: mp 322-324 °C, lit mp 295-296 °C; 1H NMR (CDC1 3 , 300 MHz) ⁇ 0.91 (s, 3H, C 18 - CH 3 ), 2.8 (m, 2H, C 6 - CH 2 ), 4.71 (s, 1H, C 3 - OH), 6.42 (s, 1H, Aromatic H), 7.15 (s, 1H, Aromatic H).
  • 2-(l-Adamantyl)estrone (also referred to herein as ZYC3) was oxidized with lead- acetate to the corresponding quinol acetate using the following procedures.
  • (alk)oxime estradiol quinols of the subject invention such as those illustrated in Figure 4, 0.5 g of hydroxylamine hydrochloride is added to 0.5 g of estradiol quinol or alkoxyamine hydrochloride) in 5 ml of ethanol, 0.5 ml of pyridine was added and the solution was refluxed overnight. After cooling, the ethanol was removed and ice- cold water was added. The mixture was stirred until the oxime crystallized.
  • RGC were incubated with glutamate (5mM), with 2-(l-adamantyl)-3- hydroxyestra-1, 3, 5 (l ⁇ )-trien-l 7-one (ZYC3), or with a combination of glutamate and various concentrations of ZYC3.
  • glutamate killed about 70% of RGC while the compound of ZYC3 alone has no affect on RGC viability.
  • glutamate killed significantly fewer cells (No statistically significant difference from RGC survival without exposure to glutamate).
  • Liquid chromatography separation was done using a Supelco (Bellfonte, PA) 5 cm x 2.1 mm i.d.
  • Discovery HS C-18 reversed-phase column with 0.25 ml/min water:methanol:2-propanol:acetic acid:dichloromethane (53:35:5:5:2, v/v) as a mobile phase.
  • the sample residues were dissolved in 40 ⁇ l of mobile phase, respectively, and 5 ⁇ l of the solution was injected for analysis.
  • Mass spectra were recorded on a quadruple ion-trap instrument (LCQ ® , ThermoFinnigan, San Jose, CA) using positive-ion atmospheric-pressure chemical ionization (APCI) as the method of ionization. MS/MS and MS 3 product-ion scans were obtained after collision-induced dissociation (CID) with helium as the target gas. Comparison with authentic reference compound (retention time, t , and mass spectra) was used for unambiguous identification of estrone. As an internal standard, l,3,5(10)-esfratrien-17c.-ethynyl-17/3-ol was added before each sample extraction.
  • Estrone and estrone quinol levels were determined by LC/APCI-MS/MS and calibration with solutions of known concentrations of estrone (0.02 ⁇ M to 11 ⁇ M) and estrone quinol (0.2 ⁇ M to 125 ⁇ M) extracted for analyses.
  • the chromatographic peak areas for estrone and estrone quinol were obtained from m/z 271 ⁇ 253 and m/z 287 ⁇
  • the rate of conversion at 37 °C and with a 10-fold access of the ubiquitous reducing agent NADPH is 6.0 x 10 "7 ⁇ 4 x 10 "8 M-min "1 , which indicates a rapid process required for the proposed action of a quinol as a prodrug.
  • Enzymes may also catalyze reductions in the eye. See Sichi H and D.W. Nebert, "In: Extrahepatic Metabolism of Drugs and Other Foreign Compounds (Gram TE, Ed.),” S.P. Medical and Scientific Books, New York, pp. 333-363 (1980), and Starka L and J. Obenberger. (In vitro estrone- estradiol-17beta interconversion in cornea, lens, iris and retina of rabbit eye," Arch Klin
  • a steroidal quinol according to the subject invention contains a hydroxyl group (i.e., 17-OH group or 10/3-OH group)
  • an "ester" moiety can replace the hydroxyl portion to form a non-acidic (neutral) ester compound.
  • a polar functional group i.e., tertiary amide or phosphate ester
  • the following compounds of Formula III, Formula Ilia and Formula Illb illustrate polar functional groups attached at the 17-OH group.
  • each R and R' is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkoxy, aralkyl, aryloxy, hydroxyalkyl, alkoxyalkyl, heteroaralkyl, heterocyclealkyl, heteroaryloxy; and heterocyclearalkoxy;
  • X is an electrolyte; and n is an integer from 1 to 20.
  • a solution of 10/3,17 ⁇ -dihydroxyestra-l,4-diene-3one (Formula I, estradiol quinol) in chloroform or ethyl acetate bromoacetic anhydride, DCC, and DMAP are added.
  • the resulting mixture is stirred at 20-25 °C for 48 hours.
  • the organic solution is extracted with water then dried over Na2SO4 and evaporated.
  • the residue is purified by chromatography (silica gel: Aldrich, Merck grade 60, 230-400 mesh, 32 x 2 cm; elution with hexane containing gradually increasing concentrations of ethyl acetate from 0 to 6%).
  • the purified residue in hexane is then placed in a closed system under argon, and trimethylamine (gas) was added at 20-25 °C then the precipitate was filtered, and rinsed with hexane.
  • the resultant prodrug of estradiol quinol (10/3,17 ⁇ -dihydroxyestra- 1,4- diene-3-one-17-acetyl-trimethylammonium bromide) should have adequate solubility and sufficient stability to allow for formulation and storage.
  • the exemplary prodrug of estrone quinol is easily converted through an enzymatic or chemical process to the active compound, estrone, within the body, preferably the eye.
  • a prodrug of Formula I can be obtained
  • R, R', X, and n are as defined above.
  • Phosphate esters can also be attached as a polar functional group to enhance water affinity of steroidal quinols.
  • phosphate ester prodrugs of estrogens according to the present invention can be prepared by an ester linkage to one of the hydroxyl groups of the head group of an steroidal quinol.
  • the prodrug of estradiol in accordance with the present invention, may be prepared using general methods as depicted in the following Schemes IHa and Illb.
  • Scheme Ilia depicted in the following Schemes IHa and Illb.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un mécanisme selon lequel des composés de quinol stéroïdien ont un effet bénéfique sur l'oeil. Lesdits composés présentent un équilibre lipophile-hydrophile favorisant la pénétration transcornéenne et se transforment facilement en composés stéroïdiens à cycle A phénolique assurant une protection et/ou le traitement de différents symptômes ou troubles de l'oeil. Ces prodrogues présentent une solubilité des lipides optimale pour la pénétration transcornéenne et se transforment facilement d'agents réducteurs endogènes en composés stéroïdiens à cycle A phénolique. Dans la mesure où ces prodrogues ont peu d'effets féminisants et une faible toxicité systémique, on peut en attendre une protection et un traitement de l'oeil contre des troubles telles que la cataracte et le glaucome, sans toutefois présenter d'effets secondaires.
EP03796804A 2002-12-09 2003-12-09 Prodrogues utilisees comme agents ophtalmiques Withdrawn EP1569648A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US43235402P 2002-12-09 2002-12-09
US432354P 2002-12-09
US405413 2003-04-01
US10/405,413 US7026306B2 (en) 2002-04-01 2003-04-01 Steroidal quinols and their use for antioxidant therapy
PCT/US2003/038987 WO2004069248A1 (fr) 2002-12-09 2003-12-09 Prodrogues utilisees comme agents ophtalmiques

Publications (2)

Publication Number Publication Date
EP1569648A1 true EP1569648A1 (fr) 2005-09-07
EP1569648A4 EP1569648A4 (fr) 2006-10-04

Family

ID=32853159

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03796804A Withdrawn EP1569648A4 (fr) 2002-12-09 2003-12-09 Prodrogues utilisees comme agents ophtalmiques

Country Status (3)

Country Link
EP (1) EP1569648A4 (fr)
AU (1) AU2003297739A1 (fr)
WO (1) WO2004069248A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2910486A (en) * 1957-12-20 1959-10-27 Searle & Co 10-hydroxyestra-1, 4-diene-3, 17-dione and acetate
US5041434A (en) * 1991-08-17 1991-08-20 Virginia Lubkin Drugs for topical application of sex steroids in the treatment of dry eye syndrome, and methods of preparation and application
US5646136A (en) * 1994-01-04 1997-07-08 Duke University Methods of inhibiting angiogenesis and tumor growth, and treating ophthalmologic conditions with angiostatic and therapeutic steroids
DE19654750A1 (de) * 1996-12-30 1998-07-02 Helmut Dr Med Zander Verwendung von Wirkstoffen mit Östrogen-Wirkung zur Vorbeugung und Behandlung von Makuladegeneration
WO2002036605A2 (fr) * 2000-11-03 2002-05-10 Washington University Structures de cycles aromatiques modifies a substitution hydroxy et a activite cytoprotectrice
WO2003084978A1 (fr) * 2002-04-01 2003-10-16 University Of Florida Hydroquinones steroides utilisees comme promedicaments d'antioxydants

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0841929B1 (fr) * 1995-08-02 2003-05-07 Darwin Discovery Limited Quinolones et leur utilisation therapeutique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2910486A (en) * 1957-12-20 1959-10-27 Searle & Co 10-hydroxyestra-1, 4-diene-3, 17-dione and acetate
US5041434A (en) * 1991-08-17 1991-08-20 Virginia Lubkin Drugs for topical application of sex steroids in the treatment of dry eye syndrome, and methods of preparation and application
US5646136A (en) * 1994-01-04 1997-07-08 Duke University Methods of inhibiting angiogenesis and tumor growth, and treating ophthalmologic conditions with angiostatic and therapeutic steroids
DE19654750A1 (de) * 1996-12-30 1998-07-02 Helmut Dr Med Zander Verwendung von Wirkstoffen mit Östrogen-Wirkung zur Vorbeugung und Behandlung von Makuladegeneration
WO2002036605A2 (fr) * 2000-11-03 2002-05-10 Washington University Structures de cycles aromatiques modifies a substitution hydroxy et a activite cytoprotectrice
WO2003084978A1 (fr) * 2002-04-01 2003-10-16 University Of Florida Hydroquinones steroides utilisees comme promedicaments d'antioxydants

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BIGSBY R M ET AL: "Protective effects of estrogen in a rat model of age-related cataracts" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE, WASHINGTON, DC, US, vol. 96, August 1999 (1999-08), pages 9328-9332, XP002980815 ISSN: 0027-8424 *
MCKINNEY K A ET AL: "Hormone replacement therapy and the eye" JOURNAL OF THE BRITISH MENOPAUSE SOCIETY, BRITISH MENOPAUSE SOCIETY, MARLOW, GB, vol. 6, no. 1, 2000, pages 15-17, XP002980814 ISSN: 1362-1807 *
PROKAI L ET AL: "CHEMICAL SHIELD MECHANISM FOR ESTROGEN NEUROPROTECTION: STEROIDAL QUINOLS AS NEW MOLECULE LEADS" AMERICAN CHEMICAL SOCIETY. ABSTRACTS OF PAPER. AT THE NATIONAL MEETING, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 225, no. 1/2, 23 March 2003 (2003-03-23), - 27 March 2003 (2003-03-27) XP008042778 ISSN: 0065-7727 *
PROKAI L: "QUINOL-BASED METABOLIC CYCLE FOR ESTROGENS IN RAT LIVER MICROSOMES" DRUG METABOLISM AND DISPOSITION, WILLIAMS AND WILKINS., BALTIMORE, MD, US, vol. 31, no. 6, June 2003 (2003-06), pages 701-704, XP008042777 ISSN: 0090-9556 *
See also references of WO2004069248A1 *

Also Published As

Publication number Publication date
EP1569648A4 (fr) 2006-10-04
AU2003297739A1 (en) 2004-08-30
WO2004069248A1 (fr) 2004-08-19
AU2003297739A8 (en) 2004-08-30

Similar Documents

Publication Publication Date Title
US7572781B2 (en) Prodrugs for use as ophthalmic agents
FI120940B (fi) Bentsopyraanijohdannaisia ja näiden farmaseuttisesti hyväksyttävät suolat, mainittujen bentsopyraanijohdannaisten ja niiden suolojen käyttö valmistettaessa estrogeenille herkän taudin hoitoon tarkoitettua lääkevalmistetta ja farmaseuttinen koostumus
CA2124932C (fr) Inhibiteurs de l'activite des hormones sexuelles steroidiennes
US20070010505A1 (en) Methods of treating disease states using antiangiogenic agents
EP1756139A2 (fr) Agents anti-angiogeniques
WO2008011005A2 (fr) Agents anti-angiogéniques
WO1996000236A1 (fr) Derive du triterpene et preparation medicinale associee
CA2414583C (fr) 7-beta-hydroxysteroides neuroprotecteurs
JP2022065030A (ja) １５β－［３－プロパンアミド］－置換エストラ－１，３，５（１０）－トリエン－１７－オン化合物および１７β－ヒドロキシステロイドデヒドロゲナ－ゼの阻害に使用するためのそれらの１７－オキシム
US7534779B2 (en) Quinol compound and pharmaceutical composition
EP2980096B1 (fr) Procédés de préparation de 2 , 3 , 5 -trihydroxy-androst-6-one et utilisation de ce composé
WO2004069248A1 (fr) Prodrogues utilisees comme agents ophtalmiques
WO2016102775A1 (fr) Promédicaments d'inhibiteurs de 17β-hsd1
GB2378898A (en) Prophylactic and therapeutic use of hydroxysteroids
PT1490392E (pt) Quinóis esteroidais como pró-fármacos de antioxidantes
US5998638A (en) Ester salt of 5α-pregn-16-en-3β-ol-20-one 3-sulfate
WO1998028324A9 (fr) Steroides substitues en position 11, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant
RU2294332C2 (ru) Стероидное соединение, его применение и способ лечения
SK2442003A3 (en) 4-Halogenated 17-methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds
FR2622194A1 (fr) Nouveaux derives de la 19-nor progesterone, leur procede d'obtention et les compositions pharmaceutiques en contenant
EP1294446A2 (fr) Composes polycycliques modifies d'alkyle ether ayant un phenol terminal et utilisations pour la protection de cellules

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050616

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20060905

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/567 20060101ALI20060830BHEP

Ipc: A61K 31/565 20060101ALI20060830BHEP

Ipc: A61K 31/566 20060101ALI20060830BHEP

Ipc: A61K 31/47 20060101AFI20040824BHEP

RIN1 Information on inventor provided before grant (corrected)

Inventor name: AGARWAL, NEERAJ

Inventor name: SIMPKINS, JAMES

Inventor name: PROKAI, KATALIN

Inventor name: PROKAI, LASZLO

RIN1 Information on inventor provided before grant (corrected)

Inventor name: AGARWAL, NEERAJ

Inventor name: SIMPKINS, JAMES

Inventor name: PROKAI, KATALIN

Inventor name: PROKAI, LASZLO

17Q First examination report despatched

Effective date: 20070604

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: C07J 1/00 20060101ALI20100914BHEP

Ipc: A61K 9/08 20060101ALI20100914BHEP

Ipc: A61P 27/02 20060101ALI20100914BHEP

Ipc: A61K 31/566 20060101ALI20100914BHEP

Ipc: A61K 31/565 20060101AFI20100914BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110218