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(12) Patent Application Publication (10) Pub. No.: US 2004/0171596 A1 Prokai Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0171596 A1 Prokai Et Al US 2004.0171596A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0171596 A1 Prokai et al. (43) Pub. Date: Sep. 2, 2004 (54) PRODRUGS FOR USE AS OPHTHALMIC Publication Classification AGENTS (51) Int. Cl. ................................................. A61K 31/56 (76) Inventors: Laszlo Prokai, Gainesville, FL (US); (52) U.S. Cl. ............................................ 514/178; 514/182 Katalin Prokai, Gainesville, FL (US); James Simpkins, Fort Worth, TX (US); Neeraj Agarwal, Fort Worth, TX (US) (57) ABSTRACT Correspondence Address: SALIWANCHIK LLOYD & SALWANCHIK The subject invention provides a mechanism by which A PROFESSIONAL ASSOCATION Steroidal quinol compounds confer beneficial ophthalmic 2421 N.W. 41ST STREET effects. The Subject compounds possess a lipophilic-hydro SUTE A-1 philic balance for transcorneal penetration and are readily GAINESVILLE, FL 32606-6669 (US) reduced into parent phenolic A-ring Steroid compounds to provide protection or treatment against various ocular Symp (21) Appl. No.: 10/731,528 toms and disorders. The compounds according to the Subject invention appear to be highly advantageous as prodrugs to (22) Filed: Dec. 9, 2003 provide protection and/or treatment against ocular disorders. Related U.S. Application Data These prodrugs confer lipid Solubility optimal for transo corneal penetration and are readily converted to endogenous (63) Continuation-in-part of application No. 10/405,413, reducing agents into active phenolic A-ring Steroid com filed on Apr. 1, 2003. pounds. To the extent that these prodrugs have reduced feminizing effects and Systemic toxicity, they would be (60) Provisional application No. 60/369,589, filed on Apr. expected to be quite advantageous for protecting or treating 1, 2002. Provisional application No. 60/432,354, filed the eye against ocular disorderS Such as cataract or glaucoma on Dec. 9, 2002. without undesired (systemic) side effects). Patent Application Publication Sep. 2, 2004 Sheet 1 of 4 US 2004/0171596 A1 6 s an 3 9n ca. a.o vars. CD a. O O t- ZYC1) (5mM Glu) FIG. 1 1 OO 5mM Glu 57O5 2 5 o s C 5 s OE R s d dh O R. s S O y E. S. + 1 uMZYC1 FIG 2 Patent Application Publication Sep. 2, 2004 Sheet 2 of 4 US 2004/0171596 A1 O OR O a) R = COCH (quinol acetate) b) Ras H (quinol) FIG. 3 OH OH RON R = H, alkyl (Me, Et) or substituted alkyl FIG. 4 Patent Application Publication Sep. 2, 2004 Sheet 3 of 4 US 2004/0171596 A1 |eA?A.InS9% 5 mM Glu FIG 5 Patent Application Publication Sep. 2, 2004 Sheet 4 of 4 US 2004/0171596 A1 FIG. 6 10 t; 1.38 min Area: 66.625O16O 50 O t: 4.50 min Area: 181767539 O .O 1.0 2.0 3.0 4.0 5.0 6.0 FIG. 7 Time (min) 6 O 4 O 2 O O OO 2O 40 160 180 m 200 22O 240 260 28O FIG. 8 100 197 8 O 6 O 4.O 2 O 211 225 107 121 133 145 O OO 120 140 160 180 200 220 240 260 280 US 2004/0171596 A1 Sep. 2, 2004 PRODRUGS FOR USE AS OPHTHALMC AGENTS even eliminating Systemic side effects is to improve ocular targeting that would allow for the use of reduced doses of the CROSS-REFERENCE TO RELATED biologically active agent in the ophthalmic drug formation. APPLICATIONS 0007 Accordingly, the direct administration to an eye 0001. This application is a continuation-in-part applica lens of estrogen having quinolines (i.e., 6-hydroxyquinoline) tion of U.S. Ser. No. 10/405,413, filed Apr. 1, 2003; which and fused quinolines that act as Steroid receptor modulators claims the benefit of U.S. provisional patent application to prevent or treat cataract disorderS has been disclosed. In Serial No. 60/369,589, filed Apr. 1, 2002. This application addition, the administration of 17-f-estradiol to the surface also claims the benefit of U.S. provisional patent application of the eye to alleviate dry-eye syndrome or keratoconjunc Serial No. 60/432,354, filed Dec. 9, 2002. tivitis Sicca has been disclosed. Glycosides of catechol estrogens have been formulated that demonstrate antioxi FIELD OF THE INVENTION dant activity to the same degree as to that of the parent catechol estrogens. Nonetheless, all of the previously dis 0002 The present invention relates to prodrugs for use as closed compounds and methods for applying estrogens to ophthalmic agents, Specifically for retinal protection. In the eye relate to compounds that lack efficient corneal particular, the present invention relates to the use of Steroidal penetration and/or are unapplicable to men because of their quinols as prodrugs of phenolic A-ring Steroid compounds to activity as a female hormone. treat and/or prevent eye pathologies. 0008 AS noted above, the major barrier to ocular drug penetration is the cornea. The cornea is composed of three BACKGROUND OF INVENTION layers: a lipid-rich epithelium, a lipid-poor Soma, and a 0003) A variety of tissues metabolize estrogen (as a lipid-rich endothelium. Therefore, an agent must possess representative phenolic A-ring Steroid) to various degrees. both lipophilic-hydrophilic balance for adequate transcor Of all of the tissues investigated, cornea appears to be the neal penetration and, thus, ocular bioavailability (Akers HJ, most active estrogen-metabolizing tissue (Starka, L and J “Ocular bioavailability of topically applied ophthalmic Obenberger, “In vitro Estrone-Estradiol-17f8 Interconver drugs.”Am Pharm, NS23:33-36 (1983)). Thus, poor ocular Sion in the Cornea, Lens, Iris and Retina of the Rabbit bioavailability is an issue for estrogens and their Synthetic Eye,’Arch Klin Exp Ophthalmol, 196:199-204 (1975)). analogs, because estrogens are highly lipid Soluble mol Estrogens have demonstrated an important role in the health ecules that are usually not amenable to adequate transcor maintenance of all mucous membranes in the body, includ neal penetration. ing the maintenance of a healthy ocular Surface. Additional 0009 Prodrugs are inactive compounds that are con Studies have revealed that the biological activity of estrogen verted in Vivo into biologically active agents by enzymatic may be effective in the protection and treatment of the eye, and/or chemical transformations. Prodrugs are advantageous including the lens and retina, against cataracts and the because they can be designed to overcome problems asso detrimental effects of glaucoma. ciated with Stability, toxicity, lack of Specificity, or limited 0004. Unfortunately, many regions of the eye are rela bioavailability, that may exist with the active form of a drug. tively inaccessible to Systemically administered estrogens. Thus, there is a need to develop effective prodrugs of For example, orally administered estrogen passes through estrogen as a medical compound. the liver before reaching estrogen Sensitive tissues. Because 0010 Estrogen quinols have been known for decades the liver contains enzymes that can inactivate the estrogen, among organic chemists (Gold A. M., and Schwenk E., the estrogen that eventually reaches tissue targeted for “Synthesis and reaction of steroidal quinols,'J Am Chem treatment is virtually ineffective. Moreover, Systemic admin Soc, 80:5683-5687 (1958)) though their metabolic formation istration of estrogen often produces undesirable Side effects, has only been reported recently (Ohe T, et al., “Novel i.e., feminizing Side effects in men. metabolic pathway of estrone and 17(3-estradiol catalyzed by 0005. As a result, topical drug delivery remains the cytochrome P-450', Drug Metab Dispos, 28:11-112 preferred route of administration to the eye. There are a (2000)). 10B-hydroxy-1,4-estradiene-3,7-dione and 103, variety of factors that affect the absorption of drugs into the 17 B-dihydroxy-1,4-estradiene-3-one were detected from the eye. These factors include: the instillation volume of the respective estrogens during metabolic oxidation catalyzed drug, the frequency of instilled drug administration, the by several cytochrome P-450 isoenzymes in rat liver Structure and integrity of the cornea, the protein level in microSomal Systems. Contrary to well-known catechol tears, the level of enzymes in tears, lacrimal drainage and metabolites of estrogens (Zhu, B. T. and Conney A. H., tear turnover rate, as well the rate of adsorption and absorp "Functional role of estrogen metabolism in target cells: tion of a drug by the conjunctiva, Sclera, and eyelids. review and perspective,” Carcinogenesis, 19:1-27 (1998)), quinols do not possess an aromatic A-ring, making their 0006 Thus, the potential treatment of ocular disorders/ biochemistry substantially different from that of catechols. conditions by estrogens or agents derived from estrogens is Studies are currently underway to assess the nature of confounded by poor ocular bioavailability of pharmacologi estrogen quinols. cally active agents and by the likelihood of triggering Systemic Side effects associated with the administration of natural (endogenous) estrogens. The latter are due to absorp BRIEF SUMMARY tion from the nasal cavity and the gastrointestinal (GI) tract 0011. The Subject invention provides materials and meth after the topically administered estrogen hormone gains ods wherein unique and advantageous Steroidal quinols are access to these pathways through its removal by the naso used for a broad range of therapeutic purposes, including the lacrimal apparatus of the eye. A potential way of reducing or treatment or prevention of ophthalmic disorders and/or US 2004/0171596 A1 Sep. 2, 2004 conditions by modulating or activating estrogen receptors. group or may have the 10-OH group esterified to decrease These disorders and/or conditions include, but are not lim lipophilicity through phosphate, or N,N,N-trialkylammo ited to, conjunctivitis, diabetic retinopathy, dry eye, glau nium esters. coma, and cataract. 0017. In another embodiment, the 3,17-keto groups of 0012. A quinol (i.e., the 10C.f3-hydroxyestra-1,4-diene quinols of the present invention can be functionalized as 3-one structures) derived Synthetically from phenolic A-ring Oxime and/or alkoximes.
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