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US20140256696A1 - Steroid conjugates - Google Patents

Steroid conjugates Download PDF

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Publication number
US20140256696A1
US20140256696A1 US14/199,514 US201414199514A US2014256696A1 US 20140256696 A1 US20140256696 A1 US 20140256696A1 US 201414199514 A US201414199514 A US 201414199514A US 2014256696 A1 US2014256696 A1 US 2014256696A1
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United States
Prior art keywords
oxo
phenanthren
cyclopenta
dihydroxy
dodecahydro
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Abandoned
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US14/199,514
Inventor
Santosh C. Sinha
Ken Chow
Liming Wang
Michael E. Garst
Mayssa Attar
Brandon D. Swift
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Allergan Inc
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Allergan Inc
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Priority to US14/199,514 priority Critical patent/US20140256696A1/en
Assigned to ALLERGAN, INC. reassignment ALLERGAN, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ATTAR, MAYSSA, SWIFT, BANDON D., CHOW, KEN, GARST, MICHAEL E., SINHA, SANTOSH C., WANG, LIMING
Publication of US20140256696A1 publication Critical patent/US20140256696A1/en
Abandoned legal-status Critical Current

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    • A61K47/481—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • 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
    • 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
    • A61P27/14—Decongestants or antiallergics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides

Definitions

  • the present invention describes steroid conjugates. These single drug entities are formed by connecting two or more steroids via a linker. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual steroid drugs.
  • a conjugate drug also referred to as a co-drug, a pro-drug, or a hybrid drug, comprises two or more different or same drugs within one single chemical entity wherein each drug contains an appropriate chemical functionality to enable them to be connected together, either directly or by means of a covalent linker, which is cleavable, biologically labile.
  • Hybrid structures can incorporate two drugs joined together by a linker moiety such as an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, which is cleaved enzymatically or hydrolytically in vivo to release the active drugs.
  • a linker moiety such as an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, which is cleaved enzymatically or hydrolytically in vivo to release the active drugs.
  • each bond has a chemical functionality such as an ester, a carbonate, an amide, a carbamate, an ether, an oxo, a ketone, an amine.
  • the single drug entity can have one ether bond connecting to one steroid and one ester bond connecting to the other steroid or one ester bond connecting to each steroid or one ether bond connecting each steroid.
  • Degradation of these covalent bonds generally, yields the corresponding acid, or alcohol by hydrolysis or a by related reaction.
  • a compound which degrades in vivo to yield the individual steroids produces the active steroid drugs at some point in the metabolic process of the claimed compound. In many cases, cleavage of the first ester bond will release one active, and cleavage of the second ester bond will release the second active.
  • the hybrid drugs of the invention provide a unique delivery of two steroids for the treatment of ophthalmic bacterial infections and for the prevention of inflammation and infection.
  • a single drug entity is advantageous to individual dosing of each drug because of the ability for simultaneous dosing and elimination of washout concerns when applying each drug separately.
  • the use of an anti-inflammatory hybrid drug is indicated where the risk of infection is high.
  • the anti-inflammatory component of the composition is useful in treating inflammation associated with physical trauma to ophthalmic tissues, inflammation associated with bacterial infections and inflammation resulting from surgical procedures.
  • the composition of the invention may also be used prophylactically in connection with various ophthalmic surgical procedures that create a risk of bacterial infection.
  • Other examples of ophthalmic conditions which may be treated with the compositions of the present invention include infective conditions associated with inflammation and where the use of anti-inflammatory is acceptable.
  • Such conditions may include, but are not limited to conjunctivitis, keratitis, blepharitis, endophthalmitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, red eye, hyperemia, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, red eye, hyperemia, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, ulceris, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation,
  • the compounds disclosed herein comprise at least one steroidal drug selected from, but not limited to: dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone.
  • the invention provides the compounds represented by a hybrid drug as described below.
  • the invention provides compounds which may comprise a linker moiety selected from, but not limited to, an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, an ethylene.
  • a linker moiety selected from, but not limited to, an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, an ethylene.
  • the invention provides compounds which may comprise a linker moiety comprising any combination of an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an ethylene, an amino, an oxo, an ethylene glycol and/or a polyethylene glycol.
  • linkers moieties and linker structures are exemplified in Table 1.
  • ester moieties comprised in the linkers are:
  • Examples of carboxylate moieties comprised in the linkers are:
  • Example of a carbonate moiety comprised in the linkers is:
  • amido moieties comprised in the linkers are:
  • Example of carbamate moiety comprised in the linkers is:
  • Example of a ketone moiety comprised in the linkers is:
  • amino moieties comprised in the linkers are:
  • Example of an oxo moiety comprised in the linker is:
  • Example of ethylene glycol moieties comprised in the linkers are:
  • Example of polyethylene glycol moiety comprised in the linkers is:
  • the invention provides compounds which may comprise a linker moiety or a linker structure selected from Table 1:
  • Preferred linkers of the invention have a carbonyl functional group at each end, in order to form a carboxylate group with the oxygen atom of the steroid.
  • Preferred linkers are: L41, L42, L44, L52, L53, L54, L55, L58, L56, L57, L60, L61, L62, L63, L64, L65, L66, L67, L68, L69, L70, L71, L76, L78, L79, L80, L81, L82, L83, L84, L90, L92, L93, L94, L95, L96, L97, L98, L99, L103, L104.
  • the compounds of the invention comprise two of prednisolone moiety such as the compounds below:
  • the compounds of the invention comprise a prednisolone moiety and a betamethasone moiety as shown below:
  • the compounds of the invention comprise a prednisolone moiety and a dexamethasone moiety as shown below:
  • the compounds of the invention comprise a prednisolone moiety and a hydrocortisone moiety as shown below:
  • the compounds of the invention comprise two hydrocortisone moieties as shown below:
  • the compounds of the invention comprise a betamethasone moiety and a dexamethasone moiety as shown below:
  • the invention provides a hybrid compound comprising two steroid moieties, or a pharmaceutical salt thereof, which are separately connected via a covalent bond to a linker such that said compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond.
  • the invention provides a hybrid compound wherein at least one steroid is selected from the group consisting of dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone.
  • the invention provides a hybrid compound, comprising two prednisolone moieties.
  • the invention provides a hybrid compound, comprising one prednisolone moiety and one betamethasone moiety.
  • the invention provides a hybrid compound, comprising one prednisolone moiety and one dexamethasone moiety.
  • the invention provides a hybrid compound, comprising one prednisolone moiety and one hydrocortisone moiety.
  • the invention provides a hybrid compound, comprising one betamethasone moiety and one dexamethasone moiety.
  • the invention provides a hybrid compound, comprising two hydrocortisone moieties.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a hybrid compound comprising two steroid moieties, which are separately connected via a covalent bond to a linker, such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said pharmaceutical composition is formulated for topical ophthalmic administration.
  • the invention provides a method comprising administration to an eye of a mammal a hybrid compound comprising two steroid moieties, which are separately connected via a covalent bond to a linker such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said method is effective in the treatment of an inflammation condition affecting said eye.
  • the invention provides a method wherein said hybrid compound has topical steroid activity upon a surface of an eye, and wherein the hybrid compound degrades on said surface into one or more of said smaller active steroids which are capable of penetrating beyond tissue of said surface.
  • the invention provides a hybrid compound comprising a linker having two bonds, wherein said bonds are asymmetrically degraded in vivo to release the two steroid moieties.
  • stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
  • pharmaceutically acceptable salts refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects.
  • pharmaceutically acceptable salts according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of the invention are able to form.
  • the acid addition salt form of a compound of the invention that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic acid and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).
  • an appropriate acid such as an inorganic
  • the base addition salt form of a compound of the invention that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like
  • an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • solvates include for example hydrates, alcoholates and the like.
  • the present invention concerns the use of a compound of the invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis.
  • the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
  • the compounds of the invention may also be administered as pharmaceutical compositions in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.
  • compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use.
  • the therapeutically efficient amount typically is between about 0.001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
  • solutions are prepared using a physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
  • the formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • a preferred surfactant is, for example, Tween 80.
  • various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations are chelating agents.
  • the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
  • the ingredients are usually used in the following amounts:
  • Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.8 antioxidant as needed surfactant as needed purified water to make 100%
  • the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye.
  • Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
  • One package may contain one or more unit doses.
  • Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops.
  • the volume of one drop usually is about 20-35 ⁇ l.
  • the patient may be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea.
  • routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery.
  • the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
  • compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof.
  • pharmaceutically acceptable means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • the compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions such as conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, ulceris, cyclitis, selected infective conjunctivitis, corneal
  • atocojunctivitis sicca dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, ulceris, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and
  • Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound.
  • a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the subject in need thereof is a mammal. In some embodiments, the mammal is human.
  • the present invention concerns also processes for preparing the hybrid compounds disclosed herein.
  • the hybrid compounds according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.
  • the synthetic scheme set forth below, illustrates how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention.
  • the carboxylic intermediate can be coupled with a polyethylene glycol to form a corresponding alcohol, which can be coupled with another succinic anhydride molecule and then with another steroid of formula R′—CH 2 —OH to form a hybrid with a polyethylene and ketone moieties.
  • the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
  • the present invention includes all pharmaceutically acceptable isotopically enriched compounds.
  • Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of hydrogen 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S.
  • the use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention.
  • These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
  • characterization of the compounds is performed according to the following methods.
  • Proton nuclear magnetic resonance ( 1 H NMR) and carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Varian 300 or 600 MHz spectrometer in deuterated solvent.
  • Chemical shifts were reported as ⁇ (delta) values in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm) and multiplicities were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
  • Data were reported in the following format: chemical shift (multiplicity, coupling constant(s) J in hertz (Hz), integrated intensity).
  • the mass spectrometry data were determined on a Shimadzu LCMS-IT-TOF instrument.
  • the formation of the hybrid compounds was checked by 1 H-NMR, comparing the chemical shifts of the protons from the CH 2 group identified in the schemes shown below, and identified as “CH 2 c ” for the starting material and as “CH 2 c* ” or “c*” for of the corresponding protons on the newly formed hybrid molecule wherein “*” indicates the hybrid compound.
  • Applicants have marked with arrows the location of these protons and the reaction site of the prodrug moiety, where available.
  • Each scheme shows the formation of the new hybrid drug.
  • Each table describes the results for the new hybrid drug and the linker number, where existing.
  • the linker moiety numbers are as described in Table 1.
  • Human recombinant carboxylesterases were purchased from a commercial vendor (BD GentestTM, Bedford, Mass.). All metabolic stability experiments were performed in triplicate in 96-well plate format.
  • the samples were analyzed by liquid chromatography with mass spectrometry (LC-MS/MS) detection to determine the metabolite concentrations resulting from the metabolism of the hybrid compounds.
  • Internal standards were used to compensate for variability from sample processing, chromatographic elution, mass spectrometer response and ion suppression by matrix components.
  • Table 9 lists the rate of metabolite formation in human recombinant carboxylesterases.

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Abstract

The present invention describes steroid conjugates. These single drug entities are formed by connecting two or more steroids via a linker. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual steroid drugs.

Description

    RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/775,216 filed Mar. 8, 2013, the disclosure of which is hereby incorporated in its entirety by reference.
    • FIELD OF THE INVENTION
  • The present invention describes steroid conjugates. These single drug entities are formed by connecting two or more steroids via a linker. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual steroid drugs.
    • SUMMARY OF THE INVENTION
  • A conjugate drug, also referred to as a co-drug, a pro-drug, or a hybrid drug, comprises two or more different or same drugs within one single chemical entity wherein each drug contains an appropriate chemical functionality to enable them to be connected together, either directly or by means of a covalent linker, which is cleavable, biologically labile.
  • Hybrid structures can incorporate two drugs joined together by a linker moiety such as an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, which is cleaved enzymatically or hydrolytically in vivo to release the active drugs.
  • By appropriate structural design of these linkers, it may be possible to control the release of each drug. When the drugs are chemically combined, the resulting hybrid will usually have different physicochemical properties compared to the individual parent drugs, which may provide superior properties for delivery when compared to delivery of a physical mixture of the drugs. The steroid moieties, of the compounds disclosed herein are connected via two covalent bonds to a linker such that said compound degrades in vivo to yield the individual steroids. Depending on the nature of the linker and depending on the nature of the compound, each bond has a chemical functionality such as an ester, a carbonate, an amide, a carbamate, an ether, an oxo, a ketone, an amine. In other words, the single drug entity can have one ether bond connecting to one steroid and one ester bond connecting to the other steroid or one ester bond connecting to each steroid or one ether bond connecting each steroid.
  • Degradation of these covalent bonds generally, yields the corresponding acid, or alcohol by hydrolysis or a by related reaction. A compound which degrades in vivo to yield the individual steroids, produces the active steroid drugs at some point in the metabolic process of the claimed compound. In many cases, cleavage of the first ester bond will release one active, and cleavage of the second ester bond will release the second active.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The hybrid drugs of the invention provide a unique delivery of two steroids for the treatment of ophthalmic bacterial infections and for the prevention of inflammation and infection. A single drug entity is advantageous to individual dosing of each drug because of the ability for simultaneous dosing and elimination of washout concerns when applying each drug separately.
  • The use of an anti-inflammatory hybrid drug is indicated where the risk of infection is high. The anti-inflammatory component of the composition is useful in treating inflammation associated with physical trauma to ophthalmic tissues, inflammation associated with bacterial infections and inflammation resulting from surgical procedures. The composition of the invention may also be used prophylactically in connection with various ophthalmic surgical procedures that create a risk of bacterial infection. Other examples of ophthalmic conditions which may be treated with the compositions of the present invention include infective conditions associated with inflammation and where the use of anti-inflammatory is acceptable. Such conditions may include, but are not limited to conjunctivitis, keratitis, blepharitis, endophthalmitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, red eye, hyperemia, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, red eye, hyperemia, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.
  • The compounds disclosed herein comprise at least one steroidal drug selected from, but not limited to: dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone.
  • In one aspect the invention provides the compounds represented by a hybrid drug as described below.
  • Figure US20140256696A1-20140911-C00001
  • In another aspect the invention provides compounds which may comprise a linker moiety selected from, but not limited to, an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, an ethylene.
  • In another aspect, the invention provides compounds which may comprise a linker moiety comprising any combination of an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an ethylene, an amino, an oxo, an ethylene glycol and/or a polyethylene glycol. Such linkers moieties and linker structures are exemplified in Table 1.
  • Examples of ester moieties comprised in the linkers are:
  • Figure US20140256696A1-20140911-C00002
  • Examples of carboxylate moieties comprised in the linkers are:
  • Figure US20140256696A1-20140911-C00003
  • Example of a carbonyl moiety comprised in the linkers is
  • Figure US20140256696A1-20140911-C00004
  • Example of a carbonate moiety comprised in the linkers is:
  • Figure US20140256696A1-20140911-C00005
  • Examples of amido moieties comprised in the linkers are:
  • Figure US20140256696A1-20140911-C00006
  • Example of carbamate moiety comprised in the linkers is:
  • Figure US20140256696A1-20140911-C00007
  • Example of a ketone moiety comprised in the linkers is:
  • Figure US20140256696A1-20140911-C00008
  • Examples of amino moieties comprised in the linkers are:
  • Figure US20140256696A1-20140911-C00009
  • Example of an oxo moiety comprised in the linker is:
  • Figure US20140256696A1-20140911-C00010
  • Example of ethylene glycol moieties comprised in the linkers are:
  • Figure US20140256696A1-20140911-C00011
  • Example of polyethylene glycol moiety comprised in the linkers is:
  • Figure US20140256696A1-20140911-C00012
  • In another aspect, the invention provides compounds which may comprise a linker moiety or a linker structure selected from Table 1:
  • TABLE 1
    Linker Moiety Number or
    Linker Structure Number
    Linker Moiety or Linker Structure n = 0 n = 1 n = 2 n = 3
    Figure US20140256696A1-20140911-C00013
         		L2 L1
    Figure US20140256696A1-20140911-C00014
         		L3
    Figure US20140256696A1-20140911-C00015
         		L4
    Figure US20140256696A1-20140911-C00016
         		L35 L5
    Figure US20140256696A1-20140911-C00017
         		L6
    Figure US20140256696A1-20140911-C00018
         		L7
    Figure US20140256696A1-20140911-C00019
         		L14
    Figure US20140256696A1-20140911-C00020
         		L15
    Figure US20140256696A1-20140911-C00021
         		L16
    Figure US20140256696A1-20140911-C00022
         		L46 L17
    Figure US20140256696A1-20140911-C00023
         		L8
    Figure US20140256696A1-20140911-C00024
         		L9
    Figure US20140256696A1-20140911-C00025
         		L10
    Figure US20140256696A1-20140911-C00026
         		L18
    Figure US20140256696A1-20140911-C00027
         		L11
    Figure US20140256696A1-20140911-C00028
         		L19
    Figure US20140256696A1-20140911-C00029
         		L12
    Figure US20140256696A1-20140911-C00030
         		L13
    Figure US20140256696A1-20140911-C00031
         		L20
    Figure US20140256696A1-20140911-C00032
         		L21
    Figure US20140256696A1-20140911-C00033
         		L22
    Figure US20140256696A1-20140911-C00034
         		L23
    Figure US20140256696A1-20140911-C00035
         		L24
    Figure US20140256696A1-20140911-C00036
         		L25
    Figure US20140256696A1-20140911-C00037
         		L26
    Figure US20140256696A1-20140911-C00038
         		L27
    Figure US20140256696A1-20140911-C00039
         		L28
    Figure US20140256696A1-20140911-C00040
         		L29
    Figure US20140256696A1-20140911-C00041
         		L30
    Figure US20140256696A1-20140911-C00042
         		L31
    Figure US20140256696A1-20140911-C00043
         		L32
    Figure US20140256696A1-20140911-C00044
         		L33
    Figure US20140256696A1-20140911-C00045
         		L34
    Figure US20140256696A1-20140911-C00046
         		L35
    Figure US20140256696A1-20140911-C00047
         		L36
    Figure US20140256696A1-20140911-C00048
         		L37
    Figure US20140256696A1-20140911-C00049
         		L38
    Figure US20140256696A1-20140911-C00050
         		L39
    Figure US20140256696A1-20140911-C00051
         		L40
    Figure US20140256696A1-20140911-C00052
         		L41
    Figure US20140256696A1-20140911-C00053
         		L42
    Figure US20140256696A1-20140911-C00054
         		L43
    Figure US20140256696A1-20140911-C00055
         		L44
    Figure US20140256696A1-20140911-C00056
         		L45
    Figure US20140256696A1-20140911-C00057
         		L47
    Figure US20140256696A1-20140911-C00058
         		L48
    Figure US20140256696A1-20140911-C00059
         		L49
    Figure US20140256696A1-20140911-C00060
         		L50
    Figure US20140256696A1-20140911-C00061
         		L51
    Figure US20140256696A1-20140911-C00062
         		L52
    Figure US20140256696A1-20140911-C00063
         		L53
    Figure US20140256696A1-20140911-C00064
         		L54
    Figure US20140256696A1-20140911-C00065
         		L55 L58
    Figure US20140256696A1-20140911-C00066
         		L56
    Figure US20140256696A1-20140911-C00067
         		L57
    Figure US20140256696A1-20140911-C00068
         		L59
    Figure US20140256696A1-20140911-C00069
         		L60
    Figure US20140256696A1-20140911-C00070
         		L61
    Figure US20140256696A1-20140911-C00071
         		L62
    Figure US20140256696A1-20140911-C00072
         		L63
    Figure US20140256696A1-20140911-C00073
         		L64
    Figure US20140256696A1-20140911-C00074
         		L65
    Figure US20140256696A1-20140911-C00075
         		L66
    Figure US20140256696A1-20140911-C00076
         		L67
    Figure US20140256696A1-20140911-C00077
         		L68 L103 L104
    Figure US20140256696A1-20140911-C00078
         		L69
    Figure US20140256696A1-20140911-C00079
         		L70
    Figure US20140256696A1-20140911-C00080
         		L71
    Figure US20140256696A1-20140911-C00081
         		L72
    Figure US20140256696A1-20140911-C00082
         		L73
    Figure US20140256696A1-20140911-C00083
         		L74
    Figure US20140256696A1-20140911-C00084
         		L75
    Figure US20140256696A1-20140911-C00085
         		L76
    Figure US20140256696A1-20140911-C00086
         		L77
    Figure US20140256696A1-20140911-C00087
         		L78
    Figure US20140256696A1-20140911-C00088
         		L79
    Figure US20140256696A1-20140911-C00089
         		L80
    Figure US20140256696A1-20140911-C00090
         		L81
    Figure US20140256696A1-20140911-C00091
         		L82
    Figure US20140256696A1-20140911-C00092
         		L83
    Figure US20140256696A1-20140911-C00093
         		L84
    Figure US20140256696A1-20140911-C00094
         		L85 L86
    Figure US20140256696A1-20140911-C00095
         		L87
    Figure US20140256696A1-20140911-C00096
         		L88
    Figure US20140256696A1-20140911-C00097
         		L89
    Figure US20140256696A1-20140911-C00098
         		L90
    Figure US20140256696A1-20140911-C00099
         		L91
    Figure US20140256696A1-20140911-C00100
         		L92
    Figure US20140256696A1-20140911-C00101
         		L93
    Figure US20140256696A1-20140911-C00102
         		L94
    Figure US20140256696A1-20140911-C00103
         		L95
    Figure US20140256696A1-20140911-C00104
         		L96
    Figure US20140256696A1-20140911-C00105
         		L97
    Figure US20140256696A1-20140911-C00106
         		L98
    Figure US20140256696A1-20140911-C00107
         		L99
    Figure US20140256696A1-20140911-C00108
         		L100 L101 L102
  • Preferred linkers of the invention have a carbonyl functional group at each end, in order to form a carboxylate group with the oxygen atom of the steroid. Preferred linkers are: L41, L42, L44, L52, L53, L54, L55, L58, L56, L57, L60, L61, L62, L63, L64, L65, L66, L67, L68, L69, L70, L71, L76, L78, L79, L80, L81, L82, L83, L84, L90, L92, L93, L94, L95, L96, L97, L98, L99, L103, L104.
  • Compounds of the invention are shown in Table 2.
  • TABLE 2
    Com-
    pound
    number IUPAC Name
    26 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-[(6-{2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
    oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl rel-butanedioate
    25 6-[(6-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-
    3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-
    oxohexyl)oxy]-6-oxohexyl 2-[(9R,10S,11S,13S,16R,17R)-9-
    fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
    24 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′-{2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}
    4,4′-octane-1,8-diyl reldi-butanedioate
    23 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-4,21-dioxo-5,8,11,14,17,20-hexaoxatetracosane-1,24-
    dioate
    22 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-4,18-dioxo-5,8,11,14,17-pentaoxahenicosane-1,21-dioate
    30 2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-
    dihydroxy-10,13,16-trimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-butanedioate
    20 2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-
    dihydroxy-10,13,16-trimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-
    [(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
    27 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,17R)-9-fluoro-11,17-dihydroxy-10,13-
    dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-
    tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
    11 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
    19 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-4-({2-[(2-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-
    dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
    3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-2-
    oxoethyl)(methyl)amino]-2-oxoethyl}amino)-4-oxobutanoate
    18 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
    2 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-4,15-dioxo-
    5,8,11,14-tetraoxaoctadecane-1,18-dioate
    10 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-2,2′-oxyd iacetate
    17 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-2,2′-oxyd iacetate
    21 4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1-{2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}
    rel-(2R)-2-am inobutaned ioate
    9 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4-{[({2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
    oxoethoxy}carbonyl)oxy]methyl} rel-(2R)-2-aminobutanedioate
    16 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}
    1′,4-methanediyl reldi-butanedioate
    8 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}
    1′,4-methanediyl reldi-butanedioate
    29 [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
    oxoethoxylcarbonyl)oxy]methyl 2-[(9R,10S,11S,13S,16R,17R)-
    9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
    7 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
    oxoethoxy}carbonyl)oxy]methyl rel-butanedioate
    15 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
    oxoethoxy}carbonyl)oxy]methyl rel-butanedioate
    6 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-3-hydroxypentanedioate
    14 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-3-hydroxypentanedioate
    13 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-butanedioate
    5 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-pentanedioate
    12 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-pentanedioate
    3 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-pentanedioate
    4 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
    6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
    [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-
    10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
    dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
    rel-butanedioate
    28 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate
    1 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-
    oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
    cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate
  • In another embodiment, the compounds of the invention comprise two of prednisolone moiety such as the compounds below:
    • bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate;
    • bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate;
    • bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-pentanedioate.
  • In another embodiment, the compounds of the invention comprise a prednisolone moiety and a betamethasone moiety as shown below:
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-pentanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-3-hydroxypentanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl rel-butanedioate;
    • 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}4′-{2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′,4-methanediyl reldi-butanedioate;
    • 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4-{[({2-[(9R,10S,115,135,165,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl} rel-(2R)-2-aminobutanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-2,2′-oxydiacetate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate.
  • In another embodiment, the compounds of the invention comprise a prednisolone moiety and a dexamethasone moiety as shown below:
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-pentanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-3-hydroxypentanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl rel-butanedioate;
    • 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′,4-methanediyl reldi-butanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-2,2′-oxydiacetate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate;
    • 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4-({2-[(2-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-2-oxoethyl)(methyl)amino]-2-oxoethyl}amino)-4-oxobutanoate;
    • 2-amino-3-{2-[(9R,105,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;
    • 4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}rel-(2R)-2-aminobutanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,18-dioxo-5,8,11,14,17-pentaoxahenicosane-1,21-dioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,21-dioxo-5,8,11,14,17,20-hexaoxatetracosane-1,24-dioate;
    • 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4,4′-octane-1,8-diyl reldi-butanedioate;
    • 6-[(6-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-[(6-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl rel-butanedioate.
  • In another embodiment, the compounds of the invention comprise a prednisolone moiety and a hydrocortisone moiety as shown below:
    • 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate.
  • In another embodiment, the compounds of the invention comprise two hydrocortisone moieties as shown below:
    • bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate.
  • In another embodiment, the compounds of the invention comprise a betamethasone moiety and a dexamethasone moiety as shown below:
    • [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;
    • 2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate.
  • In another embodiment, the invention provides a hybrid compound comprising two steroid moieties, or a pharmaceutical salt thereof, which are separately connected via a covalent bond to a linker such that said compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond.
  • In another embodiment, the invention provides a hybrid compound wherein at least one steroid is selected from the group consisting of dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone.
  • In another embodiment, the invention provides a hybrid compound, comprising two prednisolone moieties.
  • In another embodiment, the invention provides a hybrid compound, comprising one prednisolone moiety and one betamethasone moiety.
  • In another embodiment, the invention provides a hybrid compound, comprising one prednisolone moiety and one dexamethasone moiety.
  • In another embodiment, the invention provides a hybrid compound, comprising one prednisolone moiety and one hydrocortisone moiety.
  • In another embodiment, the invention provides a hybrid compound, comprising one betamethasone moiety and one dexamethasone moiety.
  • In another embodiment, the invention provides a hybrid compound, comprising two hydrocortisone moieties.
  • In another embodiment, the invention provides a pharmaceutical composition comprising a hybrid compound comprising two steroid moieties, which are separately connected via a covalent bond to a linker, such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said pharmaceutical composition is formulated for topical ophthalmic administration.
  • In another embodiment, the invention provides a method comprising administration to an eye of a mammal a hybrid compound comprising two steroid moieties, which are separately connected via a covalent bond to a linker such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said method is effective in the treatment of an inflammation condition affecting said eye.
  • In another embodiment, the invention provides a method wherein said hybrid compound has topical steroid activity upon a surface of an eye, and wherein the hybrid compound degrades on said surface into one or more of said smaller active steroids which are capable of penetrating beyond tissue of said surface.
  • In another embodiment, the invention provides a hybrid compound comprising a linker having two bonds, wherein said bonds are asymmetrically degraded in vivo to release the two steroid moieties.
  • Some compounds of the invention have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
  • The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of the invention are able to form.
  • The acid addition salt form of a compound of the invention that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic acid and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).
  • The base addition salt form of a compound of the invention that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345).
  • Compounds of the invention and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
  • In still another embodiment of the invention, there are provided methods for treating or preventing eye conditions such as: conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, in a patient suffering thereof. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms thereof.
  • The present invention concerns the use of a compound of the invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis.
  • The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
  • The compounds of the invention may also be administered as pharmaceutical compositions in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.
  • Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
  • For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • In a similar manner an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
  • The ingredients are usually used in the following amounts:
  • Ingredient Amount (% w/v)
    active ingredient about 0.001-5
    preservative   0-0.10
    vehicle  0-40
    tonicity adjustor  0-10
    buffer 0.01-10  
    pH adjustor q.s. pH 4.5-7.8
    antioxidant as needed
    surfactant as needed
    purified water to make 100%
  • The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl.
  • The patient may be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
  • In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.
  • The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions such as conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.
  • Thus, in further embodiments of the invention, there are provided methods for treating conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.
  • Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.
  • The present invention concerns also processes for preparing the hybrid compounds disclosed herein. The hybrid compounds according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The synthetic scheme set forth below, illustrates how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention.
  • Figure US20140256696A1-20140911-C00109
  • In this scheme the synthesis of hybrid compounds were started with a steroid R—CH2—OH. EDCI coupling of steroid R—CH2—OH with succinic anhydride gave a carboxylic acid intermediate. A second EDCI coupling of the carboxylic acid intermediate with steroid R′—CH2—OH yielded the desired hybrid compound.
  • The carboxylic intermediate can be coupled with a polyethylene glycol to form a corresponding alcohol, which can be coupled with another succinic anhydride molecule and then with another steroid of formula R′—CH2—OH to form a hybrid with a polyethylene and ketone moieties.
  • The following abbreviations are used in the general Scheme 1:
      • EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
      • DMAP 4-dimethylaminopyridine
      • CH2Cl2 dichloromethane
  • It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
  • It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
  • The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2H (or D) in place of hydrogen 1H (or H) or use of 13C enriched material in place of 12C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
  • The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
  • As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.
  • Compound names were generated with ACDLabs version 12.5 or ChemBioDraw Ultra version 12.0.2.
  • In general, characterization of the compounds is performed according to the following methods. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Varian 300 or 600 MHz spectrometer in deuterated solvent. Chemical shifts were reported as δ (delta) values in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm) and multiplicities were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data were reported in the following format: chemical shift (multiplicity, coupling constant(s) J in hertz (Hz), integrated intensity). The mass spectrometry data were determined on a Shimadzu LCMS-IT-TOF instrument.
  • The formation of the hybrid compounds was checked by 1H-NMR, comparing the chemical shifts of the protons from the CH2 group identified in the schemes shown below, and identified as “CH2 c” for the starting material and as “CH2 c*” or “c*” for of the corresponding protons on the newly formed hybrid molecule wherein “*” indicates the hybrid compound. Applicants have marked with arrows the location of these protons and the reaction site of the prodrug moiety, where available. Each scheme shows the formation of the new hybrid drug. Each table describes the results for the new hybrid drug and the linker number, where existing. The linker moiety numbers are as described in Table 1.
  • The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
    • EXAMPLES
  • Prednisolone reacted with another molecule of Prednisolone to form the following hybrid compounds as shown in Scheme 2 with the results described in Table 3.
  • Figure US20140256696A1-20140911-C00110
  • TABLE 3
    *Comp. CH2 c*
    Linker Structure δ(ppm) Mass
    1 L55
    Figure US20140256696A1-20140911-C00111
         		5.00 (dd, 4H) 825 (MNa+)
    2 L57
    Figure US20140256696A1-20140911-C00112
         		4.99 (dd, 4H) 1057  (MNa+)
    3 L58
    Figure US20140256696A1-20140911-C00113
         		4.99 (dd, 4H) 839 (MNa+)
  • Prednisolone reacted with one molecule of Betamethasone to form the following hybrid compounds as shown in Scheme 3 with the results described in Table 4.
  • Figure US20140256696A1-20140911-C00114
  • TABLE 4
    *Comp CH2 c*
    Linker Structure δ(ppm) Mass
    4 L55
    Figure US20140256696A1-20140911-C00115
         		5.06-4.93 (m, 4H) 857 (MNa+)
    5 L58
    Figure US20140256696A1-20140911-C00116
         		5.05-4.92 (m, 4H) 871 (MNa+)
    6 L62
    Figure US20140256696A1-20140911-C00117
         		5.10-4.95 (m, 4H) 887 (MNa+)
    7 L63
    Figure US20140256696A1-20140911-C00118
         		5.09-4.85 (m, 4H) 931 (MNa+)
    8 L59
    Figure US20140256696A1-20140911-C00119
         		5.07-4.91 (m, 4H) 963 (MH+)
    9 L60
    Figure US20140256696A1-20140911-C00120
         		5.09-4.98 (m, 4H) 946 (MNa+)
    10  L61
    Figure US20140256696A1-20140911-C00121
         		5.16-4.99 (m, 4H) 874 (MNa+)
    11  L57
    Figure US20140256696A1-20140911-C00122
         		5.03-4.96 (m, 4H) 1089  (MNa+)
  • Prednisolone reacted with one molecule of Dexamethasone to form the following hybrid compounds as shown in Scheme 4 with the results described in Table 5.
  • Figure US20140256696A1-20140911-C00123
  • TABLE 5
    *
    Comp CH2 c*
    Linker Structure δ(ppm) Mass
    12 L58
    Figure US20140256696A1-20140911-C00124
         		5.06-4.92 (m, 4H) 871 (MNa+)
    13 L55
    Figure US20140256696A1-20140911-C00125
         		5.06-4.97 (m, 4H) 857 (MNa+)
    14 L62
    Figure US20140256696A1-20140911-C00126
         		5.11-4.85 (m, 4H) 887 (MNa+)
    15 L63
    Figure US20140256696A1-20140911-C00127
         		5.10-4.86 (m, 4H) 931 (MNa+)
    16 L59
    Figure US20140256696A1-20140911-C00128
         		5.06-4.90 (m, 4H) 987 (MNa+)
    17 L61
    Figure US20140256696A1-20140911-C00129
         		5.16-5.02 (m, 4H) 873 (MNa+)
    18 L57
    Figure US20140256696A1-20140911-C00130
         		5.08-4.93 (m, 4H) 1090  (MNa+)
    19 L64
    Figure US20140256696A1-20140911-C00131
         		5.18-4.94 (m, 4H) 985 (MNa+)
    20 L65
    Figure US20140256696A1-20140911-C00132
         		5.07-4.91 (m, 4H) 944 (MNa+)
    21 L66
    Figure US20140256696A1-20140911-C00133
         		5.25-5.02 (m, 4H) 892 (MNa+)
    22 L67
    Figure US20140256696A1-20140911-C00134
         		5.08-4.96 (m, 4H) 1133  (MNa+)
    23 L68
    Figure US20140256696A1-20140911-C00135
         		5.08-4.95 (m, 4H) 1177  (MNa+)
    24 L69
    Figure US20140256696A1-20140911-C00136
         		5.08-4.91 (m, 4H) 1133  (MNa+)
    25 L70
    Figure US20140256696A1-20140911-C00137
         		5.03-4.91 (m, 4H) 1085  (MNa+)
    26 L71
    Figure US20140256696A1-20140911-C00138
         		5.08-4.91 (m, 4H) 1085  (MNa+)
  • Prednisolone reacted with one molecule of Hydrocortisone to form the following hybrid compounds as shown in Scheme 5 with the results described in Table 6.
  • Figure US20140256696A1-20140911-C00139
  • TABLE 6
    *
    Comp CH2 c*
    Linker Structure δ(ppm) Mass
    27 L57
    Figure US20140256696A1-20140911-C00140
         		5.09-4.92 (m, 4H) 1060 (MNa+)
  • Hydrocortisone reacted with another molecule of Hydrocortisone to form the following hybrid compounds as shown in Scheme 6 with the results described in Table 7.
  • Figure US20140256696A1-20140911-C00141
  • TABLE 7
    *
    Comp CH2 c*
    Linker Structure δ (ppm) Mass
    28 L55
    Figure US20140256696A1-20140911-C00142
         		5.01 (dd, 4H) 829 (MNa+)
  • Dexamethasone reacted with one molecule of Betamethasone to form the following hybrid compounds as shown in Scheme 7 with the results described in Table 8.
  • Figure US20140256696A1-20140911-C00143
  • TABLE 8
    *
    Comp CH2 c*
    Linker Structure δ(ppm) Mass
    29 L52
    Figure US20140256696A1-20140911-C00144
         		5.09-4.94 (m, 4H) 963 (MNa+)
    30 L65
    Figure US20140256696A1-20140911-C00145
         		5.10-4.95 (m, 4H) 954 (MNa+)
    • Biological Examples In Vitro Metabolic Stability in Human Recombinant Carboxylesterases
  • Human recombinant carboxylesterases were purchased from a commercial vendor (BD Gentest™, Bedford, Mass.). All metabolic stability experiments were performed in triplicate in 96-well plate format. The final incubation mixture contained 1 μM test compound and 0.1 mg/mL human recombinant carboxylesterase mixture in a final volume of 0.5 mL 0.1M potassium phosphate buffer (pH=6.0). The final percentage of solvent in the incubation was less than 1.0% to prevent inhibition of enzymatic activity. Following a pre-incubation at 37° C., test article was added to initiate the reaction. At designated time points (typically less than 60 minutes to capture the linear range of metabolite formation), 0.05 mL aliquots were removed from the incubation mixtures using a clean pipet tip and immediately placed in organic solvent to stop any esterase activity. The hydrolysis to the metabolites was confirmed to be due to esterase activity and not chemical lability.
  • The samples were analyzed by liquid chromatography with mass spectrometry (LC-MS/MS) detection to determine the metabolite concentrations resulting from the metabolism of the hybrid compounds. Internal standards were used to compensate for variability from sample processing, chromatographic elution, mass spectrometer response and ion suppression by matrix components.
  • Table 9 lists the rate of metabolite formation in human recombinant carboxylesterases.
  • TABLE 9
    Rate of Rate of
    * formation formation
    Comp Metabolite 1 Metabolite 2
    No. Structure (nM/min/mg) (nM/min/mg)
    8
    Figure US20140256696A1-20140911-C00146
         		35.1 ± 7.6  Prednisolone 74.8 ± 14.2 Betamethasone
    16
    Figure US20140256696A1-20140911-C00147
         		54.5 ± 10.4 Prednisolone 56.5 ± 7.5  Dexamethansone
  • The data demonstrate that linkage of two steroids (e.g. prednisolone, betamethasone, or dexamethasone) as a single hybrid compound was hydrolyzed enzymatically in human recombinant carboxylesterases to their respective individual steroid drugs.

Claims (14)

What is claimed is:
1. A hybrid compound comprising two steroid moieties, or a pharmaceutical salt thereof, which are connected via two covalent bonds to a linker such that said compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond.
2. The hybrid compound according to claim 1 wherein one steroid is selected from the group consisting of dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone.
3. The hybrid compound according to claim 1 wherein said linker comprises an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol moiety.
4. The hybrid compound according to claim 1, comprising two prednisolone moieties.
5. The hybrid compound according to claim 1, comprising one prednisolone moiety and one betamethasone moiety.
6. The hybrid compound according to claim 1, comprising one prednisolone moiety and one dexamethasone moiety.
7. The hybrid compound according to claim 1, comprising one prednisolone moiety and one hydrocortisone moiety.
8. The hybrid compound according to claim 1, comprising one betamethasone moiety and one dexamethasone moiety.
9. The hybrid compound according to claim 1, comprising two hydrocortisone moieties.
10. A pharmaceutical composition comprising a hybrid compound comprising two steroid moieties, which are connected via two covalent bonds to a linker such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said pharmaceuticacomposition is formulated for topical ophthalmic administration.
11. A method comprising administration to an eye of a mammal a hybrid compound comprising two steroid moieties, which are connected via two covalent bonds to a linker such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said method is effective in the treatment of an inflammation condition affecting said eye.
12. The method according to claim 11 wherein said hybrid compound has topical steroid activity upon a surface of an eye, and wherein the hybrid compound degrades on said surface into one or more of said smaller active steroids which are capable of penetrating beyond tissue of said surface.
13. The hybrid compound according to claim 1 comprising a linker having two bonds, wherein said bonds are asymmetrically degraded in vivo to release the two steroid moieties.
14. The hybrid compound according to claim 1, selected from:
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-[(6-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl rel-butanedioate
6-[(6-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4,4′-octane-1,8-diyl reldi-butanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,21-dioxo-5,8,11,14,17,20-hexaoxatetracosane-1,24-dioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,18-dioxo-5,8,11,14,17-pentaoxahenicosane-1,21-dioate
2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4-({2-[(2-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-2-oxoethyl)(methyl)amino]-2-oxoethyl}amino)-4-oxobutanoate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-2,2′-oxydiacetate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-2,2′-oxydiacetate
4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-(2R)-2-aminobutanedioate
1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4-{[({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl} rel-(2R)-2-aminobutanedioate
1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′,4-methanediyl reldi-butanedioate
1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′,4-methanediyl reldi-butanedioate
[({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl rel-butanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl rel-butanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-3-hydroxypentanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-3-hydroxypentanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-pentanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-pentanedioate
bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-pentanedioate
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate
bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate
bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate.
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