HK1242323B - Ester prodrugs of gamma-lactams and their use - Google Patents

Description

FIELD

The present invention is directed to ester prodrugs of gamma-lactam compounds as defined in the claims and their use for the treatment of ocular diseases including, among other things, glaucoma and macular degeneration.

BACKGROUND

Glaucoma is a leading cause of blindness in the world. Indeed, over 2.5 million people in the United States suffer from the disease, and millions more are at risk of developing glaucoma. As the population ages, the number of individuals suffering from glaucoma will continue to grow since the elderly are being affected disproportionally.

Based on the etiology of glaucoma, it can be classified into primary and secondary glaucoma. Primary glaucoma, also known as congenital glaucoma, can occur in the absence of other ocular conditions, and its underlying causes are not known. It is known, however, that increased intraocular pressure (IOP) observed in primary glaucoma is due to the obstruction of aqueous humor flow out of the eye. Secondary glaucoma results from another pre-existing ocular disease such as uveitis, intraocular tumor, enlarged cataract, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage. Generally, any interference with the outward flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently into the canal of Schlemm can lead to secondary glaucoma.

Current treatments for glaucoma aim to reduce the pressure in the eye by decreasing the amount of aqueous fluid being produced or alternatively by enhancing the flow of fluid out of the eye by using mechanical means. Agents for topical application used to treat glaucoma include miotics (e.g., Isopto®Carpine, Ocusert®, Pilocar®, and Pilopine®) and epinephrines (e.g., Epifrin® and Propine®), which increase the outflow of fluid; beta blockers (e.g., Betagan®, Betimol®, Betoptic®, Ocupresst, Timoptic®, Optipranalol®); carbonic anhydrase inhibitors and alpha andrenergic agonists (e.g., Alphagan®, Iopidine®, Trusopt®), which reduce the amount of fluid; and prostaglandin analogs (e.g. Lumigan®, Rescula®, Travatan®, Xalatan®), which increase the outflow of fluid through a secondary drainage route.

The topical application of ophthalmic compositions for the treatment of glaucoma requires penetration of the drug through the cornea and into the anterior chamber, which contains aqueous humor, which then drains into the conventional outflow pathway. Intraocular pressure is lowered by drugs acting in the Schlemm's canal and the uveal-scleral pathway. Penetration of the drug through the cornea requires a balance of hydrophobic and hydrophilic characteristics. In order to diffuse into the cornea the drug must be sufficiently soluble in non-polar media, and it must be sufficiently soluble in aqueous media in order to diffuse out of the cornea into the aqueous humor.

Potentially useful drugs for the treatment of glaucoma can be delivered as prodrug esters. The use of prodrug esters, which are cleaved enzymatically (e.g., in the cornea) to regenerate the active compound, can enhance penetration of the drug through the cornea into the anterior chamber. However, many esters are too hydrophobic to diffuse out of the relatively non-polar external layer of the cornea into the aqueous humor. Furthermore, such compounds are often not sufficiently soluble to formulate in aqueous solutions. Accordingly, there is a need in the art for ophthalmic compositions having the capability to penetrate through the cornea into the anterior chamber. At the same time such compositions need to exhibit sufficient hydrophilic properties to formulate in aqueous solution and to be soluble in the anterior chamber. Provided herein are compositions and methods addressing these and other needs in the art.

SUMMARY

In a first aspect, there are provided compounds having the structure of Formulae (III), (IV), (V), or (IV) or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided an ophthalmic pharmaceutical composition which includes a compound of Formulae (III), (IV), (V), or (IV) or a pharmaceutically acceptable salt thereof as disclosed herein and an ophthalmically acceptable pharmaceutical excipient.

In another aspect, there are provided compounds having Formulae (III), (IV), (V), or (IV) or a pharmaceutically acceptable salt thereof for use in a method for treating an ophthalmic disease in a subject. In some embodiments, the subject is a human. The method includes administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

In another aspect, there are provided compounds having Formulae (III), (IV), (V), or (IV) or a pharmaceutically acceptable salt thereof for use in a method for reducing corneal thickening, said method comprising administering a therapeutically effective amount of a compound as described herein to a subject in need thereof.

DETAILED DESCRIPTION I. Definitions

The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH₂O- is equivalent to -OCH₂-.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; e.g., the R and S configurations for each asymmetric center as well as cis and trans configurations. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

The compounds of the present invention may have asymmetric centers and/or geometric isomers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this invention. Additionally, as used herein the term alkyl includes all the possible isomeric forms of the alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all the positional isomers albeit only a few examples are set forth. Furthermore, all polymorphic forms, including amorphous form, and hydrates of a compound disclosed herein are within the scope of this invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention, as are enantiomers. The compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

The terms "a," "an," or "a(n)," when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.

Unless indicated otherwise, the term "derivative" in the context of a compound disclosed herein refers to a compound afforded by chemical modification, e.g., by the bonding of one or more substituent groups as described herein.

The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. See e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Additional information on suitable pharmaceutically acceptable salts can be found in REMINGTON'S PHARMACEUTICAL SCIENCES, 17th ed., Mack Publishing Company, Easton, PA, 1985 Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

Thus, in some embodiments, the compounds disclosed herein can exist as salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

The term "prodrug" is used according to its plain ordinary meaning and is intended to mean compounds that require a chemical or enzymatic transformation in order to release the active parent drug in vivo prior to producing a pharmacological effect. Prodrug preparation is well known in the art. For example, "Prodrugs and Drug Delivery Systems," which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. An "ophthalmically pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable excipient that is generally safe, non-toxic and neither biologically nor otherwise undesirable for veterinary ophthalmic use and human ophthalmic use. An "ophthalmic pharmaceutical composition" refers to a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable for veterinary ophthalmic use and human ophthalmic use.

The terms "treating" or "treatment" refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating, and/or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination. For example, the certain methods presented herein can successfully treat glaucoma by decreasing the intraocular pressure.

An "effective amount" of a compound is an amount sufficient to contribute to the treatment, prevention (e.g. prophylaxis), and/or reduction of a symptom or symptoms of a disease (e.g. glaucoma, elevated intraocular pressure, corneal thickening, and/or others identifiable to a skilled person upon a reading of the present disclosure). Where recited in reference to a disease treatment, an "effective amount" may also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of a disease, disorder or condition, or reducing the likelihood of the onset (or reoccurrence) of a disease, disorder or condition or symptoms thereof. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. In one embodiment, a prophylactically effective amount is administered in one or more administrations.

The term "topical" in the context of the compounds for use in methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject. Accordingly, the term "topical pharmaceutical composition" includes those pharmaceutical forms in which the compound is administered externally by direct contact with a topical treatment site, e.g., the eye or the skin. The term "topical ocular pharmaceutical composition" refers to a pharmaceutical composition suitable for administering directly to the eye. The term "topical epidermal pharmaceutical composition" refers to a pharmaceutical composition suitable for administering directed to the epidermal layer of the skin, e.g., the palpebra, the supercilium, the scalp, or the body. The term "topical administering" refers to administering externally by direct contact with a topical treatment site. The term "topical epidermal administering" refers to administering externally by direct contact with the epidermis. The term "topical ocular administering" refers to administering externally by direct contact with the eye.

II. Compounds

In a first aspect, there is provided a compound having the structure of Formula (III) or a pharmaceutically acceptable salt thereof:

In one embodiment, there is provided a compound having the structure of Formula (IIIa), also referred to herein as compound 3:

In one embodiment, there is provided a compound having the structure of Formula (IIIb), also referred to herein as compound 5:

In a second aspect, there is provided a compound having the structure of Formula (IV) or a pharmaceutically acceptable salt thereof:

In one embodiment, the compound has the structure of one of Formulae: or

In a third aspect, there is provided a compound having the structure of Formula (V) or a pharmaceutically acceptable salt thereof:

In one embodiment, the compound has the structure of one of Formulae or

In a fourth aspect, there is provided a compound having the structure of Formula (VI) or a pharmaceutically acceptable salt thereof:

In one embodiment, the compound has the structure of one of Formulae or

It is understood that a compound with structure of any one of Formulae (III), (IV), (V), (VI) or derivative, isomer or enantiomer thereof, can be provided, where applicable, as a pharmaceutically acceptable salt as defined herein, where the compound admits to formation of a pharmaceutically acceptable salt. In one embodiment, there is provided a pharmaceutically acceptable salt of a compound with structure of any one of Formulae (III), (IV), (V), (VI), or isomer or enantiomer thereof, wherein the compound admits to formation of a pharmaceutically acceptable salt.

III. Pharmaceutical Compositions

In another aspect, there is provided an ophthalmic pharmaceutical composition including a ophthalmically pharmaceutically excipient and a compound provided herein (e.g., a compound with structure of Formula (III), (IV), (V), (VI), or derivative, isomer or enantiomer thereof and including embodiments thereof identifiable to a skilled person upon a reading of the present disclosure).

In one embodiment, the compound has the structure of Formulae (III). In one embodiment, the compound has the structure of one of Formulae (IIIa)-(IIIb). In one embodiment, the compound has the structure of Formulae (IV). In one embodiment, the compound has the structure of one of Formulae (IVa)-(IVd). In one embodiment, the compound has the structure of Formulae (V). In one embodiment, the compound has the structure of one of Formulae (Va)-(Vh). In one embodiment, the compound has the structure of Formulae (VI). In one embodiment, the compound has the structure of one of Formulae (VIa)-(VIp).

In one embodiment, the pharmaceutical composition is a solution, emulsion, gel or foam. In one embodiment, the pharmaceutical composition is a solution. In one embodiment, the pharmaceutical composition is an emulsion. In one embodiment, the pharmaceutical composition is a gel. In one embodiment, the pharmaceutical composition is a foam.

In some embodiments, when the compounds described herein (e.g. compounds of Formula (III), (IV), (V), or (VI)) are part of a composition, the compounds are the only active ingredients which result in the biological effects described herein (e.g., reduction of intraocular pressure and others identifiable to a skilled person upon a reading of the present disclosure). The term "active ingredient" as used herein refers to a component which is responsible for the biological effects described herein (e.g. treatment of glaucoma, elevated intraocular pressure, macular degeneration and others identifiable to a skilled person upon a reading of the present disclosure), whereas the other components of the composition (e.g. excipients, carriers, and diluents) are not responsible for the biological effects, even if they have other functions in the composition which are necessary or desired as part of the formulation (e.g., lubrication, flavoring, pH control, emulsification, and other functions other than the biological effects described herein).

A. Formulations

The compounds and pharmaceutical compositions disclosed herein can be prepared and administered in a variety of forms including solution, emulsion, gel or foam. Accordingly, pharmaceutical compositions contemplated herein include a pharmaceutically acceptable carrier or excipient and one or more compounds described herein. "Solution" refers in the customary sense to a liquid pharmaceutical composition in which a compound (e.g., a compound described herein), is at least partially dissolved, preferably fully dissolved, and which can be administered as a liquid. "Emulsion" refers in the customary sense to a mixture of two or more immiscible liquids, one compound (e.g., a compound described herein or solution thereof) being dispersed through the other compound (e.g., a carrier as described herein). "Gel" refers in the customary sense to a highly viscous solution, emulsion, or colloidal suspension of a compound within a continuous fluid phase resulting in a viscous semirigid fluid. "Colloid" refers in the customary sense to a composition which includes a continuous medium throughout which are distributed small particles which do not settle under the influence of gravity. "Foam" refers in the customary sense to a composition which includes a continuous medium (i.e., solution, emulsion, gel and the like) through which gas (e.g., air) is dispersed.

Pharmaceutical compositions contemplated herein may be prepared by combining a therapeutically effective amount of at least one compound as described herein as an active ingredient in combination with one or more conventional pharmaceutically acceptable excipients, and by preparation of unit dosage forms suitable for topical use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations which include solutions, emulsions, gels and foams. Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309 .

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.

The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920 ; 5,403,841 ; 5,212,162 ; and 4,861,760 and US Patent application publication No. US 2011-0124736 A1 , also corresponding to US Patent application serial no. 12/940,711 .

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.

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.

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.

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 ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with an orifice, to facilitate application to the eye. Vials suitable for unit dose application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution, emulsion, gel or foam. One package may contain one or more unit doses.

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.

Typically, the compounds are applied repeatedly for a sustained period of time topically on the part of the body to be treated, for example, the eye. The preferred dosage regimen will generally involve regular administration for a period of treatment of at least one month, more preferably at least three months, and most preferably at least six months. The regular administration can be 1, 2, 3, 4 or even more times per day.

IV. Compounds for Use in Methods of Treatment

Provided herein are compounds having Formulae (III), (IV), (V) and (VI) for use in methods of treating ophthalmic diseases and disorders in a subject or patient. In some embodiments the subject or patient is a mammal. In preferred embodiments, the subject or patient is a human. The methods include administering a therapeutically effective amount of a compound with structure of any one of Formulae (III)-(VI) to a subject in need thereof. In one embodiment, the method includes administering a therapeutically effective amount of a compound with structure of any one of Formulae (III) to a subject in need thereof. In one embodiment, the method includes administering a therapeutically effective amount of a compound with structure of any one of Formulae (III)-(VI) or derivative, isomer or enantiomer thereof, to a subject in need thereof.

In one embodiment, there are provided compounds having Formulae (III), (IV), (V) and (VI) for use in a method for treating glaucoma, including administering to a subject in need thereof an effective amount of said compound, or an ophthalmic pharmaceutical composition as described herein. In one embodiment, there are provided compounds having Formulae (III), (IV), (V) and (VI) for use in a method for treating ocular hypertension, including administering to a subject in need thereof an effective amount of said compound, or an ophthalmic pharmaceutical composition as described herein. In one embodiment, there are provided compounds having Formulae (III), (IV), (V) and (VI) for use in a method for treating macular degeneration, including administering to a subject in need thereof an effective amount of said compound, or an ophthalmic pharmaceutical composition as described herein. In one embodiment, the disease results from increased intraocular pressure. The term "increased intraocular pressure" refers, in the customary sense, to an intraocular pressure which is greater than that which would be as judged as normal by a practitioner in the medical arts. Without wishing to be bound by any theory, it is believed that increased intraocular pressure is associated with a variety of diseases, including, for example, glaucoma.

In another aspect, there are provided compounds having Formulae (III), (IV), (V) and (VI) for use in a method for treating glaucoma or ocular hypertension, the method including administering to a subject in need thereof an effective amount of said compound, or a pharmaceutical composition as described herein, in combination with another drug useful for the treatment of glaucoma, ocular hypertension, or other condition.

In one embodiment, there is provided a combination treatment with a β-blocker (or β-adrenergic antagonist) including carteolol, levobunolol, metiparanolol, timolol hemihydrate, timolol maleate, β1-selective antagonists such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with an adrenergic agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof, and α2 -selective adrenergic agonists such as apraclonidine, brimonidine, and the like, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with a carbonic anhydrase inhibitors including acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the like, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with a cholinergic agonist including direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine, and the like, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with a chlolinesterase inhibitors such as demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with a glutamate antagonists or other neuroprotective agents such as Ca²⁺ channel blockers such as memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-1 01,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride, and the like, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with a prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, there is provided a combination treatment with a prostaglandin including travoprost, UF0-21, chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost and the like.

In one embodiment, there is provided a combination treatment with a cannabinoid including CB1 agonists such as WIN-55212-2 and CP-55940 and the like, or pharmaceutically acceptable salts or prodrugs thereof.

Further to any embodiment disclosed above of compounds having Formulae (III), (IV), (V) and (VI) for use in a method of treating an ophthalmic disease, in one embodiment the administering is topical administering.

In another aspect, there are provided compounds having Formulae (III), (IV), (V) and (VI) for use in a method for reducing corneal thickening. The method includes administering a therapeutically effective amount of said compound to a subject in need thereof. In one embodiment, the subject suffers from glaucoma. In one embodiment, the subject suffers from ocular hypertension.

EXAMPLES

Abbreviations used herein have the customary meaning in the chemical arts. Specific abbreviations include the following: TBDMS : tert-butyldimethylsilyl; DMF: N,N-dimethylformamide; EDC: N-[3-dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride; DMAP: 4-(dimethylamino)pyridine; THF: tetrahydrofuran; Bu₄NF: tetrabutylammonium fluoride; PPTS: pyridinium p-toluenesulfonate.

Example 1 (S)-2,3-dihydroxypropyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (3)

An exemplary synthesis of compound 3 is set forth in Scheme 1 following.

((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (2). (R)-(-)-2,3-O-Isopropylideneglycerol (307.9 mg, 2.33 mmol) was added to a solution of the carboxylic acid 1 (100 mg, 0.233 mmol), 4-(dimethylamino)pyridine (29.8 mg, 0.243 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (49.1 mg, 0.256 mmol) in DMF (3.0 mL) at 23 °C. After stirring for 16h the reaction solution was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO₃ then brine. The organic portion was dried (MgSO₄), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 1:1 hex/EtOAc followed by 100% EtOAc) afforded 116.8 mg (92%) of acetonide protected ester 2 as a clear, viscous oil.

(S)-2,3-dihydroxypropyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (3). The ester 2 (116.8 mg, 0.215 mmol) was stirred at 23 °C in a mixture of 1N HCl:THF (1:1, 3.0 mL) for 24h. The reaction mixture was then diluted with EtOAc and washed with water, saturated aqueous NaHCO₃ then brine. The organic portion was dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 100% EtOAc followed by 19:1 EtOAc/MeOH) to give 90.7 mg (84%) of the bishydroxy ester 3 as a clear, viscous oil.

Example 2 Synthesis of (R)-2,3-dihydroxypropyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (5).

((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (4). In accordance with the procedures described for the preparation of compound 2 above, use of 100 mg (0.233 mmol) of carboxylic acid 1 and 153.9 mg (1.165 mmol) of (S)-(+)- 2,3-O-isopropylideneglycerol afforded 118.8 mg (94%) of acetonide protected ester 4, with structure following:

(R)-2,3-dihydroxypropyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (5). In accordance with the procedures described for the preparation of compound 3 above, use of 50.0 mg (0.0.092 mmol) of ester 4 provided 38.0 mg (82%) of bishydroxy ester 5 as a clear, viscous oil, with structure following:

Example 3 Synthesis of 5-(3-((S)-1-(4-((S)-1-((tert-Butyldimethylsilyl)oxy)hexyl) phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylic acid (8)

An exemplary synthesis of compound 8 is provided in Scheme 2 following.

Methyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (6). Iodomethane (0.70 mL, 11.3 mmol) was added to a mixture of the carboxylic acid 1 (485 mg, 1.13 mmol) and potassium carbonate (1.72 g, 12.43 mmol) in DMF (10 mL) at 23 °C. The reaction was sealed and stirred for 24h. The resultant mixture was then diluted with EtOAc and water. The organic portion was separated, washed with brine, dried (MgSO₄) filtered and concentrated in vacuo. Flash column chromatography (silica gel, 1:1 hex/EtOAc followed by 100% EtOAc) afforded 496.2 mg (99%) of the methyl ester 6.

Methyl 5-(3-((S)-1-(4-((S)-1-((tert-butyldimethylsilyl)oxy)hexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (7). t-Butyldimethylsilylchloride (253.2 mg, 1.68 mmol) was added to a solution of the alcohol 6 (496.2 mg, 1.12 mmol) and imidazole (152.4 mg, 2.24 mmol) in DMF (10 mL) at 23 °C. After stirring for 16h the reaction was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO₃ then brine. The organic portion was dried (MgSO₄), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 2:1 hex/EtOAc followed by 1:1 hex EtOAc) provided 592 mg (95%) of the silyl ether 7.

5-(3-((S)-1-(4-((S)-1-((tert-Butyldimethylsilyl)oxy)hexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylic acid (8). Lithium hydroxide (4.2 mL of a 0.5 N solution in H₂O, 2.12 mmol) was added to a solution of the methyl ester 7 (592 mg, 1.06 mmol) in THF (8.4 mL) at 23 °C. The resultant mixture was stirred for 72h. The reaction was acidified with 1N HCl and then extracted with EtOAc. The organic portion was washed with brine (2X), dried (Na₂SO₄), filtered and concentrated in vacuo to give 525.9 mg (91%) of the carboxylic acid 8 as a clear, glue-like substance.

Example 4 Synthesis of (2R,3R,4S)-2,3,4,5-Tetrahydroxypentyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (11)

An exemplary synthesis of compound 11 is provided in Scheme 3 following.

((4R,4'S,5R)-2,2,2',2'-Tetramethyl-[4,4'-bi(l,3-dioxolan)]-5-yl)methyl 5-(3-((S)-1-(4-((S)-1-((tert-butyldimethylsilyl)oxy)hexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (9). ((4S,4'S,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)methanol (76.9 mg, 0.331 mmol) was added to a solution of the carboxylic acid 8 (150 mg, 0.276 mmol), 4-(dimethylamino)pyridine (35.4 mg, 0.289 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (58.2 mg, 0.303 mmol) in DMF (3.0 mL) at 23 °C. After stirring for 72h the reaction solution was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO₃ then brine. The organic portion was dried (Na₂SO₄), filtered and concentrated in vacuo. Purification of the residue by flash column chromatorgraphy (silica gel, 1:1 hex/EtOAc) afforded 171.2 mg (82%) of bis-acetonide protected ester 9 as a clear, viscous oil.

((4R,4'S,5R)-2,2,2',2'-Tetramethyl-[4,4'-bi(l,3-dioxolan)]-5-yl)methyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (10). Tetrabutylammonium fluoride (0.34 mL of a 1.0 M solution in THF, 0.339 mmol) was added to a solution of the silyl ether 9 (171.2 mg, 0.226 mmol) in THF (3.0 mL) at 23 °C. After 48h the reaction was diluted with EtOAc and washed with H₂O followed by brine. The organic portion was dried (MgSO₄), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 1:1 hex/EtOAc followed by 100% EtOAc) afforded 137.0 mg (94%) of the hydroxy ester 10.

(2R,3R,4S)-2,3,4,5-Tetrahydroxypentyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (11). The bis-acetonide 10 (45.0 mg, 0.070 mmol) was stirred at 23 °C in a mixture of 1N HCl:THF (1:1, 3.0 mL) for 48h. The reaction mixture was then diluted with EtOAc and washed with water, saturated aqueous NaHCO₃ then brine. The organic portion was dried (Na₂SO₄), filtered and concentrated in vacuo to give 32.9 mg (83%) of the ester 11 as a clear, viscous oil.

Example 5 Synthesis of (2R,3R,4S,5R)-2,3,4,5,6-Pentahydroxyhexyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (14)

(S)-2-Hydroxy-2-((4R,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethyl 5-(3-((S)-1-(4-((S)-1-((tert-butyldimethylsilyl)oxy)hexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (12). In accordance with the procedures described for the preparation of compound 9 above, use of 100 mg (0.184 mmol) of carboxylic acid 8 and 57.8 mg (0.221 mmol) of (S)-1-((4R,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethane-1,2-diol afforded 92.0 mg (64%) of bisacetonide protected ester 12, with structure following:

(S)-2-hydroxy-2-((4R,4'R,5R)-2,2,2',2'-tetramethyl-[4,4'-bi(l,3-dioxolan)]-5-yl)ethyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (13). In accordance with the procedures described for the preparation of compound 10 above, use of 92.0 mg (0.117 mmol) of silyl ether 12 provided 70.8 mg (90%) of hydroxy-ester 13, with structure following:

(2R,3R,4S,5R)-2,3,4,5,6-Pentahydroxyhexyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (14). In accordance with the procedures described for the preparation of compound 11 above, use of 45.0 mg (0.067 mmol) of bis-acetonide 13 provided 33.3 mg (84%) of ester 14 as a clear, viscous oil, with structure following:

Example 6 Synthesis of (2S,3S)-2,3,4-Trihydroxybutyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (17)

((4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((S)-1-(4-((S)-1-((tert-butyldimethylsilyl)oxy)hexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (15). In accordance with the procedures described for the preparation of compound 9 above, use of 128 mg (0.235 mmol) of carboxylic acid 8 and 57.3 mg (0.353 mmol) of (+)-2,3-O-isopropylidene-L-threitol afforded 116.7 mg (72%) of acetonide 15, with structure following:

((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (16). In accordance with the procedures described for the preparation of compound 10 above, use of 116.7 mg (0.170 mmol) of silyl ether 15 provided 55.0 mg (56%) of hydroxy-ester 16, with structure following:

(2S,3S)-2,3,4-Trihydroxybutyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (17). In accordance with the procedures described for the preparation of compound 11 above, use of 55.0 mg (0.096 mmol) of acetonide 16 provided 28.0 mg (55%) of ester 17 as a clear, viscous oil, with structure following:

Example 7 Synthesis of (2R,3R)-2,3,4-Trihydroxybutyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (20)

((4R,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((S)-1-(4-((S)-1-((tert-butyldimethylsilyl)oxy)hexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (18). In accordance with the procedures described for the preparation of compound 9 above, use of 166 mg (0.305 mmol) of carboxylic acid 8 and 74.4 mg (0.456 mmol) of (-)-2,3-O-isopropylidene-D-threitol afforded 116.1 mg (55%) of acetonide 18, with structure following:

((4R,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (19). In accordance with the procedures described for the preparation of compound 10 above, use of 116.1 mg (0.169 mmol) of silyl ether 18 provided 50.0 mg (52%) of hydroxy-ester 19, with structure following:

(2R,3R)-2,3,4-Trihydroxybutyl 5-(3-((S)-1-(4-((S)-1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-2-yl)propyl)thiophene-2-carboxylate (20). In accordance with the procedures described for the preparation of compound 11 above, use of 50.0 mg (0.087 mmol) of acetonide 19 provided 45.6 mg (98%) of ester 20 as a clear, viscous oil, with structure following:

Example 8 Exemplary aqueous stability

The compound of Formula (IIIa): was selected as an exemplary compound for evaluation of aqueous stability. In particular, the aqueous stability of the compound of Formula (IIIa) upon storage in aqueous solution at several temperatures for several weeks was evaluated by HPLC using the following conditions:

Column:	BioWidePore C18 (SUPELCO), 4.6 mm x 25 cm, 5 µm
Mobile Phase A: filtered	0.1% (V/V) trifluoroacetic acid (TFA) in di-water, 0.8 micron
Mobile Phase B:	100% acetonitrile, 0.8 micron filtered
Column temp:	Ambient
Injection volume:	30 µL
UV Detection:	214 nm
Flow:	1.0 mL/min
Run time:	25 minutes
Sample diluent:	50% acetonitrile in di-water
Gradient condition	: See Table 1

Table 1

Time (min)	% of B
0.0	20.0
1.0	20.0
16.0	90.0
18.0	90.0
19.0	20.0
25.0	20.0

and compared to a standard shown below:

The results of the stability study are shown in Table 2 below. Table 2

Standard	25 °C	100.0	100.1	101.0	101.6
	40 °C	100.0	100.1	100.1	98.6
	60 °C	100.0	99.3	97.5	95.6
	25 °C	100.0	100.8	100.4	102.6
	40 °C	100.0	100.6	99.8	101.8
	60 °C	100.0	99.0	97.4	96.3

The above results are exemplary, and based on them, the compounds described herein are expected to have similar characteristics to those of the compound of Formula (IIIa).

The foregoing descriptions details ester prodrugs of gamma-lactam compounds and use of such compounds for the treatment of ocular diseases including, among other things, glaucoma and macular degeneration, and represents the best mode contemplated.

Claims (14)

1. A compound having the structure of Formula (III), (IV), (V), or (IV) or a pharmaceutically acceptable salt thereof: or
2. The compound of claim 1 having the structure of Formula (IIIa) or (IIIb) or a pharmaceutically acceptable salt thereof:
3. The compound of claim 1 having the structure of Formula (IVa), (IVb), (IVc), or (IVd) or a pharmaceutically acceptable salt thereof:
4. The compound of claim 1 having the structure of Formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), or (Vh) or a pharmaceutically acceptable salt thereof:
5. The compound of claim 1 having the structure of Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), or (VIp) or a pharmaceutically acceptable salt thereof:
6. An ophthalmic pharmaceutical composition comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and an ophthalmically acceptable excipient.
7. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 5 or the ophthalmic pharmaceutical composition of claim 6 for use in a method of treating an ophthalmic disease in a subject, said method comprising administering a therapeutically effective amount of said compound or said ophthalmic pharmaceutical composition to a subject in need thereof.
8. The compound or the ophthalmic pharmaceutical composition for use of claim 7, wherein said administering is topical ocular administering.
9. The compound or the ophthalmic pharmaceutical composition for use of claim 7, wherein said disease is glaucoma.
10. The compound or the ophthalmic pharmaceutical composition for use of claim 7, wherein said disease is macular degeneration.
11. The compound or the ophthalmic pharmaceutical composition for use of claim 7, wherein said disease results from increased intraocular pressure.
12. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 5 or the ophthalmic pharmaceutical composition of claim 6 for use in a method of reducing corneal thickening, said method comprising administering a therapeutically effective amount of said compound or said ophthalmic pharmaceutical composition to a subject in need thereof.
13. The compound or the ophthalmic pharmaceutical composition for use of claim 12, wherein said subject suffers from glaucoma.
14. The compound or the ophthalmic pharmaceutical composition for use of claim 12, wherein said subject suffers from ocular hypertension.