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US20060135609A1 - Ophthamological drugs - Google Patents

Ophthamological drugs Download PDF

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Publication number
US20060135609A1
US20060135609A1 US11/255,478 US25547805A US2006135609A1 US 20060135609 A1 US20060135609 A1 US 20060135609A1 US 25547805 A US25547805 A US 25547805A US 2006135609 A1 US2006135609 A1 US 2006135609A1
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Prior art keywords
compound
acid
drug moiety
composition
ribitol
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US11/255,478
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Inventor
Eric Toone
David Epstein
Pratap Challa
Phillip Snyder
Xin Chen
Mitchell deLong
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Duke University
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Duke University
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Priority to US11/255,478 priority Critical patent/US20060135609A1/en
Publication of US20060135609A1 publication Critical patent/US20060135609A1/en
Assigned to DUKE UNIVERSITY reassignment DUKE UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EPSTEIN, DAVID L., TOONE, ERIC J., CHALLA, PRATAP, CHEN, XIN, DELONG, MITCHELL A., SNYDER, PHILLIP W.
Priority to US12/511,861 priority patent/US8642644B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • the present invention relates, in general, to ophthamological drugs, and, in particular, to a method of modifying ophthamological drugs so as to increase their penetration through the cornea into the anterior chamber.
  • the invention further relates to such modified drugs and to the use of same in treating diseases/disorders of the eye, such as glaucoma and other conditions related to elevated intraocular pressure.
  • Glaucoma is one of the three leading causes of blindness in the United States and a leading cause of blindness in the world. Over 2.2 million people in the United States have glaucoma, and several million more are at risk of developing the disease. As the population ages, the number of individuals with glaucoma will continue to grow since glaucoma affects the oldest individuals disproportionately.
  • Glaucoma is not just one disease, rather, it is a spectrum of conditions that share a final common pathway of acquired, progressive deterioration of the neuronal components of the optic nerve. The neuronal death results in loss of vision once a sufficient number of individual nerves are destroyed.
  • IOP intraocular pressure
  • Topical agents that are presently in use include miotics, which increase the outflow of fluid (these include Isopto®Carpine, Ocusert®, Pilocar®, and Pilopine®); epinephrines, which also increase the outflow of fluid (these include Epifrin® and Propine®); beta-blockers, which reduce the amount of fluid (these include Betagan®, Betimol®, Betoptic®, Ocupress®, Optipranalol®, and Timoptic®); and carbonic anhydrase inhibitors and alpha-adrenergic agonists, which also reduce the amount of fluid (these include Alphagan®, Iopidine®, and Trusopt®).
  • Prostaglandin analogs which are also in use, increase the outflow of fluid through a secondary drainage route (these include Lumigan®, Rescula®, Travatan®, and Xalatan®).
  • Communication oral medications include carbonic anhydrase inhibitors (such as Daranide®, Diamox®, and Neptazane®). These agents decrease aqueous humor inflow into the eye.
  • Glaucoma patients may also suffer reduced blood flow to the optic nerve and neuronal tissue, and diminished resistance of the nerve tissue to damage, and the compliance of connective tissue surrounding and supporting the optic nerve.
  • One agent, Memantine is in phase III clinical trials (Allergan) as an agent that may prove to be neuroprotective.
  • ophthamological drugs 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 (trabecular meshwork and Schlemm's canal) and the uveal-scleral pathway (unconventional outflow pathway). Intraocular pressure is lowered by drugs acting in the trabecular meshwork/Schlemm's canal and the uveal-scleral pathway. Penetration of the drug through the cornea requires a balance of hydrophobic and hydrophilic characteristics. The drug must be sufficiently soluble in non-polar media to diffuse into the cornea and sufficiently soluble in polar (aqueous) media to diffuse out of the cornea into the aqueous humor.
  • carboxylic acids e.g., phenoxyacetic acids or cinnaminic acids.
  • Carboxylic acids are typically delivered in buffered aqueous solution; near neutral pH, carboxylic acids exist as the deprotonated carboxylate salt. Ionized carboxylate salts, while soluble in aqueous solution, will not penetrate the cornea.
  • Such drugs can be delivered as pro-drug esters.
  • pro-drug esters which are cleaved enzymatically (e.g., in the cornea) to regenerate the active compound, can enhance penetration of drug through the cornea into the anterior chamber.
  • esters are too hydrophobic (non-polar) to diffuse out of the relatively non-polar external layer of the cornea (corneal epithelium) and into the aqueous humor. Further complicating delivery, such compounds are often too insoluble to formulate in aqueous solutions.
  • the present invention provides a method of preparing derivatives of ophthamological drugs that contain a carboxyl group so as to overcome solubility and corneal penetration limitations associated with such drugs.
  • the present approach results in the production of pro-drugs that can diffuse into the cornea of mammalian eyes but that are sufficiently water soluble to be released from the cornea into the aqueous humor.
  • Pro-drugs of the invention are activated by esterases in the cornea, with the result that the active drug is present in the aqueous humor of the anterior chamber.
  • the present invention relates generally to ophthamological drugs. More specifically, the inventon relates to a method of modifying (derivatizing) ophthamological drugs so as to increase their penetration through the cornea. The invention also relates to drugs modified (derivatized) in accordance with the instant method and to the use of same in treating conditions associated with elevated intraocular pressure, particularly, glaucoma.
  • the invention provides a composition comprising a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, the drug moiety comprising at least one of a phenoxyacetic acid, a cinnamic acid, and a mixture thereof.
  • the invention provides a composition comprising a compound derived from the esterification of a carboxylate functionality of a drug moiety thereof, with the proviso that the drug moiety is not a prostaglandin.
  • the invention provides a compound selected from the group consisting of:
  • the invention provides a method of treating an ophthamological disorder, said method comprising administering to a human or other animal a safe and effective amount of a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, the drug moiety comprising at least one of a phenoxyacetic acid, a cinnamic acid, and a mixture thereof.
  • the invention provides a method of determining the suitability of a compound for treating an ophthamological disorder, said method comprising providing a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, determining whether the compound releases its carboxcylic acid, in an assay under conditions mimicking conditions in an eye, within a predetermined half life, and selecting the compound for treatment of an ophthamological disorder if the compound releases its carboxcylic acid within the predetermined half life.
  • the invention provides a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, the drug moiety being at least one of travaprost, latanoprost, and bimatoprost and mixtures thereof.
  • FIG. 1 Pressure reduction observed with 5% formulation of ticrynafen-ribotol ester.
  • FIG. 2 Pressure reduction observed with 10% formulation of ticrynafen-ribitol ester.
  • FIG. 3 Pressure reduction observed with 15% formulation of ticrynafen-ribitol ester.
  • FIG. 4 Measurements of intraocular pressure in rabbits following treatment with ticyrnafen-ribitol ester ointment (10% w/w). Arrows indicate the addition of ointment on days 1, 2, and 3. Data represent mean ⁇ standard error of the mean. Single asterisk indicates significant difference between present value and the value measured at time zero for each eye, p ⁇ 0.05. Double asterisk indicates significant difference between OS (untreated) and OD (treated) eyes, p ⁇ 0.05.
  • FIG. 5 Measurements of intraocular pressure in rabbits following daily treatments (1 drop) with AR101 (compound of Formula V). Arrows indicate the addition of a loading dose (3 drops) on day 0 and day 10. Animals were left untreated on days 8 and 9. Data represent mean ⁇ standard error of the mean. Single asterisk indicates significant difference between present value and the value measured at time zero for each eye, p ⁇ 0.05. Double asterisk indicates significant difference between OS (untreated) and OD (treated) eyes, p ⁇ 0.05.
  • FIG. 6 Measurements of intraocular pressure in rabbits following treatment with 5-O-Ribitol[2,3-dichloro-4-(thiophene-2-carbonyl)]phenoxyacetate (10% and 15% in a lanolin base).
  • FIG. 7 Measurements of intraocular pressure in rabbits following treatment with 5-O-Xylitol 4-(2-phenylacryloyl)cinnamate (0.3% and 0.6% mixed equimolar with cysteine in solution).
  • FIG. 8 Measurments of intraocular pressure in rabbits following treatment with 5-O- ⁇ (9 ⁇ ,11 ⁇ ,15R)-15-[2-Benzo[b]thiophen-2-yl]-16,17,18,19,20-pentanor-5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoyl ⁇ xylitol (0.004% in solution).
  • FIG. 9 Measurements of intraocular pressure in rabbits following treatment with 1-O- ⁇ (9 ⁇ ,11 ⁇ ,15R)-15-[2-Benzo[b]thiophen-2-yl]-16,17,18,19-pentanor-5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoyl ⁇ -11-hydroxy-3,6,9-trioxaundecane (0.004% and 0.02% in solution).
  • FIG. 10 Measurements of intraocular pressure in rabbits following treatment with 11-Hydroxy-3,6,9-trioxaundecyl 4-(2-phenylacryloyl)cinnamate (0.3% and 0.6% mixed equimolar with cysteine in solution).
  • alkyl refers to a saturated or unsaturated hydrocarbon chain having 1 to 12 carbon atoms, preferably 1 to 6, more preferably 1 to 3 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl moieties have one or two branches, preferably one branch. Preferred alkyl moieties are saturated. Unsaturated alkyl moieties have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl moieties have one or two double bonds or one triple bond, more preferably one double bond. Alkyl chains may be unsubstituted or substituted with from 1 to 4 substituents.
  • Preferred substituted alkyl moieties are mono-, di-, or trisubstituted.
  • the substituents may be lower alkyl, halo, hydroxy, aryloxy, acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino moieties.
  • carboxylate and “carboxylic acid” refer to a chemical moiety characterized by a carbon atom attached to three substituents, viz., another carbon atom by a single bond, an oxygen atom by a double bond, and another oxygen atom by a single bond.
  • the shorthand “XCOO—” and “X—COOH” as used herein shall constitute shorthand for the carboxylate and the carboxylic acid moieties, respectively. In this shorthand “X” shall indicate the rest of the drug moiety that contains the carboxylic acid. It is understood that “X” must contain a carbon atom directly attached to the carboxylic acid moiety.
  • opthamological drugs refers to any chemical compound that is applied to the eye with the intent of producing a biological response or to treat a disease or condition of the eye.
  • Non-limiting examples of opthamological drugs include the prostaglandins, such as travaprost, latanoprost, bimatoprost and similar agents, phenoxyacetic acids, cinnamic and phenylproprionic acids, benzoic acids, fatty acids, and the like.
  • Conditions and diseases include but are not limited to glaucoma and macular degeneration.
  • “sugar alcohol” refers to an alcohol that contains multiple hydroxyl groups along a carbon chain. “Sugar alcohols” may be naturally occurring, or may be derived from a naturally-occurring sugar or a different sugar alcohol, or may be partially or wholly derived from a synthetic pathway. “Sugar alcohols” may have no more than one hydroxyl per carbon atom of the chain, but they may have less than a 1:1 ratio. “Sugar alcohols” must have at least one free hydroxyl besides the one that is used to create the ester linkage. The carbon chain of the sugar alcohol may have up to 9 carbon atoms, and may be entirely linear, or may be branched, or may contain rings.
  • atoms or groups of atoms may independently replace each of the hydroxyl groups as long as there is at least one free hydroxyl group remaining.
  • suitable replacement moieties include alkyl groups, chlorine atoms, methoxy groups, phenoxy groups alkoxy groups, fluorine atoms, amine groups that may be unsubstituted or mono- or di-substituted, amide groups wherein the amide is attached to the sugar alcohol via the carbon or the nitrogen of the amide.
  • the hydroxyl groups of the sugar alcohol may be linked together via ketal linkages.
  • the present invention relates to a method of preparing derivatives of ophthamological drugs that comprise a carboxyl group, including drugs suitable for use in treating glaucoma and other diseases/disorders that are associated with elevated intraocular pressure.
  • the present approach results in the production of compounds that can diffuse into the cornea of the mammalian (e.g., human) eye.
  • enzymatic activation occurs via esterases present in the cornea, resulting in the production of free acid in the anterior chamber/aqueous humor which can then enter the trabecular meshwork/Schlemm's canal or uveal-scleral pathway.
  • the carboxylate functionality of the drug is masked (protected) by esterification with a sugar alcohol.
  • esterification renders the drug sufficiently hydrophobic to permit diffusion into the cornea.
  • the polar alcohol moiety imparts sufficient aqueous solubility that release from the cornea of active drug into the aqueous humor is effected.
  • the invention includes compounds of formulas IA-C. (X—COO)-SA Formula IA
  • SA is a sugar alcohol, attached to either a primary, secondary, or tertiary hydroxyl, the sugar alcohol containing more than 3 but fewer than 9 carbons, and having a ratio of hydroxyl groups to carbons of less than 1:1, but containing at least one free hydroxyl wherein any missing hydroxyl groups are independently replaced by the following a chlorine atom, an amine group, an amido group, an amide group, a fluorine atom, a hydrogen atom, a nitrile group, an aryloxy group and any missing hydrogen groups are replaced by alkyl groups.
  • Y is independently selected from H, OH or OR
  • R is (CH 2 ) n CH 3 ;
  • n 1 to 6 (preferably, m is 1, 2, 3 or 4);
  • n is 0 to 6 (preferably, n is 0-4).
  • each Y is independently H, OH, or OR;
  • R is an alkyl group
  • n are each independently 0 to 6;
  • compounds of Formulas IA-C can be present as a pharmaceutically acceptable salt.
  • Suitable salts can be formed with pharmaceutically acceptable anions (e.g., halides, acetate, benzoate, etc.) and cations (e.g., alkali metals, alkali earth metals, alkyl ammonium, etc.).
  • Non-limiting examples of drug moiety that can be derivatized in accordance with the present invention include phenoxyacetic acids, such as ethacrynic acid and ticrynafen, cinnaminic acids, such as SA9000 and SA8248 (Santen) (Shimazaki et al, Biol. Pharm. Bull. 27:1091-1024 (2004), Shimazaki et al, Biol. Pharm. Bull. 27:846-850 (2004)) and prostaglandin derivatives, including the derivative shown in Formula II below.
  • certain presently available drugs such as Lumigan, Travatan and Xalatan, which are isopropyl esters, can be redesigned so as to be esters of sugar alcohols, as described herein.
  • Non-limiting examples of drug moieties can include: Non-steroidal anit-inflammatory agents, such as Acetylsalicylic acid (aspirin), Salicylic acid, Sulindac, Indomethacin, Naproxen, Fenoprofen, Ibuprofen, Ketoprofen, Indoprofen, Furobufen, Diflunisal, Tolmetin, Flurbiprofen, Diclofenac, Mefenamic acid, Flufenamic acid, Meclofenamic acid, Fenclozic acid, Alclofenac, Bucloxic acid, Suprofen, Fluprofen, Cinchophen, Pirprofen, Oxoprozin, Cinmetacin, Acemetacin, Ketorolac, Clometacin, Ibufenac, Tolfenamic acid, Fenclofenac, Prodolic acid, Clonixin, Flutiazin, Flufenisal, Salicylsalicylic acid, O-(
  • Non-limiting examples of prostaglandins include: Prostaglandin E 2 ; Prostaglandin F 2 ⁇ ; 15-Deoxy-16-hydroxy-16-vinylprostaglandin E 2 ; 11-Deoxy-11 ⁇ , 12 ⁇ -methanoprostaglandin E 2 ; 11-Deoxy-11 ⁇ , 12 ⁇ -difluoromethanoprostaglandin E 2 ; Prostacyclin; Epoprostenol; dl-16-Deoxy-16-hydroxy-16( ⁇ / ⁇ )-vinyl prostaglandin E 2 ; Prostaglandin E 1 ; Thromboxane A 2 ; 16,16-Dimethylprostaglandin E 2 ; (15R) 15-Methylprostaglandin E 2 (Arbaprostil); Meteneprost; Nileprost; and Ciprostene.
  • Preferred sugar alcohols suitable for use in preparing compounds of the invention include the C4 sugars threitol and erythritol, the C5 sugars arabinitol, xylitol, ribitol and lyxitol, and the C6 sugars glucitol, galactitol, mannitol, gulitol, altitol, allitol, iditol and talitol, more preferably, xylitol, ribitol, glucitol and mannitol.
  • the invention includes the use of both D and L isomers.
  • compositions of the present invention comprise a safe and effective amount of one or more compounds of Formulas IA-C, one or more pharmaceutically acceptable salts of Formulas IA-C, or mixtures thereof.
  • safe and effective amount means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • compositions of the subject invention contain a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible liquid, gel, cream or ointment diluents which are suitable for administration to a subject.
  • compatible means that the components of the composition are capable of being commingled with the compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof are gelatin, excipients, pyrogen-free water, isotonic saline, and phosphate buffer solutions.
  • a pharmaceutically-acceptable carrier to be used in conjunction with a compound is basically determined by the way the compound is to be administered.
  • the compounds of the present invention may be administered systemically. Routes of administration include transdermal; oral; parenterally, including subcutaneous or intravenous injection; topical; and/or intranasal.
  • the appropriate amount of the compound to be used may be determined by routine experimentation with animal models.
  • animal models include, but are not limited to the intact and ovariectomized rat models, the ferret, rabbit, canine, and non human primate models as well as disuse models.
  • Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels, solutions, and the like.
  • the composition is sterile and can be in dosage unit form, e.g., suitable for topical ocular use.
  • the composition can be packaged in a form suitable for metered application, such as in container equipped with a dropper.
  • compositions of the invention are a solution prepared using a physiological saline solution as a carrier.
  • the pH of the solution is, preferably, maintained between 4.5 and 8.0 using an appropriate buffer system.
  • a neutral pH is more preferred.
  • Compositions of the invention can also comprise pharmaceutically acceptable preservatives, stabilizers and/or surfactants.
  • the present invention relates to a method of treating glaucoma, or other disease or disorder of the eye related to elevated intraocular pressure.
  • the method comprises administering to a mammal (e.g., a human) in need of such treatment an amount of the compound of Formulas IA-C, or pharmaceutically acceptable salt thereof, in an amount sufficient to effect the treatment.
  • a mammal e.g., a human
  • the dosing regimen can vary with the compound used, the patient and/or the effect sought. Selection of an optimum dosing regimen can be readily made by one skilled in the relevant art.
  • the invention may provide the means to achieve enhanced penetration and yet retain hydrolysis at a rate sufficient to treat disease, but to provide an assay to determine the optimal sugar alcohol to be attached to each drug.
  • a great advantage of this invention is the ease of determining which sugar alcohol ester is the most suitable candidate for in vivo dosing for each drug. Since the sugar alcohol moiety imparts water-solubility to the compounds, an assay can be readily set up to determine the optimal sugar alcohol for each drug moiety based on the release rate thus:
  • a commercially-available preparation of esterase such as porcine liver esterase (Sigma Corp., St. Louis), is prepared at a standard concentration.
  • the drug-sugar alcohol combination dissolved in methanol or a methanol-water or methanol-acetonitrile combination, is added dropwise to the esterase and the rate at which the compound is released from the alcohol is determined.
  • the analytical technique used to determine the amount of free acid will vary with the acid used, but a typical procedure would be by TLC, or reverse-phase TLC, or HPLC or by Mass Spectroscopy.
  • TLC or reverse-phase TLC
  • HPLC or by Mass Spectroscopy.
  • One skilled in the art can readily determine the optimal analytical method for each sugar-acid pair evaluated.
  • This assay can easily be adapted to be run in a 96-well plate format, or other high-throughput method of determining activity.
  • In vivo pharmacological activity for glaucoma can be determined using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein: C. liljebris, G. Selen, B. Resul, J. Stemschantz, and U. hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
  • each drug and each disease state will have its own particular optimal delivery, and that one skilled in the art may modify the guidelines given herein. Combinations which are too quickly hydrolyzed offer no advantage over the free acids, and compounds which have no detectible hydrolysis in the assay are likewise not useful. It is the purpose of this invention to provide compounds which release their carboxcyclic acids under the conditions described, with a half-life of greater than one minute but less than seven days. A more preferred embodiment of the invention provides compounds that are released in greater than five minutes and less than 4 days, and still more preferred are compounds which are released in greater than five minutes and in less than 24 hours.
  • the ester obtained above (0.266g) was dissolved in 90% aqueous trifluoroacetic acid (10 mL) at 0° C. After being stirred at 0° C. for 1 h, the reaction solution was concentrated at reduced pressure. Excess trifluoroacetic acid was removed by azeotropic distillation with dioxane at reduced pressure. The oily residue was purified by flash chromatography (eluting with 10% MeOH in DCM+0.1% triethylamine), affording 5-O-ribitol[2,3-dichloro-4-(thiophene-2-carbonyl)]phenoxyacetate (0.11 g).
  • Ticrynafen (Formula IV) is a drug of known activity against glaucoma.
  • the free acid, as the carboxylate salt, has little or no activity presumably because penetration through the cornea into the anterior chamber is negligible.
  • Simple esters of ticrynafen are highly insoluble and also show little or no activity.
  • the ribitol ester of ticrynafen (Formula III) is completely soluble in petrolatum/lanolin mixtures. The compound reduces intraocular pressure (IOP) in a dose-dependent fashion in Dutch-Belted white rabbits (see Example 3 and FIGS. 1-4 ).
  • Ticrynafen-ribitol ester was formulated as an ointment in 5, 10, and 15% concentrations.
  • the Dutch Belted rabbit model was used to test the formulation for both pressure lowering and side effects.
  • Baseline intraocular pressures were obtained by placing one drop of proparacaine in each eye followed by pressure measurements utilizing a Pneumotonometer®. One eye of each rabbit was then given 0.1 mg of ticrynafen-ribitol ester ointment topically in the inferior conjunctival sac. The second eye was used as a control with application of lanolin ointment without drug. Repeat doses were given at 24 hour intervals for a total of three doses (0, 24, and 48 hours). Intraocular pressures were recorded every 12 hours for one week. A total of twelve rabbits received the 5% ointment, eight rabbits the 10% ointment, and eight rabbits the 15% ointment.
  • FIGS. 1, 2 and 3 Pressure reduction for each concentration is shown in FIGS. 1, 2 and 3 .
  • FIG. 4 presents the 10% data with statistically significant timepoints indicated by double asterisks.
  • Zinc chloride (13.6g, 100 mmol) was stirred with anhydrous acetone (110 mL) at room temperature for 15 min, and xylitol (7.6 g, 50 mmol) was added. After being stirred at room temperature for 24 h, the reaction solution was treated with 5N NaOH solution (180 mL), giving a two-phase solution with some white precipitates in the upper phase. The mixture was filtered off, and the filtrate was extracted with chloroform (4 ⁇ 100 mL). The combined extracts were washed with brine (2 ⁇ 60 mL), and dried over anhydrous Na 2 SO 4 . Evaporation of the solvents with rotary evaporator afforded the crude products (12 g).
  • 2,6-Lutidine (0.93 mL, 8 mmol, 8 eq) was added dropwise to an ice-cold stirred solution of 5-benzyloxyxylitol (240 mg) in anhydrous DCM (10 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) (1.38 mL, 6 mmol, 6 eq) was added dropwise.
  • TDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate
  • Tetrabutylammonium fluoride (TBAF, 1.0M solution in THF) (3.1 mL, 3.1 mmol, 14 eq) was added to a stirred solution of the ester obtained above (300 mg, 0.22 mmol) in anhydrous THF (10 mL), and the solution was stirred at room temperature for 2 h.
  • the prostaglandin derivative shown in Formula II shows strong activity against glaucoma.
  • the isopropyl ester of the Formula II compound is highly insoluble in aqueous solution ( ⁇ 0.001% in normal saline).
  • the xylitol ester shown in Formula V is soluble to at least 0.03% (see Example 6 for preparation).
  • the compound shown in Formula V is readily hydrolyzed by pig liver esterase, strongly suggesting that the compound will be cleaved by endogenous esterases, releasing active drug.
  • the xylitol prostaglandin ester of Formula V (also called AR101) was formulated as a 0.004% solution for topical administration.
  • the Dutch Belted Rabbit model was used to test the formulation for both pressure lowering and side effects.
  • Baseline intraocular pressures were obtained by placing one drop of proparacaine in each eye followed by pressure measurements with a Pneumotonometer®. One eye of each rabbit received a loading dose of 3 drops 0.004% AR101 on day 0 and day 10. One drop of AR101 was given daily on days 1-7 and 10-14. No drug was given on days 8 and 9. The contralateral control eye received balanced salt solution drops without AR101. Intraocular pressure measurements were recorded every 12 hours for two weeks.
  • FIG. 5 demonstrates pressure recordings for each eye. Statistically significant pressure reductions between eyes were observed on days 3, 7, and 11.
  • 2,6-Lutidine (7.0 mL, 60 mmol) was added dropwise to an ice-cold stirred solution of impure 5-benzyloxy-D-ribitol (2.4 g) in anhydrous DCM (90 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) (11.5 mL, 50 mmol) was added dropwise at the same temperature.
  • TDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate
  • Tetrabutylammonium fluoride (TBAF, 1.0M solution in THF) (2.27 mL, 2.27 mmol) was added to a stirred solution of the ester obtained above (220 mg, 0.16 mmol) in anhydrous THF (10 mL), and the solution was stirred at room temperature for 3 h.
  • 2,6-Lutidine (7.0 mL, 60 mmol) was added dropwise to an ice-cold stirred solution of impure 4-benzyloxy-L-threitol (3.5 g) in anhydrous DCM (100 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) (11.5 mL, 50 mmol) was added dropwise at the same temperature.
  • TDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate
  • Tetrabutylammonium fluoride (TBAF, 1.0M solution in THF) (2.28 mL, 2.28 mmol) was added to a stirred solution of the ester obtained above (230 mg, 0.19 mmol) in anhydrous THF (10 mL), and the solution was stirred at room temperature for 3 h.
  • Zinc chloride (13.6 g, 100 mmol) was stirred with anhydrous acetone (110 mL) at room temperature for 15 min, and xylitol (7.6 g, 50 mmol) was added. After being stirred at room temperature for 24 h, the reaction solution was treated with 5N NaOH solution (180 mL), giving a two-phase solution with some white precipitates in the upper phase. The mixture was filtered off, and the filtrate was extracted with chloroform (4 ⁇ 100 mL). The combined extracts were washed with brine (2 ⁇ 60 mL), and dried over anhydrous Na 2 SO 4 . Evaporation of the solvents with rotary evaporator afforded the crude products (12 g).
  • Ethacrynic acid (0.5 g, 1.65 mmol) was suspended in benzene (3.0 mL) and thionyl chloride (0.25 mL, 2 equiv), and heated to reflux for 1.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether (5 mL) and added to a refluxing suspension of glycerol (2 mL) in diethyl ether (3.0 mL). The reaction was stirred at reflux for 3 h. After cooled to room temperature, the reaction solution was concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with water and saturated NaHCO 3 .
  • Ethacrynic acid (0.46 g, 1.53 mmol) was suspended in benzene (3.0 mL) and thionyl chloride (0.23 mL, 2 equiv) and heated to reflux for 1.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting oil was dissolved in DMF (1.0 mL) was added dropwise to a suspension of erythritol (0.44 g, 2 eq) in DMF (3.0 mL). The reaction was heated to 80° C. for 1.5 h, then evaporated under reduced pressure.
  • Ethacrynic acid (0.46 g, 1.53 mmol) was suspended in benzene (3.0 mL) and thionyl chloride (0.23 mL, 2 equiv) and heated to reflux for 1.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting oil was dissolved in DMF (3.0 mL) and ribitol (0.53 g, 2 equiv) was added. The reaction was allowed to stir at room temperature overnight, then concentrated under reduced pressure. The crude products were purified by column chromatography (eluting with 15:1 EtOAc/MeOH) to give 1-O-ribitol[2,3-dichloro-4-(2-methylenebutyryl)]phenoxyacetate.
  • IOP intraocular pressure
  • 5-O-Xylitol 4-(2-phenylacryloyl)cinnamate Eyedrops containing the compound were administered twice daily for 7 days. The contralateral eye was left untreated to serve as a control. IOP was assessed concurrently with drug administration.
  • Example 1 Using the acid chloride of ticrynafen (shown in Scheme 1) and substantially the same conditions as in Example One, but substituting the 1,4-bis-TBDMS-threitol in place of the diacetone ribitol, and limiting the ratio of acid chloride and alcohol to a 1:1 ratio, the coupling of the acid and the secondary alcohol are effected.
  • the crude material is isolated and purified in the same manner as in Example I, and is further treated with TBAF to remove the silyl groups protecting the primary alcohols by the removal method of Example IV. Such manipulations are well-known to one skilled in the art. After purification, again following Example I, 2-O-ticrynafyl threitol is isolated.
  • carboxylic-ester hydrolase (CAS# 9016-18-6) is prepared in suspension as described in C. Tamm Pure Appl. Chem. 64, 1187, (1992) and M. Ohno, M. Otsuka Org. React. 37, 1, (1989), incorporated herein as reference.
  • the activity is standardized against a reference activity of 1 U corresponds to the amount of enzyme which hydrolyzes 1 micromol ethyl butyrate per minute at pH 8.0 and 25° C.
  • the 1-(2-deoxythreitol) ester of ticrynafen, from Example 8 above, is dissolved in methanol and added dropwise to the stirred solution.
  • the progress of the reaction is followed by TLC using pure ticrynafen as a reference standard. After 5 minutes, and again at doubling intervals the progess of the reaction is followed until there remains no further change in the TLC. A relative rate is determined and compared against the rate needed to ensure corneal penetration and hydrolysis for the disease in question.

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US20090318542A1 (en) 2009-12-24
US8642644B2 (en) 2014-02-04

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