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WO1988007044A1 - Derives de timolol - Google Patents

Derives de timolol Download PDF

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Publication number
WO1988007044A1
WO1988007044A1 PCT/US1988/000793 US8800793W WO8807044A1 WO 1988007044 A1 WO1988007044 A1 WO 1988007044A1 US 8800793 W US8800793 W US 8800793W WO 8807044 A1 WO8807044 A1 WO 8807044A1
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WO
WIPO (PCT)
Prior art keywords
timolol
group
recited
ester
substituted
Prior art date
Application number
PCT/US1988/000793
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English (en)
Inventor
Hans Bundgaard
Original Assignee
Insite Vision, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Insite Vision, Inc. filed Critical Insite Vision, Inc.
Publication of WO1988007044A1 publication Critical patent/WO1988007044A1/fr
Priority to NO88885098A priority Critical patent/NO885098L/no
Priority to DK642188A priority patent/DK642188A/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • this invention relates to novel transient prodrug derivatives of timolol useful in the treatment of glaucoma.
  • timolol derivatives when administered to the eye of a warm-blooded animal, e.g., to the human eye, are converted in the ocular tissue into the anti-glaucoma drug timolol.
  • the conversion of the prodrug form to timolol in the ocular tissue proceeds in transient fashion, i.e., in a manner such that as timolol itself is released, the moieties which split off are nontoxic or are metabolized to nontoxic metabolic products.
  • This invention further relates to methods for preparing these novel transient (prodrug) timolol derivatives, to pharmaceutical compositions containing such derivatives, and to methods for using such derivatives.
  • Timolol represented by the structural formula:
  • Another object of this invention is to provide prodrug forms of timolol, which prodrugs or transient derivatives, owing to their improved lipophilicity, exhibit superior bioavailability over timolol per s ⁇ when administered to the eye.
  • a further object of the present invention is to provide prodrugs of timolol which cleave in such a manner as to enable the parent drug timolol to be released at its site of therapeutic activity in the eye while the remaining cleaved moiety is non-toxic or is metabolized in a nontoxic fashion.
  • a still further object of this invention is to provide prodrugs of timolol which, when administered topically to the eye of a warm-blooded animal, e.g., a human, give rise to decreased systemic concentrations of timolol relative to administration of timolol per se in equivalent amounts, while at the same time eliciting the pharmacodynamic and therapeutically useful response of the parent timolol molecule more efficiently and prolongedly.
  • R 1 represents a branched chain alkyl group, preferably one having from 3 to 8 carbon atoms, inclusive, such as isopropyl, tert-butyl, tert-amyl (neopentyl) or isooctyl, a straight or branched chain alkenyl group, preferably one having from 2 to 6 carbon atoms, inclusive, such as propenyl, butenyl or pentenyl, an aryl group, e.g., a phenyl or naphthyl group, an alkyl-substituted aryl group, such as methylphenyl or ethylphenyl, an alkylthio-, nitro-, carbalkoxy-, alkanoyl- or alkanoyloxy-substituted aryl group, an aralkyl group, preferably an alkylene-aryl group in which the aryl moiety is a phenyl or naphthyl
  • R 1 can be unsubstituted or substituted with one or more substituents such as a halogen atom, a hydroxy group, a carbonyl group, a straight or branched-chain alkoxy group having the formula R 3 -O-, wherein R 3 represents an alkyl group or an aryl group, unsubstituted or substituted with one or more halogen atoms or hydroxy groups, an amino group having the formula -NR 4 R 5 , wherein R 4 and R 5 are the same or different and are hydrogen, an alkyl group or together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring, which in addition to the nitrogen may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, a carbamoyl group having the formula
  • R 4 and R 5 are as defined above, or an oxyacyl group having the formula R 2 COO- wherein R 2 is as defined above.
  • halogen designates fluorine, chlorine, bromine or iodine, with chlorine being preferred.
  • R1 is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur
  • this ring may, for instance, be 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-,4- or 5- oxazolyl, 2-imidazolyl, 5-isoxazolyl, or 2- or 3-furanyl.
  • Nontoxic pharmaceutically acceptable acid addition salts of the novel, lipophilic transient ester derivatives (prodrugs) oftimolol represented by formula II above also come within the scope of the invention.
  • Such salts generally include those formed using nontoxic inorganic or organic acids.
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic, p-acetamidobenzoic, glutamic, salicylic, sulfanilic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric and the like
  • organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic, p-acetamidobenz
  • cyclopropanoyl esters and substituted cyclopropanoyl esters of timolol are preferred for use in this invention and, most particularly, the 1'-methylcyclopropanoyl ester is preferred.
  • FIG. 1 is a graph comparing the total timolol concentration in the aqueous humor and plasma of pigmented rabbits at 5 and 30 minute post-instillation of 25 ⁇ l of 15 mM solutions of timolol and its prodrug O-pivalyl timolol.
  • the compounds of this invention can be prepared by a variety of synthetic routes.
  • One method comprises reacting a timolol salt, e.g. timolol hydrochloride, with an acid chloride of the formula III
  • reaction can conveniently be carried out in the absence of a solvent or in an inert solvent such as benzene, toluene, acetone, acetonitrile, dioxane, dichloromethane or the like, at a temperature of from room temperature (about- 25°C) to reflux, for from about 1 to about 100 hours.
  • a solvent or in an inert solvent such as benzene, toluene, acetone, acetonitrile, dioxane, dichloromethane or the like
  • a temperature of from room temperature (about- 25°C) to reflux, for from about 1 to about 100 hours.
  • acid chlorides acid bromides, acid anhydrides or mixed anhydrides
  • Another method of preparing the compounds of formula II utilizes as a starting material timolol in which the amino group has been conveniently protected, e.g. by a benzyl, carbobenzoxy carbonyl or t-butyloxycarbonyl group.
  • a compound of the formula III may then be reacted with N-protected timolol in a solvent such as acetone, acetonitrile, dioxane, water, pyridine or the like, at from about 0oC to reflux, for from about 1 to about 24 hours, eventually in the presence of an acid scavenger such as an alkali metal carbonate or triethylamine.
  • a solvent such as acetone, acetonitrile, dioxane, water, pyridine or the like
  • an acid scavenger such as an alkali metal carbonate or triethylamine.
  • a third method of preparing the compounds of formula II comprises reacting N-protected timolol with an acid of the formula IV R 1 -COOH
  • reaction is conducted in the presence of a suitable dehydrating agent, e.g., N,N-dicyclohexylcarbodiimide, and is conveniently carried out in an inert solvent such as dioxane, pyridine, dichloromethane or the like, at a temperature of from about 0oC to about 60°C, for from about 1 to about 48 hours.
  • a suitable dehydrating agent e.g., N,N-dicyclohexylcarbodiimide
  • an inert solvent such as dioxane, pyridine, dichloromethane or the like
  • Preferred compounds of the invention are compounds in which R 1 represents one of the following groups: decyl, dodecyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, isooctyl, 4-methylphenyl, 4-aminophenyl, 2-methylphenyl, 4-hydroxyphenyl, 2-hydroxyphenyl, 4-methox ⁇ phenyl, 2,4-dimethylphenyl, 4-dimethylaminophenyl, benzyl, 2-thienyl, 2-furanyl, cyclopropyl, cyclohexyl, cyclopentyl, 1'-methylcyclopropyl, 2'methylcyclopropyl, methoxy, ethoxy, butoxy, cyclohexyloxy, 2-acetoxyphenyl, 4-acetoxyphenyl, 2-carbamoylethyl, nicotinyl, 2-N,N- di
  • the compounds of formula II may be administered per se, or in combination with any pharmaceutically appropriate inert ophthalmic vehicle or carrier system.
  • the administered dose (either as a single dose, a daily dose, or other time-presented doses) depends on the requirements of the individual under treatment.
  • the dosage administered is, therefore, not subject to specific limits.
  • the dose of any compound of formula II will typically be an anti-glaucoma effective amount, or, expressed in another way, an amount of the compound of formula II which, inside the eye, produces an amount of timolol that achieves the desired pharmacological response.
  • the single medical doses for warm-blooded animals will be in the range of approximately 0.005 mg to 1 mg, with 0.05 mg to 0.5 mg being preferred.
  • the number of doses per day ordinarily will be 1 or 2.
  • the compounds of formula II may be administered in the form of a pharmaceutical composition, which may be a liquid application form, such as a solution, a suspension, or an emulsion, an ointment, a cream, an aerosol, a polymeric or solid controlled-release or monitoring drug delivery device (such as a membrane or capsule-type delivery system) or a polymeric solution that gels upon ophthalmic instillation, resulting in a controlled-release or monitoring drug delivery device or system.
  • a pharmaceutical composition which may be a liquid application form, such as a solution, a suspension, or an emulsion, an ointment, a cream, an aerosol, a polymeric or solid controlled-release or monitoring drug delivery device (such as a membrane or capsule-type delivery system) or a poly
  • pharmaceutically acceptable inert vehicles for use in carrier systems for the ophthalmic administration of the compounds of this invention are well known to those skilled in the art of ophthalmic pharmaceutical formulations.
  • pharmaceutically acceptable carriers for the preparation of eyedrops include conventional or common vehicle buffer systems, isotonic boric acid solutions, isotonic saline vehicles, and the like, with or without polymers or viscosity altering additives such as hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or polyacrylamide.
  • Suitable carriers for the preparation of ophthalmic oil solutions of the compounds of this invention include arachis oil, castor oil, mineral oil and the like.
  • the presently preferred administration form is an eyedrop solution.
  • a typical method for preparing aqueous eyedrops containing a compound of this invention is to dissolve the compound (e.g. as a water-soluble salt) in sterile water in a given concentration (e.g. 1-5 mg/ml), optionally adjust the pH to, e.g., 4-5 with a suitable buffer or with hydrochloric acid or sodium hydroxide, optionally add a preservative such as phenethanol or chlorobutanol, optionally add a viscosity altering additive such as methylcellulose, and sterilize the final solution by, e.g., membrane filtration.
  • a preservative such as phenethanol or chlorobutanol
  • a viscosity altering additive such as methylcellulose
  • An eyedrop preparation may also comprise the compound formulated as a sterile, solid preparation in any eyedrop container. Before dispensing, iostonic saline is added to dissolve the compound.
  • iostonic saline is added to dissolve the compound.
  • O-pivalyl timolol hydrochloride was prepared from timolol hydrochloride and pivalyl chloride by the procedure described in Example II and ioslated in 65% yield.
  • Mp 146-147oC from benzene-ethanol-petroleum ether. Analysis: Calc. for C 18 H 33 Cl N 4 O 4 S: C 49.47 H 7.61 N 12.82
  • Example V A mixture of timolol hydrochloride (3 mmol, 1.05 g) and benzoyl chloride (2 ml) was stirred at 60oC for 20 hours. After cooling, petroleum ether (20 ml) was added and a semi-solid residue precipitated. This residue was taken up in water (40 ml) and ethyl acetate (50 ml), and 2 M sodium hydroxide was added with stirring to give a pH of about 9.5. The organic layer was separated, washed with water (20 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to give O-benzoyl timolol free base as an oil.
  • Example VI A mixture of timolol hydrochloride (3 mmol, 1.05 g) and benzoyl chloride (3 ml) in acetonitrile (25 ml) was kept at 80oC for 45 hours. The solution was evaporated in vacuo and then treated as described in
  • Example V The O-benzoyl timolol fumarate isolated (80% yield) was identical to that described in Example V.
  • Example VIII A mixture of timolol maleate (2 mmol, 864 mg) and
  • O-2-Methylaminobenzoyl timolol fumarate was prepared as described in Example XXI using N- methylisatoic anhydride instead of isatoic anhydride. Yield: 70%. Mp. 165-167oC.
  • the timolol esters of this invention were shown to be hydrolyzable to the parent timolol.
  • Aqueous solutions of the esters were kept at 37oC and at various times analyzed by HPLC assays for intact esters as well as for timolol.
  • a typical HPLC assay used a reversed-phase C-8 column eluted with methanol-0.03 M K 2 PO 4 solution pH 4.5 (1:1 v/v) and with the column effluent being monitored at 294 nm. Analysis of the solutions of pH 2-10 showed a complete conversion of the esters to timolol. Some rate data for the conversion are shown in Table 1.
  • esters of this invention with acceptable shelf-lives in aqueous solutions. This is in sharp contrast for simple alkyl esters of timolol.
  • O-butyryl timolol ester was shown to possess a shelf-life of only 12 days at pH 4 and 25oC
  • the O-1'-methylcyclopropanoyl and O-2'-methylcyclopropanoyl esters had a shelf-life greater than 10 months at similar conditions.
  • For the O-2-aminobenzoate ester a shelf-life of one year at 25°C and pH 4 is obtainable.
  • Such particularly hydrolysis-stable esters are the O-cycloalkanoyl timolol esters and substituted cycloalkanoyl esters, including particularly substituted cylopropanoyl timolol esters.
  • the in vivo enzymatic hydrolysis of the present timolol prodrugs is thought to be a desired mechanism whereby timolol is released into a free form particularly suited to achieving therapeutic in vivo effects, e.g. the treatment of increased intraocular pressure associated with glaucoma.
  • stability of the present timolol prodrugs against hydrolysis while in formulated solution form is desirable in order to increase the shelf-life of the formulations
  • timolol esters of the present invention including particularly the O-cycloalkanoyl esters, and more particularly the alkyl-substituted cyclopropanoyl timolol esters, combine the desirable characteristics of high stability against hydrolysis in formulation solution and relatively labile enzymatic hydrolysis in, for example, in vivo environments associated with, for example, the intraocular environment.
  • a simple procedure to estimate the potential usefulness of a prodrug candidate in improving the therapeutic index of timolol is the ratio of corneal to conjunctival permeability coefficients. These coefficients can be obtained by monitoring the rate of appearance of prodrug and timolol across the isolated cornea or conjunctiva sandwiched between two compartments in the Ussing chamber.
  • the corneal and conjunctival permeability coefficients as well as their ratios for selected alkyl, cycloalkyl, and aryl timolol ester prodrugs are listed in Table 3.
  • prodrugs afford improved ratios of corneal to conjunctival absorption, and hence ocular to systemic absorption, when compared to timolol.
  • the respective ratios for the chemically stable prodrugs O-pivalyl, cyclopropanoyl, 1'-methylcyclopropanoyl, and 2'-methylcyclopropanoyl timolol are 0.57, 0.64, 0.77, and 0.44, all better than the ratio of 0.34 for timolol.
  • the timolol esters of the present invention were shown to be absorbed two to four times more readily across the cornea into the aqueous humor of the pigmented rabbit eye at 5 and 30 minutes postinstillation of 15 mM solutions. Surprisingly, the plasma timolol concentration at the same time points was slightly reduced.
  • the improved ocular absorption of O-pivalyl timolol suggests that the duration of intraocular pressure lowering by the timolol derived from O-pivalyl timolol may be extended by one to two half-lives in the aqueous humor, thereby leading to reduced dosing frequency and hence systemic drug load.
  • the eyes were immediately rinsed with saline and blotted dry, and about 100-150 ⁇ l of aqueous humor was aspirated from the anterior chamber.
  • aqueous humor was aspirated from the anterior chamber.
  • 5 ml of blood was collected from a precannulated ear artery and was immediately centrifuged at 4°C to yield plasma. Both aqueous humor and plasma samples were frozen immediately and stored at -20oC until assayed.
  • an aqueous humor sample was mixed with an equal volume of methanol containing 6% perchloric acid and 0.5 ⁇ g/ml propanolol. Following centrifugation, 10 to 20 ⁇ l of the supernatant was injected into the HPLC.
  • the plasma sample (2 ml) was mixed with 0.1 ml of propranolol solution (2 ⁇ g/ml) and 0.5 ml OF 1 M ammonium acetate buffer (pH 9), extracted with 5 times its volume of diethyl ether by vortexing for 1 minute, and then centrifuged at 1,500 x g for 10 minutes.
  • the upper organic layer was transferred to a 15 ml screw-capped conical centrifuge tube containing 100 ⁇ l of 0.1 N HCl, vortexed for 1 minute, and centrifuged at 1,500x g for 10 minutes.
  • the organic phase was discarded, while 10-50 ⁇ l of the aqueous phase, containing timolol, its prodrug, and propanolol, was injected into the HPLC.
  • the extraction efficiency was better than 75%, and less than 1% of prodrug was decomposed during the entire extraction procedure when conducted in the cold.
  • the HPLC procedure utilized a reversed phase ODS- C-18 column (4.6 mm x 250 mm, 5 ⁇ m) was used.
  • the mobile phase was a mixture of acetonitrile and water containing 1% triethylamine HCl at pH 3.0.
  • the proportion of acetonitrile in the mobile phase was increased linearly from 20 to 60% for the first 3 minutes and was kept at 60% for the next 15 minutes at a flow rate of 1.0 ml/minute.
  • Timolol and its prodrug were monitored at 294 nm.
  • the retention time was 7 minutes for timolol, 11.3 minutes for O-pivalyl timolol and 9.7 minutes for propranolol, the internal standard.
  • the assay sensitivity was 5 nmoles with respect to timolol and its prodrug.
  • the intra- and inter-run variations were less than 5 and 7.55, respectively.
  • the prodrug caused a 2- to 4-fold improvement in the corneal absorption of timolol coupled with a 30% and 50% reduction in plasma timolol concentration (p ⁇ 0.01) at 5 and 30 minutes, respectively, post-instillation of 15 mM timolol prodrug solution.
  • FIG. 1 illustrates that at 5 minutes, the percent of
  • O-pivalyl timolol in hydrolyzed form in the aqueous humor was 33.8%, while at 30 minutes this increased to 82.8%.
  • no intact prodrug was detected at either 5 or 30 minutes.
  • Error bars represent standard error of the mean. Asterisks denote that in each case results which were significantly different from timolol administration (p ⁇ 0.01) were obtained. Key: crosshatched columns represent timolol; barred columns represent O-pivalyl timolol.

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Abstract

Des dérivés ester transitoires lipophiles de timolol sont représentés par la formule générale (I), où R1 représente un groupe alkyle à chaîne ramifiée substitué ou non substitué, un groupe alkényle à chaîne droite ou ramifiée, un groupe aryle, un groupe aralkyle ou un groupe cycloalkyle, un anneau hétérocyclique aromatique substitué ou non substitué à 5 ou 6 éléments, qui contient un ou deux hétéroatomes choisis dans le groupe composé d'azote, d'oxygène et de soufre, ou un groupe substitué ou non substitué représenté par la formule R2-O-, où R2 représente un groupe alkyle, aryle, aralkyle ou cycloalkyle, ou par la formule R'2-CONH, où R'2 représente un groupe alkyle, aryle, aralkyle ou cycloalkyle. Sont également décrits des sels d'addition d'acide non toxiques et pharmaceutiquement acceptables desdits dérivés, ainsi que des formes promédicamenteuses du médicament timolol anti-glaucome, qui sont également utiles pour traiter le glaucome et les augmentations de pression intra-oculaire et qui présentent des caractéristiques d'absorption cornéenne améliorées et/ou des caractéristiques d'absorption conjonctivales retardées, permettant ainsi l'utilisation de doses de ces dérivés plus petites par rapport au timolol, ce qui réduit la concentration de timolol systémique tout en produisant le même effet thérapeutique.
PCT/US1988/000793 1987-03-17 1988-03-17 Derives de timolol WO1988007044A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
NO88885098A NO885098L (no) 1987-03-17 1988-11-15 Timolol-derivater.
DK642188A DK642188A (da) 1987-03-17 1988-11-17 Timolderivat

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US2661887A 1987-03-17 1987-03-17
US026,618 1987-03-17
US16727688A 1988-03-11 1988-03-11
US167,276 1988-03-11

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO1993023394A1 (fr) * 1992-05-14 1993-11-25 Valtion Teknillinen Tutkimuskeskus Procede de production du s-timolol
US5320839A (en) * 1991-10-11 1994-06-14 Alcon Laboratories, Inc. Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use
WO1995020568A1 (fr) * 1994-01-28 1995-08-03 Cal International Limited Produit pharmaceutique comportant un salicylate d'un agent beta-bloquant esterifiable
US9808531B2 (en) 2015-09-22 2017-11-07 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
CN111465394A (zh) * 2017-12-14 2020-07-28 灰色视觉公司 用于眼部递送的药物和组合物
CN112933096A (zh) * 2019-12-11 2021-06-11 中国科学院上海药物研究所 丁酰噻吗洛尔在制备治疗浅表型、混合型或深部血管瘤的药物中的用途
US11160870B2 (en) 2017-05-10 2021-11-02 Graybug Vision, Inc. Extended release microparticles and suspensions thereof for medical therapy
US11548861B2 (en) 2017-03-23 2023-01-10 Graybug Vision, Inc. Drugs and compositions for the treatment of ocular disorders

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Title
CHEMICAL ABSTRACTS, Volume 106, No. 25, issued 22 June 1987 (Columbus, Ohio, USA), CHANG et al, "Improved Corneal Penetration of Timolol by Prodrugs as a Means to Reduce Systemic Drug Load" see page 12, column 2, the Abstract No. 207149h, Invest. Ophthalmol. Visual Sci. 1987 28(3), 487-91, (Eng). *
CHEMICAL ABSTRACTS, Volume 106, No. 8, issued 23 February 1987 (Columbus, Ohio, USA) BUNDGAARD, HANS et al, "Prodrugs of Timolol for Improved Ocalar Delivery: Synthesis, Hydrolysis Kinetics and Lipophilicity of Various Timolol Esters", see page 362, columns 1-2, the Abstract No. 55749p, Int. J. Pharm. 1986, 33(1-3), 15-26 (Eng). *
See also references of EP0305496A4 *

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US5320839A (en) * 1991-10-11 1994-06-14 Alcon Laboratories, Inc. Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use
WO1993023394A1 (fr) * 1992-05-14 1993-11-25 Valtion Teknillinen Tutkimuskeskus Procede de production du s-timolol
WO1995020568A1 (fr) * 1994-01-28 1995-08-03 Cal International Limited Produit pharmaceutique comportant un salicylate d'un agent beta-bloquant esterifiable
GB2300636A (en) * 1994-01-28 1996-11-13 Cal Int Ltd Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker
US10117950B2 (en) 2015-09-22 2018-11-06 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US9956302B2 (en) 2015-09-22 2018-05-01 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US10098965B2 (en) 2015-09-22 2018-10-16 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US10111964B2 (en) 2015-09-22 2018-10-30 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US9808531B2 (en) 2015-09-22 2017-11-07 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US10159747B2 (en) 2015-09-22 2018-12-25 Graybug Visioon, Inc. Compounds and compositions for the treatment of ocular disorders
US10485876B2 (en) 2015-09-22 2019-11-26 Graybug Vision, Inc. Compounds and compositions for the treatment of ocular disorders
US11548861B2 (en) 2017-03-23 2023-01-10 Graybug Vision, Inc. Drugs and compositions for the treatment of ocular disorders
US11160870B2 (en) 2017-05-10 2021-11-02 Graybug Vision, Inc. Extended release microparticles and suspensions thereof for medical therapy
CN111465394A (zh) * 2017-12-14 2020-07-28 灰色视觉公司 用于眼部递送的药物和组合物
EP3723750A4 (fr) * 2017-12-14 2021-08-18 Graybug Vision, Inc. Médicaments et compositions à administrer par voie oculaire
CN112933096A (zh) * 2019-12-11 2021-06-11 中国科学院上海药物研究所 丁酰噻吗洛尔在制备治疗浅表型、混合型或深部血管瘤的药物中的用途
CN112933096B (zh) * 2019-12-11 2023-06-13 中国科学院上海药物研究所 丁酰噻吗洛尔在制备治疗浅表型、混合型或深部血管瘤的药物中的用途

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Publication number Publication date
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EP0305496A1 (fr) 1989-03-08

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