EA043581B1 - THERAPEUTIC AGENT FOR THE TREATMENT OF GLAUCOMA, CONTAINING AN FP RECEPTOR AGONIST AND A β-BLOCKER - Google Patents

Description

State of the art to which the invention relates

The present invention, in one embodiment, relates to a glaucoma therapeutic agent comprising an FP receptor agonist as an active ingredient, adapted for administration in combination with a β-blocker, wherein the FP receptor agonist is a compound represented by the following formula:

where all characters have the same meanings as those described below.

Introduction

Glaucoma is an eye disease characterized by impaired visual function, causing temporary or permanent visual field defects and reduced visual acuity. Aqueous humor accumulates due to impaired circulation and intraocular pressure constantly increases, which leads to compression of the optic nerve. An effective way to treat glaucoma is to reduce intraocular pressure, for example, using drug therapy (eye drops, internal medicine and infusion therapy), laser therapy and surgical therapy aimed at reducing intraocular pressure.

The FP receptor agonist used as the active ingredient in the present invention is known as a drug used as an agent for preventing and/or treating eye diseases and the like (see Patent Literature 1). Among others, 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-butene-1- yl]-7-hydroxyoctahydro2H-cyclopenta[b]oxepin-3-yl}butanoate is known as Sepetaprost (international nonproprietary name) (sometimes abbreviated as Compound A hereafter in this invention), which is currently being developed as a therapeutic agent from glaucoma.

At the location of glaucoma, a combination of commercially available drugs with different mechanisms for reducing intraocular pressure is usually used, for example, Xalacom (registered trademark), combination eye drops (combination of latanoprost and timolol maleate), Tapcom (registered trademark), combination eye drops (combination of tafluprost with timolol maleate) and the like.

On the other hand, Patent Literature 1 describes Compound A as Example 16 (25), and β-blockers are described as an example of other drugs serving to complement and/or enhance the preventive and/or therapeutic effects in the treatment of glaucoma with Compound A and the like.

Bibliography

Patent Literature 1: WO 2011/013651.

The essence of the invention

Technical problem.

An object of the present invention is to find an effective therapy for glaucoma and provide a drug.

The solution of the problem.

The inventors of the present invention have conducted intensive research to achieve this object and have consequently discovered that this object can be achieved by a combination of an FP receptor agonist and a β-blocker (hereinafter sometimes abbreviated as the combination of the present invention),

The present invention provides, for example, the following embodiments.

Embodiments include:

[1] an agent for the treatment of glaucoma or ocular hypertension containing an FP receptor agonist as an active ingredient, adapted for administration in combination with a β-blocker or a pharmaceutically acceptable salt thereof, wherein the FP receptor agonist is 2-propanyl 4{(3S ,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro2H-cyclopenta[b] oxepin-3-yl}butanoate;

[2] the agent according to [1] above, wherein the β-blocker is timolol, carteolol, levobunolol, betaxolol, nipradilol or befunolol;

[3] an agent according to [1] or [2] above, wherein the β-blocker is timolol;

[4] an agent according to any of the above [1]-[3], wherein a β-blocker or a pharmaceutically acceptable salt thereof and 2-propanil 4-{(3S,5aR,6R,7R,8aS)-6-[( 1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate are administered separately or simultaneously;

- 1 043581

[5] a pharmaceutical composition for the treatment of glaucoma or ocular hypertension containing 2propanil 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3- hydroxy-1-buten-1-yl]-7hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate and a β-blocker or a pharmaceutically acceptable salt thereof adapted for administration in combination;

[6] the pharmaceutical composition as set forth in [5] above, wherein the β-blocker is timolol, carteolol, levobunolol, betaxolol, nipradilol or befunolol;

[7] a pharmaceutical composition as defined in [5] or [6] above, wherein the β-blocker is timolol;

[8] a pharmaceutical composition according to any of the above [5]-[7], which is an eye drop or an eye ointment;

[9] a pharmaceutical composition according to any of the above paragraphs [5]-[8], which is a drug formulated for the needs of a patient;

[10] a method of treating glaucoma or ocular hypertension, comprising administering to a patient in need of treatment of glaucoma or ocular hypertension an effective amount of 2-propanyl 4{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)- 4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro2H-cyclopenta[b]oxepin-3-yl}butanoate and a β-blocker or a pharmaceutically acceptable salt, alone or simultaneously;

[11] a method of treating glaucoma or ocular hypertension, comprising administering to a patient in need of treatment of glaucoma or ocular hypertension an effective amount of 2-propanyl 4{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)- 4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro2H-cyclopenta[b]oxepin-3-yl}butanoate, further comprising administering an effective amount of a β-blocker or a pharmaceutically acceptable salts thereof;

[12] 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-butene-1- yl]7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate, which is used for the treatment of glaucoma or ocular hypertension in combination with a β-blocker or a pharmaceutically acceptable salt thereof;

[13] use of 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[( 1 E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1 butene-1 -yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate for the manufacture of an agent for the treatment of glaucoma or ocular hypertension, adapted for administration in combination with a β-blocker or a pharmaceutically acceptable salt thereof; etc. Usefulness of the invention.

The combination of the present invention is useful as a treatment for glaucoma because the combination enhances the intraocular pressure-lowering effect compared with administration of each drug alone and has the effect of maintaining the intraocular pressure-lowering effect.

Description of Embodiments (1) FP receptor agonist.

In one embodiment, the FP receptor agonist used in the combination of the present invention is 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2 ,5difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3yl}butanoate represented by the following formula described in WO 2011/013651:

mentioned.

Moreover, in another embodiment of the FP receptor agonist, mention is made of the compound represented by the general formula (I) described in WO 2011/013651:

(I)

R ⁵ where all symbols have the same meaning as those described in WO 2011/013651, and a salt, solvate or prodrug thereof is also mentioned.

All isomers are included in the present invention unless otherwise noted. For example, alkyl groups may include straight and branched groups. In addition, geometric isomers arising due to a double bond, the presence of a ring, a fused ring (E-form, Z-form, cis-form, trans-form), optical isomers possible due to the presence of an asymmetric carbon atom, etc. (R and S configurations, α- and β-configurations, enantiomers, diastereomers), optically active substances having optical activity (D-form, L-form, d-form, L-form), polar substances obtained by chromatographic separations (highly polar substances, low polarity substances), equilibrium mixtures of isomers, rotamers, and mixtures of these in any proportion, as well as racemic mixtures are entirely included in the present invention. In addition, all isomers formed by tautomerism are also included in the present invention.

Moreover, the optical isomers in the present invention may include not only isomers with 100% purity, but also optical isomers with a purity of less than 50%.

Compound A can be prepared according to Example 1 ^ Example 2 ^ Example 3 ^ Example 4 ^ Example 5 ^ Example 6 ^ Example 7 ^ Example 8 ^ Example 8 ^ Example 9 ^ Example 10 (1) ^ Example 11 ^ Example 12 ^ example 13 ^ example 14 ^ example 15 ^ example 16 (25), described in WO 2011/013651.

The dose of Compound A used in the combination of the present invention varies depending on age, body weight, symptoms, therapeutic effect, route of administration, treatment time and the like. For example, in the case of eye drops, a unit dose, one to several drops per dose, having a concentration of preferably from 0.000001 to 5, and more preferably from 0.00001 to 0.05% (w/v), may be drops into the eyes one to several times (eg, 1 to 8 times) per day per adult. Further, in the case of an ophthalmic ointment, an ophthalmic ointment having a concentration of Compound A is preferably 0.000001 to 5, more preferably 0.00001 to 0.05% (w/w), can be applied one to several times ( for example, 1 to 4 times) per day.

(2) β-blocker.

In the present invention, the β-blocker is not particularly limited, provided that the β-blocker is a drug that blocks any of the β-adrenergic receptors, that is, blocks each of the β1, β2 and β3 receptors of a plurality of adrenergic receptors of the sympathetic nerves, which is used to treat glaucoma. For example, timolol, cartolol, levobunolol, betaxolol, nipradilol, befunolol or pharmaceutically acceptable salts thereof may be mentioned in this context. Of the entire list, timolol maleate is preferred.

The dose of the β-blocker used in the combination of the present invention varies depending on age, body weight, symptom, therapeutic effect, route of administration, treatment time and the like, but a dose approved in the industry as a drug or dose may be used. lower than stated. According to the invention, doses of timolol include doses from 0.1 to 0.5, preferably from 0.25 to 0.5% (w/v). According to the invention, specific doses of carteolol include from 0.1 to 2, preferably from 1 to 2% (w/v). Specific dosages for levobunolol include 0.1 to 0.5, preferably 0.25 to 0.5% (w/v). Specific dosages for betaxolol include dosages of 0.1 to 0.5, preferably 0.25 to 0.5% (w/v). Specific doses of nipradilol include doses from 0.1 to 0.25, preferably 0.25% (w/v). Specific dosages for befunolol include dosages from 0.1 to 0.25, preferably 0.25% (w/v).

In the present invention, the salt is preferably a pharmaceutically acceptable salt and is preferably a water-soluble salt. Examples of the pharmaceutically acceptable salt include alkali metal salts (potassium, sodium and the like), alkaline earth metal salts (calcium, magnesium and the like), ammonium salts, pharmaceutically acceptable organic amine salts (such as tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.), acid addition salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate and the like), salts of organic acids (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, toluenesulfonate isethionate, glucuronate, gluconate, etc.) and the like) ) etc.

Since all of the β-blockers described above are commercially available compounds, their toxicity is low enough that they can be used safely as drugs.

Since the combination of the present invention is used for the treatment of glaucoma or ocular hypertension, both FP receptor agonist and β-blocker agents are preferably in dosage forms suitable for the treatment of diseases, for example, in the form of eye drops, ophthalmic ointment, etc. similar. Each of the agents can be presented in a separate dosage form. In addition, the combination of the present invention can be either single preparations or formulations containing both agents in appropriate amounts, for example, combination eye drops and combination eye ointments, which are preferable from the point of view of compliance with drug regulations.

Variations of the combinations of the present invention, where the FP receptor agonist and the β-blocker are used in separate formulations, include simultaneous administration and time-spaced administration. In addition, timed administration means that the FP receptor agonist and the β-blocker are administered separately at a specific time interval. Regarding the order of administration, the FP receptor agonist may be administered first and the β-blocker may be administered later, or the β-blocker may be administered first and the FP receptor agonist may be administered later.

The eye drops and eye ointments used in the combinations of the present invention can be formulated using routinely used techniques. For example, in the case of eye drops, an isotonizing agent, a buffering agent, a pH-correcting agent, a solubilizing agent, a thickening agent, a stabilizer, a preservative and the like can be added suitably as additives. In addition, stable eye drops can be obtained by adding a pH adjusting agent, a thickening agent, a dispersing agent and the like and suspending the drug.

Toxicity.

The toxicity of the combination of the present invention is sufficiently low that the combination of the present invention can be safely used as a medicine.

Application in medicine.

One type of disease that is treated by the combination of the present invention includes glaucoma and ocular hypertension. Examples of glaucoma include acute angle-closure glaucoma, chronic angle-closure glaucoma, secondary angle-closure glaucoma, primary open-angle glaucoma, secondary open-angle glaucoma, congenital glaucoma, normal ocular pressure glaucoma, and aqueous humor hypersecretion glaucoma.

In the present invention, the combination of the present invention can be administered in combination with another agent for the treatment of glaucoma to: (1) complement and/or enhance the therapeutic effects; (2) improvements in kinetics and absorption with dose reduction; and/or (3) mitigating side effects.

In the present invention, the other agent for treating glaucoma may be any known agent. Examples of other agent for treating glaucoma include a sympathetic agent (α2 agonist: for example, apraclonidine hydrochloride and the like, β2 agonist: for example, dipivefrin hydrochloride and the like), a parasympathomimetic agent (for example, pilocarpine hydrochloride, carbachol, demecarium, echothiophate or distigmine bromide and the like), sympathetic inhibitor (a1-blocker: for example, bunazosin hydrochloride and the like), prostaglandin preparation (for example, isopropyl unoprostone, latanoprost, bimatoprost, travoprost, EP2 agonist, EP4 agonist or DP agonist, etc.), inhibitor carboxylic acid anhydrase (for example, acetazolamide, diclofenamide, methazolamide, dorzolamide hydrochloride or brinzolamide and the like), hyperosmotic agent (for example, glycerol, a combination drug of glycerol and fructose or isosorbide and the like), ROCK (Rho kinase) (for example, Y-27632 and the like) and an NMDA antagonist.

Examples.

Hereinafter, the present invention will be specifically described with reference to an example, but the present invention is not limited to the examples.

2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1buten-1-yl]-7 was used -hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate (compound A). Compound A can be prepared by a known method. For example, compound A can be prepared according to Example 1 ^ Example 2 ^ Example 3 ^ Example 4 ^ Example 5 ^ Example 6 ^ Example 7 ^ Example 7 ^ Example 8 ^ Example 9 ^ Example 10 (1) ^ Example 11 ^ Example 12 ^ example 13 ^ example 14 ^ example 15 ^ example 16 (25), described in WO 2011/013651.

Biological example 1: action aimed at reducing intraocular pressure.

Compound A and a β-blocker were used as test substances. Compound A was prepared in a solution of 3 μg/ml using a vehicle (aqueous solution containing 0.3 w/v% sodium citrate, 0.5 w/v% polysorbate 80 and 0.8 w/v% sodium chloride) . Timolol (trade name: Timoptol, registered trademark) as 0.5% ophthalmic solution, Santen Pharmaceutical Co., Ltd. used as a β-blocker.

Approximately one hour before administration of vehicle and test substance to male dogs (TOYO Beagle, 16 to 42 months at baseline) that had undergone sufficient pre-acclimatization, intraocular pressure was measured in both eyes and this intraocular pressure was set as the pre-instillation intraocular pressure value ( dropwise administration). Thereafter, the test substance or vehicle was administered by instillation into the treated eyes in an amount of 30 μl each, and the intraocular pressure in each eye was measured at 2, 4, 6, 8 and 24 hours after administration. Intraocular pressure was measured using a pneumatic applanation tonometer (Model 30 Classic, Reichert, Inc.) under local anesthesia after instillation of 0.4% oxybuprocaine hydrochloride (0.4% Benoxil ophthalmic solution (registered trademark, Santen Pharmaceutical Co., Ltd.) , which is a local anesthetic.The measurement was carried out until a stable value was obtained three times in a row (the difference between the continuously obtained measured values

Claims (3)

niyami was within 0.5 mm Hg). The average of the three measured values obtained was determined as the intraocular pressure value (in mm Hg) and recorded to the nearest tenth. The value obtained by subtracting the intraocular pressure value at each time point from the intraocular pressure value before administration of the test substance and vehicle was designated as the intraocular pressure reduction width, and the average value of the intraocular pressure reduction width of each individual at each time point was designated as the average reduction width intraocular pressure. The maximum value of the average width of the decrease in intraocular pressure at each time point was designated as the maximum width of the decrease in intraocular pressure. In addition, the average width of the decrease in intraocular pressure 24 hours after drug administration was designated as the width of the decrease in intraocular pressure 24 hours after administration. The results are shown in the table. Meanwhile, if the group name contains both drug names, the order of writing determines the order of their administration. For example, the compound A timolol group means that compound A was administered first and then timolol was administered to the same eye. Group name Number of tests Maximum width of intraocular pressure reduction (mmHg ± S.E.) Width of intraocular pressure reduction 24 hours after administration (mmHg ± S.E.) Time after administration exhibiting maximum reduction in intraocular pressure (h) Vehicle 8 0.7 ±0.48 0.4 ±0.58 6 Carrier timolol 8 2.7 ±0.56 0.0 ±0.56 2 Compound A - carrier 8 5.8 ±0.35 3.5 ±0.75 6 Compound A - timolol 8 7.0 ±0.52 4.8 ±0.34 8 Timolol - compound A 8 7.1 ±0.58 4.7 ±0.57 8 As a result, it was found that the combined use of Compound A and timolol, regardless of the order of administration, demonstrated a greater effect on lowering intraocular pressure compared to the use of either agent alone. In addition, it was found that when Compound A and timolol were administered together, there was a decrease in intraocular pressure for a period of up to 24 hours after administration, and the period of maximum decrease in intraocular pressure was longer than when administered with each agent separately. Industrial Applicability The combination of the present invention has the effect of significantly reducing intraocular pressure and is therefore useful for the treatment of glaucoma or ocular hypertension. CLAIM 1. Pharmaceutical composition for the treatment of glaucoma or ocular hypertension, containing an effective amount of 2-propanyl 4-{(38.5aK,6K,7K,8aB)-6-[(1E,3K)-4-(2,5-difluorophenoxy) -3-hydroxy1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate and an effective amount of timolol or a pharmaceutically acceptable salt thereof, for ophthalmic administration in combination with a pharmaceutically acceptable carrier. 2. A method for treating glaucoma or ocular hypertension, comprising ophthalmic administration in combination to a patient in need of treatment of glaucoma or ocular hypertension, an effective amount of 2-propanyl 4-{(38.5aK,6K,7K,8a8)-6-[(1E, 3K)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate and an effective amount of timolol or a pharmaceutically acceptable salt thereof , separately or simultaneously. 3. Application of 2-propanil 4-{(38.5aK,6K,7K,8a8)-6-[(1E,3K)-4-(2,5-difluorophenoxy)-3-hydroxy-1buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate for the treatment of glaucoma or ocular hypertension in combination with timolol or a pharmaceutically acceptable salt thereof. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2