JP2002179694A - Phopshoric ester derivative and pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To create a pharmaceutical composition having extremely high safety and effectiveness and having ocular hypotensive actions, especially a compound useful as a therapeutic agent for ocular hypertension and glaucoma. SOLUTION: This phosphoric ester derivative is represented by formula (1) (wherein, R1 denotes a 1-4C alkyl group; and M1 and M2 denote each independently hydrogen or a monovalent pharmacologically acceptable alkali metal salt). The compound exhibits ocular hypotensive actions and excellent effects as a prophylactic or a therapeutic agent for ocular hypertension and glaucoma.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel phosphate derivative and a pharmaceutical composition using the same. More specifically, the present invention relates to a therapeutic agent for ocular hypertension and glaucoma.

[0002]

2. Description of the Related Art Glaucoma is a disease that is based on a sustained or repeated increase in intraocular pressure exceeding a normal range, and causes visual impairment such as organic disorder of the eye and visual field abnormality. Ocular hypertension is a case in which high intraocular pressure exceeding normal levels is observed, but visual field dysfunction is not observed. After a long course, glaucoma may develop. The goal of pharmacotherapy for ocular hypertension and glaucoma is to lower and maintain intraocular pressure to the level of healthy individuals without visual impairment.

Conventionally, as a therapeutic agent for ocular hypertension or glaucoma, a carbonic anhydrase inhibitor (oral), a hypertonic osmotic agent (injection), pilocarpine (ophthalmic solution), epinephrine and its prodrug dipivefrin (ophthalmic solution) ) And isopropyl unoprostone (ophthalmic solution) are known, and recently β-receptor blockers are frequently used, but all have many disadvantages. For example, carbonic anhydrase inhibitors can cause gastrointestinal disorders, urolithiasis, and electrolyte abnormalities. The application of sympathomimetics such as epinephrine and dipivefrin is also limited to open-angle glaucoma, rebound hyperemia due to vasoconstriction, ocular pain, bradycardia, blepharitis, and systemic heart rate May cause an increase in number, blood pressure, etc. Also, β
Eye drops containing a receptor blocker as an active ingredient act systemically on the central nervous system to cause headache and depressive symptoms, asthma-like symptoms for the respiratory system, and asthma-like symptoms for the circulatory system. Side effects such as pulse and hypotension have been reported (Pharmaceutical Journal, 28 , 705,
1992). As described above, the therapeutic agents for ocular hypertension and glaucoma, which are currently widely used, have respective problems, and there is still no satisfactory drug that can effectively lower intraocular pressure and has few side effects.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel therapeutic agent for ocular hypertension and glaucoma having an excellent intraocular pressure lowering action.

[0005]

Means for Solving the Problems As the inventors of the present invention have continued their intensive studies, they have found that a compound represented by the following general formula (1) solves the above-mentioned problem, and completed the present invention. . That is, the present invention provides a phosphate derivative represented by the following general formula (1).

[0006]

Embedded image [Wherein, R ¹ represents alkyl having 1 to 4 carbons. M ¹ and M ² independently represent hydrogen or a monovalent pharmacologically acceptable alkali metal salt. A phosphoric ester derivative represented by the formula: Hereinafter, the present invention will be described in detail.

[0007]

Embedded image [Wherein, R ¹ represents alkyl having 1 to 4 carbons. ]

The biphenyl derivative represented by the general formula (2) (1997 Patent Application No. 94460) has a vasopressin receptor antagonistic action and exhibits an excellent diuretic action. The compound of the present invention represented by the general formula (1) is characterized in that the hydroxyl group of the biphenyl derivative represented by the general formula (2) is phosphorylated. That is,
The phosphorylated esterified compound of the present invention represented by the above general formula (1) has improved water solubility as compared with the biphenyl derivative represented by the above general formula (2), and is especially useful for eye drops and intravenous administration. And the like can be used in a good form.

The compound represented by the general formula (2) has a solubility in water (25 ° C.) of about 4 μg / mL,
It is a very poorly water-soluble compound. In order to prepare these compounds into liquid preparations such as eye drops or intravenous administration, tween8
There is nothing but solubilization using commonly used surfactants such as HCO60 or polyoxyl stearate 40. For example, in the compound represented by the general formula (2), (2S, 3aR) -2-hydroxy-5- [4-[[2- (4-tolyl) benzoyl] amino] benzoyl wherein R ¹ is methyl. ] -1, 2, 3, 3a, 4, 5
-Hexahydropyrrolo [1,2-a] quinoxaline (V
P-343, Abstracts of the 118th Annual Meeting of the Japanese Pharmaceutical Society 2, 1
When 86) is prepared as a liquid agent, among various surfactants used for solubilization, a 0.5% HCO60 solution is a surfactant capable of maximizing the solubility of VP-343. However, even in such a case, it is a limit to adjust the concentration to 0.036%.

On the other hand, since the compound of the present invention represented by the above general formula (1) has a solubility of 10% or more in physiological saline, it is extremely higher than the concentration at which VP-343 can be applied as a liquid. That it can be used in the concentration range,
In addition, since it can be applied as a liquid agent in which an extra component such as a surfactant which is irrelevant to the manifestation of the action is not mixed, there is an advantage that there is little adverse effect on a living body.

The degree or persistence of the intraocular pressure lowering effect when a solution (concentration: 3.7%) of the compound of the present invention represented by the above general formula (1) prepared with physiological saline is used is extremely excellent. Thus, the results showed that the usefulness as a therapeutic agent for ocular hypertension and glaucoma was remarkably enhanced.

[0012] In the compounds of the present invention, R ¹ represents an alkyl having 1 to 4 carbon atoms. The alkyl is not particularly limited and includes, for example, methyl, ethyl, propyl, butyl, etc., which may be branched or linear. Of these, methyl is preferred.

In the compounds of the present invention, M ¹ and M ² are
Independently represents hydrogen or a monovalent pharmacologically acceptable alkali metal salt. The monovalent pharmacologically acceptable alkali metal salt is not particularly limited. For example, a sodium salt, a potassium salt, and a lithium salt are preferable, and a sodium salt, a potassium salt, and the like are particularly preferable.

The compounds of the present invention are generally more water-soluble in salt form than in free form. Therefore, when used for pharmaceutical use, it is preferable to select a compound in the form of a salt according to the use.

The compounds of the present invention include, for example, the following compounds. (1) Phosphoric acid (2R, 3aR) -5- [4-[[2-
(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxalin-2-yl sodium salt (2) phosphoric acid (2R, 3aS) -5- [4-[[2-
(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxalin-2-yl sodium salt (3) phosphoric acid (2S, 3aR) -5- [4-[[2-
(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxalin-2-yl sodium salt (4) phosphoric acid (2S, 3aR) -5- [4-[[2-
(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxalin-2-yl potassium salt (5) phosphoric acid (2S, 3aS) -5- [4-[[2-
(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] Quinoxalin-2-yl sodium salt

The compound represented by the general formula (1) is referred to as the present compound (1). The compound (1) of the present invention can be synthesized by various methods. The typical production method is illustrated below.

[0017]

Embedded image

[Reaction formula 1] is a method for producing a phosphoric ester (1) by phosphorylation and deprotection of a synthetic intermediate (3). The method of Kuo-Long Yu et al. [Tetrahedron Letters, 979-982
(1988)], the synthetic intermediate (3) was reacted with N, N-diisopropyldibenzylphosphoramidite in a dichloromethane solution in the presence of 1H-tetrazole, then oxidized with metachloroperbenzoic acid, and triphosphate was added. It can be converted into an ester (4). N, N-diisopropyldibenzylphosphoramidite can be prepared by known methods, ie, E, Uhlmann.
[Tetrahedron Letters]
ters), 1023-1026 (1986)] and the method of Tanaka et al. [Tetrahedron Letters, 199-202].
(1986)]. The phosphate ester (1) can be produced by deprotection of the phosphate triester (4) obtained above by hydrogenolysis. Also, other phosphating agents such as phosphepane [Watanabe et al.
Tetrahedron Letters, 255
-256 (1990)], N, N-diethyldibenzyl phosphoramidite [J. W. Parrich et al., Tetrahedron Letters, 101-102 (1987)], N, N-
Dimethyldibenzyl phosphoramidite [J. W. Parrich et al., Tetrahedron Letters
s), 101-102 (1987)], followed by oxidation. In addition, (1) can also be produced by a known method of directly phosphorylating the synthetic intermediate (3). For example, examples of the phosphorylating agent include acid chloride-type phosphorylating agents [phosphorus oxychloride, phenylphosphoric acid dichloride, diphenylphosphoric acid chloride, dibenzylphosphoric acid chloride, p-nitrophenylphosphoric acid dichloride, dimorpholinophosphoric acid chloride, bis ( β, β, β-trichloroethyl) phosphoric acid chloride, p-diphenyl-p ′
-Morpholinopyrophosphoric acid chloride, etc.]
Acid anhydride type phosphorylating agent [(O-benzylphosphorous acid O-
Using diphenylphosphoric acid anhydride, tetra (paranitrophenyl) pyrophosphoric acid, tetrachloropyrophosphoric acid, diphenylphosphoric acid anhydride, etc., and using imidoylphosphoric acid as an intermediate (eg, β-cyanoethylphosphoric acid and dicyclohexylcarbodiimide) , Phosphorus trichloride, tris (8
-Quinolyl) phosphoric acid, 2- (N, N-dimethylamino)
A method using other phosphorylating agents such as -4-nitrophenylphosphoric acid and phosphonium iodide. After phosphorylation by the above method, the compound of the present invention can be obtained by removing the protecting group according to the phosphorylating agent used. This can also be performed by a known method, hydrolysis with an acid or alkali, catalytic reduction, or the like.

[0019]

Embedded image

The method represented by Reaction Scheme 2 is a method for producing a synthetic intermediate (3) by subjecting an amine compound (5) and a carboxylic acid (6) to an ordinary amide bond formation reaction.

The amide bond formation reaction can be easily achieved by using known amide bond formation reaction conditions. For example, (a) acid chloride method, that is, a method in which a carboxylic acid (6) is reacted with a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc. to form an acid chloride, and the amine compound (5) is reacted therewith; B) Carbodiimide method, that is, in the presence of a carboxylic acid (6) and a condensing agent such as dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole,
A method of reacting an amine compound (5), (c) an activated ester method, that is, a method in which a carboxylic acid (6) is nitro- or halogen-substituted phenyl ester, aromatic thioester, N-hydroxysuccinate, 1-hydroxybenzotriazole ester, A method in which an activated ester such as an enol ester is used, and the amine (5) is reacted with the activated ester can be used. (D) Other methods, for example, a method in which a carboxylic acid (6) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride and the amine (5) is reacted with the carboxylic acid anhydride, and an ester of the carboxylic acid (6) with a lower alcohol A carboxylic acid (6) and an amine (5) are further reacted with triphenylphosphine, diphenylphosphine chloride, phenyl-N-phenylphosphoramidochloridate, diethylchlorophosphate. , Diethyl cyanophosphate, azide diphenylphosphate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride and the like in the presence of a condensing agent for a phosphorus compound. In particular, in the present invention, a method of treating with the amine compound (5) using an acid chloride method is advantageous because the compound of the present invention can be easily and easily obtained.

The solvent used in the reaction varies depending on the method selected, but is usually a halogenated hydrocarbon such as dichloromethane, dichloroethane and chloroform; an aromatic hydrocarbon such as benzene, toluene and xylene; diethyl ether; tetrahydrofuran; Single solvents such as ethers such as dioxane and dimethoxyethane, esters such as ethyl acetate, aprotic polar solvents such as N, N'-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide, or a mixed solvent thereof And the like.

In the reaction, the compound (6) is used in excess, or N-methylmorpholine, trimethylamine, triethylamine, N, N'-dimethylamine, pyridine,
1,5-diazabicyclo [4,3,0] nonene-5 (D
BN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-diazabicyclo [2,
In some cases, it is advantageous to carry out the reaction in the presence of an organic base such as [2,2] octane (DABCO) to facilitate the reaction, and the reaction temperature is usually about -20 to 150 ° C, preferably -5. The reaction is carried out at about 50 ° C. to about 50 ° C., and the reaction time is about 5 minutes to 18 hours, preferably about 5 minutes to 2 hours.

After introducing a protecting group into the hydroxy group of the amine compound (5), the above reaction is carried out, and the protecting group is removed to obtain the desired compound. As the protecting group, for example, Green (Greene) and Wuts (Wuts),
(Protective Groups in Organic Synthesis), and the protecting groups described in the second edition can be used as appropriate according to the reaction conditions.

[0025]

Embedded image

From (3a), the Mitsunobu reaction (O. Mitsunobu, Sy
nthesis, 1-28, 1981) to produce a compound (3b) having an inverted configuration. That is, N, N
Compound (3a) in combination with triphenylphosphine and azodicarboxylic acid such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate in an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide. Acetic acid is reacted with acetic acid in the presence of diesters to obtain an acetoxy compound (7) whose configuration is inverted. Then, the acetoxy compound (7) is used as a solvent by using water or an alcohol such as methanol or ethanol as a solvent. Alternatively, the compound (3b) can be produced by solvolysis under basic conditions.

The amine compound (5), which is the starting material in the above [Reaction formula 2], is prepared by the method of Magid Abou-Gharbia, Meier E. Freed et a.
I., J. Med. Chem., 27 , 1743 (1984) and U.S. Pat.
According to the report of No. 323, 1-fluoro-
2-nitrobenzene and trans-4-hydroxy-L
-Proline, cis-4-hydroxy-D-proline, or an alkyl ester thereof and a salt thereof such as a hydrochloride thereof to form (2R, 3aS) -2-hydroxy-1,
2,3,3a, 4,5-hexahydropyrrolo [1,2-
a] Quinoxaline (5a), (2R, 3aR) -2-hydroxy-1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline (5b) can be produced.

The reaction product obtained by each of the above production methods is isolated and purified as a free compound, its salt, hydrate or various solvates. The salt can be produced by subjecting the salt to a usual salt formation reaction.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

The compounds of the present invention may exist as racemates, optically active isomers or diastereoisomers singly or as a mixture. A racemic compound can be converted to an optically pure isomer by a general racemic resolution method [for example, a method for obtaining a diastereomer salt with a general optically active acid (tartaric acid, etc.) and performing an optical resolution]. .
The mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.

The compound of the present invention is expected to be used as a therapeutic agent for ocular hypertension and glaucoma. However, the compound of the present invention is a novel compound and can be used as a therapeutic agent for ocular hypertension and glaucoma. Can be fully expected to be used for pharmaceutical applications. Therefore, a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is also one of the present invention.

When the compound of the present invention is administered as a medicament,
The compound of the present invention includes humans as a pharmaceutical composition containing, for example, 0.1 to 99.5%, preferably 0.5 to 90%, as it is or in a pharmaceutically acceptable nontoxic and inert carrier. Administered to animals.

The carrier of the pharmaceutical composition of the present invention may be a solid,
One or more semi-solid or liquid diluents, fillers and other formulation aids are used. The pharmaceutical composition is desirably administered in a unit dosage form. The pharmaceutical composition of the present invention can be administered orally, intravenously, intraosseously, topically (eg, by nasal or ophthalmic administration) or rectally. Needless to say, the composition is administered in a dosage form suitable for these administration methods.

The dose of the compound (1) of the present invention or a salt thereof is desirably determined in consideration of the patient's condition such as age and weight, administration route, disease symptoms and severity, etc. Is the amount of the active ingredient of the present invention for adults,
In the case of oral administration per day, the range is generally 5 to 1500 mg / human, preferably 10 to 300 mg / human. In the case of intravenous administration, 0.1 to 1000
mg / human, preferably in the range of 1 to 600 mg / human, and moreover, in the case of topical administration, for example, in the case of ophthalmic administration, a concentration of 0.001 to 10% (V / W). , Preferably at a concentration of 0.01 to 2% (V / W). In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses 2 to 4 times a day.

For oral administration, solid or liquid dosage units such as powders, tablets, dragees, capsules, granules, suspensions, liquids, syrups, drops, sublingual tablets and other dosage forms are used. Can be. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. Flavoring agents as needed,
Preservatives, dispersants, coloring agents, fragrances and the like may be mixed.

Capsules are prepared by first filling the powdered powder or tablets granulated as described above in the form of a capsule, for example, a gelatin capsule, as described above. Is done. Lubricants and fluidizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, and the like may be mixed with the powdered state, and then the filling operation may be performed. it can. Disintegrators and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxystarch sodium, calcium carbonate,
Addition of sodium carbonate can improve the effectiveness of the medicament when the capsule is ingested.

Further, the fine powder of the compound of the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin and a surfactant and wrapped in a gelatin sheet to form a soft capsule. Tablets are made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and pressing. The powder mixture is prepared by mixing an appropriately powdered substance with the diluent or base described above and, if necessary, a binder (eg, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl Alcohols, etc.), dissolution retardants (eg, paraffin, wax,
Hardened castor oil, etc.), reabsorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, dicalcium phosphate, etc.) may also be used in combination. The powder mixture can be moistened with a binder such as syrup, starch paste, acacia, cellulose solution or macromolecular solution and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules.

The granules thus prepared can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil or the like as a lubricant. The lubricated mixture is then tableted. The uncoated tablets thus produced can be coated with a film or coated with sugar. Alternatively, the drug may be directly tableted after mixing with a fluid inert carrier without going through the granulating or slagging steps as described above.
Transparent or translucent protective coatings consisting of a shellac hermetic coating, coatings of sugar or polymeric materials, and polish coatings of wax can also be used.

[0039] Other oral dosage forms, such as solutions, syrups, elixirs and the like, can also be presented in dosage unit form so that a given quantity contains a fixed amount of the drug. Syrups are prepared by dissolving the compound in a suitable aqueous flavor solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols,
Polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, peppermint oil, saccharin)
Others can also be added as needed.

If desired, dosage unit formulations for oral administration may be microencapsulated. The formulation can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes, and the like. Administration into tissues can be carried out by using liquid dosage unit forms for subcutaneous / muscular or intravenous injection, for example, in the form of solutions and suspensions. These things are
A quantity of the compound is prepared by suspending or dissolving a non-toxic liquid carrier suitable for the purpose of injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Alternatively, an aliquot of the compound may be placed in a vial and the vial and its contents sterilized and sealed thereafter. Spare vials or carriers may be provided with the powdered or lyophilized active ingredient for dissolving or mixing immediately prior to administration. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives, and emulsifiers can be used in combination.

The ophthalmic administration can be carried out by using a form such as eye drops, eye ointment and the like. For eye drops,
Isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil , Sodium citrate, sodium edetate and the like; and preservatives such as benzalkonium chloride, paraben and the like.
H may be within the range acceptable for ophthalmic preparations,
A range of 8 is preferred.

For rectal administration, a suppository is used which contains a compound in which the compound is soluble or insoluble in water having a low melting point, for example, polyethylene glycol, cocoa butter, higher esters (for example, myristyl palmitate) and mixtures thereof. Can be done by

[0043]

The present invention will be described in more detail with reference to Test Examples, Reference Examples, Examples and Formulation Examples, but the present invention is not limited thereto.

Test Example 1: Intraocular pressure lowering action The compound obtained in Example 1 was dissolved in a physiological saline solution, and 3.7%
It was prepared as a test ophthalmic solution having a concentration. Six male white rabbits (weighing 2.7 to 3.4 kg) with normal intraocular pressure were used as a group, and test ophthalmic solution and control solution (saline solution) were applied to the left eye in 5 groups each.
The solution was instilled by 0 μL. After corneal surface anesthesia with 20 μL of 0.4% oxybuprocaine hydrochloride, Alcon Pneumatic
Using an Applanation Tonograph (Alcon), intraocular pressure was measured before and 1 to 6 hours after instillation. The test results (difference from intraocular pressure before administration) are shown in FIG. The horizontal axis in the figure is
The time after the instillation (hr) and the vertical axis represent the intraocular pressure difference (ΔmmHg). Each value represents a mean value ± standard deviation (the number of cases is 6). * 1 and * 2 are p <0.05 and p <0.
01 (vs. control) and Student's t-test (Stude
nt'st test) or Aspin-Welc test
h'st test). The compound of Example 1 showed a significant intraocular pressure lowering effect from 1 to 6 hours after instillation as compared to the control eyes.

Reference Example 1 (2S, 4R) -4-hydroxy-1- (2-nitrofuran)
Enyl) proline

Embedded image 5 g of trans-4-hydroxy-L-proline and 5.6 g of 1-fluoro-2-nitrobenzene were dissolved in 30 mL of dimethyl sulfoxide, and 7.5 mL of triethylamine was dissolved.
Was added, and the mixture was heated and stirred at 60 ° C. for 16 hours. After returning the reaction solution to room temperature, it was poured into ice water and washed with ether. The aqueous layer was acidified with hydrochloric acid and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography,
Elution with chloroform / methanol (98/2) gave 7.18 g (yield 71.1%) of the title compound as an oil. 71.1% yield

Reference Example 2 cis-4-hydroxy-D-proline methyl ester salt
Acid salt

Embedded image Cis-4-hydroxy-D-proline hydrochloride (J. Org. Ch.
em., 46 , 2954, 1981).
Suspended in 80 mL and cooled to −20 ° C. under thionyl chloride 2
1.7 mL was added dropwise over 1 hour. After the addition was completed, the mixture was stirred at room temperature for 1.5 hours. After concentrating the reaction solution, ether was added to the obtained residue, and the precipitated crystals were collected by filtration, washed with ether, and dried, and 15.35 g (yield: 91.3) of the title compound was obtained.
%).

Reference Example 3 (2R, 4R) -4-hydroxy-1- (2-nitrofuran)
Enyl) proline methyl ester

Embedded image Using cis-4-hydroxy-D-proline methyl ester hydrochloride obtained in Reference Example 2 and 1-fluoro-2-nitrobenzene, the same operation as in Reference Example 1 was performed to obtain the title compound. 97.2% yield

Reference Example 4 (2R, 3aS) -2-hydroxy-1,2,3,3
a, 4,5-Hexahydropyrrolo [1,2-a] quinoki
Sarin-4-one

Embedded image (2S, 4R) -4-hydroxy-1- obtained in Reference Example 1
7.17 g of (2-nitrophenyl) proline was catalytically reduced in 150 mL of methanol at room temperature in the presence of 1 g of a 10% palladium-carbon catalyst. After the completion of the reaction, the catalyst was removed and concentrated to dryness to obtain 5.24 g (yield 90.7%) of the title compound as a light brown solid.

Reference Example 5 (2R, 3aR) -2-hydroxy-1,2,3,3
a, 4,5-Hexahydropyrrolo [1,2-a] quinoki
Sarin-4-one

Embedded image (2R, 4R) -4-hydroxy-1- obtained in Reference Example 3
The title compound was obtained in the same manner as in Reference Example 4 using (2-nitrophenyl) proline methyl ester. 81.9% yield

Reference Example 6 (2R, 3aS) -2-hydroxy-1,2,3,3
a, 4,5-Hexahydropyrrolo [1,2-a] quinoki
Sarin

Embedded image In a suspension of 0.57 g of lithium aluminum hydride in 30 mL of anhydrous tetrahydrofuran, obtained in Reference Example 4 (2R,
3aS) -2-Hydroxy-1,2,3,3a, 4,5
-Hexahydropyrrolo [1,2-a] quinoxaline-4
A solution of 2.05 g of -one in 20 mL of anhydrous tetrahydrofuran was added dropwise over 30 minutes under ice cooling. After completion of the dropwise addition, the mixture was heated under reflux for 3 hours. The reaction solution was cooled on ice and ethyl acetate 100m
L was gradually added, and the mixture was further stirred at room temperature for 15 hours. Water was added to the reaction solution, and the precipitated insoluble material was separated by filtration on Celite. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated, and 1.63 g of the title compound (85.0% yield).
I got

Reference Example 7 (2R, 3aR) -2-hydroxy-1,2,3,3
a, 4,5-Hexahydropyrrolo [1,2-a] quinoki
Sarin

Embedded image (2R, 3aR) -2-hydroxy- obtained in Reference Example 5
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
The same procedure as in Reference Example 6 was carried out using 2-a] quinoxalin-4-one to obtain the title compound. 63.6% yield

Reference Example 8 (2R, 3aS) -2-hydroxy-5- [4-[[2
-(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxaline

Embedded image 1.4 g of 4-[[2- (4-tolyl) benzoyl) amino] benzoic acid was added to 2 mL of thionyl chloride, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, excess thionyl chloride was concentrated and removed. The obtained acid chloride was diluted with 10 mL of dichloromethane.
Was obtained in Reference Example 6 (2R, 3aS)-
To a 30 mL dichloromethane solution of 0.8 g of 2-hydroxy-1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline and 0.64 g of triethylamine was gradually added dropwise under ice-cooling. After stirring at room temperature for 3 hours, the reaction solution was water, 1N-sodium carbonate aqueous solution, 1N-hydrochloric acid,
And water in that order, and dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography, and eluted with methanol / chloroform (1/99). The eluate was concentrated, and the residue was recrystallized from ethyl acetate-hexane to give 1.17 g (yield: 55.0%) of the title compound.
I got

Reference Example 9 (2R, 3aR) -2-hydroxy-5- [4-[[2
-(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxaline

Embedded image (2R, 3aR) -2-hydroxy- obtained in Reference Example 7
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
The same operation as in Reference Example 8 was carried out using 2-a] quinoxaline and 4-[[2- (4-tolyl) benzoyl] amino] benzoic acid, and recrystallized from ethyl acetate-hexane to obtain the title compound. . Yield 53.5%

Reference Example 10 (2S, 3aS) -2-acetoxy-5- [4-[[2
-(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxaline

Embedded image (2R, 3aS) -2-hydroxy-5 obtained in Reference Example 8
-[4-[[2- (4-tolyl) benzoyl] amino]
Benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline 0.8 g, acetic acid 0.15 g and triphenylphosphine 0.64 g in 5 mL of anhydrous tetrahydrofuran under ice cooling. A solution of 0.49 g of diisopropyl azodicarboxylate in 2 mL of anhydrous tetrahydrofuran was gradually added dropwise. After stirring at room temperature for 2 hours, the reaction solution was concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane / ethyl acetate (1/1) to give the title compound (0.55 g, yield 6).
3.2%) as an amorphous powder.

Reference Example 11 (2S, 3aS) -2-hydroxy-5- [4-[[2
-(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxaline

Embedded image (2S, 3aS) -2-acetoxy- obtained in Reference Example 10.
0.57 g of 5- [4-[[2- (4-tolyl) benzoyl] amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline,
0.2 g of anhydrous potassium carbonate was added to 20 mL of methanol, followed by stirring at room temperature for 15 hours. After concentrating the reaction solution, the obtained residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from ethyl acetate-hexane to give the title compound (0.33 g, yield 63.2%).

Reference Example 12 (2S, 3aR) -2-acetoxy-5- [4-[[2
-(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxaline

Embedded image (2R, 3aR) -2-hydroxy-5 obtained in Reference Example 9.
-[4-[[2- (4-tolyl) benzoyl] amino]
Reference Example 1 using benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline
The same operation as in Example 0 was performed to obtain the title compound as an amorphous powder. 96.3% yield

Reference Example 13 (2S, 3aR) -2-hydroxy-5- [4-[[2
-(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxaline

Embedded image (2S, 3aR) -2-acetoxy- obtained in Reference Example 12.
Reference Example 11 using 5- [4-[[2- (4-tolyl) benzoyl] amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline The same operation as described above was performed and recrystallization from ethyl acetate-hexane gave the title compound. 88.6% yield

Reference Example 14 dibenzyl (2S, 3aR) -5- [4-[[2-
(4-tolyl) benzoyl] amino] benzoyl]-
1,2,3,3a, 4,5-hexahydropyrrolo [1,1
2-a] quinoxalin-2-yl phosphate

Embedded image (2S, 3aR) -2-hydroxy- obtained in Reference Example 13
5- [4-[[2- (4-tolyl) benzoyl] amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxaline1.006
g, N, N-diisopropyldibenzylphosphoramidite (1.035 g) was added to a dichloromethane (30 mL) solution of 1H-tetrazole (0.414 g), and the mixture was stirred at room temperature for 2 hours. Subsequently, after cooling to −40 ° C., metachloroperbenzoic acid (0.646 g, 3.75 mM) was added so as not to exceed 0 ° C.
Was added and the mixture was stirred at 0 ° C. for 45 minutes. 10% sodium thiosulfate (20 mL x 2),
The extract was washed successively with a saturated aqueous solution of sodium bicarbonate and water and then dried. After drying under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with benzene / ethyl acetate (6/4) to obtain 1.1 g (yield 72%) of the title compound as a pale yellow foam. I. R. (KBr) νcm ^-1 : 1680, 1640, ¹
600, 1505, 1320, 1000 M.P. S. (FAB): 764 (M + H)

Example 1 Phosphoric acid (2S, 3aR) -5- [4-[[2- (4-to
Ryl) benzoyl] amino] benzoyl] -1,2,2
3,3a, 4,5-hexahydropyrrolo [1,2-a]
Quinoxalin-2-yl disodium

Embedded image Dibenzyl (2S, 3aR) -5 obtained in Reference Example 14
0.85 g of [4-[[2- (4-tolyl) benzoyl] amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxalin-2-yl phosphate Was subjected to hydrogenolysis at room temperature and atmospheric pressure in the presence of 0.17 g of a 10% palladium-carbon catalyst. After completion of the reaction, the catalyst was removed and 10% N
aOH (0.89 g) was added and the mixture was concentrated under reduced pressure at 40 ° C. or lower. The residue was purified by an ODS column (methanol / water = 1/1) to give the title compound (0.55 g, yield 79%) as a yellow foam. m. p. : 216-220 ° C (decomposition) ¹ H-N. M. R. (D ₂ O) δ: 1.5-1.7 (1
H, m), 1.96 (3H, s), 2.15 to 2.45.
(2H, m), 3.2-3.35 (1H, m), 3.6
5-3.8 (1H, m), 3.85-4.05 (1H,
m), 4.8-4.95 (1H, m), 5.8-6.1
(1H, m), 6.6-7.4 (16H, m) R. (KBr) νcm ^-1 : 1660, 1630, ¹
600, 1500, 1410, 1100, 975 M.P. S. (FAB): 627 (M + 2H)

Formulation Example 1 Injection

[Table 1]

A solution prepared by dissolving 0.1 g of citric acid in 400 mL of water for injection was added to the phosphoric acid (2S, 3) prepared in Example 1.
aR) -5- [4-[[2- (4-Tolyl) benzoyl] amino] benzoyl] -1,2,3,3a, 4,5
-Hexahydropyrrolo [1,2-a] quinoxaline-2
0.5 g disodium, 0.2 g sodium citrate and 9 g sodium chloride were added. This solution was stirred at 60 ° C. to dissolve. After cooling to room temperature, the total volume was made up to 1000 mL. Membrane filter (pore size 0.2
After filtration through 2 μm), the mixture was filled in a 2 mL ampoule and heat-sterilized to prepare an injection.

Formulation Example 2 Tablet

[Table 2]

The phosphoric acid (2S, 3a) produced in Example 1
R) -5- [4-[[2- (4-Tolyl) benzoyl]
Amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxalin-2-yl disodium (25 g) was mixed with lactose (357.5 g), and then mixed with bantam mill (manufactured by Tokyo Atomizer). ).
After 100 g of corn starch was uniformly mixed with the pulverized product in a fluidized granulation coating apparatus (manufactured by Okawara Seisakusho),
150 g of a 10% aqueous solution of hydroxypropylcellulose was sprayed and granulated. After drying, pass through a 24 mesh sieve,
Next, 2.5 g of magnesium stearate was added, and a rotary tableting machine (manufactured by Kikusui Seisakusho) was used to make a tablet of 100 mg per tablet using a 6.5 mmφ × 5R mortar and punch. The tablets were coated with hydroxypropyl methylcellulose 2910 20 using a coating device (manufactured by Freund Corporation).
g, aqueous coating liquid 300 g containing 2.5 g of polyethylene glycol 6000 and 2.5 g of titanium oxide
Was sprayed and coated at 5 mg per tablet to obtain a film-coated tablet.

Formulation Example 3 Capsule

[Table 3]

The phosphoric acid (2S, 3a) produced in Example 1
R) -5- [4-[[2- (4-Tolyl) benzoyl]
Amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoxalin-2-yl disodium powder, 10 g of which contains 390 g of crystalline cellulose, 116 g of lactose, low substitution Degree hydroxypropylcellulose 50g and polyvinylpyrrolidone 30g
, And add 120 mL of ethanol and mix uniformly.
Granulated. Drying the mixture at 50 ° C. for 12-16 hours,
After passing through a 25-mesh sieve, 4 g of magnesium stearate was added thereto and mixed uniformly, and the mixed powder was filled into a first capsule in an amount of 300 mg to prepare a hard capsule containing 5 mg in one capsule.

Formulation Example 4 Eye drops

[Table 4]

In a solution of 0.04 g of benzalkonium chloride dissolved in about 800 mL of sterilized purified water, the phosphoric acid (2S, 3aR) -5- [4-[[2- (4-
Tolyl) benzoyl] amino] benzoyl] -1,2,2
3,3a, 4,5-hexahydropyrrolo [1,2-a]
Quinoxalin-2-yl disodium 1 g, boric acid 1
1 g, 2.1 g of borax and 2.4 g of sodium chloride were added and dissolved by stirring. Thereafter, the total amount was adjusted to 1000 mL, and the mixture was aseptically filtered through a membrane filter (pore size: 0.22 μm). It was filled in a 5 mL eye drop bottle to produce an eye drop.

[0068]

The compound of the present invention has the above-mentioned novel chemical structure and is a novel compound not described in any literature. Further, the pharmaceutical composition containing the compound of the present invention as an active ingredient has a reliable and excellent intraocular pressure lowering effect, and is expected to be used as a therapeutic agent for ocular hypertension and glaucoma in other pharmaceutical uses. It is.

[Brief description of the drawings]

FIG. 1 is a diagram showing the time after intraocular administration and the intraocular pressure value.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Kenji Naito 1-3-5 Nihonbashi Muromachi, Chuo-ku, Tokyo Wakamoto Pharmaceutical Co., Ltd. F-term (reference) 4C076 AA12 AA22 AA30 AA31 AA36 AA43 AA49 AA53 BB01 BB13 BB24 BB25 BB29 CC10 DD23 DD43 FF67 FF68 4C086 AA01 AA02 AA03 GA07 GA13 MA01 MA04 MA17 MA23 MA35 MA37 MA41 MA52 MA58 MA59 MA60 MA66 NA14 ZA33 4H050 AA01 AA03 AB20

Claims (10)

[Claims] 1. The following general formula (1): [Wherein, R ¹ represents alkyl having 1 to 4 carbons. M ¹ and M ² independently represent hydrogen or a monovalent pharmacologically acceptable alkali metal salt. ] The phosphoric ester derivative characterized by the above. 2. The phosphate derivative according to claim 1, wherein M ¹ and M ² are independently hydrogen or sodium. 3. The phosphate derivative according to claim 1, wherein R ¹ is methyl, and M ¹ and M ² are independently hydrogen or a monovalent pharmacologically acceptable alkali metal salt. 4. The phosphate derivative according to claim 3, wherein M ¹ and M ² are independently hydrogen or sodium. 5. A pharmaceutical composition comprising the phosphate derivative according to claim 1, 2, 3 or 4 as an active ingredient. 6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is a therapeutic agent for ocular hypertension and glaucoma. 7. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is an intraocular pressure lowering agent. 8. The pharmaceutical composition according to claim 5, 6 or 7, wherein the pharmaceutical composition is an intravenously administered agent. 9. The pharmaceutical composition according to claim 5, 6 or 7, wherein the pharmaceutical composition is for topical administration. 10. The pharmaceutical composition according to claim 5, 6 or 7, wherein the pharmaceutical composition is an ophthalmic solution.