Therapeutic agent for glaucoma containing 2-phenyl-3-oxo-2H-1,4-benzothiazine derivatives

Abstract: A therapeutic agent for glaucoma comprises 2-phenyl-3-oxo-2H-1,4-benthiazine derivatives especially (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or its salt as active ingredient and pharmaceutically acceptable excipients. The therapeutic agent lowers the intraocular pressure upon topical or systemic administration.

Description: Background of the Invention The present invention relates to the use of a 2-phenyl-3-oxo-2H-1,4-benzothiazine derivative for preparing a therapeutic agent for the treatment of glaucoma for systemic and/or topical route administration. Glaucoma is an intractable eye disease caused by an elevation of intraocular pressure with various factors. A patient with glaucoma has a risk to lose the eyesight, and various medical treatments have been proposed. US Patent 4786635 discloses the use of 2-phenyl-3-oxo-2H-1,4-benzothiazine derivatives. It is described therein that these compounds have a unique structure and are usable as a therapeutic agent for circulatory diseases, since they have a calcium antagonistic effect and a blood platelet coagulation-inhibiting effect. However, any effect of these compounds on eyes has never been known yet. It is desired to make investigations on other effects of these compounds, particularly in the ophthalmologic field. Summary of the Invention A primary object of the present invention is to utilize the compounds in the ophthalmologic field. Another object of the present invention is to provide a compound for the preparation of a therapeutic agent for the treatment of glaucoma. These and other objects of the present invention will be apparent from the following description and Examples. After investigations on the effects of these compounds on eyes, the inventors have found that they have an excellent effect in that they lower the intraocular pressure. Thus, they are usable as a therapeutic agent for the treatment of glaucoma. The present invention relates to the use of a compound for preparing a therapeutic agent for the treatment of glaucoma. The active ingredient is a compound of the following formula (I) or its salt (hereinafter referred to as the compound of the present invention): wherein R¹ represents one or more groups selected from a hydrogen atom, lower alkyl groups, halogen atoms, a nitro group, a hydroxyl group, lower alkoxy groups, lower alkanoyloxy groups, an amino group, lower alkylamino groups and lower alkoxycarbonyl groups, R² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R³ represents one or more groups selected from a hydrogen atom, lower alkyl groups, a hydroxyl group, lower alkoxy groups, halogen atoms, a nitro group, lower alkylenedioxy groups, lower alkanoyl groups, lower alkanoyloxy groups, an amino group, lower alkylamino groups, lower alkanoylamino groups and lower alkoxycarbonyloxy groups, or a group of -(CH₂) a -, R⁴ represents a hydrogen atom or a lower alkyl group, A and B may be the same or different from each other and each represents a lower alkylene group having 1 to 6 carbon atoms, and n represents 3 or 4. A further ingredient is a pharmaceutically acceptable excipient. Description of the Preferred Embodiments In the above general formula (I), the lower alkyl groups include those having 1 to 6 carbon atoms such as methyl, ethyl, propyl and hexyl groups; the halogen atoms include fluorine, chlorine, bromine, etc.; the lower alkoxy groups include those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy and hexyloxy groups; the lower alkanoyloxy groups are those having 2 to 6 carbon atoms such as acetyloxy, propionyloxy and hexanoyloxy groups; the cycloalkyl groups having 3 to 6 carbon atoms include cyclopropyl and cyclohexyl groups, etc.; the lower alkylenedioxy groups include those having an alkylene group having 1 to 6 carbon atoms between two oxygen atoms such as methylenedioxy and ethylenedioxy groups; and the lower alkanoyl groups include those having 2 to 6 carbon atoms such as acetyl, propionyl and hexanoyl groups. In this connection, it is preferable that R¹ represents a hydrogen atom or one lower alkoxy group, more preferably one lower alkoxy group, R² represents a lower alkyl group, R³ represents one lower alkylenedioxy group and R⁴ represents a lower alkyl group. Specifically, the compounds represented by the following formula (II) and their salt are the most preferred: wherein R¹¹ represents a lower alkoxy group, R¹² represents a lower alkyl group, R¹⁴ represents a lower alkyl group, A¹ and B¹ may be the same or different from each other and each represents a lower alkylene group having 1 to 6 carbon atoms, and m represents 1 to 6. The salts of these compounds are not particularly limited as long as they are acceptable as the medicine. Such salts may be hydrochlorides, sulfates, phosphates, lactates, maleates, fumarates, oxalates, methanesulfonates and p-toluenesulfonates. These compounds have stereoisomers, which are also included in the present invention. Examples of the compounds represented by the formula [I] include, 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1, 4-benzothiazine fumarate, 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]butoxy]phenyl]-4-methyl-3- oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[2-[4-[N-[2-(4-methoxyphenoxy)ethyl]-N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4,5-trimethoxy)phenoxy]ethyl]amino]propoxy]pheny l]-4-methyl-3-oxo-2H,-1,4-benzothiazine oxalate, 3,4-dihydro-2-[4-[3-N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino] propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[5-methoxy-2-[2-[N-methyl-N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]ethoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazineoxolate, 3,4-dihydro-2-[5-chloro-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate, 3,4-dihydro-2-[2-[4-[N-[2-[(5-indanyloxy)ethyl]-N-methylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate, 3,4-dihydro-2-[5-methyl-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate, 3,4-dihydro-2-[[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]-5-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate, their stereoisomers and optical isomers. Although the compounds of the present invention are useful as an effective therapeutic agent for circulatory diseases, the effect of them on eyes has never been known. After having carried out investigations for the purpose of using these compounds in the field of ophthalmology, the inventors have found that these compounds have an excellent effect by lowering the intraocular pressure. Therefore, they are usable for the preparation of a therapeutic agent for the treatment of glaucoma. To evaluate the utility of the compounds for preparing a medicament for the treatment of glaucoma, the effect of them on rabbits having a high intraocular pressure provoked by chymotrypsin was examined. The detailed data will be described below with reference to the physiological tests. When the compound was given by instillation or oral administration, the intraocular pressure was reduced to indicate that this compound is usable for preparing a therapeutic agent against glaucoma. The therapeutic agent against for glaucoma of the present invention can be used as either an agent for topical application such as eye drops or eye ointment or as an agent for systemic application such as tablets, capsules, granules and powders. Further, both forms of application can be used in combination. The dose of the compound to be administered can be suitably determined depending on the symptoms, age, dosage form, etc. In the topical application, a solution or an ointment having a concentration of 0.1 to 5 %, more preferably 0.1 to 2 %, is applied once to several times a day. In the systemic application, it is applied once to several times a day in an amount of preferably 1 to 1000 mg, more preferably 1 to 100 mg, a day. The preparation containing the compound can be produced by adding necessary excipients to the compound by an ordinary method. For example, eye drops can be produced by adding an isotonizing agent such as sodium chloride, potassium chloride or concentrated glycerol; a buffering agent such as sodium phosphate, boric acid or monoethanolamine; a stabilizer such as sodium edetate; a preservative such as benzalkonium chloride or p-hydroxybenzoate; a surfactant such as polysorbate 80 or polyoxyethylene hydrogenated castor oil; and a pH adjustor such as dilute hydrochloric acid or sodium hydroxide, if necessary. The therapeutic agent for the systemic administration such as tablets, capsules, granules and powders can be produced by adding a diluent such as lactose, starch or crystalline cellulose; a lubricant such as magnesium stearate or talc; a binder such as hydroxypropyl cellulose or polyvinylpyrrolidone; a disintegrant such as carboxymethylcellulose calcium or low substituted hydroxypropylcellulose, and a coating agent such as hydroxypropyl methylcellulose, macrogol or silicone resin, if necessary. Typical formulations of the oral preparations and ophthalmics will be given below. For the preparations for oral administrations some examples are also disclosed in US Patent 4786635. [Examples of formulations] 1) Eye drops: Formulation 1 (for 100 ml) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]-propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 0.5 g Concentrated glycerol 1.5g Polyoxyethylene hydrogenated castor oil 1.0 g Benzalkonium chloride 0.005 g Sodium edetate 0.01 g Dilute hydrochloric acid q.s. Sodium hydroxide q.s. Sterile, purified water q.s. Formulation 2 (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 1.0 g Concentrated glycerol 1.25 g Polysorbate 80 2.0 g Methyl p-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 g Dilute hydrochloric acid q.s. Sodium hydroxide q.s. Sterile, purified water q.s. Formulation 3 (for 100 ml) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 0.1 g Concentrated glycerol 2.0 g Polyoxyethylene hydrogenated castor oil 0.8 g Benzalkonium chloride 0.005 g Sodium edetate 0.01g Dilute hydrochloric acid q.s. Sodium hydroxide q.s. Sterile, purified water q.s. 2) Eye ointment: Formulation 1 (for 100 g) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 1.0 g Liquid paraffin 10 g White petrolatum 89 g Formulation 2 (for 100 g) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 2.0 g Liquid paraffin 10 g White petrolatum 88 g 3) Tablet: Formulation 1 (for 100 mg) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg The above tablet is film coated with 2 mg of ordinary coating agents such as hydroxypropyl methylcellulose, macrogol and silicone resin to prepare the desired tablet (the following formulations are treated by the same manner). Formulation 2 (for 100 mg) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 5 mg Lactose 62.4 mg Corn starch 20 mg Carboxymethylcellulose calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg Coating agent 2 mg Formulation 3 (for 100 mg) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 20 mg Lactose 51 mg Corn starch 15 mg Carboxymethylcellulose calcium 5 mg Hydroxypropylcellulose 5 mg Magnesium stearate 1 mg Talc 1 mg Coating agent 2 mg Formulation 4 (for 100 mg) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 40 mg Lactose 34 mg Corn starch 10 mg Carboxymethylcellulose calcium 5 mg Hydroxypropylcellulose 5 mg Magnesium stearate 2 mg Talc 2 mg Coating agent 2 mg Formulation 5 (for 100 mg) (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate 80 mg Lactose 69 mg Corn starch 20 mg Carboxymethylcellulose calcium 10 mg Hydroxypropylcellulose 10 mg Magnesium stearate 4 mg Talc 4 mg Coating agent 3 mg [Pharmacological Test] For evaluation of the effect of a medicine for the treatment of glaucoma, a method of adminstering the medicine to rabbits having a high intraocular pressure provoked by chymotrypsin is known [Vareilles, P. et al., Invest. Ophthalmol. 16 , 987 (1977)]. (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine fumarate was used as a typical example of the compounds of the general formula (I). It was given to the subjects by topical administration or oral administration to examine its effects. 1. Effect of instillation: (Experimental method) Rabbits having a high intraocular pressure (29 to 49 mm Hg) provoked by giving α-chymotrypsin for at least one year were used in the tests according to the method of Sears et al. [Am. J. Ophthalmol. 77 , 378 (1974)]. 50 µℓ of the eye drops of Formulation 2 in the Examples was applied to both eyes of each rabbit. The intraocular pressure was determined before the application and 0.5, 1, 2, 3 and 4 hours after the application. The intraocular pressure was determined by applying 0.4 % hydroxyprocaine hydrochloride to both eyes of the rabbit while it was lightly holded to conduct the topical anesthetization and measuring the pressure with a pneumatic tonometer. (Results) The intraocular pressure was obserbed to be lower than that determined immediately before the application of the compound of the general formula (I). The decrease was by 2.8 mmHg after 2 hours and by 2.2 mm Hg after 3 hours. 2. Effects obtained by oral administration: (Method of experiment) The experiment was conducted in the same manner as that described above. The compound of the formula (I) was suspended in 0.5 % methyl cellulose and given in an amount of 3 mg/kg or 30 mg/kg by oral administration. (Results) The intraocular pressure was lower than that determined immediately before the oral administration of the compound. The decrease was by 2.3 mmHg after 1 hour, by 3.1 mm Hg after 2 hours and by 3.0 mm Hg after 3 hours in the group to which 3 mg/kg of the compound had been administered; and by 4.5 mm Hg after 1 hour, 4.8 mm Hg after 2 hours and 5.5 mm Hg after 3 hours in the group to which 30 mg/kg of the compound had been administered. It will be apparent from the above-described experimental results that when the compound of the present invention is administered, the intraocular pressure is clearly lowered. As shown in the pharmacological tests, the compounds of the present invention have an excellent intraocular pressure-lowering effect and are useful for preparing a therapeutic agent for glaucoma.

Claims: Use of a compound represented by the following formula (I) or its salt for the preparation of a therapeutic agent for glaucoma, which therapeutic agent comprises a compound of the formula (I) or its salt as active ingredient and pharmaceutically acceptable excipients, wherein R¹ represents one or more groups selected from a hydrogen atom, lower all groups, halogen atoms, a nitro group, a hydroxyl group, lower alkoxy groups, lower alkanyloxy groups, an amino group, lower alkylamino groups and lower alkoxycarbonyl groups, wherein R² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, wherein R³ represents one or more groups selected from a hydrogen atom, lower all groups, a hydroxyl group, lower alkoxy groups, halogen atoms, a nitro group, lower alkylenedioxy groups, lower alkanoyl groups, lower alkanoyloxy groups, an amino group, lower alkylamino groups, lower alkanoylamino groups and lower alkoxycarbonyloxy groups, or a group of -(CH₂) n -, wherein R⁴ represents a hydrogen atom or a lower alkyl group, wherein A and B may be the same or different from each other and each represent a lower alkylene group having 1 to 6 carbon atoms, and wherein n represents 3 or 4. The use of claim 1, wherein R¹ represents a hydrogen atom or one lower alkoxy group, wherein R² represents a lower alkyl group, wherein R³ represents one lower alkylenedioxy group, and wherein R⁴ represents a lower alkyl group. The use of claim 2, wherein each of the lower alkoxy group, lower alkyl group and lower alkylenedioxy group have 1 to 6 carbon atoms. The use of claim 2, wherein R¹ represents one lower alkoxy group. The use of claim 4, wherein the compound is represented by the following formula (II) or its salt: wherein R¹¹ represents a lower alkoxy group, wherein R¹² represents a lower alkyl group, wherein R¹⁴ represents a lower alkyl group, wherein A¹ and B¹ may be the same or different from each other and each represents a lower alkylene group having 1 to 6 carbon atoms, and wherein m represents an integer of 1 to 6. The use of claim 5, wherein the compound is (+)-(R)-3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy)-phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine or its salts. The use of any of the preceding claims, wherein the therapeutic agent is in the form of eye drops.

Inventors: MITA SHIRO, SHIRASAWA EIICHI, MITA, SHIRO, SHIRASAWA, EIICHI
Applicants: DAIICHI SEIYAKU CO, SANTEN PHARMA CO LTD, DAIICHI PHARMACEUTICAL CO., LTD., SANTEN PHARMACEUTICAL CO., LTD
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P27, A61K9, C07D279