JPH07133225A - Ciliary muscle relaxant - Google Patents

Abstract

PURPOSE:To provide a benzothiazine derivative having excellent ciliary muscle contraction-inhibitory activity, thus useful as a therapeutic agent for esp. pseudomyopia and asthenopia. CONSTITUTION:The objective ciliary muscle relaxant containing, as active ingredient, a compound of formula I [R<1> is at least one group selected from H, alkyl, halogen, NO2, OH, alkoxyl, alkanoyloxy, amino, alkylamino and alkoxycarbonyl; R<2> is H, alkyl or 3-6C cycloalkyl; R<3> is at least one group selected from H, alkyl, OH, alkoxyl, halogen, NO2, alkylenedioxy, alkanoyl and NH2, or (CH2)n (n is 3 or 4); R<4> is H or alkyl; A and B are each 1-6C alkylene@{9147/28 }or a salt thereof. The compound of the formula I is pref. 3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4methylenedioxy) phenoxy]ethyl]amino]propoxyphenyl]-4-methyl-3oxo-2H-1,4-benzothiazine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a ciliary muscle tone relieving agent containing a benzothiazine derivative as an active ingredient.

[0002]

2. Description of the Related Art It has been reported that myopic flexion, that is, pseudomyopia, occurs in eye tissues when tension of smooth ciliary muscles is sustained (Journal of the Ophthalmological Society of Japan, 72 , 20.
83-2150 (1968)). Improvement of visual acuity was observed by instilling tropic acid amide, which has the action of ameliorating the spasms of the regulatory muscle, in this case of pseudo-myopia (Journal of Japanese Ophthalmology, 26 , 662-6).
75 (1975)). Moreover, when the ciliary muscles become tired due to overstraining, it is said that the adjustment is not performed smoothly and causes eye strain (Journal of the Japanese Ophthalmological Society, 92 , 1854-1858 (1
988)). It has been reported that eye drops of low-concentration cyclopentolate improved the accommodative power and markedly improved eye strain in VDT workers (clinical ophthalmology, 44 , 494-495).
(1990)). On the other hand, JP-A-62-123181 discloses that a benzothiazine derivative is useful as a therapeutic agent for hypertension, thrombosis, arrhythmia and the like. It has been shown that these compounds have a unique structure, their calcium antagonism has a platelet aggregation inhibitory action, and they are useful as therapeutic agents for cardiovascular diseases. Further, European Patent Publication No. 492164 discloses that these compounds are useful as a therapeutic agent for glaucoma that lowers intraocular pressure by local or systemic administration.

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention It is an object of the present invention to find out new effects, particularly in the ophthalmological field, of benzothiazine derivatives useful as medicines.

[0004]

[Means for Solving the Problems] In order to find out a new effect of the benzothiazine derivative in the field of ophthalmology, the present inventors examined the action on the ciliary muscle. As a result, it was confirmed that the benzothiazine derivative suppressed the contraction of the ciliary muscle contracted by KCl and carbachol, which was extracted from the bovine eye, and it was a therapeutic agent for pseudomyopia and eye strain. Is expected to be useful as

The present invention relates to a ciliary muscle tone relieving agent containing a compound represented by the following general formula [I] or a salt thereof (hereinafter referred to as the compound of the present invention) as an active ingredient.

[0006]

[Chemical 7] [Wherein R ¹ is selected from a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group or a lower alkoxycarbonyl group.
R ² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group,
One or more selected from a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyl group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, a lower alkanoylamino group or a lower alkoxycarbonyloxy group. Group of or
(CH _{2) n} - are shown, R ⁴ represents a hydrogen atom or a lower alkyl group, A and B or different identical 1-6
Means a lower alkylene group having 4 carbon atoms, and n is 3 or 4. ]

In the above formula [I], the lower alkyl group is 1 such as methyl group, ethyl group, propyl group and hexyl group.
A halogen atom represents fluorine, chlorine, bromine, etc., and a lower alkoxy group represents a methoxy group, an ethoxy group, a propoxy group, a hexyloxy group, etc. An alkoxy group having a carbon atom is shown, and a lower alkanoyloxy group is an alkanoyloxy group having 2 to 6 carbon atoms such as an acetyloxy group, a propionyloxy group and a hexanoyloxy group, and a cycloalkyl group is a cycloalkyl group. It represents a cyclic alkyl group having 3 to 6 carbon atoms such as a propyl group and a cyclohexyl group, and a lower alkylenedioxy group is 1 between two oxygen atoms such as a methylenedioxy group and an ethylenedioxy group. A lower alkanoyl group means an acetyl group, a propionyl group, a hexyl group. Shows the alkanoyl group having 2 to 6 carbon atoms such as alkanoyl groups.

The salt in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, for example, hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate. , Methanesulfonate, paratoluenesulfonate and the like. Further, the compound of the present invention includes stereoisomers and optical isomers, both of which are included in the present invention. Examples of the compound represented by the above general 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] phenyl] -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] ethoxyphenyl] -4-methyl-3-oxo-2H-1,4-benzothiazine oxalic acid Salt, 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, stereoisomers and optically active forms thereof.

Of these, compounds represented by the following general formula [II] and salts thereof are more preferable.

[0010]

[Chemical 8]

Of the compounds of the present invention, examples of compounds having particularly excellent action 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-2
Examples include H-1,4-benzothiazine fumarate and its stereoisomers and optically active forms. The compound of the present invention is a drug useful as a therapeutic agent for cardiovascular diseases, but only the action of lowering intraocular pressure has been known to act on the eye. Therefore, the present inventors examined further application of the compound of the present invention to the field of ophthalmology. As a result, although detailed data will be described in the section of Examples, the compound of the present invention showed a regulatory action on contraction of ciliary muscle due to hypertonicity. In general, sustained hypertension of the ciliary muscles causes false myopia (Journal of the Japanese Ophthalmological Society, 72 , 2083-2150 (1968)) and eye strain (The Japanese Society of Ophthalmological Science, 92 , 1854-). 1858 (1
988)) has been reported. INDUSTRIAL APPLICABILITY The compound of the present invention has an action of remarkably relieving hypertonicity of ciliary muscle, and is expected to be particularly useful as a therapeutic agent for pseudomyopia and eye strain.

The compound of the present invention may be administered by topical agents such as eye drops and eye ointments, or by systemic agents such as tablets, capsules, granules and powders, or they may be used in combination. . The dose of the compound of the present invention in the present invention can be appropriately selected depending on symptoms, age, dosage form, etc., but for topical agents, the concentration is 0.05% to 5%, preferably 0.1%.
% To 2% is instilled once to several times a day, and for systemic agents, 0.1 to 1000 mg per day, preferably 1 to
100 mg may be administered once or in several divided doses.
The preparation of the compound of the present invention may be prepared according to a conventional method by adding the necessary additives to the compound of the present invention according to the dosage form. For example, in the case of eye drops, sodium chloride, potassium chloride, concentrated glycerin, etc. are made isotonic. Agents, buffering agents such as sodium phosphate, boric acid, monoethanolamine, stabilizers such as sodium edetate, preservatives such as benzalkonium chloride and paraoxybenzoate, polysorbate 80, polyoxyethylene hydrogenated castor oil If necessary, a surfactant such as pH adjusting agent such as dilute hydrochloric acid or sodium hydroxide may be added. In the case of systemic agents such as tablets, capsules, granules and powders, bulking agents such as lactose, crystalline cellulose and starch, lubricants such as magnesium stearate and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone. , Disintegrants such as carboxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose,
Hydroxypropyl methylcellulose, macrogol,
A coating agent such as silicone resin may be added as necessary.

[0013]

【Example】

[Formulation Example] (+)-(R) as a typical example of the compound of the present invention
-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 ( Hereinafter, typical formulation examples of eye drops and oral preparations using Compound A of the present invention) are shown below. Regarding oral agents, JP-A-62-123181
A few examples are also disclosed. 1) Eye drops In 100 ml of formulation 1 Inventive compound A 0.5 g Concentrated glycerin 1.5 g Polyoxyethylene hydrogenated castor oil 1.0 g Benzalkonium chloride 0.005 g Sodium edetate 0.01 g Dilute hydrochloric acid Appropriate amount sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount

Formulation 2 In 100 ml of the present invention Compound A 1.0 g Concentrated glycerin 1.25 g Polysorbate 80 2.0 g Methyl paraoxybenzoate 0.026 g Propyl paraoxybenzoate 0.014 g Dilute hydrochloric acid Adequate amount Sodium hydroxide Adequate amount Sterile purified water Appropriate amount

Formulation 3 In 100 ml of Invention Compound A 0.1 g Concentrated glycerin 2.0 g Polyoxyethylene hydrogenated castor oil 0.8 g Benzalkonium chloride 0.005 g Sodium edetate 0.01 g Dilute hydrochloric acid qs Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount

2) Ophthalmic ointment Formula 1 in 100 g Compound of the present invention A 1.0 g Liquid paraffin 10 g White petrolatum 89 g Formula 2 in 100 g Compound of the present invention A 2.0 g Liquid paraffin 10 g White petrolatum 88 g

3) Tablet Formulation 1 In 100 mg of the present compound A 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg The tablet of the above formulation is coated with a coating agent. (For example, a usual coating agent such as hydroxypropylmethylcellulose, macrogol, or silicone resin) is coated with 2 mg to obtain a target tablet (the same applies to tablets having the following formulations).

Formulation 2 In 100 mg, Compound of the present invention A 5 mg Lactose 62.4 mg Corn starch 20 mg Carboxymethyl cellulose calcium 6 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 0.6 mg Coating agent 2 mg

Formulation 3 In 100 mg Inventive compound A 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 In 100 mg, Compound of the present invention A 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 In 200 mg Inventive compound A 100 mg Lactose 67 mg Corn starch 20 mg Carboxymethyl cellulose calcium 10 mg Hydroxypropyl cellulose 10 mg Magnesium stearate 4 mg Talc 4 mg Coating agent 5 mg

"Pharmacological Test" Using Compound A of the present invention as a representative example of the compound of the present invention, the effect on contraction of ciliary muscle was examined. The experiment was conducted by Lepple-Wienhues et al. (Ex.
The following method was performed according to p. Eye Res., 53, 33-38 (1991)). (Experimental method) The ciliary muscle extracted from the bovine eye was suspended in a Magnus tube filled with Krebs-Henseleit solution, and oxygen containing 5% carbon dioxide was blown into the tube. After reaching equilibrium, the ciliary muscles are pretreated with Compound A of the invention for 30 minutes before addition of KCl,
The contraction caused by KCl was recorded isometrically.

(Results) The pretreatment with the compound A of the present invention was found to control the contraction of the ciliary muscle caused by KCl, and the inhibition rate was 22.9%. Even when the substance that induces the contraction of the ciliary muscle was changed from KCl to carbachol, the compound A of the present invention showed an inhibitory effect on the contraction of the ciliary muscle. From these results, it was revealed that the compound of the present invention has an inhibitory effect on contraction of ciliary muscle.

[0024]

As shown in the pharmacological test section, the compound of the present invention has a ciliary muscle tone relieving action, and is expected to be particularly useful as a therapeutic agent for pseudomyopia and eye strain. To be done.

Claims (18)

[Claims] 1. A ciliary muscle tone relieving agent comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. [Chemical 1] [Wherein R ¹ is selected from a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group or a lower alkoxycarbonyl group.
R ² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group,
One or more selected from a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyl group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, a lower alkanoylamino group or a lower alkoxycarbonyloxy group. Group of or
(CH _{2) n} - are shown, R ⁴ represents a hydrogen atom or a lower alkyl group, A and B or different identical 1-6
Means a lower alkylene group having 4 carbon atoms, and n is 3 or 4. ] 2. The ciliary muscle tone relieving agent according to claim 1, wherein the dosage form is an eye drop. 3. The ciliary muscle tone relieving agent according to claim 1, wherein the dosage form is an oral preparation. 4. 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-
A ciliary muscle tone relieving agent containing 1,4-benzothiazine (the following formula [II]) or a salt thereof as an active ingredient. [Chemical 2] 5. The ciliary muscle tone relieving agent according to claim 4, wherein the dosage form is an eye drop. 6. The ciliary muscle tone relieving agent according to claim 4, wherein the dosage form is an oral preparation. 7. A therapeutic agent for pseudo-myopia containing a compound represented by the following general formula [I] or a salt thereof as an active ingredient. [Chemical 3] [Wherein R ¹ is selected from a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group or a lower alkoxycarbonyl group.
R ² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group,
One or more selected from a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyl group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, a lower alkanoylamino group or a lower alkoxycarbonyloxy group. Group of or
(CH _{2) n} - are shown, R ⁴ represents a hydrogen atom or a lower alkyl group, A and B or different identical 1-6
Means a lower alkylene group having 4 carbon atoms, and n is 3 or 4. ] 8. The therapeutic agent for pseudomyopia according to claim 7, wherein the dosage form is an eye drop. 9. The therapeutic agent for pseudo-myopia according to claim 7, wherein the dosage form is an oral preparation. 10. 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-
A pseudo-myopia therapeutic agent containing 1,4-benzothiazine (the following formula [II]) or a salt thereof as an active ingredient. [Chemical 4] 11. The therapeutic agent for pseudomyopia according to claim 10, wherein the dosage form is an eye drop. 12. The therapeutic agent for pseudo-myopia according to claim 10, which has an oral dosage form. 13. An agent for treating eye strain, which comprises a compound represented by the following general formula [I] or a salt thereof as an active ingredient. [Chemical 5] [Wherein R ¹ is selected from a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group or a lower alkoxycarbonyl group.
R ² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group,
One or more selected from a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyl group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, a lower alkanoylamino group or a lower alkoxycarbonyloxy group. Group of or
(CH _{2) n} - are shown, R ⁴ represents a hydrogen atom or a lower alkyl group, A and B or different identical 1-6
Means a lower alkylene group having 4 carbon atoms, and n is 3 or 4. ] 14. The therapeutic agent for eye strain according to claim 13, wherein the dosage form is an eye drop. 15. The therapeutic agent for eye fatigue according to claim 13, wherein the dosage form is an oral preparation. 16. 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-
A therapeutic agent for eye strain comprising 1,4-benzothiazine (formula [II] below) or a salt thereof as an active ingredient. [Chemical 6] 17. The therapeutic agent for eye fatigue according to claim 16, wherein the dosage form is an eye drop. 18. The therapeutic agent for eye fatigue according to claim 16, wherein the dosage form is an oral preparation.