JPS6232171B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for glaucoma. Glaucoma is a group of diseases that are based on persistent or repeated increases in intraocular pressure and cause functional and organic damage to the eye.The treatment is to bring the intraocular pressure back to normal levels in order to preserve visual function. There is an urgent need to reduce the reduction (Masayoshi Mikuni, Kazuo Iwata,
Glaucoma, Kanehara Publishing Co., Ltd., 1968). The active ingredient compounds of conventional glaucoma treatment agents include:
Various alkaloids and cholinesterase inhibitors are known. The present inventors discovered that a certain type of carbostyril derivative, which is completely unrelated in its chemical structure to the above-mentioned known compounds, exerts a relatively strong intraocular pressure-lowering effect and has low toxicity, so it can be used as a therapeutic agent for glaucoma. found that it was effective, and completed the invention based on the above knowledge (patent application 1983-10108).
(No. 54-70361). As a result of further repeated research, the present inventors found that a carbostyril derivative, which is different from the derivative related to the above-mentioned application, exhibits an intraocular pressure-lowering effect almost similar to that of the above-mentioned compound, and is therefore effective in the treatment of glaucoma. The inventors discovered that an effective compound exists and completed the present invention. That is, the present invention is based on the general formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a lower alkenyl group. R ² is a hydrogen atom or group

[Formula] (R ⁴ represents a lower alkyl group, a cycloalkyl group, or a lower alkyl group substituted with a phenyl group which may have a lower alkoxy group as a substituent on the phenyl ring).
If R ² is a hydrogen atom, R ³ is

[Formula] (R ⁴ is the same as above), and R ² is

[Formula] indicates a hydrogen atom, a hydroxyl group, a ureido group, a lower alkynyloxy group, a lower alkoxy group having a lower alkanoyl group as a substituent, a lower alkanoylamino group, or a lower alkenyloxy group. however
When R ¹ and R ³ are both hydrogen atoms, R ² is a group

It must not be [Formula] (R ⁴ ' is a lower alkyl group). ] The present invention relates to a therapeutic agent for glaucoma, which contains as an active ingredient at least one selected from carbostyril derivatives represented by the following and pharmacologically acceptable acid addition salts thereof. The carbostyril derivative represented by the above general formula [] which is used as an active ingredient in the glaucoma therapeutic agent of the present invention can be used, for example, in West German Published Patent Application No. 2302027 and German Publication No. 2302027;
2711719, U.S. Patent No. 3953456, U.S. Patent No. 4081447
and No. 4147869, or can be easily produced according to the methods described in these documents. For example, it is produced by reacting a suitable hydroxycarbostyryl derivative with epichlorohydrin, and then reacting the obtained 2,3-epoxy-propoxy compound, 3-chloro-2-hydroxy-propoxy compound, or a mixture thereof with a suitable amine. can. Each of the above-mentioned documents describes that the derivatives included in the above general formula [] can be used as therapeutic agents for arrhythmia and angina pectoris or as antihypertensive agents, but it goes without saying that the derivatives have an effect of lowering intraocular pressure. There is no disclosure whatsoever regarding its use in the treatment of glaucoma. Examples of each group represented by R ¹ to ^{R 3} in the above general formula [] include the following. Lower alkyl group: a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc. Lower alkenyl group: a linear or branched alkenyl group having 2 to 4 carbon atoms, such as vinyl, allyl,
Crotyl, 1-methylallyl group, etc. Cycloalkyl group...Cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl group, etc. A lower alkyl group substituted with a phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring... 1 to 3 linear or branched alkoxy groups having 1 to 4 carbon atoms on the phenyl ring A group in which a phenyl group, which may have
-Phenylbutyl, 1,1-dimethyl-2-phenethyl, β-3,4-dimethoxyphenethyl, 4
-methoxybenzyl, β-3,4,5-trimethoxyphenethyl group, etc. Lower alkynyloxy group: an alkynyloxy group having 2 to 4 carbon atoms, such as ethynyloxy, propynyloxy, butynyloxy, 2-methylpropynyloxy group, etc. Lower alkoxy group having a lower alkanoyl group as a substituent: an alkoxy group having 1 to 4 carbon atoms having an alkanoyl group having 2 to 5 carbon atoms as a substituent, such as methylcarbonylmethoxy, 2-methylcarbonylethoxy, 2-ethylcarbonyl Ethoxy, 3-methylcarbonylpropoxy, 4-
Methylcarbonylbutoxy, ethylcarbonylmethoxy, butylcarbonylmethoxy, 4-butylcarbonylbutoxy groups, etc. Lower alkanoylamino group: a linear or branched alkanoylamino group having 1 to 4 carbon atoms, such as formylamino, acetylamino, propionylamino, butyrylamino group, etc. Lower alkenyloxy group: a linear or branched alkenyloxy group having 2 to 4 carbon atoms, such as vinyloxy, allyloxy, crotyloxy, 1-
Methylallyloxy group, etc. The acid addition salts of the carbostyril derivatives represented by the above general formula [] include the usual pharmaceutically acceptable acid addition salts of the derivatives, such as hydrochloric acid, sulfuric acid, nitric acid,
Included are salts of hydrobromic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like. Representative examples of the active ingredient compound of the glaucoma therapeutic agent of the present invention represented by the above general formula [] include the following. Γ 5-[2-hydroxy-3-(β-3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Γ 8-methylcarbonylmethoxy-5-[2-
Hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Γ 8-hydroxy-5-[2-hydroxy-3
-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Γ 5-(2-hydroxy-3-benzylamino)propoxy-3,4-dihydrocarbostyryl Γ 5-( 2-Hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Γ 1-ethyl-5-(2-hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-[2- Hydroxy-3-isopropylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-(2-hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-[2-hydroxy-3-(β -3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Γ 8-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-ureido-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyryl Γ 8-ureido-5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-propynyloxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydro Carbostyryl Γ 8-propynyloxy-5-(2-hydroxy-3-cyclohexylamino)propoxy-
3,4-dihydrocarbostyryl Γ 8-ureido-5-(2-hydroxy-3-
cyclohexylamino)propoxy-3,4-
Dihydrocarbostyryl Γ 8-propynyloxy-5-(2-hydroxy-3-tert-butylaminopropoxy-3,
4-dihydrocarbostyryl Γ 8-butynyloxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)] propoxy-3,4-dihydrocarbostyryl Γ 8-hydroxy-5-( 2-hydroxy-3
-tert-butylamino)propoxy-3,4-
Dihydrocarbostyryl Γ 8-hydroxy-5-(2-hydroxy-3
-cyclohexylamino)propoxy-3,4
-dihydrocarbostyryl Γ 8-methylcarbonylmethoxy-5-(2-
Hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-methylcarbonylmethoxy-5-(2-
Hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-ethylcarbonylmethoxy-5-(2-
Hydroxy-3-isopropylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-(4-butylcarbonylbutoxy)-5
-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,
4-dihydrocarbostyryl Γ 5-(2-hydroxy-3-cyclooctylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-methylcarbonylmethoxy-5-[2-
Hydroxy-3-(4-phenylbutylamino)]propoxy-3,4-dihydrocarbostyrylΓ 8-propynyloxy-5-[2-hydroxy-3-(β-3,4,5-trimethoxyphene) thylamino)] propoxy-3,4-dihydrocarbostyryl Γ 8-ureido-5-[2-hydroxy-3-
(4-methoxybenzylamino)]-3,4-dihydrocarbostyryl Γ 1-methyl-5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl Γ 1-butyl-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyryl Γ 1-methyl-8-methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Γ 1-methyl-8-hydroxy-5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl Γ 8-acetylamino-5-[2- Hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Γ 8-propionylamino-5-(2-hydroxy-3-tert-butylamino)propoxy-
3,4-dihydrocarbostyryl Γ 8-allyloxy-5-[2-hydroxy-
3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Γ 1-allyl-5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl Γ 1-crotyl-5-(2-hydroxy-3-
cyclohexylamino)propoxy-3,4-
Dihydrocarbostyryl Γ 1-allyl-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyryl Γ 1-allyl-8-methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Γ 8-allyloxy-5-(2-hydroxy-
3-tert-butylamino)propoxy-3,4
-Dihydrocarbostyryl Γ 8-crotyloxy-5-(2-hydroxy-3-cyclohexylamino)propoxy-
3,4-Dihydrocarbostyril The therapeutic agent for glaucoma of the present invention is usually prepared in a suitable dosage unit form by mixing the derivative represented by the general formula [ ] or its acid addition salt with a commonly used carrier for ophthalmic preparations. be done. As the dosage unit form, various usual forms can be arbitrarily adopted, but mainly forms suitable for topical administration, such as eye ointments,
Eye drops etc. are preferably used as eye drops. It may also be in a form suitable for systemic administration, such as a tablet, granule, or injection. The dosage of the therapeutic agent of the present invention is not particularly limited, but the amount of active ingredient in the therapeutic agent is usually 0.01 per adult per day.
The amount is preferably 5 mg, preferably 0.05 to 1 mg, and administration is preferably carried out in 1 to 3 divided doses a day.
Furthermore, the amount of active ingredient in the therapeutic agent is not particularly limited and can be appropriately determined depending on the dosage form. For example, when formulated into a form suitable for topical administration such as eye drops, it is usually approx.
It is preferably in the range of 0.1 to 2% by weight. The therapeutic agent of the present invention can be manufactured by conventional methods. Specifically, it is produced by using a carbostyril derivative represented by the general formula [ ] or an acid addition salt thereof as an active ingredient, mixing this with an appropriate base, and then shaping as necessary. When the therapeutic agent is an eye ointment, eye drops, injection, etc., it is manufactured by further sterilization. In the above, the base may be appropriately determined depending on the form of the therapeutic agent. For example, when producing an eye ointment, a conventional emulsion base,
Water-soluble bases, suspendable bases, etc. can be used. Representative examples of such bases include white petrolatum, purified lanolin, liquid paraffin, and the like. Furthermore, in producing eye drops, for example, sterile distilled water can typically be used as a base. The therapeutic agent of the present invention may further contain, for example, solubilizing agents, stabilizers, buffers, antioxidants, preservatives, and the like. Examples of solubilizing agents include sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, and higher grade polyethylene glycols such as polyethylene glycol monolaurate and polyethylene glycol monooleate. Examples include fatty acid esters, polyoxyethylene fatty acid esters such as polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monooleate. Specific examples of the stabilizer include hydroxypropyl methyl cellulose, polypynyl alcohol, carboxymethyl cellulose, hydroxyethyl cellulose, glycerin, and EDTA. Examples of the buffer include sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, and sodium tartrate. Examples of the antioxidant include sodium bisulfite, sodium thiosulfite, and ascorbic acid. Chlorobutanol as a preservative
Examples include benzathonium chloride, benzalkonium chloride, cetylpyridium chloride, thimerosal, phenethyl alcohol, methylparaben, and propylparaben. Furthermore, when the therapeutic agent of the present invention is in the form of eye drops, the eye drops are preferably isotonic with lachrymal fluid;
Therefore, an isotonizing agent such as common salt can be added if necessary. Furthermore, the eye drops have a pH of 5.5 to 8.5, preferably 6.5 to 8.5.
Preferably adjusted to 7.5. The therapeutic agent for glaucoma of the present invention thus obtained is administered by various administration methods depending on its dosage unit form. For example, in the case of eye drops, they are dropped into the eye from a suitable drop container or sprayed into the eye from a spray device. In the case of eye ointment, it is applied to the eye. In the case of tablets, granules, etc., they are administered orally, and in the case of injections, they are administered subcutaneously, intramuscularly, or intravenously; in either case, the desired therapeutic effect can be achieved. Formulation examples and drug efficacy tests are listed below to explain the present invention in more detail, but the present invention is not limited thereto. Formulation example 1 8-Methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate 20mg Benzathonium chloride 0.1mg Sodium chloride 3 mg Sodium dihydrogen phosphate 5 mg Sodium hydrogen phosphate, 12H ₂ O 11.8 mg Distilled water Appropriate amount 1 ml Dissolve each of the above ingredients in distilled water, sterilize it using appropriate filter paper, and make eye drops. The glaucoma therapeutic agent of the present invention having the following form is manufactured. Production example 2 8-hydroxy-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyril hydrochloride 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate _12H2O 11.8mg Distilled water Appropriate amount 1 ml Add each of the above ingredients to distilled water The glaucoma therapeutic agent of the present invention in the form of eye drops is produced in the same manner as in Formulation Example 1. Formulation example 3 5-(2-hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl oxalate 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H ₂ O 11.8 mg Distilled water Appropriate amount Total 1 ml Each of the above components is dissolved in distilled water, and the glaucoma therapeutic agent of the present invention in the form of eye drops is prepared in the same manner as in Formulation Example 1. Formulation example 4 8-Methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate 10mg 10% benzalkonium chloride Solution 1 μ Sodium chloride 6.9 mg Sodium dihydrogen phosphate 0.4 mg Sodium monohydrogen phosphate 12H ₂ O 1.0 mg Distilled water Measurement 1 ml Dissolve each of the above ingredients in distilled water and prepare eye drops in the same manner as in Formulation Example 1. The glaucoma therapeutic agent of the present invention is prepared in the following form. Production example 5 5-(2-hydroxy-3-benzylamino)
Propoxy-3,4-dihydrocarbostyryl hydrochloride 20mg 10% benzalkonium chloride solution 1μ Sodium chloride 5.0mg Sodium monohydrogen phosphate 0.4mg Sodium dihydrogen phosphate _12H2O 1.0mg Distilled water Measurement 1 ml Above Each component is dissolved in distilled water, and the glaucoma therapeutic agent of the present invention in the form of eye drops is produced in the same manner as in Formulation Example 1. Drug efficacy test (method) Male New Zealand Albino Rabbit (body weight) was used as an experimental animal.
1.8-2.5Kg). For intraocular pressure measurement, the experimental animal is fixed in a cylindrical rabbit fixator, and intraocular pressure is measured without local anesthesia using an Alcon pneumatic applanation tonometer. Each test compound was dissolved in physiological saline at 1% (w/
v) Make a solution, add 0.01N-NaOH aqueous solution, and adjust the pH.
Adjust to 6.5-7.0. Each drug solution is administered using a microsyringe after measuring the intraocular pressure twice before administration.
Administer exactly 100μ by instillation into either the left or right eye. After applying the eyelids, hold the eyelids for 1 minute to prevent the medicine from flowing out. The effect of each test compound was examined by measuring intraocular pressure 30 minutes and 1 hour after instillation and comparing it with the previous value (pre-administration intraocular pressure). As a control test, 100μ of physiological saline containing no test compound was similarly instilled into the eyes, and the intraocular pressure was measured in the same manner. For reference, 5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride (Reference Example 1) and 5-
The same test was conducted using (2-hydroxy-3-tert-butylamino)propoxycarbostyryl hydrochloride (Reference Example 2). (Test compound) Compound A 8-methylcarbonylmethoxy-5-
[2-hydroxy-3-(β-3,4
-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate compound B 8-hydroxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy- 3,
4-dihydrocarbostyryl hydrochloride compound C 5-(2-hydroxy-3-benzylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride compound D 5-(2-hydroxy-3-cyclohexylamino)propoxy-3, 4-
Dihydrocarbostyril hydrochloride compound E 1-ethyl-5-(2-hydroxy-
3-Cyclohexylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride Compound F 8-(2-hydroxy-3-isopropylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride Compound G 8-Ureido-5-[ 2-Hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4
-Dihydrocarbostyryl hydrochloride compound H 8-Propynyloxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate compound I 8 -Acetylamino-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl hydrochloride compound J 8-allyloxy-5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride compound K 1-allyl-5-(2 -Hydroxy-
3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride The results are shown in Table 1 below.

【table】

[Table] From Table 1 above, all of the active ingredient compounds of the present invention (test compounds No. A to K) exhibit approximately the same intraocular pressure-lowering effect as the compounds of Reference Examples 1 and 2 in normal rabbits. It turns out that it does. Reference Test 1 For 3 glaucoma patients, 2 drops of the following prescription eye drops were instilled into the eyes, and the intraocular pressure was measured 1 and 2 days later. This measurement is performed between 10 and 11 a.m. using a Goldmann applanation tonometry device. (Prescription) 5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H ₂ O 11.8 mg Distilled water Approx. 1 ml Dissolve each of the above ingredients in distilled water and produce eye drops in the same manner as in Formulation Example 1. The results obtained are shown in Table 2 below.

[Table] Reference Test 2 For 3 glaucoma patients, inject 2 drops of the following prescription eye drops into the eyes, and measure the intraocular pressure in the same manner as Reference Test 1 before and 1, 4, and 24 hours after the drop. (Prescription) 5-(2-hydroxy-3-tert-butylamino)propoxycarbostyryl hydrochloride 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H ₂ O 11.8mg Distilled water Suitable Quantity : 1 ml The eye drops were produced according to Production Example 1 above. The results are shown in Table 3 below.

[Table] From Tables 2 and 3 above, it is found that the compounds of Reference Examples 1 and 2 can exhibit excellent glaucoma treatment effects. It is clear that it is effective in treating glaucoma. Acute toxicity test Regarding the active ingredient compound of the glaucoma therapeutic agent of the present invention,
An acute toxicity test was conducted on the mice by intravenous administration, and the LD ₅₀ values listed in Table 4 below were obtained.

[Table] The LD ₅₀ of Test Compound A is the value obtained by oral administration to rats (male). In addition, when the same acute toxicity test as above was conducted for other active ingredient compounds, all of them showed approximately 40 mg/Kg or more when administered intravenously to mice.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a lower alkenyl group. R ² represents a hydrogen atom or [Formula] (R ⁴ is a lower alkyl group, a cycloalkyl group, or a lower alkyl group substituted with a phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring).
If R ² is a hydrogen atom, R ³ is
[Formula] (R ⁴ is the same as above), and when R ² is a group [Formula], hydrogen atom, hydroxyl group, ureido group, lower alkynyloxy group, lower alkoxy group having a lower alkanoyl group as a substituent, lower Indicates an alkanoylamino group or a lower alkenyloxy group. however
When R ¹ and R ³ are both hydrogen atoms, R ² must not be a group [formula] (R ⁴ ' is a lower alkyl group). ] A therapeutic agent for glaucoma, comprising as an active ingredient at least one selected from carbostyril derivatives represented by the following and pharmacologically acceptable acid addition salts thereof.