WO1995031200A1

WO1995031200A1 - Pharmaceutical composition for treating glaucoma containing terazosin

Info

Publication number: WO1995031200A1
Application number: PCT/JP1995/000920
Authority: WO
Inventors: Takahiro Ogawa; Takaaki Deguchi; Katsuhiro Inada
Original assignee: Senju Pharmaceutical Co., Ltd.
Priority date: 1994-05-18
Filing date: 1995-05-15
Publication date: 1995-11-23
Also published as: CN1148810A; EP0759756A1; HUT76468A; PL317190A1; HU9603158D0; CA2187361A1; JPH10500130A; BR9507732A; AU2420195A; TW304879B

Abstract

A pharmaceutical composition for treating glaucoma which comprises (±)-4-amino-2-[4-(tetrahydro-2-furoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.

Description

Pharmaceutical composition for treating glaucoma containing terazosin

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating glaucoma which has a potent intraocular pressure lowering effect at low concentrations without causing any side effects.

BACKGROUND ART Glaucoma is a disease characterized by an abnormally high pressure within the eyeball (intraocular pressure) which provokes various associated symptoms, such as fatigability in the eye, blurred vision, pain in the eye and gradually impaired vision, eventually leading to the risk of loss of vision. In patients with this disease, the eyeball hardens like stone so it is called "stone glaucoma", and the depth of the pupil looks blue so it is called "blue glaucoma".

In the eyeball, a watery fluid (aqueous

or) circulates invariably to maintain a constant pressure within the eye (intraocular pressure = 10 to 21 mmHg). This is controlled by the circulation of blood or lymph, resilience of the eyeball, action of the innervated nerve, etc., and when either of such factors becomes abnormal, the intraocαlar pressure rises and glaucoma develops. When such abnormality is caused by ophthalmic diseases including iritis, wounds or vitreous hemorrhage, the resulting glaucoma is termed secondary glaucoma. In most cases, therapeutically problematic glaucoma is primary glaucoma, which manifests abnormalities for unknown cause.

Primary glaucoma falls into the following three categories: (1) inflammatory glaucoma whose progress is acute, (2) simple glaucoma whose progress is chronic and (3) congenital glaucoma. In order to treat glaucoma, heretofore, various drugs have been used to prevent a rise in intraocular pressure or reduce increased intraocular pressure. Intraocular pressure reducing agents known so far include sympathomimetic drugs such as epinephrine. Epinephrine has mydriatic activity and prompts angle closure when applied to narrow angle glaucoma, and sometimes causes a rapid increase in intraocular pressure and often produces an increase in blood pressure and pigmentation in the conjunctiva.

Parasympathomimetic drugs such as pilocarpine have miotic activity and thereby cause a sensation of darkness or abnormal regulation in the visual field.

In recent years, furthermore, β-adrenergic blocking agents such as timolol have been extensively used for the treatment of glaucoma because they have inhibitory activity against production of the aqueous humor (Drug Therapy - Practical Series, The Drug Treatment of Glaucoma, pp.70 to 75, 1990). Such β-adrenergic blocking agents, however, have been reported to cause systemic side effects such as bradycardia, cardiac insufficiency and asthma onset, and they cannot therefore be administered to patients with such symptoms .

It is suggested that ct_!-adrenergic blocking agents promote the aqueous outflow, and bunazosine hydrochloride can increase the choroidal blood flow and become a potential novel therapeutic agent against low tension glaucoma (Journal of Japanese Society of Ophthalmology, vol. 2 pp.710 to 714, 1991). When this compound is used for the treatment of glaucoma, however, the conjunctival hyperemia and miosis owing to its vasodilatory activity are inevitable.

On the other hand, β-adrenergic stimulants are expected to be given to such patients, but conventional β- adrenergic stimulants such as sulbutamol fail to exhibit satisfactory activity unless applied at high concentrations. Their administration at high concentrations causes marked conjunctival hyperemia, and their continuous administration is regarded as impossible.

As described above, no satisfactory therapeutic agents for glaucoma that have few side effects described above and are effective at a low concentration have so far been found. By the way, in recent years, it has been reported that (± )-4-amino-2-[4-(tetrahydro-2-f royl)-1-piperazinyl]- 6, 7-dimethoxyquinazoline (hereinafter referred to as terazosin) and its pharmaceutically acceptable acid addition salts, particularly its hydrochloride salt (hereinafter referred to as terazosin hydrochloride), are useful as hypotensive agents (JP-A 52-48678). In addition, it is reported that terazosin hydrochloride dihydrate is less water- soluble but far more stable in an aqueous solution than terazosin hydrochloride (anhydride), and thus is more suitable for parenteral administration (JP-B 2-31078).

BRIEF DESCRIPTIONS OF DRAWINGS Fig. 1 is a graph showing time-course changes of intraocular pressure in normal pigmented rabbits when each test drug or physiological saline was instilled to their eyes. Time (hour) after instillation is plotted as abscissa and intraocular pressure (mmHg) as ordinate. Each value represents mean ± S.E. (the number of animals is 10). In Fig. 1, the symbol "a" designates physiological saline, and the symbols "b" , "c", "d", "e" and "f" designate 0.003 %, 0.01 %, 0.03 %, 0.1 % and 0.3 % aqueous solutions of terazosin hydrochloride, respectively. The symbols "*i" and "*2" designate p<0.05 and p<0.01 (vs Control), respectively, which were analyzed using Dunnett's test. Fig. 2 is a graph showing time-course changes of intraocular pressure of fellow (non-treated) eyes of normal pigmented rabbits when each test drug or physiological saline was instilled into one of their eyes. Time (hour) after instillation is plotted as abscissa and intraocular pressure (mmHg) as ordinate. Each value represents mean ± S.E. (the number of animals is 10). In Fig. 2, the symbol "a" designates physiological saline, and the symbols "b", "c", "d", "e" and "f" designate 0.003 %, 0.01 %, 0.03 %, 0.1 % and 0.3 % aqueous solutions of terazosin hydrochloric:;, respectively.

Fig. 3 is a graph showing time-course changes of pupil diameter in normal pigmented rabbits when each test drug or physiological saline was instilled into their eyes. Time (hour) after instillation is plotted as abscissa and pupil diameter (mm) as ordinate. Each value represents mean ± S.E. (the number of animals is 10). In Fig. 3, the symbol "a" designates physiological saline, and the symbols "b", "c", "d", "e" and "f" designate 0.003 %, 0.01 %, 0.03 %, 0.1 % and 0.3 % aqueous solutions of terazosin hydrochloride, respectively.

Fig. 4 is a graph showing time-course changes of intraocular pressure in normal pigmented rabbits when 0.5% timolol maleate ophthalmic solution or physiologically saline was instilled into their eyes. Time (hour) after instillation is plotted as abscissa and intraocular pressure (mmHg) as ordinate (the number of animals is 10). In Fig. 4, the symbols "a" and "g" designate physiological saline and 0.5 % timolol maleate ophthalmic solution, respectively. Fig. 5 is a graph showing intraocular pressure reducing activity of each test drugs and 0.5 % timolol maleate ophthalmic solution when they were instilled into eyes of normal pigmented rabbits . The ordinate represents areas under curve of time (AUC) (mmHg*time) from the first instillation to 8 hours after then. AUC was determined using intraocular pressure before instillation as a baseline value. In Fig. 5, the symbols "b", "c", "d", "e" and "f" designate 0.003 %, 0.01 %, 0.03 %, 0.1 % and 0.3 % aqueous solutions of terazosin hydrochloride, respectively, and the symbol "g" designates 0.5 % timolol maleate ophthalmic solution. The symbols "*l" and "*2" designate p<0.05 and p<0.01 (vs timlol maleate), respectively, which were analyzed using Dunnett's test.

DISCLOSURE OF INVENTION The present inventors conducted intensive research to find a drug that has no defects (side effects) of conventional drugs as mentioned above and has intraocular pressure reducing activity at low concentrations . As a result, the present inventors have found that terazosin hydrochloride described in the above publications has unexpectedly excellent intraocular pressure reducing activity and few side effects, while it is effective at lower concentrations. Thus, the present invention has been completed. The present invention is to provide a novel and useful pharmaceutical composition for treating glaucoma that is free from the above defects (side effects) and has potent intraocular pressure reducing activity at low concentrations.

That is, the present invention provides a pharmaceutical composition for treating glaucoma which comprises (+ )-4-amino-2-[4-(tetrahydro-2-furoyl )-1- piperazinyl]-6,7-dimethoxyquinazoline (i.e. , terazosin) of the formula :

or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloride, sulfate, etc., and those with organic acids such as maleate, tartrate, citrate, etc. Among the salts, the hydrochloride (i.e., terazosin hydrochloride) is preferable, and terazosin hydrochloride dihydrate is more preferable.

Physicochemical properties and production process of terazosin or its pharmaceutically acceptable acid addition salts used as an active ingredient of the pharmaceutical composition of the present invention are described, for example, in the above-mentioned JP-A 52-48678.

Since the pharmaceutical composition of the present invention, as demonstrated by the test examples below, has an excellent intraocular pressure reducing effect at low concentrations and has low toxicity, it can be used as an effective drug in the treatment of various types of glaucoma.

In using terazosin or its pharmaceutically acceptable acid addition salt as an active ingredient of the pharmaceutical composition, such active ingredient can usually be mixed with per se known pharmacologically acceptable carriers, excipients, diluents, etc., and processed according to known methods into preparations for parenteral application such as ophthalmic solutions, ophthalmic ointments, injectable solutions, etc., or preparations for oral administration such as tablets, capsules, granules, etc.

When the pharmaceutical composition of the present invention is used in the form of an ophthalmic solution, for example, the composition may contain various type of additives which are conventionally formulated into ophthalmic solutions, such as buffers, isotonizing agents, preservatives, solubilizers (stabilizers), pH regulating agents, thickening agents, chelating agents, etc., as far as they would not affect adversely the objective of the present invention. The buffers include, for example, phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, a ino acids, etc.

The isotonizing agents include, for example, sugars such as sorbitol, glucose, mannitol, etc., polyhydric alcohols such as glycerol, polyethylene glycol, propylene glycol, etc., and salts su h as sodium chloride, etc.

The preservatives include, for example, benzalkonium chloride, benzethonium chloride, p-hydroxybenzoic acid esters such as methyl and ethyl hydroxybenzoates, etc. , benzyl alcohol, phenethyl alcohol, sorbic acid or its salts, thimerosal, chlorobutanol, etc.

The solubilizers (stabilizers) include, for example, cyclodextrins and their derivatives, water-soluble polymers such as polyvinylpyrrolidone and the like, surfactants, etc. The pH regulating agents include, for example, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc.

The thickening agents include, for example, hydroxy- ethylcelluloεe, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and their salts, etc.

The chelating agents include, for example, sodium edetate, sodium citrate, condensed sodium phosphate, etc. 5 When the pharmaceutical composition of the present invention is used as an ophthalmic ointment, purified lanolin, petrolatum, plastibase, liquid paraffin, polyethylene glycol, etc. are suitably employed as an ophthalmic ointment base.

Furthermore, the pharmaceutical composition of the 1.0 present invention can also be used in the form of preparations for oral administration such as tablets, capsules, granules, etc., or in the form of injectable solutions.

The pharmaceutical composition of the present invention can be used for treating glaucoma in mammals such 15 as humans, dogs, cats, rabbits, horses, cattle, etc.

The dose of the pharmaceutical composition of the present invention varies depending upon the route of administration, symptoms, age and body weight of a patient, etc. and, when it is used in the form of an ophthalmic 20 solution for an adult patient with glaucoma, for example, it is desirable that an ophthalmic solution containing as the active ingredient terazosin or its pharmaceutically acceptable acid addition salt at concentrations ranging from about 0.001 to 3.0 w/v %, preferably ranging from about 0.01 to 1.0 w/v %, is applied at a dose of one to several drops once to six times a day according to the severity of the symptoms.

When the pharmaceutical composition of the present invention is used in the form of an ophthalmic ointment, it is desirable that an ophthalmic ointment containing as the active ingredient terazosin or its pharmaceutically acceptable acid addition salt at concentrations ranging from about 0.001 to 10 w/w %, preferably ranging from 0.01 to 1.0 w/w %, is applied once to four times or so a day according to the severity of the symptoms.

The pharmaceutical composition of the present invention may contain one or more other therapeutic agent for glaucoma, unless it is contrary to the objective of the present invention. The pharmaceutical composition of the present invention may contain other drugs having different efficacies, unless it is contrary to the objective of the present invention.

The following examples and test examples further illustrates the present invention in detail and clarify the effects of the present invention, but are not to be understood to limit the scope of this invention. EXAMPLES Example 1

Ophthalmic solution

An ophthalmic solution was prepared according to the following prescription by a conventional method:

Terazosin hydrochloride dihydrate 0.12 g

(0.1 g when calculated in terms of terazosin) Cone, glycerol 2.6 g

Sodium acetate 0.1 g Benzalkonium chloride 0.005 g

Dilute hydrochloric acid Appropriate amount

(pH 6.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml. Example 2

Ophthalmic solution

Terazosin hydrochloride dihydrate 0.036 g (0.03 g when calculated in terms of terazosin)

Sodium chloride 0.9 g

Sodium acetate 0.1 g

Polyvinylpyrrolidone 0.5 g

Benzalkonium chloride 0.01 g Dilute hydrochloric acid Appropriate amount (pH 4.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml. Example 3 Ophthalmic solution

Terazosin hydrochloride dihydrate 0.36 g

(0.3 g when calculated in terms of terazosin) Sodium chloride 0.9 g

Dibasic sodium phosphate 0.1 g

Sodium edetate 0.05 g

Benzalkonium chloride 0.01 g

Sodium hydroxide Appropriate amount (pH 7.0)

Sterile purified water was added to the above ingredients to a final volume of 100 ml. Example 4

Ophthalmic solution An ophthalmic solution was prepared according to the following prescription by a conventional method: Terazosin hydrochloride dihydrate 0.36 g

(0.3 g when calculated in terms of terazosin) Cone, glycerol 2.6 g Sodium acetate 0.1 g Benzalkonium chloride 0.005 g

Dilute hydrochloric acid Appropriate amount

(pH 6.0) Sterile purified water was added to the above ingredients to a final volume of 100 ml.

Example 5

Ophthalmic ointment

An ophthalmic ointment was prepared according to the following prescription by a conventional method: Terazosin hydrochloride dihydrate 3.6 g

(3.0 g when calculated in terms of terazosin) Liquid paraffin 1.0 g

White petrolatum Appropriate amount

Total amount 100 g Test Example 1

Intraocular pressure reducing effect of terazosin hydrochloride dihydrate instilled into one of the eyes in individual pigmented rabbits having normal intraocular pressure and its effect on the intraocular pressure of the fellow (untreated) eyes:

Sixty male pigmented rabbits (Dutch belted rabbits) , weighing about 2 kg were confirmed that they have no ocular abnormalities, and then were bred in a breeding room maintained at a temperature of 24.4 ± 4 °C and a humidity of 55 ± 15 %. Each of them was given lOOg of solid food (Labo RG-RO, manufactured by Nihon Nohsan kogyo K.K.) per -'ay and allowed free access to tap water as drinking water.

As the test drugs, the following aqueous solutions were used: aqueous solutions of terazosin hydrochloride dihydrate containing terazosin at concentrations of 0.003 w/v%, 0.01 w/v%, 0.03 w/v%, 0.1 w/v% and 0.3 w/v% (referred to as the 0.003% aqueous solution of terazosin hydrochloride, 0.01% aqueous solution of terazosin hydrochloride, 0.03% aqueous solution of terazosin hydrochloride, 0.1% aqueous solution of terazosin hydrochloride, and 0.3% aqueous solution of terazosin hydrochloride, respectively). Physiological saline was used as a control.

Sixty rabbits bred as described above were divided into six groups each consisting of 10 rabbits. 50 μl of one of the test drugs or physiological saline was applied to one eye of each rabbit, and the other eye was left untreated. Before instillation and 0.5, 1, 2, 4, 6 and 8 hours after instillation, intraocular pressure of both eyes of each animal was determined using pneumatonograph (manufactured by Alcon Co.; hereinafter referred to as "PTG").

Time-course changes of intraocular pressure after instillation of each test drug and physiological saline are shown in Fig. 1 (for treated eyes) and in Fig. 2 (for non- treated eyes) . As is evident from the results shown in Fig. 1, topical application of the 0.3 % aqueous solution of terazosin hydrochloride significantly decreased intraocular pressure, and the decrease was maintained 30 minutes to 6 hours after instillation and reached a peak decrease in intraocular pressure of 7.3 mmHg one hour after instillation. A significant decrease in intraocular pressure was observed from 30 min to 4 hours after instillation of the 0.1 % aqueous solution of terazosin hydrochloride, and the maximum decrease in intraocular pressure, 6.0 mmHg, was obtained one hour after instillation. Topical application of the 0.03 % aqueous solution of terazosin hydrochloride significantly decreased intraocular pressure 30 minutes to 2 hours after instillation, and the maximum decrease, 5.9 mmHg was achieved one hour after instillation. Intraocular pressure was significantly reduced by the 0.01 % aqueous solution of terazosin hydrochloride one hour after instillation, and the maximum decrease in intraocular pressure was 4.1 mmHg. The maximum decrease in intraocular pressure, 2.2 mmHg, was found 30 min after instillation of the 0.003 % aqueous solution of terazosin hydrochloride, but the decrease was not significant.

As is apparent from the results shown in Fig. 2 (for non-treated eyes), no significant change was observed in intraocular pressure of the untreated eyes of the animals in any group treated with the test drug. Therefore, it may be concluded that terazosin hydrochloride does not aifect the other non-treated eyes . Test Example 2

Effect of terazosin hydrochloride dihydrate instillation on pupil diameter in pigmented rabbits:

In each of the sixty rabbits which were given 50 μl of each test drug or physiological saline to one eye (with the other untreated) under Test Example 1, the pupil diameter was measured for both eyes using a micrometer caliper before instillation and 0.5, 1, 2 and 4 hours after topical application of each test drug or physiological saline.

Changes in pupil diameter in the eyes treated with each test drug and physiological saline are shown in Fig. 3. As is evident from the results shown in Fig. 3, the pupil diameter of the eyes treated with each of the test drugs varied within a normal range, and no significant change in the pupil diameter was found in any groups. Therefore, it can be concluded that terazosin hydrochloride has no effect on the pupil diameter. Test Example 3

Comparison of a reduction of intraocular pressure caused by instillation of terazosin hydrochloride dihydrate with that caused by a positive control drug (0.5 % timolol maleate ophthalmic solution) in pigmented rabbits with normal intraocular pressure: In each of ten rabbits bred in the same manner as that described in the above Test Example 1, 0.5% timolol maleate ophthalmic solution (50 μl) as a positive control drug was applied to one eye and physiological saline (50 μl) to the other eye. The intraocular pressure was measured for both eyes using PTG before instillation and 0.5, 1, 2, 4, 6 and 8 hours after topical application of each solution; The results are shown in Fig. 4.

As is apparent from the results shown in Fig. 4, instillation of the positive control, 0.5% timolol maleate ophthalmic solution, caused only a slight degree of maximum decrease (2.5 mmHg) in intraocular pressure one hour after application, while no significant change was observed in the intraocular pressure in comparison with that for physiological saline-treated eyes.

The reduction of intraocular pressure caused by topical application of each test drug or 0.5 % timolol maleate ophthalmic solution in pigmented rabbits with normal intraocular pressure were compared in terms of areas under curves (AUC) of time from the first instillation to 8 hours after then, with the intraocular pressure before topical application being defined as a baseline value. The results are shown in Fig. 5.

As is clear from the results shown in Fig. 5, terazosin hydrochloride produced a concentration-dependent and significant reduction of intraocular pressure in pigmented rabbits with normal intraocular pressure within the range of concentrations from 0.003% to 0.3%. The intraocular pressure reducing activity at the concentration of 0.1% proved to be higher than that of the 0.5% timolol maleate ophthalmic solution.

Test Example 4

(1) Acute toxicity test of terazosin hydrochloride in mice, rats and dogs: The acute toxicity (expressed as a value of 50% lethal dose (LD₅₀)) of terazosin hydrochloride administered via oral, subcutaneous and intravenous routes was examined in ICR mice and Wistar rats. The lethal dose of terazosin hydrochloride in oral administration was also examined in beagle dogs.

Terazosin hydrochloride suspended in tragacanth was given orally to mice and rats by an oral gavage. Mice and rats were also treated with terazosin hydrochloride dissolved in physiological saline by subcutaneous or intravenous injection into the tail vein using a syringe. In addition^', gelatin capsules packed with terazosin hydrochloride were used for oral administration to dogs. The results are shown in Table 1 Table 1

LD₅ o (mg/kg) Lethal dose (mg/kg) mouse rat dog male female male female male female

Oral administration >8000 >8000 >8000 >8000 700 700

Subcutaneous administration 1523 956 1163 1050 - -

Intravenous administration 237 262 350 361 - -

(2) Test for ocular local toxicity of terazosin hydrochloride dihydrate topically applied in the form of 0.03%, 0.1% and 0.3% ophthalmic solution for 28 consecutive days in rabbits:

Twenty-four male Japanese white rabbits (6 rabbits per group) were used for this experiment. As a test drug, 0.03% terazosin hydrochloride ophthalmic solution, 0.1 % terazosin hydrochloride ophthalmic solution, and 0.3% terazosin hydrochloride ophthalmic solution were used. As a control, physiological saline was used. Each of the test drugs or physiological saline was instilled into the right eye at a dose of one drop (0.05 ml) four times a day at 3-hour intervals for 28 consecutive days. Thus, their ocular toxicity was evaluated in terms of the items mentioned below. In each rabbit, the left eye was not treated. Observation was done on the following items (1) to (6):

(1) Death and general conditions;

All the animals were observed daily for death and general conditions .

(2) Measurement of body weight and food consumption;

The animals were weighed and the food consumption was determined weekly.

(3) Gross observation of the anterior ocular segment; Based on the modified Draize method, gross observation of the anterior ocular segment was carried out weekly.

(4) Corneal test

The cornea was observed weekly using a test paper impregnated with fluorescein.

(5) Evaluation of the corneal epithelium using a scanning electron microscope;

After instillation of each test drug, the morphology of the corneal epithelium was observed using a scanning electron microscope.

(6) Evaluation of the cornea, conjunctiva and retina using an optical microscope;

After instillation of each test drug, microscopic examinations of the cornea, conjunctiva and retina were performed with an optical microscope. As a result, (1) no dead animals and no abnormalities in general conditions, (2) no abnormality in body weight and food consumption were observed in any of the groups which were treated with the 0.03%, 0.1% and 0.3% terazosin hydrochloride ophthalmic solutions during the period of application of these test drugs. (3) Gross observation of the anterior ocular segment revealed no abnormality related to any test drug, except that very slight redness of the conjunctiva, which was evaluated as normal, was observed in the treated eyes of some test animals. Furthermore, (4) corneal test, (5) evaluation of the corneal epithelium under a scanning electron microscope, and (6) evaluation of the cornea, conjunctiva and retina under an optical microscope also showed no abnormalities related to any test drug. The above results of the various tests demonstrated that the pharmaceutical composition of the present invention containing terazosin hydrochloride has no effect on the fellow (i.e., non-treated) eye or the pupil diameter, and has few side effects (toxicity) as well as excellent intraocular pressure reducing activity at a low concentration. The pharmaceutical composition of the present invention is thus a clinically very safe drug.

As described above, the pharmaceutical composition of the present invention can advantageously be used for the treatment of various types of glaucoma because of its excellent intraocular pressure reducing activity at a low concentration and its low toxicity.

Claims

1. A pharmaceutical composition for treating glaucoma which comprises (± )-4-amino-2-[4-(tetrahydro-2- furoyl)-l-piperazinyl]-6 , 7-dimethoxyquinazoline of the formula:

2. The pharmaceutical composition according to claim 1, which is an ophthalmic solution.

3. The pharmaceutical composition according to claim 1, which is an ophthalmic ointment.

4. A process for producing a pharmaceutical composition according to claim 1, which comprises mixing (±)- 4-amino-2- [ 4- ( tetrahydro-2-furoyl )-l-piperazinyl]-6,7- dimethoxyquinazoline or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

5. A method of treating glaucoma in a mammal in need thereof which comprises administering to such mammal an effective amount of (+)-4-amino-2-[4-(tetrahydro-2-furoyl)-l- piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof.

6. Use of (+)-4-amino-2-[4-(tetrahydro-2-furoyl)-l- piperazinyl]-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for treating glaucoma.