Technical field
[0001]
　The present invention relates to a drug therapy for the prevention or treatment of glaucoma or ocular hypertension.
Background technique
[0002]
　The glaucoma, intraocular pressure rises due to various etiologies, the optic nerve is impaired atrophy, Kitashi the abnormal visual field, visual acuity is a disease decreases. For once not the optic nerve that caused the atrophy was restored, on that leads to blindness and allowed to stand for glaucoma, even if successfully treated remain in the status quo, recovery is an intractable disease can not be expected. Although not accompanied abnormal visual field is in the long term it is likely to develop into glaucoma ocular hypertension also fraught with similar risks.
[0003]
　Glaucoma is congenital glaucoma, secondary glaucoma, are divided into three types of primary glaucoma. Congenital glaucoma has stunted growth in birth corner, is glaucoma that occurs in order to drainage of the aqueous humor is impeded. Secondary glaucoma glaucoma caused by obvious causes such as inflammation and injury, others have caused eye injuries uveitis and eyes, bleeding diabetes, even by such long-term use of steroid hormones used in the treatment of other diseases to develop. Primary glaucoma is a generic term for what the cause is not clear, often seen in people of middle-aged and elderly, is the most common type among glaucoma. Primary glaucoma and secondary glaucoma, by clogging how the aqueous humor flow, is further divided into two types of open-angle glaucoma angle-closure glaucoma. Further, without an increase in intraocular pressure, but there are many patients who develop normal tension glaucoma, primary goal of glaucoma treatment anyway is to lower the intraocular pressure.
[0004]
　Method of treating glaucoma, or if the angle-closure glaucoma patients when uncontrolled intraocular pressure has caused an acute glaucoma attack in drugs, laser treatment (laser trabeculoplasty) or surgical treatment (trabeculectomy Although surgery and trabeculotomy), or the like is performed, drug therapy is used as the first choice. The drug therapy of glaucoma, sympathomimetic agents (nonselective stimulants such as epinephrine, apraclonidine, alpha, such as brimonidine 2 stimulant), sympatholytic agents (timolol, befunolol, carteolol, nipradilol, Betakisoru, levobunolol , beta-blockers such as Mechipuranoru (Metipranolol), alpha such bunazosin hydrochloride 1 blockers), parasympathomimetics (pilocarpine, etc.), carbonic anhydrase inhibitors (acetazolamide, etc.), prostaglandins (isopropyl unoprostone, latanoprost, travoprost, bimatoprost, tafluprost and the like) and the like are used.
[0005]
　Among these agents, brimonidine is the type of drugs that lower the intraocular pressure by promoting aqueous outflow through the inhibition and uveoscleral outflow tract aqueous production, clinically and is widely (et Document 1).
[0006]
　On the other hand, as a candidate for glaucoma based therapeutics novel mechanism of action machine, Rho kinase inhibitors have been found (Patent Documents 1-2). Rho kinase inhibitors, lowers the intraocular pressure by promoting aqueous outflow from the trabecular meshwork outflow pathway (Non-Patent Document 2), suggested that by further its action cytoskeletal changes in trabecular meshwork cells is (non-Patent documents 2 and 3).
[0007]
　Furthermore, the glaucoma or ocular hypertension, for the purpose of enhancing intraocular pressure, has also been possible to use a combination of drugs having intraocular pressure lowering effect. For example, in Non-Patent Document 4 discloses that the combined use of eye pressure lowering laxative action mechanism wide. Also, alpha and Rho inhibitor K-115 2 there is a report that was evaluated in mice reduction of intraocular pressure effects of the combination of stimulant brimonidine (Non-Patent Document 5) has a combination of K-115 in Burimojinin administration 1.5 hours after the conditions are as were no significant intraocular pressure lowering action for a single administration of K-115.
[0008]
　Therapeutic agent or method of treating glaucoma or ocular hypertension is still hard to say that satisfactory in terms of potency and duration of intraocular pressure effect. In particular angle closure glaucoma patients glaucoma attack, special conditions such as post-neovascular glaucoma and surgery, may become very high intraocular pressure, must be reduced as soon as possible intraocular pressure in order to suppress the disorder of optic nerve cells . From such a background, the intraocular pressure-lowering effect there is a more immediate effect is a powerful therapeutic agent for glaucoma has been demanded.
CITATION
Patent Literature
[0009]
Patent Document 1: WO 00/09162 Patent
Patent Document 2: JP-A 11-349482 JP
[0010]
Non-Patent Document 1: Arch. Ophthalmol. , 113 (12), 1514-1517 (1995)
Non-Patent Document 2: IOVS, 42 (1) , 137-144 (2001)
Non-Patent Document 3: IOVS, 42 (5) , 1029-1037 (2001)
Non-Patent Document 4: Exp. Opin. Emer. Drugs, 12 (2), 313-327 (2007)
Non-Patent Document 5: Japanese back of the eye 27 would Pharmacological gist set, typically 18,59 (2007)
Summary of the Invention
Problems that the Invention is to Solve
[0011]
　The present invention, intraocular pressure lowering action has potent fast-acting and its duration is prolonged, relates to providing a drug therapy for the prevention or treatment of glaucoma or ocular hypertension.
Means for Solving the Problems
[0012]
　The present inventors have made intensive studies to solve the above problems, (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (hereinafter, sometimes referred to as compound 1) or a salt thereof, or a α a solvate thereof 2 by administering a combination of a brimonidine is stimulant, intraocular pressure-lowering effect with a powerful and fast-acting is exhibited , its duration was found to be extended and. In rabbits, alpha 2 stimulants prior to intraocular pressure effects of eye side, alpha present in peripheral nerve synapses 1 occurs transient increase in intraocular pressure effect based on adrenergic, then local eye of adrenaline alpha 2 intraocular pressure is said to decrease due to an increase in aqueous humor outflow from the receptor inhibition and uveal strength of aqueous humor production film outflow path through (Current eye research, 5 (9 ), 665-676 ( 1986), Ann NY Acad Sci, 763, 78-95 (1995)). Therefore, when combined with Compound 1 and Burimojinin, short by strong intraocular pressure effect is expressed is quite surprising.
[0013]
　Specifically, the present invention according to the following inventions.
　1) for glaucoma prevention or treatment, (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt or solvate thereof and Arufa 2 combination of a stimulant.
　2) alpha 2 agonists is brimonidine or a combination of the above 1) is a salt or solvate thereof.
　3) Formulation above 1) or 2) a combination of.
　4) (S) - (- ) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-comprising homopiperazine agent and alpha 2 agent comprising a stimulant a kit comprising a combination of the above 1) or 2).
　5) for ocular hypertension prevention or treatment, (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvent hydrate and Arufa 2 combination with a stimulant.
　6) alpha 2 agonists are a combination of the 5) it is brimonidine or a salt or solvate thereof.
　7) a formulation combination of the above 5) or 6).
　8) (S) - (- ) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-comprising homopiperazine agent and alpha 2 agent comprising a stimulant a kit comprising a combination of the above 5) or 6).
　9) As a first agent (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine administering a formulation comprising a then a second α as agents 2 combination of the above 5) or 6) a kit comprising the steps of administering a formulation comprising a stimulant.
　10) (S) - (- ) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and alpha 2 combining the stimulant glaucoma prevention or treatment method which comprises administering Te.
　11) (S) - (- ) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and alpha 2 combining the stimulant ocular hypertension preventive or therapeutic method which comprises administering Te.
　12) for producing glaucoma prophylactic or therapeutic agent, S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvent hydrate and Arufa 2 combination with a stimulant.
　13) for producing ocular hypertension preventive or therapeutic agent, S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, or solvates and α of 2 combination of stimulant.
Effect of the invention
[0014]
　According to the present invention, the intraocular pressure lowering effect has a strong fast acting, and can be the duration to provide a preventive or therapeutic means is extended glaucoma or ocular hypertension.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015]
FIG. 1 is a graph showing the time course of intraocular pressure in each dose group. Intraocular pressure indicated by the change value from the initial intraocular pressure (mean ± standard error). □: brimonidine alone administration group, ○: (S) - (-) - Compound 1 alone administration group, ●: brimonidine and Compound 1 in combination administration group, statistical analysis: # p <0.05, ## p <0.01 vs. compound 1 group, $$$ p <0.001 vs. brimonidine group.
DESCRIPTION OF THE INVENTION
[0016]
　Used in the present invention (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (Compound 1) are substance P antagonism, leukotriene D4 antagonism and a compound having a Rho kinase inhibitory action, known methods, for example, can be prepared by methods described in WO 99/20620.
[0017]
　The salt of compound 1, such as hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, salts of inorganic acids such as hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and salts with organic acids such as camphorsulfonic acid, especially the hydrochloride, are preferred.
[0018]
　Compound 1 or a salt thereof can also be present as a hydrate or solvate not unsolvated form only. Hydrates are preferred, in the present invention is intended to include all crystalline forms and hydrated or solvate.
[0019]
　On the other hand, alpha 2 as the stimulant may be one useful in treating glaucoma have intraocular pressure lowering action. Α having a reducing intraocular pressure 2 Examples of stimulants, clonidine, apraclonidine, brimonidine, and the like. For example Burimojinin is, Bioorganic & Medicinal Chemistry Letters (1995 ), 5 (19), can be prepared by known methods described in 2255-8, and the like.
[0020]
　The salt of Burimojinin, such as hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, salts of inorganic acids such as hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and salts with organic acids such as camphorsulfonic acid, particularly tartaric acid is preferred.
[0021]
　Burimojinin or a salt thereof can also be present as a hydrate or solvate not unsolvated form only. Hydrates are preferred, in the present invention is intended to include all crystalline forms and hydrated or solvate.
[0022]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt or solvate thereof (compound 1) and alpha 2 -agonist and If combined using, as shown in examples described later, immediately powerful and synergistic intraocular pressure lowering action after dosing is observed. In addition, this powerful intraocular pressure-lowering effect lasts for several hours. Thus, these combinations are useful as a preventive or therapeutic agent for glaucoma or ocular hypertension, these combined administration are useful as medication for preventing or treating glaucoma and ocular hypertension. Examples of the glaucoma, for example, primary open angle glaucoma, normal tension glaucoma, aqueous humor production excessive glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid glaucoma, cystic glaucoma of the lens, dye glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, and the like. In addition, the ocular hypertension, also called ocular hypertension, optic nerve refers to the symptoms that indicate a clear lesion is not observed despite abnormally high intraocular pressure, high intraocular pressure expression, such as post-operative, many ocular pressure state is the inclusion of.
[0023]
　, For the prevention or treatment of glaucoma or ocular hypertension of the present invention (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof (compound 1) and alpha 2 in combination with stimulants, compounding agent (glaucoma prophylactic or therapeutic agents, prophylactic or therapeutic agent for ocular hypertension), in each of the effective amount suitable compounding ratio also those that have been formulated in one dosage form, or may be a kit to be used separately at a same time or interval obtained by formulating an agent containing an effective dose of each alone.
[0024]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt or solvate thereof (compound 1) and alpha 2 agonists and If the formulated separately may be respectively the preparation of a formulation according to known methods. For example, (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or formulation of a salt or solvate thereof, the Patent Document 1 and it can be prepared by reference to formulation examples described in WO 97/23222. Also, alpha 2 if stimulant brimonidine, can be prepared by reference to Formulation Examples described in WO 92/13855 and the like. It is also possible to use commercially available preparations for brimonidine.
[0025]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, or a α solvate thereof 2 formulations were formulated and stimulant even when preparing, it can be prepared according to known methods. For example eye drops, isotonic agents, buffering agents, surfactants, and used as needed, such as preservatives, can be prepared. pH may, if the acceptable range for ophthalmic formulation, the range of pH 4 ~ 8 are preferred.
[0026]
　The formulations, ophthalmic preparations, particularly preferably used as the eye drop, such eye drops, aqueous ophthalmic solution, non-aqueous eye drops, suspension eye drop agents, emulsifiable eye drops, either eye ointments good. Such formulations, as a composition suitable for administration form, a pharmaceutically acceptable carrier as needed, for example, tonicity agents, chelating agents, stabilizing agents, pH adjusting agents, preservatives, antioxidants , solubilizing agents, and formulating a viscosity-increasing agent such as, it can be prepared by known (formulation) to the person skilled in the art.
[0027]
　When preparing eye drops, for example, sterile purified water desired above components, the aqueous solvent such as physiological saline, or cottonseed oil, soybean oil, sesame oil, dissolved or suspended in non-aqueous solvents vegetable oils such peanut oil and the like , adjusted to a predetermined osmotic pressure, it can be carried out by subjecting the sterilization filtration sterilization or the like. In the case of preparing ophthalmic ointments, in addition to the various components may include an ointment base. Examples of the ointment bases, but it is not limited to, petrolatum, liquid paraffin, oil base such as polyethylene; oil phase and emulsion base and the water phase is emulsified by a surfactant or the like; hydroxypropylmethylcellulose, carboxymethylcellulose , water-soluble base such as made of polyethylene glycol, and the like preferably.
[0028]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or α of a salt thereof or a solvate thereof 2 The combination of stimulant, If a kit for the prevention or treatment of glaucoma or ocular hypertension were the as formulated above (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1 , 4-homopiperazine or a drug comprising a salt thereof or pharmaceutical and prostaglandins comprising a solvate thereof separately packaged respectively, the pharmaceutical formulation of each from each package at the time of administration can be designed to be used is taken out. Further, each of the pharmaceutical formulations, it is also possible to keep the package in a form suitable for coadministration at each time.
[0029]
　（Ｓ）－（－）－１－（４－フルオロ－５－イソキノリンスルホニル）－２－メチル－１，４－ホモピペラジン若しくはその塩又はそれらの溶媒和物とα2刺激薬とを組み合わせて緑内障若しくは高眼圧症の予防又は治療のために用いる場合、その投与量は、患者の体重、年齢、性別、症状、投与形態及び投与回数等によって異なるが、通常は成人に対して、（Ｓ）－（－）－１－（４－フルオロ－５－イソキノリンスルホニル）－２－メチル－１，４－ホモピペラジン若しくはその塩又はそれらの溶媒和物として、１日０．０２５～１００００μｇ、好ましくは０．０２５～２０００μｇ、より好ましくは０．１～２０００μｇの範囲が挙げられ、α2刺激薬として、１日３～１００００μｇ、好ましくは３０～３０００μｇの範囲が挙げられる。α2刺激薬について具体例を挙げれば、例えばブリモニジンの場合１日３０～３００μｇが通常使用される。
　尚、（Ｓ）－（－）－１－（４－フルオロ－５－イソキノリンスルホニル）－２－メチル－１，４－ホモピペラジン若しくはその塩又はそれらの溶媒和物とα2刺激薬とを配合した製剤として投与する場合には、１日の投与量が上記の各成分の量またはそれ以下になるように、配合割合を適宜選択した製剤を調製すればよい。
[0030]
　Moreover, the administration frequency is not particularly limited, but is preferably administered in single or divided doses, in the case of liquid eye drops, may be one to several drops instilled once. If the kit may be administered alone formulation simultaneously or may be administered at an interval of 5 minutes to 24 hours. When administered at intervals as a first agent (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine comprising the formulation administered, then α as the second agent 2 preferably as the procedure of administering the formulation comprising a stimulant.
　The present invention will be described below in more detail, the present invention is not limited thereto.
Example
[0031]
　Example 1 (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (Compound 1) and alpha 2 usefulness in combination with stimulant the investigate and compare the effect on reducing intraocular pressure for both drugs were administered alone or in combination to laboratory animals.
[0032]
1. Preparation of test compound solution
　A. Preparation of the solution of Compound 1
　(S) - (-) - 1-a (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine monohydrochloride dihydrate in saline after dissolving, sodium dihydrogen phosphate, by addition of sodium hydroxide solution to neutralize the (pH 6.0), to prepare a solution of compound 1 of the desired concentration.
　B. alpha 2 receptors prepared agonists such
　commercial brimonidine (Senju Pharmaceutical Co., Aifagan ophthalmic solution 0.1%) was used as such.
[0033]
2. Test method
　The compound 1 and brimonidine was examined intraocular pressure effects when coadministered. As a control, it was also examined intraocular pressure effects when the compound 1 was administered alone alone or brimonidine.
[0034]
　A. Drug and animals used in the test
　solution of Compound 1: 0.4% solution (instillation volume: 50 [mu] L)
　brimonidine 0.1% ophthalmic solution (eye drops volume: 50 [mu] L)
　Experimental animals: White rabbits (sex: male, group 10 mice )
　B. Administration and measurement method
(1) co-administration of both agents
　1) to 4% oxybuprocaine hydrochloride ophthalmic solution (trade name: a Benokishiru 0.4% solution) in both eyes of the experimental animals was one drop instilled topically anesthetized (data the eye-side only).
　2) The intraocular pressure just before test compound solution administration set to the measured initial intraocular pressure.
　3) instilled a solution of compound 1 in one eye of the experimental animals, followed by brimonidine solution was instilled into same eye.
　4) 0.5 hours for both drugs instillation, 1 hour, 2 hours, 3 hours, after instillation and local anesthesia for 4 hours and 0.4% after 5 hours oxybuprocaine hydrochloride ophthalmic solution in both eyes dropwise, intraocular pressure It was measured.
(2) single administration of Compound 1
　performs a single instillation of Compound 1, was tested in the same measurement time as in the above-mentioned combination administration test.
(3) alone brimonidine
　test solution alone administration of the compound 1 instead of the brimonidine, another test was carried out in the same manner as the monotherapy study.
[0035]
3. Results and Discussion
　The results of the tests are shown in Table 1 and Figure 1. Note intraocular pressure showing the change value from the initial intraocular pressure. Further, the statistical processing, Stat Preclinica Client 1.1, using a parametric Tukey multiple comparison.
[0036]
[Table 1]

[0037]
　As seen from Table 1, the combination of Compound 1 and Burimojinin, intraocular pressure effects of immediate was confirmed. Especially in 0.5 hours after instillation, despite the absence of intraocular pressure effects in Burimojinin alone, synergistic and potent intraocular pressure act by 2-drug was expressed. As is clear from FIG. 1, compound 1 and combination group of brimonidine, drug alone administration group, namely, shows excellent intraocular pressure lowering action than Compound 1 administration group or brimonidine administered group, also of action It was also improved sustainability.
　From the above, by combining the compound 1 and brimonidine, it was found that a strong intraocular pressure effect than earlier, as well as improving the prolonged effect obtained.
Industrial Applicability
[0038]
　Of the invention (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and alpha 2 between the stimulant combination, excellent intraocular pressure effects, and has a prolonged effect and immediate, are useful as medicaments for the prevention or treatment of glaucoma or ocular hypertension.

The scope of the claims
[Claim 1]
　For glaucoma prevention or treatment, (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-and homopiperazine or a salt thereof, or a solvate α 2 the combination of the stimulant.
[Claim 2]
　alpha 2 The combination of claim 1 stimulant is brimonidine or a salt or solvate thereof.
[Claim 3]
　The combination according to claim 1 or 2 is a formulation.
[Claim 4]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine agents and α comprising 2 consisting comprising the stimulant drugs the combination according to claim 1 or 2 is a kit.
[Claim 5]
　For ocular hypertension prevention or treatment, (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt or solvate thereof and Arufa 2 combination of a stimulant.
[Claim 6]
　alpha 2 stimulant combination according to claim 5 which is brimonidine or a salt or solvate thereof.
[Claim 7]
　The combination of claim 5 or 6 is formulation.
[8.]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine agents and α comprising 2 consisting comprising the stimulant drugs the combination of claim 5 or 6 is a kit.
[Claim 9]
　A first agent (S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine administering a formulation comprising a then a second agent alpha 2 the combination of claim 5 or 6 is a kit comprising the steps of administering a formulation comprising a stimulant.
[Claim 10]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and alpha 2 in combination with a stimulant administered glaucoma prevention or treatment method characterized by.
[Claim 11]
　(S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and alpha 2 in combination with a stimulant administered ocular hypertension preventive or therapeutic method characterized by.
[Claim 12]
　For the manufacture of glaucoma prophylactic or therapeutic agent, S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt or solvate thereof and Arufa 2 combination of a stimulant.
[Claim 13]
　For the production of ocular hypertension preventive or therapeutic agent, S) - (-) - 1- (4- fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvent hydrate and Arufa 2 combination with a stimulant.