Therapeutic agent for gait disturbance

Abstract

The present invention relates to a therapeutic agent for a gait disturbance of a patient associated with an ischemic disease, the therapeutic agent containing, as an active ingredient, a heterocyclic derivative represented by general formula (1) or a pharmaceutically acceptable salt thereof. In formula (1), R1 and R2, which may be the same or different, each represent aryl that may be substituted; R3 and R4, which may be the same or different, each represent a hydrogen atom or alkyl; R5 represents a hydrogen atom, alkyl or a halogen atom; Y represents N or N→O; A represents NR6 and R6 represents a hydrogen atom, alkyl or the like; D represents alkylene or alkenylene that may be substituted with hydroxy; E represents phenylene or a single bond; G represents O, S, or the like; and Q represents carboxy, alkoxycarbonyl, or the like.

Description

Gait disorder treatment

[0001] The present invention relates to a therapeutic agent for gait disturbance in patients with ischemic disease, which comprises, as an active ingredient, a heterocyclic derivative represented by the following general formula (1) (hereinafter referred to as "the heterocyclic derivative (1)") or a pharmaceutically acceptable salt thereof:

[0002]

[0003] In formula (1), R １ , R ２ are the same or different and represent aryl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano, and nitro; R ３ , R ４ are the same or different and represent a hydrogen atom or alkyl; R ５ represents a hydrogen atom, an alkyl atom, or a halogen atom; Y represents N or N→O; A represents NR ６ represents R ６ represents a hydrogen atom, an alkyl, an alkenyl, or a cycloalkyl; D represents an alkylene or alkenylene optionally substituted with hydroxy, or A and D together represent a divalent group represented by the following formula (2):

[0004]

[0005] [In formula (2), r represents an integer of 0 to 2, q represents 2 or 3, and t represents an integer of 0 to 4.] E represents phenylene or a single bond, or D and E together represent a divalent group represented by the following formula (3):

[0006]

[0007] [In formula (3), u represents an integer of 0 to 2, and v represents 0 or 1.] G represents O, S, SO, or SO ２Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by the following formula (4):

[0008]

[0009] [In formula (4), R ７ represents amino, monoalkylamino, dialkylamino, or hydroxy, or any one of the following groups 1) to 4) which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an alkyl, a haloalkyl, an arylalkyl, an alkoxy, an alkylthio, an alkoxyalkyl, an alkylsulfonyl, hydroxy, an amino, a monoalkylamino, a dialkylamino, a carboxy, a cyano, and a nitro; 1) an alkyl, 2) an aryl, 3) an aryloxy, or 4) a heterocyclic group.

[0010] Gait disorders are caused by neurological or ischemic diseases and significantly reduce the quality of life of patients. Patients with ischemic diseases are prone to blood clots due to reduced blood flow, and when blood flow to the legs in particular is insufficient, symptoms such as a cold sensation, numbness, and pain appear, and if the condition worsens, walking becomes difficult.

[0011] Cilostazol, a PDE3 inhibitor, has been approved in Japan as a drug used to improve various ischemic symptoms, such as ulcers, pain, and coldness, associated with chronic arterial occlusion (Non-Patent Document 1).

[0012] Prostaglandin I ２ Beraprost sodium, a derivative of the drug, has been approved in Japan as a drug used to improve ulcers, pain, and coldness associated with chronic arterial occlusion (Non-Patent Document 2).

[0013] However, neither compound has been approved as a drug for use in improving gait disorders in patients with ischemic disease.

[0014] On the other hand, the heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof is capable of inhibiting prostaglandin I ２It has been described that the heterocyclic derivative (1) is useful as a receptor agonist in the treatment of ischemic diseases, such as pulmonary hypertension and chronic arterial occlusion (Patent Document 1). However, it has not been reported that the heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof improves coldness, numbness, and pain in patients with ischemic diseases, or further improves gait disturbance in patients with ischemic diseases.

[0015] WO 02 / 088084

[0016] Cilostazol package insert Beraprost sodium package insert

[0017] An object of the present invention is to provide a novel therapeutic agent for treating gait disturbance in patients with ischemic disease.

[0018] The present inventors have found that the heterocyclic derivative (1) exhibits antithrombotic activity in rats and can improve gait disturbance caused by ischemia, and have thus completed the present invention.

[0019] One embodiment of the present invention includes, for example, a therapeutic agent for gait disturbance in patients with ischemic disease, which comprises the heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] According to the present invention, it is possible to provide a therapeutic agent for gait disturbance in patients with ischemic disease, which can be used safely.

[0021] Figure 1 shows the effect of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as "Compound A") on improving gait disturbance in a rat ischemic gait disturbance model. The vertical axis represents walking distance (m), and the horizontal axis represents the number of days after surgery (days). In the figure, circles represent the sham-operated group, squares represent the control group, and triangles represent the Compound A-administered group.

[0022] In the heterocyclic derivative (1), for example, R １ , R ２ are the same or different, and are phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, alkyl and alkoxy; R ３ , R ４are the same or different and are a hydrogen atom or an alkyl, and R ５ is a hydrogen atom, Y is N, and A is NR ６ and R ６ is alkyl, D is alkylene, E is a single bond, G is O, Q is carboxy or a group represented by formula (4), and R ７ is preferably a compound in which:

[0023] 1) alkyl, 2) aryl, 3) aryloxy, 4) heterocyclic group.

[0024] Specifically, for example, Compound A and 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (hereinafter referred to as "Compound B") are preferred.

[0025] The "alkyl" in the present invention includes linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl. In particular, alkyl groups having 1 to 4 carbon atoms are preferred.

[0026] In the present invention, the alkyl moiety of "haloalkyl," "arylalkyl," "alkylthio," "alkoxyalkyl," "alkylsulfonyl," "monoalkylamino," "dialkylamino," "monoalkylcarbazoyl," and "dialkylcarbamoyl" can be the same as the alkyl defined above.

[0027] In the present invention, "alkoxy" includes linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, and isohexyloxy. In particular, alkoxy having 1 to 4 carbon atoms is preferred.

[0028] In the present invention, the alkoxy moiety of the "alkoxycarbonyl" and "alkoxyalkyl" may be the same as the above-mentioned alkoxy.

[0029] In the present invention, "alkenyl" includes linear or branched alkenyls having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. Alkenyls having 3 or 4 carbon atoms are particularly preferred.

[0030] In the present invention, "cycloalkyl" includes those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, those having 5 to 7 carbon atoms are preferred.

[0031] In the present invention, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0032] In the present invention, the "aryl" includes those having 6 to 10 carbon atoms, such as phenyl, 1-naphthyl, and 2-naphthyl. Phenyl is particularly preferred.

[0033] In the present invention, the aryl moiety of "arylalkyl" and "aryloxy" can be the same as the aryl described above.

[0034] In the present invention, "alkylene" refers to a straight-chain or branched alkylene having 1 to 8 carbon atoms, such as methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, and octamethylene. Among these, alkylene having 3 to 6 carbon atoms is preferred, and alkylene having 4 carbon atoms is particularly preferred.

[0035] The "alkenylene" in the present invention includes linear or branched alkenylenes having 2 to 8 carbon atoms, such as ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, and 2-hexenylene. Examples of the alkylene include 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene, and 7-octenylene. Among these, alkylenes having 3 to 6 carbon atoms are preferred, and alkylenes having 4 carbon atoms are particularly preferred.

[0036] The "heterocyclic group" in the present invention can be exemplified by the following (1) or (2): (1) A 5- or 6-membered aromatic ring group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, or a benzene-condensed ring thereof, in which when the ring-constituting atom is a nitrogen atom or a sulfur atom, the nitrogen atom or sulfur atom may form an oxide. For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-indolyl, 2-furanyl, 3-furanyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothienyl, 1,3-oxazol-2-yl, 4-isoxazolyl, 2-thiazolyl, 5-thiazolyl, 2-benzothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, and 1,3,5-triazin-2-yl can be mentioned. (2) A 4- to 8-membered saturated ring group or a benzene-fused ring group thereof, which may contain 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms, which may be the same or different, as ring-constituting atoms, and when the ring-constituting atom is a nitrogen atom or a sulfur atom, such a nitrogen atom or sulfur atom may form an oxide. Examples of such groups include piperidino, piperazinyl, 3-methylpiperazin-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, and 2-tetrahydrofuranyl.

[0037] The heterocyclic derivative (1) can be synthesized by the method described in the aforementioned Patent Document 1 (WO 02 / 088084).

[0038] The heterocyclic derivative (1) can be used as a medicine either as a free base or as an acid, but can also be used in the form of a medically acceptable salt by a known method.

[0039] Examples of the "salt" when the present heterocyclic derivative (1) exhibits basicity include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, and salts with organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid.

[0040] When the heterocyclic derivative (1) is acidic, examples of the "salt" include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.

[0041] The heterocyclic derivative (1) exists as geometric isomers (Z- and E-isomers), and each geometric isomer and a mixture thereof are also included in the heterocyclic derivative (1). Furthermore, the heterocyclic derivative (1) also includes one having an asymmetric carbon, and each optical isomer and their racemates are also included in the heterocyclic derivative (1). Optical isomers can be produced by optically resolving the racemate obtained as described above using an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid) by a known method, taking advantage of its basicity, or by using a previously prepared optically active compound as a starting material.

[0042] The therapeutic agent for gait disorders according to the present invention can be used, for example, to improve the walking distance and walking time of patients.

[0043] In one aspect of the present invention, improvement in a patient's walking distance and walking time may include, for example, improvement in maximum and / or pain-free walking time and / or distance.

[0044] In one embodiment of the present invention, the patient is, for example, a patient with ischemic disease, preferably a patient with peripheral arterial disease, more preferably a patient with chronic arterial occlusion or arteriosclerosis obliterans, and even more preferably a patient with arteriosclerosis obliterans.

[0045] In one embodiment of the present invention, the patient with ischemic disease is, for example, a patient classified into at least one selected from Fontaine Classification I to IV, preferably a patient classified into Fontaine Classification II or higher, and more preferably a patient classified into Fontaine Classification II.

[0046] In one embodiment of the present invention, a patient with ischemic disease has, for example, an ankle brachial index (ABI) at rest of 0.99 or less, preferably 0.90 or less.

[0047] The therapeutic agent for gait disorders according to the present invention can contain the heterocyclic derivative (1) as it is or in a pharmaceutically acceptable non-toxic and inert carrier in an amount within the range of 0.01 to 99.5%, preferably within the range of 0.5 to 90%.

[0048] The carrier may be a solid, semi-solid or liquid diluent, a filler or other formulation auxiliary, and one or more of these may be used.

[0049] The therapeutic agent for gait disorders according to the present invention can be in the form of a solid or liquid dosage unit, and can be in any form, such as an oral preparation (e.g., powder, capsule, tablet, sugar-coated preparation, granule, powder, suspension, liquid, syrup, elixir, or troche), or a parenteral preparation (e.g., injection, suppository). It may also be a sustained-release preparation. Among these, oral preparations such as tablets are particularly preferred.

[0050] The powder can be produced by grinding the heterocyclic derivative (1) into an appropriate fine powder.

[0051] Powders can be prepared by crushing the heterocyclic derivative (1) into suitable fine particles and then mixing it with a similarly crushed pharmaceutical carrier, for example, an edible carbohydrate such as starch or mannitol. Optionally, flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, etc. can be added.

[0052] Capsules can be produced by first filling the powdered or powdered formulations prepared as described above, or the granulated formulations described in the tablet section, into capsule shells such as gelatin capsules. Capsules can also be produced by mixing a lubricant or a flow agent, such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, with the powdered or powdered formulation and then filling the capsules. The addition of a disintegrant or solubilizer, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, or sodium carbonate, can improve the efficacy of the pharmaceutical when the capsule is ingested. Alternatively, a fine powder of the heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and then enclosed in a gelatin sheet to form a soft capsule.

[0053] Tablets can be produced by adding an excipient to powdered present heterocyclic derivative (1) to prepare a powder mixture, granulating or slugging it, adding a disintegrant or lubricant, and then compressing the mixture into tablets.

[0054] The powder mixture can be prepared by mixing the appropriately powdered heterocyclic derivative (1) with a diluent or base. If necessary, binders (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retardants (e.g., paraffin), resorbents (e.g., quaternary salts), adsorbents (e.g., bentonite, kaolin), etc. can be added.

[0055] The powder mixture can be first moistened with a binder, such as syrup, starch paste, gum arabic, cellulose solution, or polymer solution, mixed by stirring, and then dried and milled to form granules. Instead of granulating the powder in this manner, it is possible to first run the powder through a tablet press, and then break up the resulting imperfectly formed slugs into granules. The granules thus produced can be lubricated with the addition of stearic acid, a stearate salt, talc, mineral oil, or the like to prevent them from sticking together.

[0056] Alternatively, tablets can be produced by mixing the heterocyclic derivative (1) with a fluid inert carrier and then directly compressing the mixture into tablets, without going through the above-mentioned granulation or slugging steps.

[0057] The tablets thus produced may be film coated or sugar coated. Transparent or translucent protective coatings such as a sealing coating of shellac, coatings of sugar or polymeric materials, and polishing coatings made from wax may also be used.

[0058] Other oral administration preparations, such as liquids, syrups, troches, and elixirs, can also be made into dosage unit forms so that a given amount thereof contains a given amount of the present heterocyclic derivative (1).

[0059] Syrups can be prepared by dissolving the heterocyclic derivative (1) in a suitable flavored aqueous solution, while elixirs can be prepared using a non-toxic alcoholic carrier.

[0060] Suspensions can be prepared by dispersing the heterocyclic derivative (1) in a non-toxic carrier, and if necessary, solubilizers, emulsifiers (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (e.g., peppermint oil, saccharin), etc. can be added.

[0061] If necessary, the dosage unit formulation for oral administration can be microencapsulated. The formulation can also be coated or embedded in a polymer, wax, etc. to provide extended action or sustained release.

[0062] Parenteral preparations can be in the form of liquid dosage units, such as solutions or suspensions, for subcutaneous, intramuscular, or intravenous injection. These parenteral preparations can be prepared by suspending or dissolving a predetermined amount of the heterocyclic derivative (1) in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Non-toxic salts or salt solutions can be added to make the injection isotonic. Stabilizers, preservatives, emulsifiers, etc. can also be added.

[0063] Suppositories can be prepared by dissolving or suspending the heterocyclic derivative (1) in a low-melting, water-soluble or insoluble solid, such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils [e.g., Witepsol (registered trademark)], higher esters (e.g., myristyl palmitate), or mixtures thereof.

[0064] The dosage of the therapeutic agent for gait disorders according to the present invention varies depending on the patient's condition, such as body weight and age, the route of administration, the severity of symptoms, and the like. Generally, for an adult, the amount of the heterocyclic derivative (1) is in the range of 0.001 mg to 100 mg per day, and more preferably in the range of 0.01 mg to 10 mg. In some cases, a lower dose may be sufficient, while in other cases a higher dose may be required. The agent can be administered once to several times a day, or at intervals of one day to several days.

[0065] For example, for adults, the heterocyclic derivative (1) can be orally administered twice daily after meals at a starting dose of 0.1 mg or 0.2 mg, and the maintenance dose can be determined by increasing the dose by 0.2 mg at intervals of 7 days or more up to the maximum tolerated dose while checking the tolerability of the subject. The maximum dose is, for example, 0.8 mg to 1.6 mg, and both doses can be orally administered twice daily after meals.

[0066] The present invention will be explained in more detail below with reference to test examples, but the present invention is not limited to the scope shown below.

[0067] Test Example 1: FeCl in rats ３Antithrombotic Effect in Induced Thrombosis Model (1) Method for Preparing Vehicle Methylcellulose (Metolose, SM-400, Shin-Etsu Chemical Co., Ltd.) was dissolved in distilled water to prepare a 0.5 w / v % aqueous methylcellulose solution.

[0068] (2) Preparation of Drug Solutions (a) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (Compound A) A 10 mg / mL suspension of Compound A in 0.5 w / v% aqueous methylcellulose solution was prepared by adding 0.5 w / v% aqueous methylcellulose solution to Compound A. (b) Beraprost Sodium A 1.0 mg / mL suspension of beraprost sodium in 0.5 w / v% aqueous methylcellulose solution was prepared by adding 0.5 w / v% aqueous methylcellulose solution to Beraprost sodium. (c) Cilostazol A 150 or 50 mg / mL suspension of cilostazol was prepared by adding 0.5 w / v% aqueous methylcellulose solution to Cilostazol.

[0069] (3) Test method Urethane (Wako Pure Chemical Industries, Ltd.) was dissolved in saline (Otsuka Pharmaceutical Factory) to prepare a 0.3 g / mL solution. Rats were anesthetized by subcutaneously administering 4 mL of the urethane saline solution per kg of body weight (1.2 g / kg). If the anesthetic effect was insufficient, the dose was increased by approximately 10% of the initial dose. Male Wistar rats aged 9 to 10 weeks were used.

[0070] The abdomen of the rat was incised to expose the duodenum, and the drugs were administered at a dose of 1 mL / kg for Compound A and beraprost sodium, and 2 mL / kg for cilostazol, using a 26G needle and syringe 2-3 mm downstream from the boundary between the stomach and duodenum.

[0071] The skin of the right thigh of the rat was incised, the femoral artery was exposed, and the vein and nerve were dissected. Parafilm was placed under the dissected femoral artery to completely separate the femoral artery, vein, and nerve. The probe of a laser Doppler flowmeter (ALF21, Advance) was placed on the femoral artery to begin measuring blood flow (mL / min / g).

[0072] The compound A administration group received 10 w / w% FeCl 60 minutes after administration, the beraprost sodium administration group received 30 minutes after administration, and the cilostazol administration group received 120 minutes after administration. ３ A filter paper (2 mm x 5 mm) soaked in the aqueous solution was placed in the femoral artery, and changes in blood flow were recorded using a biometric data processing system (FLO-WB, Omega Wave Co., Ltd.).

[0073] (4) Results In the vehicle-administered control group, blood vessels were occluded an average of approximately 12 to 15 minutes after thrombus formation was induced. On the other hand, in the group administered 10 mg / kg of compound A, administration 60 minutes before thrombus formation significantly extended the vascular occlusion time to approximately 22 minutes. In the group administered 1 mg / kg of beraprost sodium, administration 30 minutes before thrombus formation significantly extended the occlusion time to approximately 43 minutes. In the group administered 0.3 mg / kg of beraprost sodium, the occlusion time was not extended, and a prolonged decrease in blood pressure (25%) was observed. Cilostazol did not extend the occlusion time at either dose.

[0074] Test Example 2: Gait improvement in a rat ischemic gait disorder model (1) Test method Wistar rats (male, 7 weeks old) (Charles River Japan) were subjected to walking training using a treadmill (MK-680, Muromachi Kikai Co., Ltd.) for three consecutive days, 6, 5, and 4 days before surgery. The baseline walking distance was measured on the day before surgery, and the animals were divided into groups and underwent either a sham surgery or the iliac artery ligation surgery described in i) below.

[0075] After the surgery, the sham-operated group and the control group were given a 0.5 w / v% aqueous methylcellulose solution, and the drug-administered group was given a suspension containing 0.6 mg / mL of compound A (vehicle: 0.5 w / v% aqueous methylcellulose solution). Starting one day after the surgery, compound A (3 mg / kg) was orally administered twice daily for 9 days.

[0076] The walking time was measured 3 days, 7 days, and 10 days after surgery, and the walking distance was calculated based on the measured walking time.

[0077] i) Iliac Artery Ligation Surgery Method Rats were anesthetized by intraperitoneal administration of 50 mg / kg pentobarbital sodium (Somnopentyl®, Schering-Plough Animal Health). If anesthesia was insufficient, additional Somnopentyl® was administered in 0.02-0.03 mL increments (pentobarbital sodium amount: 1.3-1.9 mg). Under anesthesia, the abdomen was incised along the midline, and the left and right common iliac arteries were exposed. Sutures (Nescosture Silk Blade No. 4, Alfresa Pharma) were placed around the common iliac arteries on both sides, and the central side of each suture was ligated at one site each using a ligation clip (Weck Hemoclip, small, Teleflex Medical). The left and right iliac arteries were then ligated at one site each using sutures. After ligation, the peritoneum and muscle layer of the midline abdominal incision were sutured with sutures, and the skin was sutured. An appropriate amount of Terramycin ointment (containing oxytetracycline hydrochloride and polymyxin B sulfate, Pfizer) was applied to the sutured area, and Vixillin® S for injection (50 mg potency of ampicillin sodium, 50 mg potency of cloxacillin sodium, Meiji Seika Kaisha) was dissolved in 1 mL of physiological saline (Otsuka Pharmaceutical Factory), and 0.1 mL of this solution was injected intramuscularly into the thigh. In the sham-operated group, both common iliac arteries were similarly exposed and sutured, but no ligation was performed. After the sutures were removed, the abdomen was closed. The iliac artery ligation was performed by the data manager, and this information was not disclosed to the walking test personnel until the end of the study.

[0078] ii) Method for Measuring Walking Time: The speed of the treadmill belt was increased in 5 m / min increments from 15 m / min to 35 m / min every 3 minutes. The time at which the rat stepped onto the electrical stimulation board at the rear end of the belt was recorded as the dropout time, and the time it took for the rat to drop out five times was recorded as the walking time. The walking test was performed by two testers. Simultaneously with the start of the treadmill, the start buttons of stopwatches (S058, Seiko S-Yard) installed on each of the five lanes were pressed, and the dropout times were recorded as split times. After the measurement, the dropout times were recorded in the walking test record. The measurement was performed blind so that the testers could not identify which group each rat belonged to.

[0079] iii) Walking training method In order to acclimate the rats to walking on a treadmill, walking training was performed 6, 5, and 4 days before surgery, and individuals suitable for walking on a treadmill were selected during this period. Rats that refused to walk during walking training or frequently dropped out or turned around were excluded from use as they were deemed unsuitable for the treadmill walking test.

[0080] (2) Results As shown in FIG. 1, administration of Compound A significantly improved the gait disturbance caused by ischemia due to iliac artery ligation.

[0081] The control group was evaluated by t-test or Welch test compared to the sham-operated group (##: p<0.01), and the drug-administered group was evaluated by t-test compared to the control group (**: p<0.01).

[0082] Test Example 3: Improvement of gait disturbance in patients with arteriosclerosis obliterans In a placebo-controlled, double-blind comparative study, Japanese patients with arteriosclerosis obliterans (selected based on resting ABI, etc.) were administered a placebo or 0.1 to 1.6 mg of selexipag twice daily for 24 to 36 weeks (dose titration period: 8 to 20 weeks, dose maintenance period: 16 weeks).

[0083] Improvement in the patient's walking disorder was confirmed using a treadmill, including maximum walking time (Gartner method).

Claims

1. The composition contains 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid or 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, or a medicamentarily acceptable salt thereof as an active ingredient, A therapeutic agent for gait disturbance administered to patients with ischemic disease, starting with administering 0.1 mg or 0.2 mg of the active ingredient twice a day, and increasing the dose by 0.2 mg at intervals of 7 days or more up to the maximum tolerated dose.

2. A therapeutic agent for gait disorders as described in claim 1, having a maximum dose of 0.8 mg to 1.6 mg.

3. A composition comprising 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid or 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, or a medicamentarily acceptable salt thereof as an active ingredient, A therapeutic agent for gait disturbance, which is administered to a patient with ischemic disease in an amount of 0.1 to 1.6 mg of the active ingredient twice a day for 24 to 36 weeks.

4. A therapeutic agent for treating walking disorders as described in claim 3, wherein the dose adjustment period of the active ingredient is 8 to 20 weeks.

5. A therapeutic agent for gait disorders as described in claim 3 or 4, wherein the dose maintenance period of the active ingredient is 16 weeks.

6. A therapeutic agent for a gait disorder described in any one of claims 1 to 5, containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide or a pharma- ceutical acceptable salt thereof as an active ingredient.

7. A therapeutic agent for gait disturbance described in any one of claims 1 to 6, wherein the patient with ischemic disease is a patient with chronic arterial occlusion disease or obliterative arteriosclerosis.

8. The therapeutic agent for gait disturbance according to any one of claims 1 to 7, wherein the patient suffering from an ischemic disease is a patient suffering from arteriosclerosis obliterans.

9. The therapeutic agent for gait disturbance according to claim 8, wherein the patient with arteriosclerosis obliterans is a patient classified into at least one selected from Fontaine classification I to IV.

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