JP7010404B1 - Gait disorder treatment agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for a gait disorder of a patient with an ischemic disease. SOLUTION: The present invention provides a therapeutic agent for gait disorder of a patient with an ischemic disease, which contains a heterocyclic derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. TIFF0007010404000005.tif25114 (R1, R2: substituted / unsubstituted aryl. R3, R4: H, alkyl. R5: H, alkyl, halogen. Y: N, N → O. A: NR6 (R6: H, alkyl, etc.). D: alkylene, alkenylene which may be substituted with hydroxy. E: phenylene, single bond. G: O, S, etc. Q: carboxy, alkoxycarbonyl, etc.) [Selection diagram] None.

Description

The present invention is a heterocyclic derivative represented by the following general formula (1) (hereinafter, “the present heterocyclic derivative (1)).
". ) Or a pharmaceutically acceptable salt thereof as an active ingredient, and the present invention relates to a therapeutic agent for gait disorders in patients with ischemic diseases.

In formula (1), R ¹ and R ² are the same or different, halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy. Represents an aryl optionally substituted with 1 to 3 substituents selected from the group consisting of, cyano and nitro;
R ³ and R ⁴ represent the same or different hydrogen atom or alkyl;
^R5 represents a hydrogen atom, an alkyl or halogen atom;
Y represents N or N → O;
A stands for NR ⁶ and R ⁶ stands for hydrogen atom, alkyl, alkenyl or cycloalkyl;
D represents an alkylene or alkenylene which may be substituted with hydroxy, or A
And D together represent a divalent group represented by the following equation (2);

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

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

[In formula (4), R ⁷ is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl. Represents any of the following groups 1) -4) which may be substituted with 1 to 3 substituents selected from the group consisting of amino, dialkylamino, carboxy, cyano and nitro;
1) Alkyl,
2) Aryl,
3) Aryloxy,
4) Heterocyclic group. ]

Gait disturbance is a disorder caused by neurological diseases and ischemic diseases, and significantly lowers the patient's QOL. Patients with ischemic diseases are prone to thrombosis due to decreased blood flow, and symptoms such as coldness, numbness, and pain appear, especially when the blood flow through the legs is insufficient, and when it worsens, walking becomes difficult.

Cilostazol, a PDE3 inhibitor, has been approved in Japan as a drug used to improve various ischemic symptoms such as ulcers, pain and cooling sensations due to chronic arterial occlusion (
Non-Patent Document 1).

Beraprost sodium, which is a prostaglandin I ₂ derivative, has been approved in Japan as a drug used for improving ulcers, pain and cold sensation associated with chronic arterial occlusion (Non-Patent Document 2).

However, neither compound has been approved as a drug used to improve gait disturbance in patients with ischemic disease.

On the other hand, the heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof is prostaglandin I ₂
It is described that the receptor agonist is useful for the treatment of ischemic diseases such as pulmonary hypertension and chronic arterial occlusion (Patent Document 1). However, the heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof improves cooling sensation, numbness, and pain in patients with ischemic disease.
Furthermore, it has not been reported to improve gait disturbance in patients with ischemic disease.

International Publication No. 02/088084

Cilostazol package insert Beraprost Sodium Package Insert

An object to be solved by the present invention is to provide a therapeutic agent for gait disturbance in a patient with a novel ischemic disease.

The present inventor has found that the present heterocyclic derivative (1) exhibits an antithrombotic effect in rats and can improve gait disturbance due to ischemia, and completed the present invention.

As one aspect of the present invention, for example, a therapeutic agent for gait disturbance in a patient with an ischemic disease, which contains the heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient, can be mentioned.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a therapeutic agent for gait disturbance in a patient with an ischemic disease that can be safely used.

FIG. 1 shows 2- {4- [N- (5,6-diphenylpyrazine-2-yl) -N-isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide in a rat ischemic gait disorder model. , "Compound A") shows the effect of improving gait disturbance. The vertical axis represents the walking distance (m), and the horizontal axis represents the number of postoperative days (days). In the figure, the circles represent the sham surgery group, the square marks represent the control group, and the triangle marks represent the compound A administration group.

In the present heterocyclic derivative (1), for example,
R ¹ and R ² are phenyls which are the same or different and may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, alkyls and alkoxys.
R ³ and R ⁴ are the same or different, hydrogen atom or alkyl.
R ⁵ is a hydrogen atom,
Y is N,
A is NR ⁶ and R ⁶ is alkyl.
D is alkylene and
E is a single bond,
G is O,
Q is a carboxy or a group represented by the formula (4), and R ⁷ is an amino, a monoalkylamino, a dialkylamino, or a hydroxy, or a halogen atom, an alkyl, a haloalkyl, an arylalkyl, an alkoxy, an alkylthio, an alkoxyalkyl. , Alkoxysulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,
A compound which is any of the following groups 1) to 4) which may be substituted with 1 to 3 substituents selected from the group consisting of cyano and nitro is preferable.

1) Alkyl,
2) Aryl,
3) Aryloxy,
4) Heterocyclic group.

Specifically, for example, compound A and 2- {4- [N- (5,6-diphenylpyrazine-).
2-Il) -N-isopropylamino] butyloxy} acetic acid (hereinafter referred to as "Compound B") is preferable.

The "alkyl" in the present invention is a linear or branched chain having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
-Butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl can be mentioned. In particular, those having 1 to 4 carbon atoms are preferable.

Alkyl of "haloalkyl", "arylalkyl", "alkylthio", "alkoxyalkyl", "alkylsulfonyl", "monoalkylamino", "dialkylamino", "monoalkylcarbazoyl" and "dialkylcarbamoyl" in the present invention. As a part, the same thing as the above-mentioned alkyl can be mentioned.

The "alkoxy" in the present invention is a linear or branched chain having 1 to 6 carbon atoms.
For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy can be mentioned. In particular, those having 1 to 4 carbon atoms are preferable.

Examples of the alkoxy portion of the "alkoxycarbonyl" and "alkoxyalkyl" in the present invention include the same alkoxy moieties as described above.

The "alkenyl" in the present invention is a linear or branched chain having 2 to 6 carbon atoms.
For example, 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, 5-hexenyl can be mentioned. .. In particular, those having 3 or 4 carbon atoms are preferable.

Examples of the "cycloalkyl" in the present invention include 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 preferable.

Examples of the "halogen atom" in the present invention include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The "aryl" in the present invention includes those having 6 to 10 carbon atoms, for example, phenyl and 1
-Naftyl and 2-naphthyl can be mentioned. In particular, phenyl is preferred.

Examples of the aryl portion of "arylalkyl" and "aryloxy" in the present invention include the same aryl portions as described above.

The "alkylene" in the present invention is a linear or branched chain having 1 to 8 carbon atoms.
For example, methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene can be mentioned. In particular, those having 3 to 6 carbon atoms are preferable, and those having 4 carbon atoms are particularly preferable.

The "alkenylene" in the present invention includes linear or branched chains having 2 to 8 carbon atoms, for example, ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, and the like. 1-Pentenylen, 2-Pentenylen, 3-Pentenylen,
4-Pentenylene, 4-Methyl-3-Pentenylene, 1-Hexenylene, 2-Hexenylene, 3-Hexenylene, 4-Hexenylene, 5-Hexenylene, 1-Heptenylene, 2-
Heptenilen, 3-Heptenilen, 4-Heptenilen, 5-Heptenilen, 6-Heptenilen, 1-octenilen, 2-octenilen, 3-octenilen, 4-octenilen, 5
-Octenilen, 6-octenilen, 7-octenilen can be mentioned. In particular, those having 3 to 6 carbon atoms are preferable, and those having 4 carbon atoms are particularly preferable.

Examples of the "heterocyclic group" in the present invention include 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 fused ring thereof, wherein the ring-constituting atom is nitrogen. In the case of an atom or a sulfur atom, such a nitrogen atom or a sulfur atom may form an oxide. For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolill, 3-indrill, 2-furanyl, 3-furanyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothienyl, 1,3-oxazol-2. -Il, 4-isooxazolyl, 2-thiazolyl, 5-thiazolyl, 2-benzothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazole-1-yl, 1H-tetrazole-5-yl, 2H-tetrazol-5-yl, 2-pyridyl, 3-pyridyl,
Examples thereof include 4-pyridyl, 3-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, and 1,3,5-triazine-2-yl.
(2) As ring-constituting atoms, nitrogen atom, oxygen atom or sulfur atom are the same or different from 1 to 1.
When a saturated ring group having a 4- to 8-membered ring or a benzene-fused ring group thereof and the ring-constituting atom is a nitrogen atom or a sulfur atom, the nitrogen atom or the sulfur atom contains an oxide. It may be formed. For example, piperidino, piperazineyl, 3-methylpiperazine-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, 2-tetrahydrofuranyl can be mentioned.

The heterocyclic derivative (1) can be synthesized by the method described in Patent Document 1 (Pamphlet No. 02/08884).

The heterocyclic derivative (1) can be used as a pharmaceutical as a free base or acid,
It can also be used in the form of a medically acceptable salt by a known method.

When the heterocyclic derivative (1) exhibits basicity, examples of the "salt" include hydrochloric acid, sulfuric acid, nitrate, phosphoric acid, hydrofluoric acid, or a salt of an inorganic acid of hydrobromic acid, or acetic acid. List organic acid salts of tartrate acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or camphorsulfonic acid. Can be done.

Examples of the "salt" when the heterocyclic derivative (1) is acidic include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.

The heterocyclic derivative (1) has geometric isomers (Z-form and E-form), and each geometric isomer and a mixture thereof are also included in the heterocyclic derivative (1). Further, although some of the present heterocyclic derivatives (1) have asymmetric carbons, each optical isomer and these racemates are also included in the present heterocyclic derivative (1). The optical isomer is an optically active acid (for example, tartaric acid, dibenzoyl tartaric acid, mandelic acid, etc.) by utilizing the basicity of the racemate obtained as described above.
It can be optically resolved by a known method using 10-camphorsulfonic acid), or can be produced by using an optically active compound prepared in advance as a raw material.

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 a patient.

As one aspect of the present invention, the improvement of the walking distance and the walking time of the patient includes, for example, the improvement of the maximum and / or painless walking time and / or the distance.

In one aspect of the invention, the patient is, for example, a patient with ischemic disease, preferably a peripheral arterial disease, more preferably a patient with chronic arterial occlusion or arteriosclerosis obliterans, and even more preferably an occlusion. Patients with sexual arteriosclerosis.

As one aspect of the present invention, patients with ischemic disease may be referred to, for example, from Fontaine Classification I-.
Patients classified into at least one selected from IV, preferably Fontain
Patients classified into e-classification II or higher, more preferably patients classified into Fontaine classification II.

As one aspect of the present invention, a patient with an ischemic disease may be, for example, a resting ABI (ankle).
(Brachial index: ankle-brachial blood pressure ratio) is, for example, 0.99 or less, preferably 0.90 or less.

The therapeutic agent for gait disorders according to the present invention comprises the present heterocyclic derivative (1) as it is or in a pharmaceutically acceptable non-toxic and inert carrier in the range of 0.01 to 99.5%. Preferably 0.
It can be contained in the range of 5 to 90%.

Examples of the carrier include solid, semi-solid or liquid diluents, fillers and other prescribing aids. One or more of these can be used.

The therapeutic agent for walking disorders according to the present invention is a solid or liquid dose unit, such as a powder, a capsule, a tablet, a sugar coating, a granule, a powder, a suspension, a liquid, a syrup, an elixir, or a troche. It can take any form of an orally-administered preparation, an injection, a suppository or the like, which is a parenteral-administered preparation.
It may be a sustained release preparation. Among them, orally-administered preparations such as tablets are particularly preferable.

The powder can be produced by making the present heterocyclic derivative (1) into an appropriate fineness.

The powder can be produced by refining the heterocyclic derivative (1) to an appropriate degree and then mixing it with a similarly finely divided pharmaceutical carrier such as starch, edible carbohydrates such as mannitol. A flavoring agent, a preservative, a dispersant, a coloring agent, a fragrance and the like can be arbitrarily added.

Capsules are first produced by filling the powdered powder, powder, or granules as described in the section of tablets into the outer skin of a capsule such as a gelatin capsule. can do. By mixing lubricants and fluidizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol with powdered powders and powders, and then performing a filling operation. It can also be manufactured. When a capsule is ingested with the addition of disintegrants and solubilizers such as carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, sodium carbonate. The effectiveness of the drug can be improved. Further, the fine powder of the heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped with a gelatin sheet to form a soft capsule.

Tablets are produced by adding an excipient to the powdered present heterocyclic derivative (1) to prepare a powder mixture, granulating or slagging, then adding a disintegrant or lubricant, and then tableting. can do.

The powder mixture can be produced by mixing an appropriately powdered heterocyclic derivative (1) with a diluent or a base. Binders (eg, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retarders (eg, paraffin), reabsorption agents (eg, quaternary salts), as required. Adsorbents (eg bentonite, kaolin) and the like can be added.

The powder mixture can be first moistened with a binder, for example, syrup, starch paste, gum arabic, cellulose solution or polymer substance solution, stirred and mixed, dried and pulverized to form granules. Instead of granulating the powder in this way, it is also possible to first place it in a locker and then crush the resulting incompletely formed slag into granules. To the granules made in this way,
By adding stearic acid, stearate, talc, mineral oil or the like as a lubricant, it is possible to prevent them from adhering to each other.

The tablets can also be produced by directly tableting the heterocyclic derivative (1) after mixing it with a fluidly inert carrier without going through the steps of granulation and slag formation as described above. can.

The tablets thus produced can be film-coated or sugar-coated. A transparent or translucent protective coating consisting of a shellac hermetically sealed coating, a coating of sugar or polymer material and a polishing coating of wax can also be used.

Other orally administered preparations such as liquids, syrups, lozenges and elixirs can also be in dose unit form such that a fixed amount thereof contains a certain amount of the heterocyclic derivative (1).

The syrup agent can be produced by dissolving the present heterocyclic derivative (1) in an appropriate flavor aqueous solution. Elixirs can be prepared by using a non-toxic alcoholic carrier.

The suspending agent can be produced by dispersing the present heterocyclic derivative (1) in a non-toxic carrier. If necessary, solubilizers, emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor-imparting agents (eg, peppermint oil, saccharin) and the like can be added. can.

If desired, dose-based formulations for oral administration can be microencapsulated. The formulation can also be coated or embedded in polymers, waxes, etc. to prolong the duration of action and provide sustained release.

The parenteral preparation can be in the form of a liquid dose unit for subcutaneous / muscular or intravenous injection, eg, in the form of a solution or suspension. In the parenteral administration preparation, a fixed amount of the heterocyclic derivative (1) is suspended or dissolved in a non-toxic liquid carrier suitable for the purpose of injection, for example, an aqueous or oily medium, and then the suspension is prepared. Alternatively, it can be produced by sterilizing the solution. Non-toxic salts or salt solutions can be added to make the injection isotonic. Further, stabilizers, preservatives, emulsifiers and the like can also be added.

The suppository is a solid in which the heterocyclic derivative (1) is soluble or insoluble in water having a low melting point, for example, polyethylene glycol, cocoa butter, semi-synthetic fats and oils [eg, Witepsol (registered trademark)], higher esters ( For example, it can be produced by dissolving or suspending it in palmitic acid myristyl ester) or a mixture thereof.

The dose of the therapeutic agent for gait disorder according to the present invention varies depending on the patient's condition such as body weight and age, administration route, degree of symptom, etc. The appropriate amount of the drug is in the range of 0.001 mg to 100 mg per day, and 0.01 mg to 10 mg.
It is more preferably in the range of mg. In some cases, less than this may be sufficient, and vice versa. In addition, it can be administered once to several times a day or at intervals of one to several days.

For example, for adults, take 0.1 mg or 0.2 mg of the heterocyclic derivative (1) at a time, 2 times a day.
It can be started by oral administration after the round, and the maintenance dose can be determined by increasing the dose by 0.2 mg as a single dose to the maximum tolerated dose at intervals of 7 days or more while confirming the tolerability of the subject. .. The maximum dose is, for example, 0.8 mg to 1.6 mg, and any dose can be orally administered twice daily after meals.

Hereinafter, the present invention will be described in more detail with reference to test examples, but the present invention is not limited to the scope shown below.

Test Example 1: Antithrombotic effect in rat FeCl ₃ induced thrombus model (1) Method of preparing medium Methyl cellulose (Metrouse, SM-400, Shin-Etsu Chemical Co., Ltd.) was dissolved in distilled water to dissolve it.
A 0.5 w / v% methylcellulose aqueous solution was prepared.

(2) Method for preparing chemical solution (a) 2- {4- [N- (5,6-diphenylpyrazine-2-yl) -N-isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide (compound A)
A 0.5 w / v% methylcellulose aqueous solution was added to compound A to prepare a compound A: 10 mg / mL suspension in a 0.5 w / v% methylcellulose aqueous solution.
(B) Beraprost sodium Add 0.5w / v% methylcellulose aqueous solution to beraprost sodium and add 0.5w.
Beraprost sodium in / v% methylcellulose aqueous solution: 1.0 mg / mL aqueous solution was prepared.
(C) Cilostazol Add 0.5 w / v% methylcellulose aqueous solution to cilostazol to add cilostazol:
150 or 50 mg / mL suspensions were prepared.

(3) Test method Urethane (Wako Pure Chemical Industries, Ltd.) was dissolved in physiological saline (Otsuka Pharmaceutical Factory) to prepare 0.3 g / mL. 4 mL (1.2 g / k) of urethane physiological saline solution under the skin of a rat per 1 kg of body weight
g) Administered and anesthetized. When the effect of anesthesia was insufficient, the dose was appropriately increased in units of about 10% of the initial dose. As rats, male Wistar rats aged 9 to 10 weeks were used.

An incision was made in the abdomen of the rat to expose the duodenum, and the drug was injected 2-3 mm downstream from the boundary between the stomach and duodenum using a 26 G needle and syringe. It was administered at a dose of kg.

A skin incision was made in the right thigh of the rat to expose the femoral artery and the veins and nerves were detached. A parafilm was placed under the exfoliated femoral artery to completely separate the femoral artery from the veins and nerves. A laser Doppler blood flow meter (ALF21, Advance) probe was applied onto the femoral artery to start measuring blood flow (mL / min / g).

60 minutes after administration of compound A, 30 minutes after administration of beraprost sodium, and 120 minutes after administration of syrostazole, a filter paper (2 mm × 5 mm) impregnated with 10 w / w% FeCl ₃ aqueous solution was applied to the femoral artery. Place and change the blood flow in the biometric data processing system (F)
LO-WB, Omega Wave Co., Ltd.) was used for recording.

(4) Results In the control group to which the medium was administered, the blood vessels were occluded about 12 to 15 minutes on average after the induction of thrombus formation. On the other hand, in the 10 mg / kg administration group of compound A, the vascular occlusion time was about 22 by administration 60 minutes before the induction.
Significantly extended to minutes. In the 1 mg / kg administration group of beraprost sodium, the occlusion time was significantly extended to about 43 minutes by administration 30 minutes before the induction. In addition, 0 of beraprost sodium
.. In the 3 mg / kg administration group, the obstruction time was not prolonged, and the blood pressure decreased for a longer period of time (25).
%) Was observed. Both doses of cilostazol did not prolong the occlusion time.

Test Example 2: Gait improvement in rat ischemic gait disorder model (1) Test method For Wistar rats (male, 7 weeks old) (manufactured by Charles River Japan), treadmill (MK-680, Muromachi Kikai Co., Ltd.) 6) of walking training performed by surgery
I went there for 3 consecutive days 5 days ago, 4 days ago. On the day before the operation, the previous value of the walking distance was measured, the animals were grouped, and the sham operation or the iliac artery ligation operation described in i) below was performed.

After the operation, a suspension containing 0.5 w / v% methylcellulose aqueous solution in the sham operation group and the control group, and compound A at 0.6 mg / mL in the drug-administered group (medium: 0.5 w / v%). Compound A (3 mg / kg) 9 1 day after surgery using an aqueous solution of methyl cellulose)
It was orally administered twice a day for a day.

The walking time was measured 3 days, 7 days, and 10 days after the operation. The walking distance was calculated based on the measured walking time.

i) Method of iliac artery ligation surgery Rats were anesthetized by intraperitoneally administering 50 mg / kg of pentobarbital sodium (Somnopentyl (registered trademark), Schering-Plough Animal Health). If anesthesia is not enough, use Somnopentil® 0.02-0.03 mL
(Pentobarbital sodium amount: 1.3 to 1.9 mg) was additionally administered. An incision was made in the abdomen along the median under anesthesia to expose the left and right common iliac arteries. Sutures (Nescoster Silk Blade No. 4, Alfresa Pharma) are hung on the common iliac arteries on both sides, and the central side of the suture is ligation clip (Weck Hemoclip, small, Telefl).
Each one was ligated using ex Medical). Furthermore, the left and right iliac arteries were ligated one by one with sutures. After ligation, the peritoneum and muscular layer of the midline laparotomy were sutured using sutures, and the skin was sutured. Teramycin ointment (oxytetheracycli) on the sutured part
Apply an appropriate amount of bixylin (registered trademark) S (ampicillin sodium 50 mg titer, cloxacillin sodium 50 mg titer, Meiji Confectionery) for injection in 1 mL of physiological saline (Otsuka) It was dissolved in saline (Otsuka Pharmaceutical Factory), and 0.1 mL of this was injected intramuscularly into the thigh. Similarly, for the sham surgery group, both common iliac arteries were exposed, sutured, and no ligation was performed.
The abdomen was closed after the suture was removed. The iliac artery was ligated by the data management personnel, and the information was not disclosed to the gait test personnel until the test was completed.

ii) How to measure walking time Increase the speed of the treadmill belt from 15m / min to 35m / min in 3 minute increments 5
The speed was increased stepwise by m / min, and the time when the rat got on the electrical stimulation plate at the rear end of the belt was recorded as the dropout time, and the time until the rat dropped off 5 times was defined as the walking time. The walking test was conducted by two people in charge of the walking test, and at the same time as the start of the treadmill, the start button of the stopwatch (S058, Seiko Esyard) provided for each of the five lanes was pressed, and the dropout time was recorded as the split time. Then, after the measurement, the dropout time was described in the walking test record. The measurements were performed under the blind so that the gait tester would not know which group.

iii) Walking training method In order to adapt the rat to walking on the treadmill, walking training is performed 6 days, 5 days, and 4 days before the operation, and individuals suitable for walking on the treadmill are selected during this period. did. Individuals who refused to walk during walking training and those who frequently dropped out or turned over were excluded from use as individuals who were not suitable for the walking test on a treadmill.

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

The evaluation was t-test or Welch for the control group and for the sham surgery group.
Evaluated by test (##: p <0.01). The drug-administered group was evaluated by t-test with respect to the control group (**: p <0.01).

Test Example 3: Improvement of gait disturbance in patients with arteriosclerosis obliterans As a placebo-controlled double-blind comparative study, Japanese patients with arteriosclerosis obliterans (ABI at rest)
Placebo or selexipag 0.1 to 1.6 mg was administered twice daily for 24 to 36 weeks (dose adjustment period: 8 to 20 weeks, dose maintenance period: 16 weeks).

The improvement of the patient's gait disorder was confirmed using a treadmill, such as the maximum walking time (Gartner method).

Claims (2)

2- {4- [N- (5,6-diphenylpyrazine-2-yl) -N-isopropylamino] butyloxy} acetic acid or 2- {4- [N- (5,6-diphenylpyrazine-2-yl)) -N-Isopropylamino] Butyloxy} -N- (Methylsulfonyl) acetamide, or a pharmaceutically acceptable salt thereof , as an active ingredient, a therapeutic agent for gait disorders in patients with arteriosclerosis obliterans . The therapeutic agent for gait disorders according to claim 1, wherein the patient with arteriosclerosis obliterans is a patient classified into at least one selected from Fontaine classifications I to IV.

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