WO2009154246A1

WO2009154246A1 - Therapeutic agent for erectile dysfunction

Info

Publication number: WO2009154246A1
Application number: PCT/JP2009/061071
Authority: WO
Inventors: 雅也東岡
Original assignee: 日本新薬株式会社
Priority date: 2008-06-19
Filing date: 2009-06-18
Publication date: 2009-12-23

Abstract

Provided is a therapeutic agent for erectile dysfunction containing as the effective component a heterocyclic derivative represented by general formula (1) or a pharmaceutically acceptable salt thereof. In formula (1), R1 and R2 may be the same or different, each representing an optionally substituted aryl group; R3 and R4 may be the same or different, each representing a hydrogen atom or an alkyl group; R5 represents a hydrogen atom, an alkyl group or a halogen atom; Y represents N or N?O; A represents NR6, where R6 represents a hydrogen atom, alkyl group etc.; D represents an optionally hydroxyl group substituted alkylene or alkenylene group; E represents a phenylene group or a single bond; G represents O, S etc.; Q represents a carboxyl group, alkoxycarbonyl group etc.

Description

Erectile dysfunction treatment

The present invention is a treatment for erectile dysfunction comprising, as an active ingredient, a heterocyclic derivative represented by the following general formula (1) (hereinafter referred to as “the present heterocyclic derivative (1)”) or a pharmaceutically acceptable salt thereof. It relates to the agent.

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

[In the formula (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 formula (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 the formula (4), R ⁷ is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 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) A heterocyclic group. ]

Erectile dysfunction (Electile Dysfunction: ED) refers to a state in which satisfactory sexual intercourse cannot be performed because an effective erection cannot be obtained during sexual intercourse, and is positioned as one of so-called sexual dysfunctions. Erectile dysfunction tends to increase with age, but this increases with increasing age and increases the number of underlying diseases such as heart disease, diabetes, hypertension, hyperlipidemia, arteriosclerosis, and treats these underlying diseases. Therefore, the use of antihypertensives, hypoglycemic agents, etc. taken for this reason is also considered as a cause. Other causes are thought to be smoking, lack of exercise, and stress.

As a treatment for erectile dysfunction, inhibitors of phosphodiesterase 5 are used as first-line drugs. Of patients receiving phosphodiesterase 5 inhibitors, 20-30% are ineffective.
For patients inhibitors of phosphodiesterase 5 is invalid, intracavernosal injection of prostaglandin E ₁ has been performed.

On the other hand, this heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof has already been reported to be useful as a PGI ₂ receptor agonist in the treatment of pulmonary hypertension and obstructive arteriosclerosis ( For example, see Patent Document 1).

International Publication No. 02/088084 Pamphlet

An object of the present invention is mainly to provide a novel therapeutic agent for erectile dysfunction.

The present inventor has found that the present heterocyclic derivative (1) increases penile intracavernous pressure in rats, and has completed the present invention.

As this invention, the erectile dysfunction therapeutic agent which contains this heterocyclic derivative (1) or its pharmaceutically acceptable salt as an active ingredient can be mentioned, for example.

FIG. 1 shows the variation of the value obtained by dividing the intracavernosal pressure by the blood pressure. The vertical axis represents penile intracavernous pressure / blood pressure (ratio to pre-dose value;%), and the horizontal axis represents time (minutes) after administration. In the figure, the circles indicate the control group, and the squares indicate 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} acetic acid (hereinafter “compound A”). )), The triangular mark indicates 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide ( Hereinafter, each group to which “Compound B” is administered is represented.

FIG. 2 shows the variation of penile intracavernous pressure. The vertical axis represents penile intracavernous pressure (ratio to pre-dose value;%), and the horizontal axis represents time (min) after administration. In the figure, a circle represents a control group, a square represents a group to which Compound A was administered, and a triangle represents a group to which Compound B was administered.

In the present heterocyclic derivative (1), for example,
R ¹ and R ² are the same or different and are phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy;
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or alkyl;
R ⁵ is a hydrogen atom,
Y is N,
A is NR ⁶ , 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), R ⁷ is amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4) optionally substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro Compounds that are groups are preferred.
1) alkyl,
2) aryl,
3) Aryloxy,
4) Heterocyclic group

Specifically, for example, Compound A and Compound B are preferable.

The “alkyl” in the present invention is a linear or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. In particular, those having 1 to 4 carbon atoms are preferred.

“Haloalkyl”, “arylalkyl”, “alkylthio”, “alkoxyalkyl”, “alkylsulfonyl”, “monoalkylamino”, “dialkylamino”, “monoalkylcarbazoyl” and “dialkylcarbamoyl” in the present invention Examples of the moiety include the same alkyl groups as those described above.

In the present invention, “alkoxy” is a straight or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Examples include butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy and isohexyloxy. In particular, those having 1 to 4 carbon atoms are preferred.

Examples of the alkoxy moiety of “alkoxycarbonyl” and “alkoxyalkyl” in the present invention include the same as the above alkoxy.

In the present invention, “alkenyl” is linear or branched having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples thereof include 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. In particular, those having 3 or 4 carbon atoms are preferred.

Examples of “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 preferred.

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

In the present invention, “aryl” includes 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl. In particular, phenyl is preferred.

As the aryl moiety of “arylalkyl” and “aryloxy” in the present invention, the same aryl as the above aryl can be exemplified.

As the “alkylene” in the present invention, linear or branched ones having 1 to 8 carbon atoms such as methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, Examples include hexamethylene, heptamethylene, and octamethylene. In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.

As the “alkenylene” in the present invention, linear or branched ones 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, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1-heptenylene, 2- Examples include heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene and 7-octenylene. . In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.

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 condensed ring thereof, wherein the ring-constituting atom is nitrogen In the case of an atom or a sulfur atom, such a 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-oxazole-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, 1,3,5- Mention may be made of triazin-2-yl.
(2) A 4- to 8-membered saturated ring group, or a benzene condensed ring group thereof, which may contain 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms which are the same or different as ring constituent atoms And when a ring member atom is a nitrogen atom or a sulfur atom, this nitrogen atom and sulfur atom may form the oxide. For example, piperidino, piperazinyl, 3-methylpiperazin-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, 2-tetrahydrofuranyl can be mentioned.

The present heterocyclic derivative (1) can be synthesized by the method described in Patent Document 1 (International Publication No. 02/088084 pamphlet).

The present heterocyclic derivative (1) can be used as a medicine as a free base or acid, but can also be used in the form of a medically acceptable salt by a known method.
As the “salt” when the present heterocyclic derivative (1) is basic, for example, a salt of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, or hydrobromic acid, or acetic acid, List organic acid salts of tartaric 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 do.
Examples of the “salt” when the present 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 present heterocyclic derivative (1) has geometric isomers (Z-form and E-form), and each geometric isomer and a mixture thereof are also included in the present heterocyclic derivative (1). In addition, some of the heterocyclic derivatives (1) have asymmetric carbons, but each optical isomer and their racemates are also included in the heterocyclic derivatives (1). The optical isomer is obtained from the racemate obtained as described above using its basicity and using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid), It can be optically resolved by a known method, or can be produced using a previously prepared optically active compound as a raw material.

Examples of erectile dysfunction according to the present invention include diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic surgery for prostatectomy, aging, There may be mentioned vascular erectile dysfunction associated with arteriosclerosis.

The therapeutic agent for erectile dysfunction according to the present invention preferably comprises the present heterocyclic derivative (1) in the range of 0.01 to 99.5% as it is or in a pharmaceutically acceptable non-toxic and inert carrier. Is contained in the range of 0.5 to 90%.

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

The therapeutic agent for erectile dysfunction according to the present invention is a solid or liquid dosage unit, such as powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, lozenge and the like. Any form of a parenteral preparation such as an oral preparation, an injection, an ointment, and a cream can be used. It may be a sustained-release preparation. Among these, parenteral preparations are preferable, and injections, ointments and lotions are particularly preferable.

The powder can be produced by making the present heterocyclic derivative (1) fine.

The powder can be produced by making the present heterocyclic derivative (1) fine and then mixing it with a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol. A flavoring agent, a preservative, a dispersing agent, a coloring agent, a fragrance | flavor, etc. can be added arbitrarily.

Capsules are manufactured by first filling the powdered powdered powder or powder as described above into granules as described in the section of tablets, for example, into capsule shells such as gelatin capsules. can do. Lubricants and fluidizers such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powder and powder, and then filled. It can also be manufactured. When disintegrators and solubilizers are added, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate The effectiveness of the medicine can be improved. Alternatively, the fine powder of the present heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant and wrapped in a gelatin sheet to form a soft capsule.

Tablets are manufactured by adding excipients to the powdered heterocyclic derivative (1) to form a powder mixture, granulating or slugging, then adding a disintegrant or lubricant, and then tableting. can do.
The powder mixture can be produced by mixing the present heterocyclic derivative (1), which has been appropriately pulverized, with a diluent or a base. If necessary, a binder (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), a dissolution retardant (for example, paraffin), a resorbent (for example, a quaternary salt), An adsorbent (for example, bentonite, kaolin) or the like can be added.
The powder mixture can first be moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules. Instead of granulating the powder in this way, it is also possible to first crush the tablet and then crush the resulting incomplete form of slag into granules. By adding stearic acid, stearate, talc, mineral oil or the like as a lubricant to the granules thus produced, it is possible to prevent them from adhering to each other.
Moreover, a tablet can also be manufactured by directly compressing after mixing this heterocyclic derivative (1) with a fluid inert carrier, without going through the granulation and slagging steps as described above. it can.
Film tablets and sugar coatings can be applied to the tablets thus produced. A transparent or translucent protective coating made of a shellac hermetic coating, a coating of sugar or polymer material and a polishing coating made of wax can also be used.

Other oral dosage forms such as solutions, syrups, troches, and elixirs may also be in dosage unit form so that a given amount contains a certain amount of the heterocyclic derivative (1).

The syrup can be produced by dissolving the present heterocyclic derivative (1) in a suitable flavor aqueous solution. An elixir can be produced 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 and emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin), etc. may be added. it can.

If necessary, a dosage unit formulation for oral administration can be microencapsulated. The formulation can also be extended in action time or sustained release by being coated or embedded in a polymer, wax or the like.

The parenteral preparation can be a liquid dosage unit form for injection into subcutaneous, intramuscular, intravenous or intracavernosal bodies, for example, an injection having a solution or suspension form. Moreover, it can be made into the semi-solid form for applying to a penis, for example, an ointment, a lotion agent.

An injection having the form of a solution or suspension is obtained by suspending or dissolving a certain amount of the heterocyclic derivative (1) in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium. The suspension or solution can then be sterilized. Non-toxic salts and salt solutions can be added to make the injection solution isotonic. In addition, stabilizers, preservatives, emulsifiers, and the like can be added.

The ointment can be produced, for example, by mixing the present heterocyclic derivative (1) and a base such as a hydrophobic base or a hydrophilic base. Moreover, a preservative, antioxidant, etc. can also be added.

The lotion can be produced, for example, by adding the present heterocyclic derivative (1) and a solvent, an emulsifier, a suspending agent and the like to an aqueous liquid such as normal water or purified water, and dissolving or dispersing it. A preservative or the like can also be added.

The dose of the therapeutic agent for erectile dysfunction 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 amount is suitably in the range of 0.001 mg to 100 mg per dose, more preferably in the range of 0.01 mg to 10 mg. In some cases, a lower dose may be sufficient, and vice versa.

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
(1) Test method The penile intracavernous pressure was measured according to the method of Teiweira et al. (The Journal of Pharmaceutical and Experimental Therapeutics, Vol. 315, p. 155-162, 2005).
SD rats (male, 7 weeks old) (manufactured by SLC Japan) were anesthetized by subcutaneously administering 4 mL of 300 mg / mL urethane per 1 kg body weight of the rat, and fixed in the dorsal position. After securing an artery from the left hind limb and inserting a polyethylene tube (PE60; manufactured by Becton Dickinson), blood pressure (MAP) was measured via a blood pressure transducer (manufactured by Nippon Koden Kogyo Co., Ltd., the same applies hereinafter). Penile intracavernous pressure (ICP) was measured via a blood pressure transducer after inserting a 25 gauge needle into the left cavernous body.
After inserting a silicon tube with a 25 gauge needle at the tip of the right cavernous body, the test substance was administered from the silicon tube at 0.333 mL per 1 kg body weight of the rat.
After administration of the drug, the penile intracavernous pressure and blood pressure were recorded over time, and the values obtained by dividing the penile intracavernous pressure and penile intracavernous pressure by the blood pressure (ICP / MAP) were expressed as 100% before drug administration. did. The penile intracavernous pressure and the value obtained by dividing the penile intracavernous pressure by the blood pressure are used as indicators of erectile activity (see The Journal of Pharmaceutical Therapies, Vol. 315, p. 155-162, 2005). ).
As the test substance, an aqueous solution containing Compound A at 3 mg / mL [medium: 5 w / v% glucose aqueous solution (manufactured by Otsuka Pharmaceutical Co., Ltd., the same shall apply hereinafter)], or an aqueous solution containing Compound B at 3 mg / mL (medium: 5 w / v% glucose aqueous solution) was used. The control group was administered with 5 w / v% glucose aqueous solution as a vehicle. Four rats were used per group.
(2) Results As shown in FIGS. 1 and 2, administration of Compound A or Compound B increased the value of the penile intracavernous pressure divided by the blood pressure and the value of the penile intracavernous pressure. Thus, it is clear that Compound A and Compound B can have an effect on erectile dysfunction.

Claims

A therapeutic agent for erectile dysfunction containing, as an active ingredient, a heterocyclic derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof;

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

[In the formula (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 formula (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 the formula (4), R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 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) A heterocyclic group. ]
In the heterocyclic derivative (1), R 1 and R 2 are the same or different and are phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy,
R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
R 5 is a hydrogen atom,
Y is N,
A is NR 6 , 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 amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4), which may be substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro The therapeutic agent for erectile dysfunction according to claim 1, which is a group.
1) alkyl,
2) aryl,
3) Aryloxy,
4) Heterocyclic group
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 pharmaceutically acceptable salt thereof as an active ingredient.