WO1999065525A1

WO1999065525A1 - Ocular tension lowering agents and phosphoric ester derivatives

Info

Publication number: WO1999065525A1
Application number: PCT/JP1999/003277
Authority: WO
Inventors: Yasuhiro Ohtake; Akira Naito; Yoko Tanaka; Kenji Naito; Hidehiko Matsukawa
Original assignee: Wakamoto Pharmaceutical Co., Ltd.
Priority date: 1998-06-19
Filing date: 1999-06-18
Publication date: 1999-12-23
Also published as: AU4168999A

Abstract

Ocular tension lowering agents useful in the treatment and prevention of glaucoma and ocular hypertension, which contain as the active ingredient chemical substances exhibiting vasopressin V1 receptor antagonism; and phosphoric ester derivatives represented by general formula (1).

Description

Specification

Intraocular pressure lowering agents and phosphate derivatives

TECHNICAL FIELD The present invention relates to an intraocular pressure lowering agent to be applied to treatment and prevention of glaucoma and ocular hypertension. The present invention further relates to a novel phosphate derivative. Background art

Glaucoma is a disease caused by sustained or repeated rises in intraocular pressure (intraocular pressure) beyond the normal range, causing organic damage to the eyes and visual impairments such as abnormal visual fields. . Ocular hypertension is a disease in which intraocular pressure is higher than normal, but does not impair visual function, and may develop into glaucoma after a long course. The goal of pharmacotherapy for glaucoma and ocular hypertension is to reduce and maintain intraocular pressure to a healthy level without visual impairment by intraocular pressure-lowering drugs. As an application for glaucoma and ocular hypertension, conventionally, a carbonic anhydrase inhibitor (oral, ophthalmic solution), hypertonic osmotic agent (injection), pilocarpine (ophthalmic solution), epinephrine and its prodrug dipivefrin (Ophthalmic solution),) 3 receptor blocker (Ophthalmic solution) and isopropyl unoprostone (Ophthalmic solution) are known, but all have many defects. For example, taking a carbonic anhydrase inhibitor may cause gastrointestinal disorders, urolithiasis, and electrolyte abnormalities. The application of sympathomimetics such as epinephrine and dipivefrin is also limited to open-angle glaucoma, as well as rebound hyperemia due to vasoconstriction, eye pain, bradycardia, mydriasis, and systemic heart rate May cause an increase in number and blood pressure. 3) Eye drops containing 3 receptor blockers as active ingredients have side effects such as headache and depressive symptoms in the central nervous system, asthma-like symptoms in the respiratory system, bradycardia and hypotension in the circulatory system. It has been reported to occur (Pharmaceutical Journal, 28, 705, 1992). Isopropyl unoprostone eye drops have a high incidence of corneal epithelial damage as a side effect. As described above, there are problems with each of the intraocular pressure lowering agents that are currently widely used, and there is still no satisfactory drug that reduces intraocular pressure more effectively and has few side effects. To date, various vasopressin receptor antagonists have been used to treat heart failure, edema such as cerebral edema, ascites, pulmonary edema, arginine vasopressin hypersecretion syndrome, renal failure, hepatitis, hypertension, cirrhosis, hyponatremia, hypokalemia It has been developed for the treatment of diabetes and circulatory insufficiency and diuretics (JP-A-7-2800, JP-A-3-173870, JP-A-4-321669, JP-A-4-154765). JP-A-6-172317, JP-A-5-132466, International Publication WO 95 03305, JP-A 5-320135, International Publication WO 94/12476, JP-A 6-157480 JP, JP-A-6-21 1800, International Publication W094 14796, International Publication WO 94 20473, JP-A-6-16643, JP-A-7-157486, JP-A 7-179430, etc. ).

Regarding the effect of vasopressin on intraocular pressure, the intravenous administration of desmopressin (a vasopressin analog) (Ivnest. Oph tha lmol. Vis. Sci., 29, 406-410, 1988) It has an intraocular pressure increasing effect, as reported in the third ventricular administration of vasopressin (Invest. Ophthalmol. Vis. Sc, 25, 932-937, 1984) It has been reported. On the other hand, continuous infusion of isotonic vasopressin into the anterior chamber suppressed intraocular pressure elevation (Exp. Eye Res., 65, 517–531, 1997), and intravenous vasopressin was significantly reduced. It has also been reported to have an intraocular pressure-lowering effect, such as lowering intraocular pressure (Neuropeptide, 29, 193-203, 1995).

Regarding the distribution of vasopressin receptor in ocular tissues, experiments using a vasopressin receptor antagonist showed that vasopressin V1 receptor was converted to human retinal pigment epithelial cultured cells (Curr. Eye Res., 10, 81 1 -816 , 1991) Dinus excision It is reported to be present in the short posterior ciliary artery (J. Vase. Res., 34, 464-472, 1997).

As described above, it has been reported that vasopressin receptors are distributed in ocular tissues.However, it has been reported that vasopressin has an opposing effect of increasing or decreasing intraocular pressure. The physiological significance is unknown at all. Summary of the Invention

In view of the above-mentioned circumstances, the present invention provides a novel intraocular pressure lowering agent having an excellent intraocular pressure lowering effect and having few side effects for application to treatment and prevention or prevention of glaucoma and ocular hypertension. The purpose is to do so.

A first aspect of the present invention is an intraocular pressure-lowering agent comprising a compound having a vasopressin V1 receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient. A second aspect of the present invention is an ester phosphate derivative represented by the following general formula (1).

In the formula, R ¹ represents hydrogen or alkyl having 1 to 4 carbon atoms, M ¹ and M ² may be the same or different, and may be hydrogen or a monovalent pharmacologically acceptable alkyl. Represents potassium metal salt. Detailed Disclosure of the Invention

A first aspect of the present invention is an intraocular pressure-lowering agent comprising a compound having a vasopressin V1 receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient. Hereinafter, the present invention will be described in detail.

Vasopressin is a peptide hormone consisting of nine amino acids, which binds to its receptor to exert antidiuretic and vasopressor effects.

Vasopressin receptors are broadly classified into two types: cyclic AMP-independent V1 receptors and cyclic AMP-dependent V2 receptors. It has been clarified that the expression of the antidiuretic effect of vasopressin is mediated through the V2 receptor in the renal collecting duct, and the expression of the vasopressor effect is mediated by the V1 receptor in vascular smooth muscle. As used herein, the compound having vasopressin V1 receptor antagonistic activity means not only a compound having selective antagonistic activity on vasopressin V1 receptor, but also a compound having vasopressin V1 and V2 receptors. A compound having an antagonistic action is also meant. The compound having a vasopressin V1 receptor antagonistic effect used in the present invention is not particularly limited as long as it has a vasopressin V1 receptor antagonistic effect. For example, 1- {1-[4- (3-A Cetylaminopropoxy) benzoyl] —4-piperidyl} -3,4-dihydro-12 (1H) —quinolinone (hereinafter OPC-21268), SR49059,

A compound represented by the following general formula (1) (hereinafter, referred to as compound (1));

(Wherein, R ¹ represents hydrogen or alkyl having 1 to 4 carbon atoms, and Μ ¹ and Μ ² may be the same or different, and are hydrogen or monovalent pharmacologically acceptable. Represents an alkali metal salt>

A compound represented by the following formula (Α) (ΥΜ087, hereinafter referred to as compound (Α));

A compound represented by the following general formula (Β) (hereinafter, referred to as compound (Β));

(R ¹ represents hydrogen or alkyl having 1 to 4 carbon atoms)

It is a peptide [β-me rcapto- / 3, ] 3- e ye 1 om ethy 1 enepropi ony l 1, 〇- ^{^{Me- Ty r 2, A rg 8}} ] - vasopressin , and the like.

In the above compound (1), R ¹ represents hydrogen or alkyl having 1 to 4 carbon atoms. The alkyl having 1 to 4 carbon atoms is not particularly restricted but includes, for example, methyl, ethyl, propyl, butyl and the like, and these may be branched or linear. Of these, methyl is preferred. R ¹ may be in any of the ortho, meta and para positions.

In the above compound (1), M ¹ and M ² may be the same or different and represent hydrogen or a monovalent pharmacologically acceptable alkali metal salt. The monovalent pharmacologically acceptable alkali metal salt is not particularly limited, and examples thereof include a sodium salt, a potassium salt, and a lithium salt. Of these, sodium salts and potassium salts are preferred.

The above compound (1) is generally more water-soluble in salt form than in free form. Therefore, when used for pharmaceutical applications, it is preferable to select a compound in the form of a salt according to the application.

Examples of the compound (1) include the following compounds.

(1) Phosphoric acid (2R, 3aR) 5- [4-[[2- (parathryl) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyrrole [1 , 2—a] Quinoxaline mono-2-yl disodium

(2) Phosphoric acid (2R, 3aS) 5- (4-[[2- (para-tolyl) benzoy ] Amino] benzoyl] — 1,2,3,3a, 4,5_hexahydropyro mouth [1,2-a] quinoxaline-2-yl disodium

(3) Phosphoric acid (2 S, 3 aR) — 5— [4— [[2- (parathryl) benzoy] amino] benzoyl] 1,2,3,3a, 4,5-hexahydropyro [1 , 2-a] Quinoxaline-2-yl disodium

(4) Phosphoric acid (2 S, 3 aR) 5- [4-[[2- (parathryl) benzoy] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyro [1 , 2-a] Quinoxaline-2-yl dipotassium

(5) Phosphoric acid (2 S, 3 a S) — 5 -— [4 — [[2- (parathryl) benzoy] amino] benzoyl] —1,2,3,3a, 4,5-hexahydropyro [

1, 2-a] Quinoxaline-2-yl disodium

(6) Phosphoric acid (2R, 3 aR) — 5 -— [4-[(2-phenylpentyl) amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyrole [1,1 2—a] Quinoxaline—2-yl disodium

(7) Phosphoric acid (2R, 3aS) -5- [4-[(2-phenylpentyl) amino] benzoyl] —1,2,3,3a, 4,5-hexahydropyro [ 1,2—a] Quinoxaline mono-2-yl disodium

(8) Phosphoric acid (2 S, 3 aR) — 5— [4 — [(2-phenylbenzoyl) amino] benzoyl] —1, 2, 3, 3a, 4, 5-hexahydropyrole [1 , 2—a] Quinoxaline-2-yl disodium

(9) Phosphoric acid (2 S, 3 aR) — 5— [4— [(2-phenylbenzoyl) amino] benzoyl] — 1, 2, 3, 3 a, 4, 5—Hexahydropyrole [1 , 2—a] Quinoxaline-2-yl dipotassium

(10) Phosphoric acid (2S, 3aS) — 5— [4 — [(2-phenylbenzoyl) amino] benzoyl] —1,2,3,3a, 4,5-hexahydropyrole [1,21a] Quinoxaline-2-yl disodium

(1 1) Phosphoric acid (2R, 3 aR) — 5— [4-[[2- (Ortho-tolyl) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyro Mouth [1, 2-a] quinoxaline-2-yl disodium (1 2) Phosphoric acid (2R, 3aS) — 5 -— [4 — [[2- (orthotolyl) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyro Mouth [1, 2—a] quinoxaline-2-yl disodium

(1 3) Phosphoric acid (2 S, 3 a R) — 5— [4-[[2- (Ortho-tolyl) benzoyl] amino] benzoyl] — 1, 2, 3, 3a, 4, 5— Hexahydropyro mouth [1,2-a] quinoxaline-2-yl disodium

(14) Phosphoric acid (2 S, 3 aR) — 5— [4— [[2- (Ortho-tolyl) benzoyl] amino] benzoyl] -1,2,3,3a, 4,5-hexahydropyro 1,2—a] Quinoxaline mono-peroxide 2 potassium

(1 5) Phosphoric acid (2 S, 3 aS) 1 5— [4— [[2- (Ortho-tolyl) benzoyl] amino] benzoyl] —1, 2, 3, 3a, 4, 5— Hexahydropyro mouth [1, 2-a] quinoxaline-2-yl disodium

(1 6) Phosphoric acid (2R, 3 aR) — to 5— [4 — [[2- (methatritoyl) benzoyl] amino] benzoyl] — 1, 2, 3, 3a, 4, 5— Xahydropyrro [1,2-a] quinoxaline-2-yl disodium

(17) Phosphoric acid (2R, 3aS) 1-5— [4 — [[2- (methatritolyl) benzoyl] amino] benzoyl] —1,2,3,3a, 4,5 —Hexahydropyro mouth

[1,2-a] Quinoxaline-2-yl disodium

(1 8) Phosphoric acid (2 S, 3 aR)-5-[4-[[2- (meth-tolyl) benzoyl] amino] benzoyl] — 1, 2, 3, 3a, 4, 5 — Hexahydropyro mouth

[1, 2—a] Quinoxaline-2-yl disodium

(19) Phosphoric acid (2 S, 3 aR) — to 5— [4 — [[2- (methatritolyl) benzoyl] amino] benzoyl] — 1, 2, 3, 3a, 4, 5— Xahydropyro mouth

[1, 2-a] Quinoxaline—2-yl dipotassium

(20) Phosphoric acid (2 S, 3 aS) — 5— [4— [[2- (Methanol) benzoyl] amino] benzoyl] — 1, 2, 3, 3 a, 4, 5— Hexahydropyro [1,2-a] quinoxaline-2-yl disodium

The above compound (A), that is, 4 '-[(2-methyl-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine-6-yl) carbonyl]- 2-Fenylpenzanilide hydrochloride has been used as a therapeutic agent for congestive heart failure, a therapeutic agent for renal disease and a diuretic (Journa 1 of Pharmacology and Experimental Therapeutics, 282 (1 ), 301-308, 1997; Eur. J. Pharmacol., 3_2_2 (2), 225-230, 1997). The inventors of the present invention show that the above compound (A) exerts an intraocular pressure lowering action which cannot be predicted from the above-mentioned known drug effects, and is expected ophthalmic diseases such as glaucoma, ocular hypertension, and normal tension glaucoma. Was found to be suitable as a therapeutic agent.

The above compound (A) can be produced, for example, using the method described in Example 18 of International Publication WO95 / 03305.

The compound (B) is a biphenyl derivative represented by the general formula (B). In the above compound (B), R ¹ represents hydrogen or alkyl having 1 to 4 carbons. The alkyl having 1 to 4 carbon atoms is not particularly restricted but includes, for example, methyl, ethyl, propyl, butyl and the like, and these may be branched or linear. Of these, methyl is preferred. R ¹ may be in any of the ortho, meta and para positions.

The above compound (B) is not particularly limited, but in particular, R ¹ is in the para-position and is methyl (2S, 3aR) _2-hydroxy-5_ [4 — [[2 -— (para-tolyl Benzoyl] amino] benzoyl] 1-1,2,3,3a, 4,5-hexahydropyro [1,2-a] quinoxaline (hereinafter referred to as VP-343) and R ¹ are in the ortho position, Methyl (2 S, 3 aR) — 2-hydroxy-5- [4 — [[2- (orthotolyl) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyrro Mouth [1,2-a] Quinoxaline (hereinafter referred to as VP-386) is preferred.

Although VP-343 is known to have a diuretic effect, the inventors of the present invention show that VP-343 exerts an intraocular pressure lowering effect that cannot be predicted from the above-mentioned known medicinal effects, causing glaucoma and ocular hypertension. It has been found that the composition is suitable as a therapeutic agent for ophthalmic diseases such as bariasis and normal tension glaucoma.

VP— 386 is a new compound where R ¹ is in the ortho position and is methyl It has the structural features described above. VP-386 has an ability to bind to vasopressin V1 receptor and has vasopressin V1 receptor antagonism. Based on these properties, VP-386 exhibits an excellent intraocular pressure lowering effect and is suitable as a therapeutic agent for expected ophthalmic diseases such as glaucoma, ocular hypertension, and normal tension glaucoma.

OPC—2 1 2 6 8 (Hy pertention, 23, 2 17-2 2 2, 1 994) is a selective vasopressin V 1 receptor antagonist, and SR49 059 is a selective vasopressin Is a VI receptor antagonist, and the compound (A) (YM087; J. Pharma col. Ex p. Ther., 282, 311-308, 199 7) Vasopressin VI and V 2 receptor antagonist, VP- 343 is a vasopressin V 1 and V 2 receptor antagonist, [] 3 _mercapto—) 3, β-eyelome thylenepropionyl ¹ , O— Me— Ty r ² , A rg ⁸ ] — vasopressin (V 2 255; J. Med. Chem., 23, 364, 1980) is a peptide-selective vasopressin V 1 receptor antagonist Agent.

When the compound having vasopressin V1 receptor antagonism used in the intraocular pressure-lowering agent of the present invention is a basic compound, its pharmacologically acceptable salt includes, for example, hydrochloride, sulfate And inorganic or organic salts such as nitrate, phosphate, hydrobromide, tartrate, acetate, citrate, fumarate, maleate and oxalate. . When the compound having vasopressin V 1 receptor antagonistic activity used in the intraocular pressure lowering agent of the present invention is an acidic compound, examples of the pharmacologically acceptable salt thereof include a sodium salt, a potassium salt, Calcium salt, lithium salt, and magnesium salt can be exemplified.

As mentioned above, vasopressin receptors have been reported to be distributed in ocular tissues.However, it has been reported that vasopressin has an opposing effect of increasing or decreasing intraocular pressure. Physiological significance is unknown at all, and it is very difficult to predict from a known drug effect that a compound having the above-mentioned vasopressin V1 receptor antagonistic activity has an excellent intraocular pressure lowering effect.

According to the present invention, it has become clear for the first time that compounds having an antagonistic effect on vasopressin V1 receptor among vasopressin receptors have an intraocular pressure lowering effect . The present invention has been completed based on this finding.

In the present invention, the compound having a vasopressin VI receptor antagonistic action exerts an excellent intraocular pressure lowering action and has extremely few side effects. Therefore, an intraocular pressure-lowering agent can be obtained by using a compound having vasopressin VI receptor antagonistic activity as an active ingredient, which is suitable as a therapeutic and / or prophylactic agent for glaucoma and ocular hypertension. Therefore, the intraocular pressure lowering agent containing the compound having vasopressin V1 receptor antagonistic activity of the present invention as an active ingredient can be used as a glaucoma treatment agent, a glaucoma prevention agent, a treatment agent for ocular hypertension, and a prevention agent for ocular hypertension. The intraocular pressure lowering agent of the present invention also includes a glaucoma treatment agent, a glaucoma prevention agent, an ocular hypertension treatment agent, and an ocular hypertension prevention agent.

The intraocular pressure lowering agent of the present invention can also be used as a therapeutic or preventive agent for normotensive glaucoma exhibiting a condition in which intraocular pressure does not increase.

The dose of the compound having vasopressin V1 receptor antagonism used in the intraocular pressure lowering agent of the present invention is determined in consideration of the patient's condition such as age, body weight, etc., administration route, disease symptoms and severity, etc. Can be set as appropriate. For example, in the case of intravenous administration, the amount of the active ingredient of the intraocular pressure-lowering agent of the present invention for an adult is preferably 0.1 to 100 mg Z per day, more preferably 1 to 100 mg Z human. 660 O mg Z human. In the case of topical administration, for example, in the case of ophthalmic administration, the active ingredient concentration of the intraocular pressure-lowering agent of the present invention for an adult is preferably 0.001 to 10% (V / W), More preferably, it is 0.01-2% (V / W). In the case of oral administration, the amount of the active ingredient of the intraocular pressure lowering agent of the present invention for an adult is preferably 5 to 150 Omg Z per day, more preferably 10 to 300 mg / human. mg Z human.

However, depending on the condition of the recipient, lower doses may be sufficient, and conversely, higher doses may be required. In addition, it may be divided and administered 2 to 4 times a day.

The intraocular pressure-lowering agent of the present invention is produced by mixing a compound having vasopressin V1 receptor antagonistic activity or a pharmacologically acceptable salt thereof with a conventional pharmaceutical carrier and preparing an appropriate dosage form. Can be.

When the intraocular pressure-lowering agent of the present invention is administered as a pharmaceutical composition to animals including humans, the compound having vasopressin V1 receptor antagonism is added to the pharmaceutical composition as it is, Alternatively, it is preferably contained in a pharmaceutically acceptable nontoxic and inert carrier, and the content is preferably 0.1 to 99.5% by weight, more preferably. Or 0.5 to 90% by weight.

Examples of the carrier include solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries, which may be used alone or in combination of two or more. Good.

The intraocular pressure lowering agent of the present invention is preferably administered in a dosage unit form. The administration method of the intraocular pressure-lowering agent of the present invention is not particularly limited, and examples thereof include local administration such as tissue administration, intravenous administration, ophthalmic administration, and nasal administration, oral administration, and rectal administration. Can be mentioned.

The dosage form of the intraocular pressure lowering agent of the present invention is not particularly limited. For example, a dosage form suitable for the above-mentioned administration method can be appropriately selected.

The intraocular pressure lowering agent of the present invention may be administered in a tissue or intravenously using a liquid dosage unit form such as a solution or suspension for subcutaneous, intramuscular or intravenous injection. In this case, a non-toxic salt or salt solution may be added to make the injection liquid isotonic. The above-mentioned liquid preparation or suspension suspends or dissolves a certain amount of the compound having vasopressin VI receptor antagonistic activity in a non-toxic liquid carrier such as an aqueous or oily medium suitable for injection, and then suspends the solution. It can be manufactured by sterilizing a suspension or solution.

The above liquid preparation or suspension may be produced by placing a certain amount of a compound having vasopressin V1 receptor antagonistic activity in a vial, and then sterilizing and sealing the vial and its contents.

In order to dissolve or mix the intraocular pressure lowering agent of the present invention immediately before administration, in addition to the powdered or freeze-dried compound having vasopressin V1 receptor antagonistic activity, a preliminary vial or carrier is prepared. Is also good.

When the intraocular pressure-lowering agent of the present invention is administered by eye, forms such as eye drops and eye ointments can be used. The eye drops may contain a stabilizer, a preservative and the like. The pH of the above-mentioned eye drops is not particularly limited as long as it is within the range permitted by ophthalmic preparations.

When the intraocular pressure-lowering agent of the present invention is used as an eye drop or an ointment, its usage and dosage are It is selected according to the patient's condition, age, etc., but in the case of eye drops, it is usually preferable to apply 1 to 5 drops per time, 2 to 4 times a day, and in the case of eye ointments It is usually preferable to apply an appropriate amount to the conjunctival sac once to three times a day.

When the intraocular pressure-lowering agent of the present invention is orally administered, examples of the dosage form include powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, Solid or liquid dosage units, such as sublingual tablets and other dosage forms, may be mentioned.

The above powder is produced by appropriately reducing a compound having vasopressin V1 receptor antagonistic activity.

The above powder is prepared by appropriately reducing a compound having vasopressin V1 receptor antagonistic activity to a fine powder, and then mixing with a pharmaceutical carrier such as edible carbohydrates such as starch and mannitol, and other additives. Can be manufactured. The tablets can be made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and tableting. The above powder mixture is obtained by mixing a powdered compound having vasopressin VI receptor antagonistic activity with the above diluent or base, and if necessary, a binder, a dissolution retarder, a reabsorbent, An adsorbent or the like may be used in combination.

The powder mixture can be granulated by first moistening with a binder and then forcing through a sieve. Further, the powder mixture may be granulated by crushing the imperfect slag obtained after applying the powder mixture to a tableting machine.

The granules thus produced can be prevented from sticking to each other by adding a lubricant. The lubricated mixture may then be tableted, and the resulting uncoated tablet may be coated with a film or coated with sugar. In addition, the intraocular pressure reducing agent of the present invention may be directly tableted after mixing with a fluid inert carrier without going through the steps of granulation and slag formation as described above. The intraocular pressure lowering agent of the present invention may be provided with a transparent or translucent protective coating composed of a sealing film of Sierrac, a coating of sugar or a polymer material, and a polishing coating composed of wax. .

The above capsules are manufactured by filling powdered powder and powder or granulated powder and powder into a capsule made of gelatin such as gelatin. Can be. The addition of a disintegrant or a solubilizer to the above capsules can improve the efficacy of the medicine when the capsules are taken.

Alternatively, a fine powder of a compound having a vasopressin VI receptor antagonistic action may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, a surfactant or the like, and this may be wrapped in a gelatin sheet to form a soft capsule.

The intraocular pressure-lowering agent of the present invention can be in another oral administration form such as a solution, syrup, elixir, suspension and the like, and the dosage unit is such that a certain amount contains a certain amount of the drug. It can be in the form. The syrup can be produced by dissolving a compound having vasopressin VI receptor antagonistic activity in an appropriate aqueous flavor solution, and the elixir can be produced by using a nontoxic alcoholic carrier. it can. The suspension can be formulated by dispersing a compound having vasopressin V1 receptor antagonistic activity in a non-toxic carrier.

The dosage unit formulation for oral administration of the intraocular pressure-lowering agent of the present invention may be, if necessary, encapsulated in a mouth or encapsulated in a polymer, wax or the like. As a result, the action time of the intraocular pressure lowering agent of the present invention can be extended and sustained release can be achieved.

When the intraocular pressure-lowering agent of the present invention is administered rectally, a suppository in which a compound having vasopressin V1 receptor antagonistic activity is mixed with a water-soluble or insoluble low-melting-point solid carrier and a mixture thereof is used. Can be used.

The lubricant and fluidizing agent are not particularly limited, and include, for example, colloidal silicic acid, talc, stearic acid, magnesium stearate, stearic acid salts such as calcium stearate, solid polyethylene glycol, mineral oil, etc. Can be listed. These may be used alone or in combination of two or more. The disintegrant and solubilizer are not particularly limited, and include, for example, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxystarch sodium, calcium carbonate, sodium carbonate, ethoxylation Isostearyl alcohols, polyoxyethylene sorbitol esters, and the like. These may be used alone or in combination of two or more. The binder is not particularly limited, and examples thereof include syrup, starch paste, arabic gum, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, and polyvinyl alcohol. These may be used alone or in combination of two or more.

The dissolution retardant is not particularly limited, and examples thereof include paraffin, wax, and hydrogenated castor oil. These may be used alone or in combination of two or more.

The reabsorbent is not particularly limited, and examples thereof include quaternary salts. These may be used alone or in combination of two or more.

The adsorbent is not particularly restricted but includes, for example, bentonite, kaolin, dicalcium phosphate and the like. These may be used alone or in combination of two or more.

The emulsifier is not particularly limited, and examples thereof include polyoxyethylene sorbitol esters. These may be used alone or in combination of two or more.

The flavor enhancer is not particularly limited, and includes, for example, pamint oil and saccharin. These may be used alone or two or more of them may be used in combination. Examples of the stabilizer include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; Examples thereof include nonionic surfactants such as polyoxyethylene sorbitan monoolate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil, sodium citrate, and sodium edetate. These may be used alone or in combination of two or more. Examples of the preservative include benzalkonium chloride and paraben. These may be used alone or in combination of two or more.

The carrier is not particularly limited, and examples thereof include higher esters such as polyethylene glycol, cocoa butter, and myristyl palmitate. These may be used alone or in combination of two or more. A method of applying the above-mentioned intraocular pressure-lowering agent of the present invention to an animal including a human for the purpose of treatment and / or prevention and treating (treating) the same is also one of the present invention. It is also possible to use the compound having vasopressin V1 receptor antagonistic activity for industrial production (Manu facturng) of the above-mentioned intraocular pressure lowering agent of the present invention.

This is one of the present invention.

The intraocular pressure lowering agent, the therapeutic agent for glaucoma, and the therapeutic agent for ocular hypertension of the present invention are all drugs containing a compound having vasopressin V1 receptor antagonistic activity as an active ingredient. As long as it contains a compound having a receptor antagonism, it is within the scope of the present invention regardless of whether or not it contains other components.

Since the intraocular pressure lowering agent, the therapeutic agent for glaucoma, and the therapeutic agent for ocular hypertension of the present invention can be administered as a pharmaceutical composition to animals including humans, the pharmaceutical composition for reducing intraocular pressure, the therapeutic agent for glaucoma, respectively. It can be referred to as a pharmaceutical composition or a pharmaceutical composition for treating ocular hypertension.

A second aspect of the present invention is an ester phosphate derivative represented by the following general formula (1).

In the formula, R ¹ represents hydrogen or alkyl having ¹ to 4 carbon atoms; M ¹ and M ² may be the same or different; and hydrogen or a monovalent pharmacologically acceptable alkali Represents a metal salt.

In the compound (1) of the present invention, R ¹ , M ¹ and M ² are as described in the first present invention. As the compound (1) of the present invention, the compound exemplified in the first present invention Can be mentioned.

The compound (1) of the present invention is a compound represented by the above formula (B), Is characterized by being phosphorylated. That is, the phosphorylated esterified compound (1) of the present invention has improved water solubility as compared with the compound (B), and can be suitably used particularly for liquids such as eye drops and intravenous drugs. .

The compound (B) has a solubility in water (25 ° C.) of about 4 / z gZmL and is a very poorly water-soluble compound. To prepare liquids such as eye drops and intravenous drugs using such poorly water-soluble compounds, a commonly used surfactant such as tween 80, HCO60 or polyoxyl stearate 40 is used. It must be solubilized using For example, among the above compounds (B), when R ¹ is in the para-position and VP-343, which is methyl, is used to prepare a liquid preparation, among various surfactants used for solubilization, 0.5% HC-60 solution is the surfactant that can maximize the solubility of VP-343, but it can be adjusted to 0.056% concentration even with 0.5% HC-60 solution. That is the limit.

On the other hand, since the compound (1) of the present invention has a solubility of 10% or more in physiological saline, it can be used in an extremely high concentration range as compared with VP-343. Further, according to the compound (1) of the present invention, a liquid preparation can be prepared without using an extra component such as a surfactant which is irrelevant to the manifestation of the action of the liquid. Obtainable.

The degree or duration of the intraocular pressure lowering effect when a solution (concentration: 3.7%) prepared by dissolving the compound (1) of the present invention in physiological saline is extremely excellent. The liquid preparation using (1) is extremely useful as a therapeutic agent for glaucoma and ocular hypertension.

The compound (1) of the present invention can be synthesized by various methods. The typical production method is illustrated below.

[Reaction formula 1]

In the formula, R ¹ , M ¹ and M ² are as described above, and Bn represents benzyl.

[Reaction formula 1] is a method for producing the phosphoric ester (1) of the present invention by phosphorylation and deprotection of the synthetic intermediate (2). According to the method of Kuo-Long Yu et al. [Tetrahedron Letters, 979-982 (1988)], the above synthetic intermediate (2) was converted to 1H-tetrazo-one. After reacting with N, N-diisopropyldibenzylphosphoramidite in a dichloromethane solution in the presence of toluene, the reaction is oxidized with metabenzo-perbenzoic acid to obtain the phosphoric acid triester (3). N, N-diisopropyldibenzylphosphoramidite can be prepared by a known method, that is, the method of E, Uh 1 mann et al. [Tetrahedron Letters, 1023- 1026 ( 1986)] and the method of Tanaka et al. [Tetrahedron Letters, 199-202 (1986)]. Next, the phosphate ester (3) of the present invention can be produced by deprotecting the phosphate triester (3) by hydrogenolysis. Also, other phosphating agents, for example, phosphepane [Watanabe et al., Tetraedron Letters, 255-256 (1990)], N, N-getyldibenzylphosphoramidite [J. W. Perlich et al., Tetrahedron Letters, 101-102 (1987)], N, N-dimethyldibenzyl phosphoramidite [JW Perlich et al., Tetrahedron Letters (Te tr a edr on Letters), 101-102 (1987)], and then oxidizing. Further, the compound (1) of the present invention can also be produced by a known method of directly phosphorylating the synthetic intermediate (2). Known methods for direct phosphorylation include, for example, a method using an acid chloride-type phosphorylating agent as a phosphorylating agent, a method using an acid anhydride-type phosphorylating agent as a phosphorylating agent, and imidoylphosphoric acid as an intermediate. Other phosphorylating agents such as phosphoric acid trisalt, tris (8-quinolyl) phosphoric acid, 2- (N, N-dimethylamino) -144-trophenylphosphoric acid, and phosphonimoxide for And other methods.

Examples of the acid chloride-type phosphorylating agent include phosphorus oxychloride, phenylphosphoric acid dichloride, diphenylphosphoric acid chloride, dibenzylphosphoric acid chloride, p-nitrophenylphosphoric acid dichloride, dimorpholinophosphoric acid chloride, bis (/ 3, β,) 3-trichloroethyl chloride) phosphoric acid chloride, ρ-diphenyl-ρ, monomorpholinopyrophosphoric acid chloride and the like.

Examples of the acid anhydride-type phosphorylating agent include: benzylphosphorous acid, diphenylphosphoric anhydride, tetra (paranitrophenyl) pyrophosphoric acid, tetrachloropyrophosphoric acid, and diphenylphosphoric acid anhydride And the like.

Examples of the imidoylphosphoric acid include, for example, compounds obtained from / 3-cyanoethylphosphoric acid and dicyclohexylcarposimide.

After phosphorylation by these methods, in order to obtain the compound (1) of the present invention, the protecting group may be removed depending on the phosphorylating agent used. This can also be performed by a known method such as hydrolysis with an acid or alkali and catalytic reduction.

[Reaction formula 2]

(4) (2)

In the formula, R ¹ is as described above.

The method represented by [Reaction formula 2] is a method for producing the above-mentioned synthetic intermediate (2) from the above-mentioned amine compound (4) and the above-mentioned carboxylic acid (5) using a usual amide bond formation reaction. .

The amide bond formation reaction can be easily performed using known amide bond formation reaction conditions. Examples of the known amide bond forming reaction include (i) an acid chloride method, (mouth) a carbodiimide method, (8) an activated ester method, and (2) other methods. (Ii) The acid chloride method is a method in which a halogenating agent is reacted with the carboxylic acid (5) to form an acid chloride, which is then reacted with the amine compound (4). Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphorus pentachloride and the like.

(Port) The carpoimide method is a method in which the carboxylic acid (5) is reacted with the amine derivative (4) in the presence of a condensing agent. Examples of the condensing agent include dihexyl carbyl imide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, and carbonyldiimidazole.

(8) The activated ester method is a method in which the carboxylic acid (5) is converted into an activated ester, and the carboxylic acid (5) is reacted with the amine (4). Examples of the activated ester include nitro- or halogen-substituted phenyl esters, aromatic thioesters, N-hydroxysuccinates, 1-hydroxybenzotriazole esters, phenolic esters and the like.

(2) Other methods include, for example, a method in which the carboxylic acid (5) is converted to a carboxylic anhydride with a dehydrating agent such as acetic anhydride, and the amine (4) is reacted with the carboxylic acid (5). ) And an ester of a lower alcohol with the amine compound (4) under high pressure and high temperature, and a method of reacting the carboxylic acid (5) with the amine compound (4) in the presence of a condensing agent for a phosphorus compound. And the like. Examples of the condensing agent for the phosphorus compound include, for example, triphenylphosphine, diphenylphosphine chloride, phenyl-1-N-phenylphosphoramide chloride, methylchlorophosphate, getyl cyanophosphate, azide diphenylphosphate, bis ( 2 -oxo-3 -oxazolidinyl) phosphinic chloride and the like.

Among these, the method of reacting the above-mentioned amine compound (4) with the above-mentioned carboxylic acid (5) using an acid chloride method is preferred in that the compound (1) of the present invention can be obtained easily and easily.

The solvent used for the amide bond formation reaction varies depending on the method selected. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; Jetlje Ethers such as mono-ter, tetrahydrofuran, dioxane and dimethoxyethane; esters such as ethyl acetate; single solvents such as aprotic polar solvents such as N, N'-dimethylformamide, dimethylsulfoxide and hexamethylphosphoric acid triamide; Or a mixed solvent thereof.

When the carboxylic acid (5) is used in excess or the reaction is carried out in the presence of an organic base in the above amide bond formation reaction, it may be advantageous in that the reaction proceeds smoothly. Examples of the organic base include N-methylmorpholine, trimethylamine, triethylamine, Ν, Ν′-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1, Examples thereof include 8-diazabicyclo [5,4,0] indene-7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO).

The reaction temperature of the amide bond formation reaction is preferably about 120 to 150 ° C, more preferably about 15 to 50. The reaction time of the amide bond formation reaction is preferably about 5 minutes to 18 hours, and more preferably about 5 minutes to 2 hours.

After introducing a protecting group into the hydroxy group of the amine compound (4), the above-mentioned synthesis intermediate (2) can be obtained by performing the amide bond formation reaction and then removing the protecting group. Examples of the protecting group include protecting groups described in “Greene” and “Wuts”, ^ Protective Group Organic Synthesis (2nd edition) ”. It can be appropriately used depending on the reaction conditions.

[Reaction formula 3]

(2a) (6) (2b) wherein R ¹ is as described above.

Mitsunobu reaction (O. M its uno bu, Syn the Using sis, 1-28, 1981), the above compound (2b) having a reversed configuration can be produced. That is, the compound (2a) is reacted with acetic acid in an aprotic polar solvent in the presence of triphenylphosphine and azodicarboxylic diesters to convert the acetoxide (6), whose steric configuration is inverted, to the compound (2a). And then solvolyzing the acetoxide (6) under acidic or basic conditions using water or an alcohol such as methanol or ethanol as a solvent to obtain the compound (2b ) Can be manufactured.

Examples of the aprotic polar solvent include N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide.

Examples of the azodicarboxylic diesters include, for example, ethyl azodicarboxylate, diisopropyl azodicarboxylic acid, and dibenzyl azodicarboxylate.

The above-mentioned amine compound (4), which is a starting material of the above [Reaction formula 2], is obtained from Magid Abou—Gharbia, Meier E. Freedeta 1., J. Med. Chem., 2_7_, 1743 (1984) ) And U.S. Pat. No. 4,446,323, as starting materials, 1-fluoro-2-nitrobenzene and trans-4-hydroxy-L-proline, cis-4-hydroxy-D-proline, or their alkyl esters and their hydrochloric acid. By using a salt such as a salt, it is possible to obtain (2R, 3aS) —2-hydroxy-1,2,3,3a, 4,5-hexahydropyro [1,2-a] quinoxaline (4a) , (2R, 3aR) —2-Hydroxy-1,2,3,3a, 4,5-hexahydropyro mouth [1,2-a] quinoxaline (4b).

The reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt thereof, a hydrate or various solvates. The salt can be produced by subjecting the salt to a usual salt formation reaction.

Isolation and purification can be performed using ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

The compound (1) of the present invention includes racemates, optically active isomers, and diastereomers. May exist alone or as a mixture. The racemate can be converted into an optically pure isomer by a general racemic resolution method such as a method of optically resolving a diastereomer salt with a general optically active acid (tartaric acid or the like). The mixture of diastereomers can be separated by a conventional method such as fractional crystallization or chromatography.

The compound (1) of the present invention is a novel compound, and the indication of the pharmaceutical composition containing the compound (1) of the present invention as an active ingredient is not particularly limited. Examples thereof include ocular hypertension and glaucoma. it can. The compound (1) of the present invention also has a diuretic effect, and a pharmaceutical composition containing the compound (1) of the present invention as an active ingredient can be used as a diuretic. Therefore, a pharmaceutical composition comprising the compound (1) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is also one of the present invention. In recent years, the number of patients with normal tension glaucoma has increased.In addition to conventional intraocular pressure-lowering drugs, drugs that prevent glaucomatous optic neuropathy, namely blood circulation in the optic nerve head There is a need for improving drugs and optic nerve protectants. The major blood vessel that nourishes the optic papilla is the short posterior ciliary artery. Compounds having a vasopressin VI receptor antagonistic action have an inhibitory effect on vasopressin-induced contraction of the short posterior ciliary artery (J. Vase. Res., 34, 464-472, 1997). It has the effect of improving the circulation of the part. Therefore, the intraocular pressure-lowering agent characterized in that a compound having a vasopressin V1 receptor antagonistic activity of the present invention or a pharmacologically acceptable salt thereof is used as an active ingredient, has an effect of improving the circulation of the optic papilla. It is also extremely useful as a novel therapeutic or prophylactic agent for glaucoma. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Test Examples, Reference Examples, Examples, and Formulation Examples, but the present invention is not limited thereto. Test example 1: Intraocular pressure lowering effect

ゥ The effect of intraocular pressure lowering by ophthalmic administration was studied using a heron.

Compound phosphoric acid (2S, 3aR) obtained in Example 1—5— [4 — [[2 -— ( Para-tolyl) benzoyl] amino] benzoyl] _ 1,2,3,3a, 4,5-hexahydropyro [1, 2-a] quinoxaline-peroxide disodium (hereinafter referred to as VP-382) Was dissolved in physiological saline to prepare a test ophthalmic solution having a concentration of 3.7%. Six male white rabbits with normal intraocular pressure (weighing 2.7 to 3.4 kg) were taken as one group, and 50 L of test ophthalmic solution or control solution (saline) was instilled into the left eye. After corneal surface anesthesia with 0.2% of 4% oxybupro hydrochloride 20 L ophthalmic instillation, use A 1 c On Pneumatic Applan ation on Tonog ra ph (manufactured by Aleon) to pre- and post-instillation Intraocular pressure was measured for up to 6 hours. The test results (difference from intraocular pressure before administration) are shown in Table 1. In addition, * and ** indicate p-0.05 and p-0.01 (vs. control group), respectively, and the student's t test (Student; 'sttest) or the aspin-welch test ( A spin—We lch 'sttest). The test ophthalmic solution administration group showed a significant intraocular pressure lowering effect from 1 to 6 hours after instillation compared to the control group.

Table 1 Intraocular pressure-lowering effect of the compound of Example 1 (VP-382) by instillation

Intraocular pressure difference (AmmHg)

Compound VP-382

Time after administration Concentration (%)

(Hours) Physiological saline solution 3.7

1 3.2 ± 3.2--1.7 ± 1.2 **

2 2.8 Sat 2.5--1.3 Sat 1.6 **

3 2.2 Sat 3.5--3.5 ± 2.1 **

4 0.8 ± 3.6 — 3.5 workers 1.6 *

5 1.7 ± 2.6 1 2.0 Sat 2.7 *

6 0.0 ± 3.0 one 0.2 person 3.8 The numerical value is the average soil standard deviation of n = 6 cases

Significant difference in intraocular pressure in saline group

* p <0.05, ** p <0.01

(Student st test or Asp in-Welch st test) Test examples 2 to 4: IOP lowering effect

ゥ The effect of intraocular pressure lowering by intravenous administration was studied using a heron. The compounds (VP-383, VP-384, VP-385) obtained in Examples 2 to 4 were dissolved in physiological saline to a concentration of 15 mgZmL to prepare an intravenous preparation.

Male white rabbits with normal intraocular pressure (weighing 2.7-3.4 kg) were grouped into 6 birds, and the compounds obtained in Examples 2-4 were intravenously administered to give SmgZkg. The intraocular pressure lowering effect of the intravenously administered drug was examined. In the same manner as in Example 1, intraocular pressure was measured before intravenous administration and up to 4 hours after intravenous administration. The negative control was compared with the intravenous injection of the present invention using a solvent.

The test results (difference from intraocular pressure before administration) are shown in Tables 2 to 4. *, ** and *** indicate p <0.05, p <0.01 and <0.001, respectively (vs. control group), which were analyzed in the same manner as in Example 1. The groups administered with the compounds obtained in Examples 2 to 4 showed a significant intraocular pressure lowering effect as compared with the control group.

Table 2 Intraocular pressure-lowering effect of intravenous administration of the compound of Example 2 (VP-383)

Intraocular pressure difference (AmniHg)

Compound VP-383

Time after administration Concentration (mg / kg)

(Time) Physiological saline 3

0.5 3.0 ± 2.0 one 2.7 ± 4.9 *

1 3.0 Sat 1.8 1 1.5 Sat 2.8 **

2 3.2 Sat 2.2 One 2.3 ± 3.8 **

3 4.3 person 1.5 one 1.3 soil 2.1 ***

4 8.2 Sat 2.2 2.5 Sat 3.9 **

The numerical values are the average soil standard deviation of n = 6 cases.

Significant difference in intraocular pressure in saline group

* p <0.05, ** p <0. OK *** p <0.001

(Student 'st test or Aspin-Welch st test) Table 3 Intraocular pressure-lowering effect of intravenous administration of the compound of Example 3 (VP-384)

Intraocular pressure difference (AmmHg)

Compound VP-384

Time after administration Concentration (mg / kg)

(Time) Physiological saline 3

0.5 2.8 Sat 3.0 — 0.8 ± 2.3 *

1 1.2 Sat 3.1 — 2.2 ± 3.4

2 One 1.0 ± 2.3 — 1.5 ± 2.1

3 1.7 Sat 1.5 0.7 ± 3.7

4 1.7 Sat 2.7 1.7 Sat 2.0 The numerical value is the standard deviation of n = 6 cases

Significant difference in intraocular pressure in saline group

* p <0.05 (Students / test) Table 4 Intravenous administration of the compound of Example 4 (VP-385)

Intraocular pressure difference (AmmHg)

Compound VP-385

Time after administration Concentration (mg / kg)

(Time) Physiological saline 3

0.5 0.2 Sat 2.1 — 2.3 ± 2.7

1 1.0 soil 4.6 — 3.3 ± 2.3

2 — 2.7 ± 3.3 — 6.3 ± 3.2 *

3 1 2.3 Sat 3.1 — 3.5 ± 2.6

4 2.8 Sat 5.4 1.8 ± 2.8 The numerical values are the mean soil standard deviation of n = 6 cases

Significant difference in intraocular pressure in saline group

* p <0.05 (Student's t test) Test Example 5: Intraocular pressure lowering effect

The above compound (A) was dissolved in a 0.5% 11 <060 solution to a concentration of 0.3% to prepare a test ophthalmic solution.

A group of 6 to 12 male white rabbits with normal intraocular pressure (body weight: 2-3 kg), and instilled 50 L of test ophthalmic solution or control solution (ophthalmic solution containing no compound (A)) on the left eye Then, the intraocular pressure lowering effect of the eye drops of the present invention was examined. In the same manner as in Example 1, Intraocular pressure was measured before and up to 4 hours after instillation. As a negative control, a solvent was used and compared with the ophthalmic solution of the present invention.

Table 5 shows the test results (difference from intraocular pressure before administration). * Indicates ρ <0.05 (vs. control group), and these were analyzed by the Student's t-test (Stude η stte st). The test ophthalmic solution-administered group showed a significant intraocular pressure lowering effect 3 hours after instillation as compared to the control group. Table 5 Intraocular pressure lowering effect of compound (A) by eye drops

Intraocular pressure difference (AmmHg)

Compound Compound (A)

Time after administration Concentration (%)

(Time) saline 0.3

1 0.8 1.8 1.8 0.2 2.4

2 3.9 ± 3.6 1.8 ± 2.0

3 4.4 ± 3.1 2.6 Sat 1.8 *

4 9.0 ± 3.1 8.8 ± 2.3

The figures are the average soil standard deviation of n = 12 cases

Significant difference in intraocular pressure in saline group

* p <0.05 (Student's t test) Test Example 6: Intraocular pressure lowering effect

ゥ The effect of intraocular pressure lowering by intravenous administration was studied using a heron.

Compound (A) was dissolved in N, N-dimethylformamide to a concentration of 15 mgZmL to prepare an intravenous formulation.

Male white rabbits with normal intraocular pressure (weighing 2.7-3.4 kg) were grouped into groups of 5-6, using the compound (A) described above before intravenous administration and in the same manner as in Example 2. Intraocular pressure was measured up to 6 hours after intravenous administration. As a negative control, a solvent was used and compared with the intravenous injection of the present invention.

Table 6 shows the test results (difference from intraocular pressure before administration). In addition, ** and *** indicate P 0.01 and <0.001 (solvent group), respectively, and these were analyzed in the same manner as in Example 1. The compound (A) administration group showed a significant intraocular pressure lowering effect 1 to 4 hours after intravenous administration as compared to the control group. Table 6 Intraocular pressure-lowering effect of intravenous administration of compound (A)

Intraocular pressure difference (AmmHg)

Compound Compound (A)

Time after administration Concentration (mg / kg

(Time) Physiological saline 3

0.5 0.8 2.9 1 1.0 ± 1.0

1 1.3 ± 0.8 — 1.8 ± 1.3 ***

2 2.3 Sat 2.5 1 3.6 Sat 1.1 ***

3 2.8 ± 3.1 — 3.0 ± 0.7 **

4 3.7 1.9 1.9 1.2 Sat 1.6 ***

5 4.7 2.1 2.1 2.6

6 6.2 Sat 2.3 4.4 N 1.5 The mean is the standard soil standard deviation of n = 6 (saline solution) and 5 (compound (A))

Significant difference in intraocular pressure in saline group

** p <0.01, *** p <0.001

(Student st test or Aspin-Welch's st test) Test example 7: Intraocular pressure lowering effect

1. Compound used

As the compounds used, OPC-21268 and VP-343 having vasopressin VI receptor antagonistic activity, OPC-31260 and SR-121463A which are selective vasopressin V2 receptor antagonists were used.

2. Synthesis of compound used

The compounds used were synthesized according to the method described in J. Med. Chem., 3_6, 2011-2017, 1993 for 〇PC-21268, and in International Publication W〇98 / 43976 for VP-343, respectively. The method described, SR-121463A was performed according to the method described in PCTZ FR 96 01666, and OPC-31260 was performed according to the method described in J. Med. Chem., 3_9. 3547-3555, 1996.

3. Preparation of administration sample

OPC-21268, VP-343 and SR_121463 Α are 50mgZmL, 15mgZmL and 15m respectively in 100% dimethylformamide The concentration was adjusted to gZmL, and PC-31260 was adjusted to 3.lmg / mL with physiological saline.

4. Test contents

Male white rabbits with normal intraocular pressure (weight 2.2-3.4 k), 5-9 birds per group, OPC-21268 and OPC-31260 were lmg OmgZkg, SR-121463A and VP-343. Was administered at a dose of 3 mg / kg intravenously, and intraocular pressure was measured in the same manner as in Example 1. A negative control was set for each compound, and the respective solvents were used and compared with the intravenous injection of the present invention.

5. Results

Test results by intravenous administration of OPC-21268 (1 Omg / kg), VP-343 (3 mg / kg), OPC-31260 (1 Omg / kg), SR-121463 A (3 mgZkg) Tables 7, 8, 9, and 10). * And ** indicate p <0.05 and p <0.01 (vs. control group), respectively, which were analyzed in the same manner as in Example 1.

As a result, OPC-21268 and VP-343 having vasopressin VI receptor antagonistic activity showed a significant intraocular pressure lowering effect after intravenous administration as compared with the control group. On the other hand, for the selective vasopressin V2 receptor antagonists OPC-31260 and SR-121463A, no significant difference from the control group was observed at any time after intravenous administration.

Table 7 Intraocular pressure lowering effect of intravenous administration of OPC-21268 Intraocular pressure difference (ΔηιπιΗε)

Compound OPC-21268

Time after administration Dose (mskg)

(Time) Solvent 10

0.5 1.3 Sat 1.2 -1.8 Sat 1.3 * *

1 1.3 1.9 -1.8 ± 1.9 *

2 2.0 ± 2.3 -1.2 ± 2.3 *

3 0.5 ± 1.9 -0.4 ± 1.1

4 2.5 people 2.7 2.0 ± 1.6

The figures are n == average soil standard deviation of 5-6 cases

Significant difference in intraocular pressure of vehicle group

* ρ <05, * * ρ <0.01

(Student st test or Aspin-Welch st test) Table 8 Intraocular pressure lowering effect of intravenous administration of VP-343 Intraocular pressure difference (mm mmHg)

Compound VP-343

Time after administration Dose (mg / ks :)

(Time) Solvent 3

0.5 -0.5 Sat 2.3 -1.4 ± 1.7

1 0.7 Sat 2.2 -1.4 ± 2.1

2 1.5 ± 2.8 -1.6 ± 2.7 *

3 2.5 ± 2.0 0.2 ± 1.9 *

4 2.8 2.0 2.0 ± 1.0

5 4.3 ± 3.1 4.8 ± 0.4

6 5.7 person 2.2 4.0 ± 2.5 The numerical value is the average soil standard deviation of n = 5 to 6 cases

Significant difference in intraocular pressure between vehicle group * p 0.05

(Student st test or Aspin-Welch st test) Table 9 Intraocular pressure lowering effect of intravenous administration of 0PC-31260

Intraocular pressure difference (ΔηιπιΗε)

Compound OPC-31260

Time after administration Dose (mg / kg)

(Time) Solvent 10

0.5 0.4 person 2.1 2.0 person 1.0

1 1.3 Sat 2.4 -0.4 2.4

2 -0.4 Sat 1.9 -1.3 Sat 1.0

3 0.6 ± 2.1 0.1 ± 1.5

4 0.9 ± 2.5 1.6 ± 3.0

The numerical values are η = mean soil standard deviation of 9 cases. Table 10 0 Intravenous administration of SR-12 63A ¾

Intraocular pressure difference (ΔιηπιΗε)

Compound SR-121463A

Time after administration Weight (mg / kg)

(Time) Solvent 3

1 0.0 ± 2.9 -0.4 ± 2.5

2 -1.2 Sat 6.8 -1.4 Person 4.6

3 -0.6 Sat 3.0 3.4 Sat 6.0

4 8.6 ± 2.9 7.4 ± 5.1

The numerical value is η = average soil standard deviation of 5 cases. Test example 8: Intraocular pressure lowering effect

A peptidic selective vasopressin V 1 receptor antagonist [One me rcapto- β,] 3- eyel ome t hy lenepropio ny l 1, 〇 one ^{^{Me -Ty r 2, A rg 8}} ] -vasopressin ( hereinafter peptidic A selective vasopressin V1 receptor antagonist, Sigma, V2255, J. Med. Chem., 2_3, 364, 1980) was dissolved in physiological saline to a concentration of 1 g / mL. Adjusted intravenous dosage.

Male white rabbits with normal intraocular pressure (weight 2.2-3.4 kg) 5-9 birds per group, 1 l / ^ gZkg of peptide-selective vasopressin V 1 receptor antagonist vein After intravenous administration, the intraocular pressure was measured in the same manner as in Example 1. As a negative control, a solvent was used and compared with the intravenous injection of the present invention.

Table 11 shows the test results (differences from intraocular pressure before administration). * And ** indicate p <0.05 and p <0.01, respectively (vs. control group), which were analyzed in the same manner as in Example 1. The peptide-selective vasopressin V1 receptor antagonist administration group having vasopressin V1 receptor antagonistic activity showed a significant intraocular pressure lowering effect after intravenous administration as compared to the control group. Table 11 1 Peptide-selective vasopressin VI receptors

Intraocular pressure lowering by intravenous administration of antagonist

Intraocular pressure difference (AmmHg)

Compound Peptide selective vasopressin VI

I—Receptor antagonist

Time after administration Dose

(Time) Solvent 1

0.25 3.6 ± 2.1 1 1.0 4.9 *

0.5 3.4 Sat 4.4 0.8 ± 4.8

1 2.4 ± 3.8 one 2.2 ± 3.2 *

2 2.8 ± 3.1 1 1.7 Sat 6.9

3 0.6 ± 4.5 1 4.2 6.6

4 4.8 4.0 4.0 4.3 ± 6.3 *

5 3.8 ± 3.5 I 6.3 Sat 6.0 **

6 4.6 ± 6.0 7.0 ± 6.3 **

24 3.0 Sat 4.2 1.7 Person 6.2 The numerical value is n = Average soil standard deviation of 5 to 6 cases

Significant difference in intraocular pressure of vehicle group

* p <0.05, * * p <0.01

(Student's t test or Asp in-Welch st test) Test example 9: Vasopressin receptor binding test

Sprague-Dawley The kidneys removed from female rats were minced, homogenized with 5 OmM Tris-HCl pH 7.4, and then 50,000 Xg at 4 For 20 minutes. A 10-fold amount of buffer was added to the obtained sediment, and the mixture was centrifuged again under the same conditions and washed. Further, a buffer solution was added to the obtained sediment to prepare a rat kidney crude membrane fraction so that the protein amount became 10 mg / mL. Using this rat kidney臓粗membrane fraction prepared ^[3 H] - A rg- vasopressin VI antagonist ^([3 H] vasopressin V 1-en evening agonist: 2 nM) and crude membrane fraction 5000 g and a test compound ( 10- ⁸ M) and, ImM magnesium chloride, 60 minutes in 2mM potassium chloride and 0.1% © sheet buffer in a total amount of 1000 L containing serum albumin and incubated at 25. Thereafter, the incubation solution was aspirated using a cell harvester, and the free ligand and excess buffer were removed by passing through a filter paper, and the labeled ligand bound to the receptor was trapped on the filter paper. Removed this filter paper, after thoroughly dried, the liquid scintillator Isseki mixed first and to measure the bound to the membrane by liquid scintillation one Shiyonkaun evening one ^[3 H] vasopressin V 1 antagonists amount below the binding inhibition rate It was calculated from the equation. VP-386 was used as a test compound. The results are shown in Table 12 below. Inhibition rate (%) = 100— (BN) / (B.N) × 100

B: amount of binding known amount of test compound and ^[3 H] vasopressin V 1-en evening in the presence of agonist ^[3 H] vasopressin V 1-en evening agonist of the membrane

B. : Amount of [ ³ H] Vasopressin V1 antagonist bound to membrane when test compound is removed

N: binding amount table 12 for the excess of vasopressin (10- ⁶⁾ ^[3 H] vasopressin VI en evening Gonisu Bok membranes in the presence of

Test Example 10: Diuretic effect

Male SPF rats with S pra gu e-Dawley (body weight 240-320 g (8 weeks old) were subjected to the experiment in groups of 6 or more. After fasting for 16 to 20 hours, and acclimated for 1 hour in the metabolic cage, a solution of the test compound dissolved in physiological saline was intravenously administered at a dose of 3 mgZ kg. Immediately after administration of the test compound, a physiological saline solution (25 mL / kg) was orally loaded. Thereafter, the rats were returned to the metabolic cage, urine collected from immediately after the administration of the test compound for 4 hours, and the urine volume was measured. Physiological saline was used as a control. The test compounds were VP-382, the compound obtained in Example 1, VP-383, the compound obtained in Example 2, VP-384, the compound obtained in Example 3, and The compound VP-385 obtained in Example 4 and the compound VP-387 obtained in Example 5 were used.

The results are shown in Table 13 below. All compounds showed significant diuretic effects. Table 13

Numerical values are mean soil standard errors of n = 6 or 8 cases

Significant difference in intraocular pressure between control (administered saline) group

* ρ <0.05 (As in-Welch 'st test)

Formulation example Injection

Composition

VP- 382 1.Omg

Cuic acid 0.2 mg

Sodium citrate 0.4mg

Sodium chloride 18.Omg

Suitable amount of water for injection

Total volume 2. OmL In a solution of 0.1 g of quinic acid in 40 OmL of water for injection, 0.5 g of VP-382 produced in Example 1, 0.2 g of sodium citrate, and 9 g of sodium chloride g was added. This solution was stirred at 6 Ot to dissolve the added compound. After cooling the obtained solution at room temperature, the total amount was adjusted to 100 OmL. The above solution was filtered through a membrane filter (pore size 0.2, filled into 2 mL ampoules, and sterilized by heating to prepare an injection. Formulation Example 2 Tablets

Composition

[Tablets]

VP— 382 5. Omg

71.5 mg corn starch 20. Omg hydroxypropylcellulose 3. Omg magnesium stearate 0.5 mg Subtotal 100 mg

[Coating]

Hydroxypropyl methyl cell mouth 2910 4. Omg Polyethylene Dalicol 6000 0.5 mg Titanium oxide 0.5 mg Subtotal 5 mg αn “105 mg VP—382 25 g produced in Example 1 and lactose 357.5 g, and then pulverized with a bantam mill (manufactured by Tokyo Atomizer Co., Ltd.). The resulting granules were dried, passed through a 24-mesh sieve, then added with 2.5 g of magnesium stearate, and then rotary-tableted (Kikusui Seisakusho) 6.δδιιη A tablet of 10 Omg per tablet was prepared using an X5R mortar. The tablets are sprayed with 300 g of an aqueous coating solution containing 2010 g of hydroxypropylmethyl cellulose, 2.5 g of polyethylene glycol 6000 and 2.5 g of titanium oxide using a coating device (manufactured by Freund Corporation). Then, 5 mg was coated per tablet to obtain a film-coated tablet. Formulation Example 3 Capsules

Composition

VP- 382 5. Omg

Microcrystalline cellulose 195. Omg

Lactose 58.Omg

Low substituted hydroxypropylcellulose 25.Omg

Polyvinylpyrrolidone 15.Omg

Magnesium stearate 2. Omg

A total of 300 mg VP-382 produced in Example 1 was powdered, and 10 g of the powder was added with 390 g of crystalline cellulose, 116 g of lactose, 50 g of low-substituted hydroxypropylcellulose, and 30 g of polyvinylpyrrolidone. Then, 12 OmL of ethanol was added, mixed uniformly, and granulated. The granulated mixture was dried at 50 ^ for 12 to 16 hours, passed through a 25-mesh sieve, and 4 g of magnesium stearate was added and mixed uniformly. Filled to Omg to give a hard capsule containing 5 mg per capsule. Formulation Example 4 Eye drops

Composition

VP- 382 5 Omg

Boric acid 55 Omg

Borax 10 5mg

Sodium chloride 12 Omg

Benzalkonium chloride 0 2mg

Distilled water for injection

Total volume 5.OmL To a solution of 0.04 g of benzalkonium chloride dissolved in about 80 OmL of sterilized purified water Then, 1 g of VP-382 produced in Example 1, 1 g of boric acid, 2.1 g of borax and 2.4 g of sodium chloride were added and dissolved with stirring. The solution was aseptically filtered with a pore size of 0.22 m). The obtained solution was filled into a 5 mL eye drop bottle to produce an eye drop. Formulation Example 5 Injection

Composition

Compound (A) 3.

Concentrated glycerin 5.

Polyethylene glycol 4000 20.

10% lactic acid 2,

Water for injection

A total volume of about 2,5 L of distilled water for injection was heated to about 60 ° C, and 5.2 g of concentrated glycerin, 20 g of polyethylene glycol 4000, and 10 g of 10% lactic acid were added. Add and dissolve enough

m m m m m

After dissolving, 3.0 g of the compound (A) was finally dissolved by stirring, and it was confirmed that the L g g g g pH was 3.5. Finally, add distilled water for injection to make up the total volume to 2 L, filter with a sterilizing filter, fill in glass ampoules in 2 mL portions and seal, then sterilize at 1 15 for 30 minutes, and then quickly with water The mixture was cooled to room temperature to prepare an injection. Formulation Example 6 Tablet

Composition

[Tablets]

Compound (A) 5. Omg

7 1.5 mg

Cornstarch 20. Omg Hydroxypropylcellulose 3. Omg

Magnesium stearate 0.5 mg Subtotal 100 mg

[Coating]

Hydroxypropyl methylcellulose 29 1 0 4.Omg Polyethylene glycol 6000 0.5 mg Titanium oxide 0.5 mg Subtotal 5 mg a et `` 105 mg A film-coated tablet was obtained in the same manner as in Formulation Example 2 using Compound (II). Formulation Example 7 Capsules

Composition

Compound (A) 50 mg

Microcrystalline cellulose 95 Omg

58 Omg

Low substituted hydroxypropylcellulose 25 Omg

Polyvinylpyrrolidone 15 Omg

Magnesium stearate 2 Omg

Hard capsules were obtained in the same manner as in Formulation Example 3, using a total of 300 mg of Compound (A) _c Formulation Example 8 Eye drops

Composition suitable 2 o

m m m

Compound (A) Omg

G g

Suitable amount of sodium hydroxide

Hydrochloric acid

Benzalkonium chloride 0.

HC060 25

Distilled water for injection

Total volume 5, benzalkonium chloride 0.048 in 0.5% HCO 60, approx. 80 OmL, add 3 g of compound (A), stir and dissolve, and adjust to PH4 with sodium hydroxide and hydrochloric acid. Was adjusted to 100 OmL, and filtered aseptically through a membrane filter (pore size: 0.22 im). Filled into a 5mL eye drop bottle to produce eye drops

Formulation Example 9 Injection

Composition

OPC-21268 3. Omg concentrated glycerin 5.2 mg polyethylene glycol 4000 20. Omg 10% lactic acid 2. Omg water for injection

Total volume 2. OmL An injection was prepared in the same manner as in Preparation Example 5 using OPC-21268. Formulation Example 10 Tablet

composition

m

OPC— 21268 5. Omg lactose 71.5 mg corn starch 20. Omg hydroxypropylcellulose 3. Omg magnesium stearate 0.5 mg

Subtotal 100 mg

[Coating]

Hydroxypropyl methylcellulose 2910 4.Omg Polyethylene glycol 6000 0.5 mg Titanium oxide 0.5 mg Subtotal 5 mg

□ υΓ 105 mg

Film-coated tablets were obtained using OPC-21268 in the same manner as in Formulation Example 2, Formulation Examples Capsules

Composition

OPC-21268 5. Omg Microcrystalline cellulose 195. Omg Lactose 58. Omg Low substituted hydroxypropylcellulose 25. Omg Polyvinylpyrrolidone 15. Omg Magnesium stearate 2. Omg

300 mg in total

Hard capsules were obtained in the same manner as in Preparation Example 3 using OPC-21268. Formulation Example 12 Eye drops

Composition

To a solution of benzalkonium chloride 0.048 in 0.5% HCO 60 (approximately 80 OmL) was added 3268 g of PC-212, and the mixture was stirred and dissolved.The mixture was adjusted to pH 7 with sodium hydroxide and hydrochloric acid. The volume was adjusted to 100 OmL, and the solution was aseptically filtered through a membrane filter (pore size: 0.22 m). The solution was filled in a 5 mL eye drop bottle to produce an eye drop. Reference example 1

(2 S, 4 R) 4-hydroxy-11- (2-nitrophenyl) proline

OH

COOH trans-14-hydroxy-L-proline 5 g and 1-fluoro-2-ditrobenzene 5.6 g were dissolved in dimethylsulfoxide 3 OmL, 7.5 mL of triethylamine was added, and the mixture was heated and stirred at 60 for 16 hours. . After returning the reaction solution to room temperature, it was poured into ice water and washed with ether. The aqueous layer was acidified with hydrochloric acid and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with chloroform / methanol (98-2) to give 7.18 g (yield 71.1%) of the title compound as an oil. Yield 71.1%

¹ HN. MR (CDC 13) δ: 2.2-1-2.25 (lH, m), 2.45-2.53 (1H, m), 2.70 (1H, dd, J = 1 1) 0, 1.5 Hz), 3.79 (1H, dd, J = 11.0, 3.6Hz), 4.20—5 55 (3H, m), 6.72-6.82 (lH, m), 6.91—6.97 (1

H, m), 7.32-7.40 (1H, m), 7.73 (1H, dd, J = 8.1, 1.5Hz)

I.R. (neat) レ cm-3440, 1750, 1605, 1560, 1505, 1480, 1440, 1270, 1175 Reference Example 2

Cis-4-hydroxy-D-proline methyl ester hydrochloride

HQ,

ヽ N · ■ "'COOCH3

hHC1

Cis-4-Hydroxy-D-proline hydrochloride (J. Org. Chem., §_, 2954, 1981) 15. Suspension of 53 g in 180 mL of methanol, cooling to 20 and thionyl chloride 21. 7 mL was added dropwise over 1 hour, and then stirred at room temperature for 1.5 hours. After concentrating the reaction solution, ether was added to the obtained residue, and the precipitated crystals were collected by filtration, washed with ether, and dried to give 15.35 g (yield: 91.3%) of the title compound.

¹ HN. MR (DMSO-d ₆ ) δ: 2.13-2.23 (1Η, m), 2.26-2.38 (lH, m), 3.14-3.30 (3H, m ), 3.75 (3H, s), 4.35-4.43 (1H, m), 4.45-4.56 (1H, m), 8.80-9.32 (lH, m ), 10.35—10.87 (1 H, m) I.R. (KBr) vcm- ¹ : 3400, 3000, 1725, 1580, 1380, 1250, 1095 Reference Example 3

(2 R, —4 R) 4-hydroxy-11- (2-nitrophenyl) proline methyl ester

Using cis-4-hydroxy-D-proline methyl ester hydrochloride obtained in Reference Example 2 and 1-fluoro-2-nitrobenzene, the title compound was obtained in the same manner as in Reference Example 1.

97.2% yield

1 HN. MR (CDC 1 ₃ ) (5: 2.16-2.26 (1 H, m), 2.50-2.62 (1H, m), 2.91 (1H, d, J = 9 OHz), 3.4 1 -3.48 (1H, m), 3.57 (1H, dd, J = 10.5, 5.4Hz), 3.75 (3H, s), 4.40 -4. 55 (2H, m), 6.81-6.89 (2H, m), 7.35-7.43 (lH, m), 7.64-7.79 (1 H, m)

I.R. (neat) vcm- ¹ : 3450, 1740, 1605, 1510, 1350, 1280, 1210, 1180 Reference Example 4

(2R, 3aS) 1-hydroxy-1-, 2,3,3a, 4,5-hexahydropyrro [1,2-a] quinoxaline-1-one

7.17 g of (2 S, 4R) —4-hydroxy-1- (2-nitrophenyl) proline obtained in Reference Example 1 was catalytically reduced at room temperature in the presence of 1 g of 10% palladium-carbon catalyst in 15 OmL of methanol. . After completion of the reaction, the catalyst was removed and the reaction solution was concentrated to dryness to obtain 5.24 g (yield: 90.7%) of the title compound as a pale brown solid.

1 HN. MR (DMSO-d ₆ ) <5: 1.96—2.14 (2H, m), 3.00 (1H, dd, J = 10.3, 2.4 Hz), 3.65 ( 1H, dd, J = 10.3, 5.6Hz), 3.85 (1H, dd, J = 9.8, 6.6Hz), 4.39-4.48 (1H, m), 6.53 (1H, d, J = 7.8Hz), 6.61 -6.69 (1H, m), 6.80 (1H, dd, J = 7.8, 1.5Hz), 6 86 (1H, td, J = 7.8, 1.5Hz), 10.30 (1 H, brs)

I. R. (KB r) v cm- ¹ 3400 680 5 20, 1440, 420, 1 380 1 320 Reference Example 5

(2R 3 aR) 2-Hydroxy '2 3 3 a 45 -Hexahydropyro mouth “1„ 2 &]-Quinoxaline-4-one

The title compound was obtained in the same manner as in Reference Example 4 using (2R 4R) -4 hydroxy-11 (2-nitrophenyl) proline methyl ester obtained in Reference Example 3. Yield 8 1.9%

^{_{. 1 HN MR (CDC 1 3}} ) δ: 2. 03 (1H, brs), 2. 3 1- 2. 42 (lH m), 2. 55- 2. 68 (lH m), 3. 30 (1 H, dd J = 10.35.1 Hz), 3.48—3.54 (lH m), 3.62 (1H, t J = 8.1 Hz) 4.55—4.62 (1 H m) 6.61 (1H d, J = 7.1Hz) 6.72-6.82 (2H, m), 6.93-7.01 (lH m), 8.20 (lH brs)

I. R. (KB r) v cm- ¹ : 3440, 3200, 1695, 1610, 1505, 1430, 1400, 1350, 1320, 1005 Reference example 6

_ (2R, 3aS) — 2-Hydroxy- ^ 2,3,3_3a, 4-5-hexahydropyrro [1 2—a] quinoxaline

Lithium aluminum hydride 0.57 g suspension in anhydrous tetrahydrofuran 30 In mL, add (2R, 3aS) —2-hydroxy-1,2,3,3a, 4,5-hexahydropyrro [1,2—a] quinoxaline-4-one obtained in Reference Example 4 .05 g of an anhydrous tetrahydrofuran solution (2 OmL) was added dropwise over 30 minutes under ice-cooling, followed by heating to reflux for 3 hours. The reaction solution was cooled on ice, 10 OmL of ethyl acetate was gradually added, and the mixture was further stirred at room temperature for 15 hours. Water was added to the reaction solution, and the precipitated insoluble material was separated by filtration on celite. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 1.63 g (yield 85.0%) of the title compound.

H-N. M. R. (CDC) δ: 58-1.69 (1Η, m), 2.

06-2.15 (lH, m), 2.76-2.86 (lH, m), 3.33 (1 H, d, = 10.6 Hz), 3.51 -3.59 (2H, m ), 3.78-3.90 (1H, m), 4.59 (1H, t, J = 4.6Hz), 6.43 (1H, d, J = 7.3Hz), 6.52 -6.60 (2H, m), 6.67-6.75 (1H, m)

I. R. (KB r) v cm " ¹ : 3520, 3350, 2850, 1600, 1 520, 1460, 1440, 1360, 1320, 1260 Reference Example 7

(2R, -3aR) 2-Hydroxy-1, _2, _3, -3a, -4, -5-hexahydropyro mouth _ "1, 1, 2-a] quinoxaline

, OH

(2R, 3 aR) — 2-Hydroxy-1,2,3,3a, 4,5-hexahydropyrro [1,2-a] quinoxaline-4-one obtained in Reference Example 5 The title compound was obtained in the same manner as in 6.

Yield 63.6%

^{_{. 1 HN MR (CDC 1 3}} ) δ:. 1. 55 (1 Η, ddd, J = 13. 9, 9. 2, 6. 2Hz), 2. 39-2 51 (lH, m), 3. 1 1 (1H, t, J = 9.2Hz), 3.25-3.54 (5H, m), 4.55—4.65 (1H, m), 6.43 (1H, dd, J = 7.7.5 .5Hz), 6.5 1-6.72 (3H, m)

I.R. (KBr) vcm- ¹ : 3330, 2840 1600, 1515, 1505, 1360, 1315 Reference Example 8

(2 R, 3 a S) 2-Hydroxy 5— [4— [[2 _ (parathryl) benamino] be- 1, 2, — 3, — 3 a, 4, 5-hexahydropyrro

Π [2-a] quinoxaline

4-[[2-Hydroxylatel) benzoyl) amino] 1.4 g of benzoic acid was added to 2 mL of thionyl chloride, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, excess thionyl chloride was concentrated and removed. A solution of the obtained acid chloride in 1 OmL of dichloromethane was obtained in Reference Example 6 (2R, 3aS) —2-hydroxy-1,2,3,3a, 4,5-hexahydropyrochloride. [1,2-a] Quinoxaline (0.8 g) and triethylamine (0.64 g) were gradually added dropwise to 3 OmL of a dichloromethane solution under ice-cooling. After stirring at room temperature for 3 hours, the reaction solution was washed sequentially with water, 1N-sodium carbonate aqueous solution, 1N-hydrochloric acid, and water, and dried over anhydrous magnesium sulfate. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography, and eluted with methanol Z chromatography (199). The eluate was concentrated, and the residue was recrystallized from ethyl acetate-hexane to obtain 1.17 g (yield: 55.0%) of the title compound.

m. p .: 163-16.5. C

^{_{. 1 HN MR (CDC 1 3}} ) δ: 1. 60 - 1. 72 (1 H, m), 1. 85- 1. 91 (1H, m), 2. 21 (1 H, dd, J = 12 8, 5.1 Hz), 2.36 (3H, s), 2.43-2.53 (lH, m), 3.45 (1H, dd, J = 11.0, 4. 0Hz), 3.56 (1H, d, J = 1 1.OH z), 3.98-4.16 (1H, m), 4.65-4.72 (1H, m), 4.98-5.10 (lH, m), 6.35 (1H, t , J = 7.3 Hz), 6.

46-6.54 (2H, m), 6.91-7.00 (2H, m), 7.05 (2H, d, J = 8.8Hz), 7.22 (2H, d, J = 8. 1 Hz), 7.29-7.37 (4H, m), 7.38-7.57 (3H, m), 7.85-7.90 (1H, m)

I.R. (KBr) vcm- ¹ : 3390, 29 10, 1620, 1600, 1

520, 1405, 1320, 1270, 1250, 1 180 Reference 9

(2 R, —3 aR) 2-hydroxy-1 5— [4— [— [2- (para-tolyl) benzoyl] amino] benzoyl] —— 1, 2, _3, 3 a, 4, —5— Hexahydropyro

(2R, 3 aR) —2-Hydroxy-1,2,3,3a, 4,5-hexahydropyrro [1,2-a] quinoxaline obtained in Reference Example 7 and 4-[[2- Using (parathryl) benzoyl] amino] benzoic acid, recrystallized from ethyl acetate-hexane in the same manner as in Reference Example 8 to obtain the title compound.

Yield 53.5%

m.p.:163-164:

H-N.M.R. (CDC 1658-1.73 (1H, m),

95 (1H, d, J = 5.1Hz), 2.36 (3H, s), 2.44 (1H, qu in t., J = 6.2Hz), 2.67 (1H, t, J = 10.7 Hz), 3.12-3. 19 (1H, m), 3.17—3.82 (2H, m), 4.64 to 4.78 (1H, m), 4.83- 4.97 (lH, m), 6.36 (1H, t, J = 8.1 Hz), 6.47-6.58 (2H, m), 6.91—7.08 (4H, m), 7.21 (2H, d, J = 8.1 Hz), 7.27-7.34 (4H, m), 7.36-7.56 (3H, m), 7.81 — 7.88 (lH, m)

I. R. (KB r) Les cm-. , 1630, 1605, 1515, 1505, 1410, 1320 Reference Example 10

(2 S, 3 a S) —2-Acetoxy 5— [4-C [2- (para-tolyl) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyro [1,22a] quinoxaline

(2R, 3aS) —2-Hydroxy-5— [4 — [[2- (para-tolyl) benzoyl] amino] benzoyl] obtained in Reference Example 8 1, 2, 3, 3a, 4 5,5-Hexahydropyrro [1,2-a] quinoxaline 0.8 g, 0.15 g of acetic acid and 0.64 g of triphenylphosphine in 5 mL of anhydrous tetrahydrofuran under ice-cooling under ice-cooling 0.45 g of anhydrous tetrahydrofuran solution (2 mL) was slowly added dropwise. After stirring at room temperature for 2 hours, the reaction solution was concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane ethyl acetate (1Z1) to give 0.55 g (yield: 63.2%) of the title compound as an amorphous powder.

^{_{. 1 HN MR (CDC 1 3}} ) δ: 1. 58- 1. 71 (1H, m), 1. 95 (1 H, d, J = 5. 13Hz), 2. 36 (3H, s), 2 44 (3H, s), 2.67 (1H, t, J = 10.7Hz), 3.12—3.19 (1H, m), 3.17-3.82 (2H, m) , 4.64-4.78 (lH, m), 4.83—4.97 (1H, m), 6.36 (1H, t, J = 8.1Hz), 6 47-6.58 (2H, m), 6.91-7.08 (4H, m), 7.21 (2H, d, J = 8.1 Hz), 7.27-7.34 (4H , m), 7.36—7.56 (3H, m), 7.81 -7.88 (1H, m)

I.R. (KB r) レ cm-3400, 1630, 1605, 1515, 1505, 1410, 1320 Reference example 1 1

(2 S, — 3 a S) 2-Hydroxy-l-52 [4 -— [[2 -— (para-tolyl) benamino]] 2, — 3, — 3 a, —4, 5-hexahydropyrro

(2S, 3aS) -1-2-acetoxy-5- [4 — [[2- (para-tolyl) benzoyl] amino] benzoyl] obtained in Reference Example 10-1,2,3,3a, 4 0.57 g of 1,5-hexahydropyro [1,2-a] quinoxaline and 0.2 g of anhydrous carbon dioxide were added to 2 OmL of methanol, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction solution, the obtained residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was recrystallized from ethyl acetate to give 0.33 g (yield 63.2%) of the title compound.

m.p .: 163—164

^{_{. 1 HN MR (CDC 1 3}} ) δ: 1. 58- 1. 73 (1 Η, m), 1. 95 (1 H, d, J = 5. 1Hz), 2. 36 (3H, s), 2.44 (1 H, qu in t., J = 6.2 Hz), 2.67 (1 H, t, J = 10.7 Hz), 3.12—3.19 (1H, m), 3. 17-3.82 (2H, m), 4.64 — 4.78 (1H, m), 4.83-4.97 (1H, m), 6.36 (1H, t, J = 8.1 Hz), 6.47 -6. 58 (2H, m), 6.91 -7. 08 (4H, m), 7.21 (2H, d, J = 8.1 Hz), 7.27 -7. 34 ( 4H, m), 7.36-7.56 (3H, m), 7.81-7.88 (1H, m)

. I R. (KB r) v cm '1: 3400, 1630, 1 605, 1 5 1 5, 1 505, 141 0, 1 320 Reference Example 12

— (2 S, — 3 aR) _— 2-Acetoxy-[4-_ [[2—— (para-tolyl) benzyl] amino] benzoyl] 1,2,3,3a, 4,5— Hexahydropyro

(2R, 3aR) —2-Hydroxy—5— [4 — [[2-H, obtained in Reference Example 9. Lathril) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyrro [1,2—a] Using quinoxaline, the title compound is amorphous powder in the same manner as in Reference Example 10. As obtained.

Yield 96.3%

^{_{. 1 HN MR (CDC 1 3}} ) (5: 1. 67- 1. 80 (1 H, m), 2. 1 1 (3H, s), 2. 3 1 (1H, dd, J = 5. 1 , 2.5 Hz), 2.36 (3H, s), 2.43—2.55 (lH, m), 3.50—3.65 (2H, m), 3.91-4.06 (1H, m), 4.99—5.12 (1H, m), 5.48-6.04 (lH, m), 6.37 (1H, t, J = 7.3Hz), 6 48-6.55 (2H, m), 6.94-7.09 (4H, m), 7.21 (2H, d, J = 7.7Hz), 7.28-7.58 (5H , M), 7.6 1—7.71 (2H, m), 7.87 (1H, d, J = 7.7Hz)

I.R. (KB r) レ cm- 3270, 1740, 1640, 1600, 1510, 1400, 1320, 1245 Reference Example 13

(2 S, 3 aR) —2-Hydroxy-1-5 -— [4-[[2- (parathryl) benzoyl] amino] benzoyl] — 1,2,3,3a, 4,5-hexahydropyro mouth [1 , 2—a] Quinoxaline (VP—343)

(2 S, 3 aR) —2-Acetoxy—5— [4 — [[2- (parathryl) benzoyl] amino] benzoyl] obtained in Reference Example 12—1, 2, 3, 3a, 4, 5 The title compound was obtained by recrystallization from ethyl acetate-hexane in the same manner as in Reference Example 11 using hexahydropyrro [1,2-a] quinoxaline.

88.6% yield

m.p .: 163-164.5

¹ HN. MR (CDC 13) 60—1.72 (1H, m), 1

85- 1.91 (1H, m), 2.21 (1H, dd, J = 12.8, 5.1 Hz), 2.36 (3H, s), 2.43—2.53 (lH , M), 3.45 (1H, dd, J = 11.0, 4.0Hz), 3.56 (1H, d, J = 11.0Hz), 3.98-4.16 (1H, m), 4.65-4.72 (1H, m), 4.98-5.10 (lH, m), 6.35 (1H, t, J = 7.3Hz), 6.46 -6. 54 (2H, m), 6.91-7.00 (2H, m), 7.05 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.2 9-7. 37 (4H, m), 7.38-7.57 (3H, m), 7.85—7.90 (1H, m)

I. R. (KB r) v cm- ¹ : 3390, 29 10, 1620, 1600, 1 520, 1405, 1320, 1270, 1250, 1 180 Reference Example 14-: I 6

Using the appropriate starting materials, the following compounds were produced in the same manner as in Reference Examples 1 to 13.

Reference Example Number 2 Position 3a Position Rl Physical Properties

14 R R H mp 164-165 in

15 R S H mp 243- 244 in

16 S R 2 -Me m 178- 180 ^

(V P— 386) Spectrum--Evening 1)

1) ¹ HN. MR (CDC 1) δ: 62-76 (m, 1H),

2.10 (s, 3Η), 2.17-2.28 (m, 1H), 2.46-2.64 (m, 1H), 3.41 -3.50 (m, 1H), 3 53—3.61 (m, 1H), 3.99-4.15 (m, 1H), 4.66-4.71 (m, 1H), 4.97-5.05 (m , 1H), 6.31—6.41 (m, 1H), 6.47-6.57 (m, 2H), 6.92-6.99 (m, 3H), 7.22- 7.39 (m, 7H), 7.48— 7.58 (m, 2H), 7.99— 8.16 (m, 1H)

I.R. (KBr) vcm- ¹ : 3432, 2924, 603, 1508, 408, 1321, 1180, 849, 739

S. (FAB): 504 (M + 1) Reference example 1

Dibenzyl (2 S, 3 aR) — 5 -— [4-C [2 -— (para-tolyl) benzoyl] amino] benzoyl] —1,2,3,3a, 4,5-hexahydropyro [1, — 2—a] Quinoxaline-1-yl phosphate

(2S, 3aR) obtained in Reference Example 13 — 2-hydroxy-5— [4 — [[2- (palatolyl) benzoyl] amino] benzoyl] —1,2,3,3a, 4,5— Hexahydropyro mouth [1,2-a] quinoxaline 1.006 g, 1H-tetrazole 0.414 g in dichloromethane solution 3 OmL To 3 OmL, add 1.035 g of N, N-diisopropyldibenzylphosphoramidite, and add 2 g at room temperature. Stirred for hours. Subsequently, the reaction solution was cooled to −40, and 6 mL of a dichloromethane solution of perchlorobenzoic acid (0.646 g, 3.75 mM) was added without exceeding 0, followed by stirring at 0 for 45 minutes. The extract was washed successively with 10% sodium thiosulfate (20 mL × 2), a saturated aqueous solution of sodium bicarbonate and water, and dried. After evaporating to dryness under reduced pressure, the residue was applied to a silica gel column chromatography and eluted with ethyl benzeneacetate (6-4) to obtain 1.1 g (yield 72%) of the title compound as a pale yellow foam.

I. R. (KB r) v cm- ¹ : 1680, 1640, 1600, 1505, 1320, 1000

M.S. (FAB): 764 (M + H) + Example 1

Phosphoric acid (2 S, — 3 aR) 5 -_ [4-[[2-— (para-tolyl) benzoyl] ano] benzoyl] 1, 2, 3, 3 a, 4, 5-hexahydropyrole [1, 2a] Quinoxaline-1-yl-2 disodium (VP——382) —

Dibenzyl (2S, 3aR) obtained in Reference Example 14—5— [4 — [[2- (para-tolyl) benzoyl] amino] benzoyl] —1,2,3,3a, 4,5— Hexahydropyrro [1,2-a] quinoxaline-2-ylphosphoate 0.85 g of methanol solution 2 OmL in hydrogen at room temperature and atmospheric pressure in the presence of 10% palladium-carbon catalyst 0.17 g Decomposed. After completion of the reaction, the catalyst was removed, 10% NaOH (0.89 g) was added, and the mixture was concentrated under reduced pressure at 40 at the following. The residue was purified by an ODS column (methanol Z water = 1: 1) to give 0.55 g (yield 79%) of the title compound as a yellow foam.

m. p .: 2 16-22 O: (decomposition)

1 HN. MR (D ₂ 0) δ: 1.5-1.7 (1 H, m), 1.96 (3 H, s), 2.15-2.45 (2H, m), 3 2—3.35 (1H, m), 3.65-3.8 (lH, m), 3.85—4.05 (1H, m), 4.8—4.95 (lH, m ), 5.8—6.1 (lH, m), 6.6—7.4 (16H, m)

I.R. (KBr) vcm- ¹ : 1660, 1630, 1600, 1500, 1410, 1100, 975

M.S. (FAB): 629 (M + 2H) + Examples 2 to 5

_T that the following compounds were prepared in the same manner as in Example 1

OPO (ONa) ₂

Disposed R ¹ Physical Properties of the arrangement 3 a position of Example No. 2 of

2 R R H Yellow powder, mp293 -295 ^ (decomposed)

(VP—383) Spectral Day 'Even 1)

3 R S H yellow powder, mpl50 -160 * C (decomposition)

(VP-384) Suktordeichi 'Even 2)

4 R R 4-Me yellow powder, mpl91- -199 (decomposition)

(VP-385) Spectlde 'Evening 3)

5 S R 2-Me yellow powder, mp214- -216 (decomposed)

(VP-387) Spectlde-Evening 4)

1) ¹ HN. MR (D _z O) δ: 1.86—2.22 (1H, m), 2.62-2.76 (lH, m), 3.01—3.17 (1Η, m), 3.37-3.46 (1H, m), 3.82—3.98 (1H, m), 3.98-4.08 (1H, m), 4.67-4. 81 (1H, m), 5.01—5.12 (1H, m), 6.63–6.75 (lH, m), 6.94—7.02 (lH, m), 7.

27-7.37 (lH, m), 7.42-7.49 (2H, m), 7.53-7.68 (8H, m), 7.69-7.77 (2H, m), 7.79-7.89 (2H, m)

I. R. (KB r) レ cm- Β Β Β β, 1605, 1508, 1412, 1

323, 1 100, 982, 847, 745, 584, 408

M.S. (FAB): 614 (M + H) +

^{. 2) 1 HN MR (D} 2 〇) δ: 1. 59- 1. 70 ( 1 H, m), 2. 43 - 2. 58 (2H, m), 3. 38- 3. 44 (1H, m), 3.49 (1

H, d, J = 10.3 Hz), 3.98-4.08 (1H, m), 4.86—4.93 (1H, m), 5.00 (1H, quint, J = 3.7 Hz), 6.29-6.34 (1H, m), 6.57 (2H, d, J = 8.1 Hz), 6.93-6.98 (lH, m), 7. 28-7.62 (13 H, m)

I.R. (KBr) L cm- ¹ : 3444, 1603, 1508, 1412, 1 321, 1087, 745

M.S. (FAB): 614 (M + H) +

3) ¹ HN. MR (CD ₃ OD) δ: 1.76 (1H, dt, J = 1.1.7, 9.3 Hz), 2.30 (3H, s), 2.53 (1H, qu) int, J = 5.9Hz), 2.70-2.78 (1H, m), 3.25 (1H, dd, J = 9.8, 6.8Hz), 3.63—3.74 (lH, m ), 3.88 (1 H, d, J = 9.8, 6.8 Hz), 4.76 (1 H, br), 4.93—5.03 (1H, m), 6.32 (1H , t, J = 7.3 Hz), 6.59—6.62 (2 H, m), 6.91 -6.97 (1H, m), 7.15 (2H, d, J = 7 8 Hz), 7.28—7.59 (10 H, m)

1. R. (KB r) v cm- ¹ : 3396, 1605, 1508, 141 0, 1 321, 1 274, 1094, 982, 90 1, 822, 746, 567

M.S. (FAB): 628 (M + H) +

4) ¹ HN. MR (CD ₃ OD) δ: 1.62-1.70 (1 H, m),

2.24 (3H, s), 2.48-2.73 (2H, m), 3.28-3.57 (lH, m), 3.84-3.97 (lH, m), 4. 04-4.23 (1H, m), 4.74-5.22 (2H, m), 6.3 1—6.46 (1H, m), 6.60 -6.73 (2H, m ), 6.95-7.09 (1 H, m), 7.24-7.88 (12H, m)

I.R. (KBr) vcm " ¹ : 3424, 1632, 1522, 141 0, 1 323, 1085, 980, 837, 750, 68 1

M.S. (FAB): 629 (M + 2H) + industrial applicability

The intraocular pressure lowering agent of the present invention has the above-mentioned structure, and is characterized by containing, as an active ingredient, a compound having a vasopressin V1 receptor antagonistic action or a pharmacologically acceptable salt thereof, and has no side effects. It has an excellent intraocular pressure lowering effect, and can be used as a glaucoma application agent and an ocular hypertension application agent for the treatment and prevention or prevention of glaucoma and ocular hypertension. The compound (1) of the present invention has the above-mentioned novel chemical structure and is a novel compound not described in any literature.

Claims

The scope of the claims

An intraocular pressure lowering agent comprising a compound having a receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient.

2. The intraocular pressure lowering agent according to claim 1, wherein the intraocular pressure lowering agent is a therapeutic agent for glaucoma or an ocular hypertension.

3. The compound having vasopressin VI receptor antagonistic activity includes a compound represented by the following general formula (1), a compound represented by the following formula (A), and 1- {1-1-1 [3- (3-α) Cetylaminopropoxy) benzoyl] _4-piperidyl} —3,4-dihydrido—2 (1H) —quinolinone, which is at least one compound selected from the group consisting of: intraocular pressure reduction according to claim 1 or 2. Agent.

(Wherein, R ¹ represents hydrogen or alkyl having 1 to 4 carbon atoms, M ¹ and M ² may be the same or different, and are hydrogen or monovalent pharmacologically acceptable Represents an alkali metal salt.)

(A)

4. The intraocular pressure-lowering agent according to claim 1, 2 or 3, wherein the dosage form is an intravenous administration.

5. The intraocular pressure lowering agent according to claim 1, wherein the dosage form is a topical administration agent.

6. The intraocular pressure lowering agent according to claim 1, 2 or 3, wherein the dosage form is an eye drop.

7. A phosphate derivative represented by the following general formula (1).

In the formula, R ¹ represents hydrogen or alkyl having 1 to 4 carbon atoms, and M ¹ and M ² may be the same or different, and are hydrogen or monovalent pharmacologically acceptable Al force represents a metal salt.

8. The phosphate derivative according to claim 7, wherein R ¹ is methyl.

9. The phosphate derivative according to claim 7, wherein M ¹ and M ² may be the same or different, and are hydrogen or sodium.