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WO1999065525A1 - Agents permettant d'abaisser la tension oculaire et derives d'ester phosphorique - Google Patents

Agents permettant d'abaisser la tension oculaire et derives d'ester phosphorique Download PDF

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Publication number
WO1999065525A1
WO1999065525A1 PCT/JP1999/003277 JP9903277W WO9965525A1 WO 1999065525 A1 WO1999065525 A1 WO 1999065525A1 JP 9903277 W JP9903277 W JP 9903277W WO 9965525 A1 WO9965525 A1 WO 9965525A1
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WO
WIPO (PCT)
Prior art keywords
compound
intraocular pressure
vasopressin
benzoyl
agent
Prior art date
Application number
PCT/JP1999/003277
Other languages
English (en)
Japanese (ja)
Inventor
Yasuhiro Ohtake
Akira Naito
Yoko Tanaka
Kenji Naito
Hidehiko Matsukawa
Original Assignee
Wakamoto Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP18805898A external-priority patent/JP2002179573A/ja
Priority claimed from JP18806298A external-priority patent/JP2002179694A/ja
Priority claimed from JP09689299A external-priority patent/JP2002179591A/ja
Application filed by Wakamoto Pharmaceutical Co., Ltd. filed Critical Wakamoto Pharmaceutical Co., Ltd.
Priority to AU41689/99A priority Critical patent/AU4168999A/en
Publication of WO1999065525A1 publication Critical patent/WO1999065525A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • 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.
  • 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.
  • a carbonic anhydrase inhibitor oral, ophthalmic solution
  • hypertonic osmotic agent injection
  • pilocarpine ophthalmic solution
  • epinephrine and its prodrug dipivefrin
  • 3 receptor blocker Ophthalmic solution
  • isopropyl unoprostone Ophthalmic solution
  • taking a carbonic anhydrase inhibitor may cause gastrointestinal disorders, urolithiasis, and electrolyte abnormalities.
  • epinephrine and dipivefrin are 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.
  • 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.
  • 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).
  • 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).
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • compound (1) A compound represented by the following general formula (1) (hereinafter, referred to as compound (1));
  • R 1 represents hydrogen or alkyl having 1 to 4 carbon atoms
  • ⁇ 1 and ⁇ 2 may be the same or different, and are hydrogen or monovalent pharmacologically acceptable.
  • a compound represented by the following general formula ( ⁇ ) (hereinafter, referred to as compound ( ⁇ ));
  • R 1 represents hydrogen or alkyl having 1 to 4 carbon atoms
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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, ⁇ -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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the carrier examples 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.
  • 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.
  • 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.
  • a preliminary vial or carrier is prepared. Is also good.
  • the intraocular pressure-lowering agent of the present invention 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.
  • the intraocular pressure-lowering agent of the present invention When 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.
  • 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.
  • 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.
  • a disintegrant or a solubilizer to the above capsules can improve the efficacy of the medicine when the capsules are taken.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • R 1 represents hydrogen or alkyl having 1 to 4 carbon atoms
  • M 1 and M 2 may be the same or different
  • R 1 , M 1 and M 2 are as described in the first 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.
  • a commonly used surfactant such as tween 80, HCO60 or polyoxyl stearate 40 is used.
  • 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.
  • 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).
  • the above synthetic intermediate (2) was converted to 1H-tetrazo-one.
  • 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)].
  • the phosphate ester (3) of the present invention can be produced by deprotecting the phosphate triester (3) by hydrogenolysis.
  • other phosphating agents for example, phosphepane [Watanabe et al., Tetraedron Letters, 255-256 (1990)], N, N-getyldibenzylphosphoramidite [J. W.
  • 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.
  • 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, ⁇ ,) 3-trichloroethyl chloride) phosphoric acid chloride, ⁇ -diphenyl- ⁇ , 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.
  • imidoylphosphoric acid examples include, for example, compounds obtained from / 3-cyanoethylphosphoric acid and dicyclohexylcarposimide.
  • 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.
  • 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.
  • 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).
  • the halogenating agent include thionyl chloride, oxalyl chloride, phosphorus pentachloride and the like.
  • 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.
  • a condensing agent include dihexyl carbyl imide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, and carbonyldiimidazole.
  • 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).
  • the activated ester include nitro- or halogen-substituted phenyl esters, aromatic thioesters, N-hydroxysuccinates, 1-hydroxybenzotriazole esters, phenolic esters and the like.
  • condensing agent for the phosphorus compound examples 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.
  • 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.
  • 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.
  • the carboxylic acid (5) 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.
  • the organic base include N-methylmorpholine, trimethylamine, triethylamine, ⁇ , ⁇ ′-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.
  • the above-mentioned synthesis intermediate (2) can be obtained by performing the amide bond formation reaction and then removing the protecting group.
  • 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.
  • aprotic polar solvent examples include N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide.
  • azodicarboxylic diesters examples 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.
  • 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.
  • 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.
  • Test example 1 Intraocular pressure lowering effect
  • 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.
  • Example 2 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.
  • test results 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.
  • 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.
  • Example 2 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 ⁇ ⁇ 0.05 (vs. control group), and these were analyzed by the Student's t-test (Stude ⁇ 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
  • Compound (A) was dissolved in N, N-dimethylformamide to a concentration of 15 mgZmL to prepare an intravenous formulation.
  • Example 2 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)
  • Test example 7 Intraocular pressure lowering effect
  • 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.
  • OPC-21268, VP-343 and SR_121463 ⁇ 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.
  • 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.
  • OPC-31260 and SR-121463A no significant difference from the control group was observed at any time after intravenous administration.
  • Test example 8 Intraocular pressure lowering effect
  • a peptidic selective vasopressin V 1 receptor antagonist [One me rcapto- ⁇ ,] 3- eyel ome t hy lenepropio ny l 1, ⁇ 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.
  • Example 1 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
  • 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.
  • test compounds 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.
  • Hydroxypropyl methyl cell mouth 2910 4.
  • Omg Polyethylene Dalicol 6000 0.5 mg Titanium oxide 0.5 mg
  • 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. ⁇
  • a tablet of 10 Omg per tablet was prepared using an X5R mortar.
  • Example 4 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
  • Polyethylene glycol 4000 20 Polyethylene glycol 4000 20.
  • 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
  • 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
  • OPC-21268 3. Omg concentrated glycerin 5.2 mg polyethylene glycol 4000 20. Omg 10% lactic acid 2. Omg water for injection
  • OPC— 21268 5.
  • OPC-21268 5.
  • 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.
  • reaction solution was washed sequentially with water, 1N-sodium carbonate aqueous solution, 1N-hydrochloric acid, and water, and dried over anhydrous magnesium sulfate.
  • 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.
  • 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.
  • 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.

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Abstract

Cette invention concerne des agents qui permettent d'abaisser la tension oculaire et qui sont utiles dans le traitement et la prévention de glaucomes et de l'hypertension oculaire. Ces agents contiennent, en qualité d'ingrédient actif, des substances chimiques qui présentent un antagonisme envers le récepteur de vasopressine V1. Cette invention concerne également des dérivés d'ester phosphorique qui correspondent à la formule générale (1).
PCT/JP1999/003277 1998-06-19 1999-06-18 Agents permettant d'abaisser la tension oculaire et derives d'ester phosphorique WO1999065525A1 (fr)

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AU41689/99A AU4168999A (en) 1998-06-19 1999-06-18 Ocular tension lowering agents and phosphoric ester derivatives

Applications Claiming Priority (6)

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JP10/188062 1998-06-19
JP10/188058 1998-06-19
JP18805898A JP2002179573A (ja) 1998-06-19 1998-06-19 緑内障治療剤及び高眼圧症治療剤
JP18806298A JP2002179694A (ja) 1998-06-19 1998-06-19 リン酸エステル誘導体及び医薬組成物
JP11/096892 1999-04-02
JP09689299A JP2002179591A (ja) 1999-04-02 1999-04-02 眼圧下降剤

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001054698A1 (fr) * 2000-01-26 2001-08-02 Warner-Lambert Company Procede permettant d'empecher ou de traiter des occlusions intestinales postoperatoires
US6903091B2 (en) 2001-04-12 2005-06-07 Wyeth Biphenyl vasopressin agonists
US7053083B2 (en) 2001-04-12 2006-05-30 Wyeth Cyclohexylphenyl vasopressin agonists

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0636608A1 (fr) * 1993-07-30 1995-02-01 Sanofi Dérivés du 1-benzènesulfonyl-1,3-dihydro-indol-2-one, leur préparation, les compositions pharmaceutiques en contenant
WO1995018105A1 (fr) * 1993-12-24 1995-07-06 Sanofi Derives de 1,3-dihydroindol-2-one substitues en 3 par un groupe azote comme agonistes et/ou antagonistes de la vasopressine et/ou de l'ocytocine
EP0694536A1 (fr) * 1994-07-05 1996-01-31 Sanofi Dérivés de 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one, leur préparation, et compositions pharmaceutiques les contenant
EP0709386A1 (fr) * 1993-07-21 1996-05-01 Yamanouchi Pharmaceutical Co. Ltd. Derive de benzazepine de fusion et composition pharmaceutique renfermant ce derive
WO1998043976A1 (fr) * 1997-03-31 1998-10-08 Wakamoto Pharmaceutical Co., Ltd. Derives de biphenyle et compositions medicinales

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0709386A1 (fr) * 1993-07-21 1996-05-01 Yamanouchi Pharmaceutical Co. Ltd. Derive de benzazepine de fusion et composition pharmaceutique renfermant ce derive
EP0636608A1 (fr) * 1993-07-30 1995-02-01 Sanofi Dérivés du 1-benzènesulfonyl-1,3-dihydro-indol-2-one, leur préparation, les compositions pharmaceutiques en contenant
WO1995018105A1 (fr) * 1993-12-24 1995-07-06 Sanofi Derives de 1,3-dihydroindol-2-one substitues en 3 par un groupe azote comme agonistes et/ou antagonistes de la vasopressine et/ou de l'ocytocine
EP0694536A1 (fr) * 1994-07-05 1996-01-31 Sanofi Dérivés de 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one, leur préparation, et compositions pharmaceutiques les contenant
WO1998043976A1 (fr) * 1997-03-31 1998-10-08 Wakamoto Pharmaceutical Co., Ltd. Derives de biphenyle et compositions medicinales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KRUSZYNSKI M. et al., "Antivasopressor Antagonists of Arginine-vasopressin", J. MED. CHEM., April 1980, Vol. 23, No. 4, pages 364-368. *
OHTAKE Y. et al., "Novel Vasopressor V2 Receptor-selective Antagonist", BIOORG. MED. CHEM., June 1999, Vol. 7, No. 6, pages 1247-1254. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001054698A1 (fr) * 2000-01-26 2001-08-02 Warner-Lambert Company Procede permettant d'empecher ou de traiter des occlusions intestinales postoperatoires
US6645959B1 (en) 2000-01-26 2003-11-11 Warner-Lambert Company Method for treating postoperative ileus
US6903091B2 (en) 2001-04-12 2005-06-07 Wyeth Biphenyl vasopressin agonists
US7053083B2 (en) 2001-04-12 2006-05-30 Wyeth Cyclohexylphenyl vasopressin agonists
US7223752B2 (en) 2001-04-12 2007-05-29 Wyeth Biphenyl vasopressin agonists
US7329653B2 (en) 2001-04-12 2008-02-12 Wyeth Cyclohexylphenyl vasopressin agonists
US7465722B2 (en) 2001-04-12 2008-12-16 Wyeth Biphenyl vasopressin agonists

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