WO2001062724A1 - Derives de prostaglandine e - Google Patents

Derives de prostaglandine e Download PDF

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Publication number
WO2001062724A1
WO2001062724A1 PCT/JP2001/001496 JP0101496W WO0162724A1 WO 2001062724 A1 WO2001062724 A1 WO 2001062724A1 JP 0101496 W JP0101496 W JP 0101496W WO 0162724 A1 WO0162724 A1 WO 0162724A1
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WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
prostaglandin
smooth muscle
vascular smooth
Prior art date
Application number
PCT/JP2001/001496
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English (en)
Japanese (ja)
Inventor
Fumie Sato
Tohru Tanami
Hideo Tanaka
Naoya Ono
Makoto Yagi
Hitomi Hirano
Original Assignee
Taisho 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.)
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Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU2001235990A priority Critical patent/AU2001235990A1/en
Publication of WO2001062724A1 publication Critical patent/WO2001062724A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel prostagnadin E derivative, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition containing the same and having an excellent smooth muscle growth inhibitory action and the like.
  • Prostaglandins (hereinafter referred to as “PG”) are known to exert various important physiological actions in trace amounts.
  • PG Prostaglandins
  • a large number of derivatives, including natural PG have been synthesized with the intention of applying PG to medicines, and their biological activities have been studied and reported in numerous documents.
  • Such documents include, for example, Japanese Patent Application Laid-Open No. 52-104446 and US Patent Nos. 4,131,738.
  • Physiological actions of PG and its derivatives include vasodilatory action, inflammation action, platelet aggregation inhibitory action, uterine muscle contraction action, intestinal contraction action, intraocular pressure lowering action, etc., cardiomyocardial infarction, angina, It is useful for treatment or prevention of arteriosclerosis, hypertension, induction of labor, etc.
  • PTCA percutaneous coronary angioplasty
  • PTCA has the problem that within a few months after surgery, coronary artery restenosis appears at a frequency of 30 to 40%.
  • Vascular smooth muscle cells are thought to be deeply involved in the occurrence of such restenosis (see Ross, R. (1993) Nature 362, 801-809).
  • the migration of vascular smooth muscle cells from the intima to the media and proliferation in the media are deeply involved in the mechanism of restenosis, and compounds that suppress this are effective drugs for preventing restenosis.
  • no clinically useful drug has yet been found. Disclosure of the invention
  • An object of the present invention is to provide a compound having a vascular smooth muscle growth inhibitory activity, which is highly expected as an agent for preventing or treating diseases such as restenosis after PTCA, and a pharmaceutical composition containing such a compound. I do.
  • the present inventors have conducted intensive studies and found that the novel PGE derivative represented by the following formula (I) has a vascular smooth muscle growth inhibitory effect and is useful as a pharmaceutical composition.
  • the present invention has been completed.
  • the present invention provides a compound represented by the formula (I):
  • m represents an integer of 1 to 4
  • n represents an integer of 0 to 3
  • p represents an integer of 0 to 2
  • q represents an integer of 1 to 4
  • Y represents an ethylene group
  • Z represents S (O) p , 0, an ethylene group, a vinylene group or an ethynylene group
  • R 1 represents a cycloalkyl group having 3 to 10 carbon atoms, and a hydrogen atom having 1 carbon atom.
  • R 2 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl having 3 to 10 carbon atoms; Or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter referred to as “PGE derivative or the like”).
  • the present invention provides a method for producing a PGE derivative represented by the formula (I) in a pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing a body or the like.
  • the present invention provides a vascular smooth muscle growth inhibitor containing a PGE derivative represented by the formula (I) or the like as an active ingredient, an agent for preventing a disease or condition caused by vascular smooth muscle proliferation, and a vascular smooth muscle proliferation.
  • the present invention provides a method for preventing a disease or medical condition caused by vascular smooth muscle proliferation, which comprises administering the above pharmaceutical composition to human, and a vascular smoothing method comprising administering the above pharmaceutical composition to a patient.
  • a method for treating a disease or medical condition caused by muscle growth is provided.
  • the present invention 0, the use of the above-mentioned PGE derivative or the like for the prevention or treatment of a disease or medical condition caused by vascular smooth muscle proliferation, and the use of a vascular smooth muscle proliferating agent or a disease or medical condition caused by vascular smooth muscle proliferation. It is intended to provide use of the above PG II derivative or the like for producing a prophylactic or therapeutic agent.
  • the configuration of the substituent bonded to the vinylene group may be any of ⁇ and ⁇ .
  • the alkyl group having 1 to 10 carbon atoms may be linear or branched, and examples thereof include a methyl group, an ethyl group, an ⁇ -propyl group, an isopropyl group, an ⁇ -butyl group, an isobutyl group, and a tert-butyl group.
  • n-pentyl isopentyl, 2-ethizolepropyl, n-hexyl, isohexyl, 1-ethylbutyl, n-heptyl, isoheptyl, n-octyl , N-Noel group, n-decyl group, 2,4-dimethynolepentinole group, 2-ethylpentyl group, 2-ethylhexyl group, 2-propylpentyl group, 2-propylhexyl group, 2, 6-dimethylheptyl group and the like.
  • the alkenyl group having 2 to 10 carbon atoms may be linear or branched, for example, a butyl group, an aryl group, a butenyl group, a 3-pentenyl group, a 4-hexenyl group, and a 5-heptenyl group A 4-methyl-13-pentenyl group, a 2,4-dimethyl-3-pentenyl group, a 6-methyl-5-heptenyl group, and a 2,6-dimethyl-5-heptenyl group.
  • the alkynyl group having 2 to 10 carbon atoms may be either straight-chain or branched, and includes, for example, an ethur group, a 2-propyl group, a 3-butyl group, a 3-pentynyl group, and a 3-pentynyl group.
  • —Hexinole group, 4 1-hexinole group, 1-methinolepenta-1 3 Ininole group, 2-methylinolepenter 3-inole group, 1-methinolehexa 3-ininole group, 2-methylhexa 3-inyl group and the like.
  • Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclobutynol group, a cyclopentynol group, a cyclohexynole group, a cycloheptynol group, a cyclooctyl group, a cyclonol group, and a cyclodecyl group.
  • Examples of the cycloalkyl group having 3 to 10 carbon atoms in which a hydrogen atom is substituted with an alkyl group having 1 to 4 carbon atoms include, for example, methylcyclopropyl group, methylcyclohexyl group, ethylcyclohexyl group, and propylcyclononyl. And the like.
  • Examples of the cycloalkylalkyl group having 4 to 13 carbon atoms include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentynoletyl group, a cyclohexynolemethynol group, a cyclohexynoletinol group, and a cycloalkyl group.
  • Examples include a heptinolemethyl group and a cyclononylbutyl group.
  • crosslinked cyclic hydrocarbon group examples include a bornyl group, a norbornyl group, an adamantyl group, a pininole group, a thiol group, a caryl group, a camphanyl group, and the like.
  • Pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with ammonium chloride; methylamine, dimethizoleamine; Salts with amines such as pliers / reamine, benzinoleamine, piperidine, monoethanolamine, diethanolamine, monomethinole monoethanolamine, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane, etc. It is the c hydrate which may be mentioned, as long as it is pharmaceutically acceptable, and there is no particular limitation on the number of water binding to PGE derivatives of 1 molecule.
  • n in the formula (I) is preferably an integer of 1 to 3.
  • n is preferably an integer of 0 to 2.
  • p may be any integer from 0 to 2, and is preferably 0.
  • q is preferably 2 or 3.
  • Y may be any of an ethylene group, an (E) vinylene group, a (Z) vinylene group, and an ethynylene group, and is preferably an (E) vinylene group, a (Z) vinylene group, or an ethylene group.
  • Z is preferably an ethylene group, ⁇ , S, S (O).
  • R 1 is a hydrogen atom substituted with a substituent Unsubstituted cycloalkyl group having 4 to 7 carbon atoms, linear or branched alkyl group having 4 to 8 carbon atoms, branched alkenyl group having 6 to 1 ⁇ carbon atoms, 6 to 1 carbon atoms A branched alkynyl group of 0 is preferred.
  • the configuration may be either R or S. Alternatively, it may be racemic.
  • R 2 is preferably a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, and an isobutyl group.
  • the bond between the carbon atom at position 7 and the carbon atom at position 8 (denoted as position 8 in Tables 1 and 2), the bond between the carbon atom at position 11 and the sulfur atom (see Tables 1 and 2)
  • the configuration of the bond between the carbon atom at position 15 and the hydroxyl group (described as position 15 in Tables 1 and 2) and j3 may be either j or j3.
  • the PGE derivative and the like of the present invention are those wherein m, n, p and q in the formula (I) are any of the above-mentioned preferred integers, and Y, Z and RR 2 are any of the above-mentioned preferred groups.
  • RR 2 is any of the more preferred groups described above.
  • prostaglandin E derivatives of the present invention particularly preferred ones are shown in Tables 1 and 2 as Compounds 1 to 48.
  • Z 1 represents ethylene group, vinylene group, ethynylene group, o S
  • S 2 represents ethylene group, vinylene group, ethynylene group, 0 SS (O) pl
  • Et represents ethyl group
  • TB S represents a tert- butyldimethylsilyl group
  • R 3 is an alkyl group or carbon number 3 to 0 1 1 carbon atoms
  • a compound of the formula (III ') is used.
  • the compound of formula (III) is used to obtain a compound of the ren group, and is reacted at about 030 ° C.
  • Base resins such as organic amines, polyvinylpyrrolidone, diisopropylaminomethyl-polystyrene, (piperidinomethyl) polystyrene) or, if necessary, radical generators (eg, azobisisobutyl nitrile, azobiscyclohexanecarbo-tolyl, peroxide peroxide) About 0.0012 equivalents in an inert solvent (for example, benzene, toluene, xylene, n-xane, n-pentane, acetone, chlorophonolem, etc.). By reacting at 00 ° C, a compound of the formula (VI) is obtained.
  • an inert solvent for example, benzene, toluene, xylene, n-xane, n-pentane, acetone, chlorophonolem, etc.
  • the compound of formula (VI) is treated with methanol, ethanol, acetonitrile or methanol using hydrofluoric acid, pyridinum poly (hydrogen fluoride), hydrochloric acid, etc.
  • a mixed solvent thereof or a mixed solvent thereof and water tert-butyldimethylsilyl group, which is a protecting group for a hydroxyl group, is removed under a condition usually used to obtain a compound of the formula (VII).
  • An organic acid eg, formic acid, acetic acid, etc.
  • an inorganic acid eg, formic acid, acetic acid, etc.
  • an organic solvent eg, methanol, ethanol, ethyl acetate, dioxane, etc.
  • sulfuric acid, hydrochloric acid, etc. at about 0 to 60 ° C. to obtain a compound of the formula (VIII).
  • a compound of the formula (VIII) is compounded with about 1 to 5 equivalents of the compound of the formula (IX) and, if necessary, an amine (eg, triethylamine, diisobutylamine, etc.) or an Radical generator (e.g., azobisisobutyl mouth-tolyl, azobiscyclohexanecarbonitrile, benzoyl peroxide, triethylporan, etc.) About 0.05 to 2 equivalents of an inert solvent (e.g., benzene, toluene, xylene, n —Hexane, n-pentane, acetone, black honolem, etc.) and react at about 1780 to 100 ° C.
  • R 2 is a group other than a hydrogen atom (ie, R 3 ) p is 0, and the formulas according to the present invention, each having a different configuration at the 1-position
  • R 2 is a hydrogen atom in (I), P GE derivative of a compound formula of the present invention p is 0 (lb) or (lb ') is obtained.
  • Enzymes include enzymes produced by microorganisms (for example, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas) and enzymes prepared from animal organs (for example, prepared from pig liver and pig knee). Enzymes).
  • Lipase VII manufactured by Sigma and derived from Candida microorganism
  • Lipase AY manufactured by Amano Pharmaceutical and derived from Candida microorganism
  • Lipase PS Amano Pharmaceutical, derived from a microorganism of the genus Pseudomonas
  • Lipase MF Amano Pharmaceutical, PLE (prepared from pig liver, manufactured by Sigma)
  • Lipase II OOSMM prepared from pig kidney
  • lipoprotein lipase prepared from staple knee, manufactured by Tokyo Chemical Industry Co., Ltd.
  • the amount of the enzyme to be used may be appropriately selected according to the titer of the enzyme and the amount of the substrate [compound of the formula (Ia) or (Ia ')], but is usually about 0.1 to 20% by weight of the substrate.
  • c the reaction temperature is double is from about 2 5 ⁇ 5 0 ° C, preferably about 30 to 40 ° C.
  • the compound of the formula (Ia) or (Ia ') is converted to an oxidizing agent such as sodium metaperiodate, aqueous hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and tert-butyl hydroperoxide.
  • R 2 is a hydrogen atom other than a hydrogen atom in the formula (I)
  • it is oxidized by reacting it in getyl ether, methanol, ethanol, methylene chloride, water or a mixed solvent thereof at about 120 to 50 ° C. in the group (i.e., R 3)
  • PGE derivatives of p is 1 or 2 (i.e., p 1) compound formula of the present invention (I c) or (I c ') are obtained.
  • the PGE derivative of the formula (Id) or (Id ') can be obtained by hydrolyzing the compound of (Ic') in the same manner as in (6) above.
  • the pharmaceutical composition of the present invention will be described.
  • the pharmaceutical composition of the present invention contains a PGE derivative represented by the above formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
  • the pharmaceutical composition of the present invention can be used as a vascular smooth muscle cell growth inhibitor, and can be used for diseases and conditions caused by vascular smooth muscle cell proliferation, in particular, for thickening or obstruction of blood vessels due to vascular smooth muscle cell proliferation. It is useful as a prophylactic or therapeutic agent.
  • the pharmaceutical composition of the present invention has a high vascular smooth muscle growth inhibitory effect, and is therefore useful as a preventive or therapeutic agent for restenosis after PTCA.
  • composition of the present invention may be used as a vascular smooth muscle growth inhibitor as a preventive or therapeutic agent for diseases and conditions caused by proliferation of vascular smooth muscle cells such as arteriosclerosis, in addition to restenosis after PTCA.
  • vascular smooth muscle growth inhibitor as a preventive or therapeutic agent for diseases and conditions caused by proliferation of vascular smooth muscle cells such as arteriosclerosis, in addition to restenosis after PTCA.
  • the pharmaceutical composition of the present invention can be systemically or locally administered orally or parenterally, such as rectally, subcutaneously, muscle, intravenously, transdermally, and the like. Of these, oral administration and intravenous administration are preferred.
  • the pharmaceutical composition of the present invention can be produced by mixing a pharmaceutically acceptable carrier, which is usually used, with a PGE derivative or the like.
  • a pharmaceutical composition for oral administration is obtained by adding an excipient, a binder, a disintegrant, a bulking agent, a coating agent, a sugar coating, or an aqueous or non-aqueous solvent to a PGE derivative or the like, It can be manufactured in the form of tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, and the like according to a conventional method.
  • compositions for intravenous administration include aqueous or non-aqueous solutions, emulsions, suspensions, or solid preparations to be dissolved in an injection solvent immediately before use, according to a conventional method. Can be manufactured. Further, the PGE derivative of the present invention can also be formulated by forming an inclusion compound with «or ⁇ -cyclodextrin or methylated cyclodextrin. Further, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like.
  • the dosage of the PGE derivative etc. of the present invention varies depending on the disease, symptom, body weight, age, sex, administration route, etc., but it is preferably 0.1 ng to 10 mg / day for an adult, and is preferably once a day. Or, it is administered in several divided doses. When used as a vascular smooth muscle growth inhibitor, the dose is preferably 1 ng to 1 mgZ days for an adult, which is administered once or several times a day.
  • the amounts are administered sequentially.
  • Example 1 (2) Substantially the same as in Example 1 (2) except that methyl 5-mercaptopentanoate was used in place of methyl 5-mercaptopentanoate in Example 1 (2).
  • (17 R) 3-oxa 6-thia 17, 20 dimethynole 13, 14 -didehydro 1 PGE methylenoleestenol 11, 15 -bis (tert-butyldimethylsilyl ether) Obtained.
  • Example 1 (4) instead of (17R) —6_thia_17,20—dimethyl-13,14_didehydro_PGEi methyl ester, the above (2) (17R) _3-oxer 6-thia-17,20-dimethyl-13,14-didedrawing was carried out in substantially the same manner as in Example 1 (4) using the compound obtained in (1). PG methinoleester was obtained.
  • Example 1 (2) In the same manner as in Example 1 (2), except that in Example 1 (2), methyl 5-mercapto-13-thia-monopentanoate was used instead of methyl 5-mercaptopentanoate. , (17 R) — 3,6-dithia-17,20—dimethyl-13,14_didehydro PGE i methylester-11,15-bis (tert-butyldimethinoresilyl ether) and (17R) — 3,6-dithia — 17,20-dimethinole 13, 1 4-didehydro 8] 3—PGE1 5-bis (tert-butyldimethylsilyl ether) was obtained.
  • IR (neat); 3400, 2953, 2929, 2871, 1746, 1740, 1461, 1436, 1407, 1381, 1352, 1284, 1 2 0 2, 1 1 5 3, 1 0 50, 100 9, 7 14, 5 9 3 cm_l 0
  • the embodiments of the compound prepared in Example 24, 2 5, or 44 respectively 1 X 1 0- 3 M increasing ⁇ medium supplemented with ethanol solution 5 mu 1 at a concentration of (SG 2) 4 9 0 ⁇ 1 was added.
  • 3 Eta - added thymidine (Daiichi Pure Chemicals) at 0. O lmc i / Ueru after 24 hours of cultivation, the culture supernatant to suction removal removed by and washed with phosphate buffer (PBS).
  • PBS phosphate buffer
  • the PGE derivative and the like of the present invention exhibit an excellent inhibitory action on proliferation of vascular smooth muscle cells, and a pharmaceutical composition containing the same can be used as a prophylactic or therapeutic agent for diseases or conditions caused by proliferation of vascular smooth muscle cells. It is useful as a therapeutic agent, particularly as an agent for suppressing the thickening or obstruction of blood vessels, and particularly as a preventive or therapeutic agent for restenosis after PTCA caused by thickening of blood vessels due to proliferation of vascular smooth muscle cells.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne de nouveaux dérivés de prostaglandine E de formule (I), les sels pharmaceutiquement acceptables de ces derniers ou les hydrates de ces derniers et des compositions pharmaceutiques contenant ces composés qui présentent un effet inhibiteur sur la prolifération des muscles lisses vasculaires et qui sont utiles en tant que médicaments prophylactiques ou thérapeutiques pour la resténose post ACTP et d'autres maladies. Dans la formule (I), Y représente éthylène ou autre ; Z représente S(O)p ou autre ; R1 représente cycloalkyle C¿3-10? ou autre ; R?2¿ représente hydrogène ou autre ; m représente un entier compris entre 1 et 4 ; n représente un entier compris entre 0 et 3 ; p représente un entier compris entre 0 et 2 ; et q représente un entier compris entre 1 et 4.
PCT/JP2001/001496 2000-02-28 2001-02-28 Derives de prostaglandine e WO2001062724A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001235990A AU2001235990A1 (en) 2000-02-28 2001-02-28 Prostaglandin e derivatives

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JP2000052556 2000-02-28
JP2000-52556 2000-02-28

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1219601A1 (fr) * 1999-09-10 2002-07-03 Taisho Pharmaceutical Co., Ltd Derives de prostaglandine
WO2003007941A1 (fr) * 2001-07-16 2003-01-30 F. Hoffmann-La Roche Ag Derives de pyrrolidone comme antagonistes de prostanoide
US7608637B2 (en) 2001-07-23 2009-10-27 Ono Pharmaceutical Co., Ltd. Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as the active ingredient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218566A (en) * 1977-03-30 1980-08-19 American Cyanamid Company 11-(2-Hydroxyethylthio) prostenoic acid E and F series derivatives
EP0051284A1 (fr) * 1980-10-31 1982-05-12 Teijin Limited Dérivés thiaprostaglandines E1, leur préparation et medicaments contenant ces composés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218566A (en) * 1977-03-30 1980-08-19 American Cyanamid Company 11-(2-Hydroxyethylthio) prostenoic acid E and F series derivatives
EP0051284A1 (fr) * 1980-10-31 1982-05-12 Teijin Limited Dérivés thiaprostaglandines E1, leur préparation et medicaments contenant ces composés

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1219601A1 (fr) * 1999-09-10 2002-07-03 Taisho Pharmaceutical Co., Ltd Derives de prostaglandine
EP1219601A4 (fr) * 1999-09-10 2004-10-27 Taisho Pharmaceutical Co Ltd Derives de prostaglandine
WO2003007941A1 (fr) * 2001-07-16 2003-01-30 F. Hoffmann-La Roche Ag Derives de pyrrolidone comme antagonistes de prostanoide
US6849657B2 (en) 2001-07-16 2005-02-01 Syntex (U.S.A.) Llc 2-pyrrolidone derivatives as prostanoid agonists
CN100371322C (zh) * 2001-07-16 2008-02-27 霍夫曼-拉罗奇有限公司 作为前列腺素类化合物激动剂的2-吡咯烷酮衍生物
US7608637B2 (en) 2001-07-23 2009-10-27 Ono Pharmaceutical Co., Ltd. Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as the active ingredient
US8207223B2 (en) 2001-07-23 2012-06-26 Ono Pharmaceutical Co., Ltd. Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as active ingredient

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