WO2007072782A1 - Carboxylic acid derivative or salt thereof - Google Patents

Carboxylic acid derivative or salt thereof Download PDF

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Publication number
WO2007072782A1
WO2007072782A1 PCT/JP2006/325197 JP2006325197W WO2007072782A1 WO 2007072782 A1 WO2007072782 A1 WO 2007072782A1 JP 2006325197 W JP2006325197 W JP 2006325197W WO 2007072782 A1 WO2007072782 A1 WO 2007072782A1
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Prior art keywords
methyl
amino
benzoic acid
lower alkyl
ylmethyl
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PCT/JP2006/325197
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French (fr)
Japanese (ja)
Inventor
Hideki Kubota
Issei Tsukamoto
Koji Kato
Yuta Fukuda
Kazunori Kamijo
Kei Ohnuki
Yusuke Hirano
Toru Watanabe
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Astellas Pharma Inc.
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Publication of WO2007072782A1 publication Critical patent/WO2007072782A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
    • C07D305/12—Beta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is useful as a medicine, particularly as a therapeutic agent for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc.
  • the present invention relates to a novel carboxylic acid derivative.
  • Overactive bladder is a pathological condition complaining of urgency regardless of incontinence, and is usually accompanied by frequent urination and nocturia (Non-patent Document 1).
  • anticholinergic drugs are mainly used for the treatment, and some treatment results have been shown.
  • it has been reported that it is difficult to use for patients with benign prostatic hyperplasia and the elderly because of the known side effects such as rheumatoid arthritis, constipation, and blurred vision and the risk of urinary retention. .
  • Prostaglandin E is a bioactive substance with arachidonic acid as a precursor.
  • EP1, EP2, EP3 and EP4 which are G protein-coupled receptors.
  • Patent Document 3 suggests that PGE may affect lower urinary tract function.
  • spine In recent years, spine
  • Non-Patent Document 4 abnormal urinary function in urethral stricture model mice is EP1 receptor Disappeared by KO and abnormal urination due to intravesical injection of PGE
  • EP1 Receptor Antagonist is a frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis It is considered useful as a therapeutic agent for lower urinary tract diseases such as prostatitis.
  • EP1 receptor antagonists have different mechanisms of action, side effects unique to anticholinergic drugs This can be expected to be avoided, and it can be expected to be effective for patients who have not shown efficacy with anticholinergic treatment. In addition, this drug acts on sensory nerves and is expected to have a stronger effect of improving subjective symptoms. Furthermore, it has been reported that it has an effect of improving the pathological condition without lowering the urination efficiency of rats with spinal cord injury (Non-Patent Document 5), and it can be expected that it can be safely administered to patients with benign prostatic hyperplasia and the elderly.
  • PGE is produced locally with inflammation and tissue damage, and enhances the inflammatory response.
  • EP1 receptor antagonists have shown efficacy in inflammatory pain (Non-patent document 6), postoperative pain (Non-patent document 7), and neuropathic pain (Non-patent document 8).
  • Non-patent Document 9 the clinical effect of EP1 receptor antagonist administration on acetic acid-induced visceral pain has also been reported. Based on the above, EP1 receptor antagonists are considered to be useful as therapeutic agents for various pains.
  • an EP1 receptor antagonist has an action of suppressing abnormal formation of colonic mucosa abnormal crypts and intestinal polyps (Patent Document 2), and EP1 receptor antagonists are used for colon cancer, bladder It is considered useful as a therapeutic agent for cancer, prostate cancer and the like.
  • Patent Document 3 discloses a compound represented by the formula (A)!
  • R 4 there is no disclosure of a substituted lower alkyl substituted with a heterocyclic group, which is a feature of the compound of the present invention.
  • Patent Document 4 discloses a compound represented by the formula (B).
  • R1 represents isopropyl, isobutyl, 2-methyl-2-propyl, cyclopropylmethyl, methyl, ethyl, propyl, 2-propenyl, or 2-hydroxy-2-methylpropyl. (See the official gazette for the symbol.)
  • Patent Document 5 discloses compounds represented by the formula (C) including a wide range of compounds.
  • X or Q may be an optionally substituted phenylene or an optionally substituted single.
  • the chemical structure is different from the compound of the present invention in that it does not have a cyclic structure such as cyclic heteroarylene.
  • Patent Document 6 published after the priority date of the present application discloses a compound represented by the formula (D).
  • ring A represents an optionally substituted 5- to 8-membered heterocycle. For other symbols, refer to this publication.
  • the chemical structure is different from that of the compound of the present invention in that the ring A is a 5- to 8-membered heterocyclic ring which may be substituted.
  • Non-Patent Document 1 “Neurourology and Urody namics” (UK), 2002, 21st pp.167-78
  • Non-Patent Document 2 “Urological Research” (USA), 1990, No. 18 ⁇ No. 5, P.349- 52
  • Non-Patent Document 3 “The Journal of Urology” (USA), June 1995, No. 153, No. 6, p.2034-8
  • Non-Patent Document 4 "Journal of the Japanese Urological Association", February 2001, No. 92, No. 2, p. 304
  • Non-Patent Document 5 "Proceedings of the 89th Annual Meeting of the Japanese Urological Association", Kobe, 2001 , MP-305
  • Non-Patent Document 6 “Anesthesiology”, (USA), November 2002, No. 97, No. 5, p.1254-62
  • Non-Patent Document 7 “Anesthesia and Analgesia” (USA), December 2002, No. 95, No. 6, p.1708-12
  • Non-Patent Document 8 “Anesthesia and Analgesia” (USA), October 2001, No. 93, No. 4, p.1012-7
  • Non-Patent Document 9 “Gastroenterology”, January 2003, No. 124, No. 1, p.18-25
  • Patent Document 1 US Patent Application Publication No. 2005Z0020646 Specification
  • Patent Document 2 Pamphlet of International Publication No. 00Z069465
  • Patent Document 3 Pamphlet of International Publication No. 98Z027053
  • Patent Document 4 International Publication No. 02Z072564 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 00Z020371
  • Patent Document 6 International Publication No. 06Z121097 Pamphlet
  • An EP1 receptor antagonist can be expected to be a highly safe therapeutic agent for lower urinary tract disease with few side effects such as phlegm and urinary retention. Accordingly, the present inventors have intensively studied compounds having an EP1 receptor antagonistic activity for the purpose of providing novel compounds useful for the treatment of lower urinary tract diseases and the like. As a result, it can be substituted as a substituent on the N atom of the sulfonamide, but may have a lower alkyl group substituted with a heterocyclic group. The present invention was completed by discovering that the novel carboxylic acid derivative shown has a potent EP1 receptor antagonistic action.
  • R 1 and R 2 the same or different, H, halogen, lower alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, or a carbon atom to which R 1 and R 2 are bonded.
  • a 5- to 8-membered cycloalkene ring or a benzene ring may be formed.
  • A: substituted ! may be a heterocyclic group
  • substituted ! may, file, or substituted, may be monocyclic heteroaryl
  • substituted ! may, phenylene, substituted !, may! /, Monocyclic heteroalkylene
  • X lower alkylene, lower alkylene, -0-lower alkylene-, or -lower alkylene -o-,
  • Y a single bond, lower alkylene, lower alkylene, or -o-lower alkylene
  • A is oxygen-containing 4- to 6-membered saturated heterocyclic group or nitrogen-containing 5- to 6-membered heteroaryl
  • B is a ring, or N or O.
  • A is a group selected from the group consisting of oxetal, tetrahydrofuryl, tetrahydrobiral, pyridyl, pyrajur, imidazolyl, and virazolylca
  • B is selected from phenyl, thiazolyl, furyl, and pyridyl
  • A is selected from the group power in which A is also oxetanyl and pyridylca.
  • R 3 is —OH, R 1 and R 2 are the same or different, and H, halogen, lower alkyl, halogeno lower alkyl, ⁇ 0-lower alkyl, or R 1 and R 2 are bonded.
  • the method includes administering to a patient a therapeutically effective amount of the compound according to [1], frequent urination with overactive bladder, urinary incontinence, lower urinary tract symptoms with prostatic hypertrophy, interstitial cystitis, A method for treating lower urinary tract disease comprising prostatitis,
  • the compound of the present invention has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, It is useful as a therapeutic agent for lower urinary tract diseases such as interstitial cystitis and prostatitis.
  • lower means 1 to 6 carbon atoms (hereinafter abbreviated as C) unless otherwise specified.
  • “Lower alkyl” means C alkyl. Specifically, methyl, ethyl, n-propyl
  • Mouth pill isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like can be mentioned.
  • it is C alkyl, more preferably methyl,
  • “Lower alkylene” is a divalent group formed by removing one hydrogen from any position of C alkyl.
  • Means group Specific examples include methylene, ethylene, methylmethylene, dimethylmethylene, trimethylene, tetramethylene, and propylene. Preferred are methylene, ethylene and trimethylene, and more preferred are methylene and ethylene.
  • “Lower alkellene” is formed by removing one hydrogen atom at any position of the C alkell 2
  • Means a valent group include beylene, probelene, 1-butylene, 2-butene. Biylene is preferred.
  • Halogen means a halogen atom. Specific examples include fluoro, black mouth, bromo and iodine. Fluoro and black mouth are preferred.
  • halogeno lower alkyl means a group substituted with the above “halogen” in the same or different one or more arbitrary hydrogen atom forces of the “lower alkyl”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Trifluoromethyl is preferred.
  • “5- to 8-membered cycloalkene ring” means carbonization of C having 1 or 2 double bonds in the ring.
  • Specific examples include cyclopentene, cyclopentagen, cyclohexene, cyclohexagen, cycloheptene, cyclootaten and the like. Cyclopentene is preferred.
  • “Monocyclic heteroaryl” is a monocyclic 5- to 6-membered aromatic ring group containing 1 to 4 heteroatoms selected from 0, S and N forces, and S or a ring atom N may be oxidized to form an oxide.
  • Specific examples include pyridyl, pyridazyl, pyrimidyl, pyrajyl, triazinyl, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. .
  • Nitrogen-containing 5- to 6-membered heteroaryl refers to the ring structure in the above “monocyclic heteroaryl”. It means a cyclic group containing at least one N as a constituent atom. Specific examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • Pyridyl, pyrazyl, thiazolyl, imidazolyl, pyrazolyl and oxadiazolyl are preferable, and pyridyl, pyrazinyl, thiazolyl, imidazolyl and pyrazolyl are more preferable.
  • “5- to 6-membered heteroaryl containing at least one N or 0” means that the above “monocyclic heteroaryl” always contains one N and / or 0 as a ring-constituting atom, Furthermore, it means a cyclic group which may contain one S. Specific examples include pyridyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl and the like. Pyridyl, thiazolyl and furyl are preferred.
  • the “monocyclic heteroarylene” means a divalent group formed by removing one arbitrary hydrogen on the ring atom of the “monocyclic heteroaryl”. Specifically, pyridine, pyridazine, pyrimidine, pyrazine, triazine, flanged, thiophene, pyrrole, oxazole, isoxazole, oxadiazol, thiazole, and thiadiazole Imidazole dil, triazole dil, tetrazol dil and the like. Pyridine diyl and thiophen diyl are preferable.
  • Heterocyclic group means a saturated, unsaturated or partially unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N forces, 8 Means a 14-membered bicyclic heterocyclic group or an 11-20 membered tricyclic heterocyclic group.
  • the ring atom S or N may be acidified to form an oxide or dioxide, or a bridged ring or spiro ring may be formed.
  • the monocyclic heterocyclic group examples include pyridyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, furyl, dihydrofuryl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, and pyrazol.
  • Examples include ryl, triazolyl, tetrazolyl, oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and the like.
  • bicyclic heterocyclic group examples include indolyl, Examples include benzofuranyl, dihydrobenzofuranyl, benzocenyl, benzoid oxazolinole, benzoimidazolyl, benzothiazolyl, indazolyl, quinolyl, quinazolinyl, quinoxalinyl, cinnoyl and the like.
  • Specific examples of the tricyclic heterocyclic group include force rubazolyl and attalizyl.
  • it is a 4- to 6-membered monocyclic heterocyclic group, more preferably oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, and still more preferably oxetanyl, Tetrahydrofuryl, pyridyl, pyrajur, thiazolyl, imidazolyl, pyrazolyl.
  • Oxygen-containing 4- to 6-membered saturated heterocyclic group is a 4- to 6-membered saturated hetero group containing at least one or more 0 as a ring constituent atom in the "heterocyclic group”. Means a cyclic group.
  • Examples include oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, morpholinyl, oxazepanyl, dioxol, and dioxal. Preferred are oxetal, tetrahydrofuryl and tetrahydroviral, and more preferred are oxetal and tetrahydrofuryl.
  • substituent in the “optionally substituted heterocyclic group” of A preferably lower alkyl, halogen, halogeno lower alkyl, —OH, —O-lower alkyl, —O-halogeno lower alkyl, -Troca and the like, more preferably lower alkyl, halogen, and -O-lower alkyl, still more preferably lower alkyl.
  • B “Substituted, may be a monocyclic heteroaryl”, and the same “Substituted !, may be As a substituent in the ⁇ monocyclic heteroarylene '', preferably a lower alkyl, a halogen, a halogeno lower alkyl, a -0-lower alkyl, a -o-halogeno lower alkyl, a cyanide and a -tro force, More preferred are lower alkyl, halogen and -0-lower alkyl, and even more preferred are lower alkyl and halogen.
  • A is preferably an optionally substituted oxetanyl, tetrahydrofuryl, tetrahydroviral, pyridyl, pyrajyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, more preferably each substituted. May be oxetal, tetrahydrofuryl, pyridyl, pyrajyl, imidazolyl, pyrazolyl, and more preferably oxetanyl and pyridyl which may be substituted.
  • the substituent on A the substituents described above are preferable.
  • B is preferably an optionally substituted thiazolyl, furyl, pyridyl, or phenol, and more preferably an optionally substituted thiazolyl or vinyl.
  • substituent on B the substituents described above are preferable.
  • C is preferably an optionally substituted phenylene, thiopheneyl, or pyridinezyl, and more preferably an optionally substituted phenylene.
  • substituent on C the substituent described above or unsubstituted is more preferable, and unsubstituted is more preferable.
  • R 2 is preferably the same or different and is H, lower alkyl, halogen, —O-lower alkyl, or halogeno lower alkyl.
  • Another preferred embodiment of R 2 is the case of forming a cyclopentene ring together with the carbon to which R 1 and R 2 are attached.
  • Luka lower alkyl optionally substituted with a selected group), more preferably-
  • X is preferably -0-lower alkylene-, more preferably -0-methylene-.
  • Y is preferably a single bond.
  • Z is preferably methylene, methylmethylene, or ethylene, more preferably Tylene.
  • a particularly preferred embodiment of the present invention is a compound capable of combining each preferred group described in the above (1) to (8).
  • compound (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers such as (R) and (S) isomers may exist based on this.
  • optical isomers such as (R) and (S) isomers may exist based on this.
  • the present invention includes all of these optical isomers and mixtures thereof.
  • the present invention includes pharmacologically acceptable prodrugs of Compound (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, OH, COH, or the like of the present invention by solvolysis or under physiological conditions.
  • Shape prodrug is a compound having a group that can be converted to an amino group, OH, COH, or the like of the present invention by solvolysis or under physiological conditions.
  • Examples of the group to be formed include groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), No. 7 Molecular design 163-198. .
  • the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid , Lactic acid, Malic acid, Tartaric acid, Chenic acid, Methanesulfonic acid, Ethanesulfonic acid, P-Toluenesulfonic acid, Aspartic acid, Carboxylic acid with organic acids such as glutamic acid, sodium, potassium, magnesium, calcium, aluminum And inorganic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortho salts, and ammonium salts.
  • the present invention also includes various hydrates and solvates of the compound of the present invention and pharmaceutically acceptable salts thereof, and polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • an appropriate protecting group a group that can be easily converted into the functional group
  • functional groups include amino groups, hydroxyl groups, and carboxyl groups
  • protecting groups include Greene and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999). And the like, and these may be appropriately selected and used according to the reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.
  • the prodrug of compound (I) can be produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound (I).
  • the reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • This step is a step for producing the compound (I) of the present invention by alkylating the compound (II) with the compound (III) having a leaving group.
  • the leaving group represented by Lv can be any leaving group commonly used in nucleophilic substitution reactions. Sulfonoxy such as tansulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., sulfonyl such as lower alkyl sulfole, arylsulfol and the like are preferably used.
  • an alkyl iodide usually used by those skilled in the art can be employed.
  • esters such as ethyl acetate, ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane, dichloromethane, 1,2-dichloroethane , Halogenated hydrocarbons such as black mouth form, ⁇ , ⁇ -dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), acetonitrile
  • the reaction can be carried out in a solvent inert to the reaction, or a solvent such as alcohols at room temperature to heating under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used
  • metal salt bases potassium carbonate, In the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy, etc. may be advantageous for the smooth progress of the reaction. is there.
  • Aromatic hydrocarbons such as toluene and benzene, triphenylphosphine, tri-n-butylphosphine, tris (dimethylamino) phosphine, triphenylphosphite, diphenoxyphenylphosphine, diphenyl (2-pyridyl) in solvents such as DMF )
  • phosphine such as (4-dimethylamino) diphenylphosphine
  • azodicarboxylate such as jetylazodicarboxylate, diisopropylpropyl dicarboxylate, dimethylazodicarboxylate, etc. It can also be performed at room temperature.
  • R represents lower alkyl, and other symbols have the same meanings as described above.
  • a compound of the invention which is R 3 months OR by hydrolysis from (Ia), R 3 is - a step for producing a OH der Ru present compound (Ib).
  • the hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in “Protective Groups in Organic Synthesis (3rd edition, 1999)”.
  • the starting compound used for the production of the compound (I) of the present invention can be easily produced, for example, using the following method, a known method, or a modified method thereof.
  • This step is a step for producing compound (VI) by alkylating compound (IV) with compound (V) having a leaving group.
  • the alkylation in this step can be performed in the same manner as in Production Method 1.
  • This step is a step for producing compound (VII) by -trolation of compound (VI).
  • Nitration can be carried out by a method that can be generally employed by those skilled in the art.
  • concentrated nitric acid can be used as a nitrating agent in a solvent such as acetic acid or concentrated sulfuric acid.
  • This step is a step for producing the compound (vm) by reducing the nitro compound ( ⁇ ).
  • a nitro group reduction reaction that can be generally employed by those skilled in the art can be used for the reduction reaction of the nitro group. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride, and a hydrogenation reaction using palladium-carbon or the like as a catalyst.
  • This step is a step of producing compound (VII) by alkylating compound (IX) with compound (V) having a leaving group.
  • the alkylation in this step can be carried out by the same method as Production method 1.
  • This step is a step for producing the compound (vm) by reducing the nitro compound ( ⁇ ). This reduction of the -tro group can be carried out in the same manner as in the third step of raw material synthesis 1. [0039] (Raw material synthesis 3)
  • This step is a step of producing compound (II) by sulfonating compound (X) with compound (XI).
  • halogen such as black mouth and bromo is preferably used.
  • the reaction for example, the conditions of sulfoniru ⁇ described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” can be applied. Specifically, the reaction can be carried out in the absence of a solvent or in a solvent such as tetrahydrofuran, methylene chloride, and acetonitrile, in the presence of a base such as triethylamine and pyridine, if necessary, under cooling or under reflux with heating.
  • a base such as triethylamine and pyridine
  • the compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphic substance thereof.
  • the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • optical isomers can be separated by selecting an appropriate raw material compound or by utilizing the difference in physical and physical properties between isomers.
  • optical isomers can be obtained by stereochemically pure isomers by general optical resolution methods (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Can lead to. It can also be produced from a suitable optically active raw material compound.
  • HEK293 cells stably expressing rat EP1 receptor (American type culture) • Collection (American Type Culture Collection), 96-well poly-D-lysine-coated plate (trade name: Biocoat PDL96W Black / Clear) to be 2 X 10 4 cells / well the day before the experiment First, it was dispensed to Nippon Betaton Dickinson Co., Ltd., and the medium containing 10% urinary fetal serum (FBS) at 37 ° C and 5% carbon dioxide (CO) (trade name: DMEM, Invito
  • the culture medium was loaded with a loading buffer (fluorescent labeling reagent (trade name: Fluo3-AM, Dojindo), 4 ⁇ of washing solution: Nontas balanced salt solution (HBSS), 20 mM 2- [4- (2-hydroxyl Chill) -1-piperadyl-ethane] sulfonic acid (HEPES) -sodium hydroxide (NaOH), 2.5 mM probenecid, 0.1% ushi serum albumin (BSA)) and left at room temperature for 3 hours, The cells are washed with a plate washer (trade name: ELx405, BIO-TEK Instruments, Inc.) in which a washing solution is set.
  • HBSS Nontas balanced salt solution
  • HEPES 2- [4- (2-hydroxyl Chill) -1-piperadyl-ethane] sulfonic acid
  • NaOH sodium hydroxide
  • BSA 0.1% ushi serum albumin
  • the concentration that inhibits 50% is the IC value.
  • Control Compound J Compound disclosed in Patent Document 4, Example 2 (71) Test Example 2 Receptor binding experiment using cells expressing EP1 receptor
  • Rat EP1 receptor has a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) at the N-terminus. ) And a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) and subcloned into an expression vector (trade name: pCEP4, Invitrogen) (the amino acid sequences of the signal peptide and the FLAG sequence are described in Patent Document 6) See).
  • This rat EP1 expression vector was transformed into HEK293EBNA cells (Ameri can Type) using a transfer reagent (trade name: Fugene-6, Roche Diagnostics). Culture Collection)), then 37 ° C, 5% CO, 1
  • the cells were cultured in a medium containing 0% FBS (trade name: DMEM, Invitrogen) for 2 days.
  • the cultured cells are collected, treated with a cell lysate (20 mM Tris (hydroxymethyl) aminomethane (Tris) buffer pH 7.5, 5 mM ethylenediamine tetraacetic acid (EDTA)), and centrifuged (23000 rpm, 25
  • the membrane preparation was roughly adjusted by min x 2).
  • MES ethanesulfonic acid
  • KOH potassium hydroxide
  • ImM EDTA ImM EDTA
  • MgCl lOmM magnesium chloride
  • 0.02% 3-[(3-Colamidopropyl) dimethylammonio] propane
  • the filter is trapped on a filter 1-96, GF / B, Perkin Elma Co., Ltd., and the combined radioactivity is microplate (trade name: Micro Cinch 20, Perkin Elma Co.) using a microplate scintillation counter (product) Name: Top Count, Notcard Inc.).
  • -PGE binding inhibitory activity is measured by adding 2.5 nM 3 H-PGE and the compound of the present invention.
  • Ki IC / (1 + ([C] / Kd))
  • [C] represents the 3 H-PGE concentration used in the reaction system.
  • Test Example 3 Effects of compounds on changes in intravesical pressure in rats treated with sulprostone
  • sulprostone (0.3 mg / kg, sc) was administered to the rat, and the intravesical pressure curve 1 hour later was used as the pre-test compound administration value. Thereafter, the test compound was administered to the femoral vein, and the intravesical pressure was measured for up to 90 minutes. The inhibition rate by the test compound was calculated when the difference between the pre-test compound administration value and the sulprostone pre-administration value was 100%.
  • sulprostone administration resulted in bladder overactivity such as decreased urination interval, increased basal pressure, increased maximum urinary pressure, and decreased compliance.
  • the compound of the present invention improved the bladder overactivity.
  • Test Example 4 Effects of compounds on acetic acid-induced frequent urination rats
  • Wistar male rats (Charles River Inc.) weighing 200 to 450 g were used for the experiment. Under anesthesia with pentobarbital (50 mg / kg, i.p.), a midline incision was made in the abdomen to expose the bladder, and residual urine in the bladder was removed with a syringe equipped with a 27G needle. Thereafter, 0.5% to 0.7 mL of 1% acetic acid solution was injected into the bladder and closed. Two days later, the experiment was conducted. Rats were placed in metabolic cages and acclimated for 1 hour, then the test compound was administered, and changes in urinary weight were measured continuously for 6 hours immediately thereafter. The effective bladder capacity was calculated by dividing the total urination volume by the total number of urinations.
  • Inhibitory activity 1 (%) 100—V / V X 100
  • control compound J (the compound disclosed in Patent Document 4, Example 2 (71)) has an inhibitory activity I power of S37% and an inhibitory activity II of 71%, whereas for example the compound of Example 51 Inhibitory activity I was 6% and inhibitory activity II was 7%.
  • the compound of the present invention has a strong EP1 receptor antagonistic action and satisfactorily improves frequent urination.
  • the compound of the present invention has favorable properties as a pharmaceutical product, such as being excellent in metabolic stability and causing little drug interaction.
  • the compound of the present invention is highly safe and useful as a therapeutic agent for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc. It is.
  • a preparation containing one or more of the compounds (I) or a salt thereof of the present invention as an active ingredient is usually used using a pharmaceutical carrier, excipient, etc. that are usually used in the art. It can be prepared by this method.
  • Administration is oral by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intraarticular, intravenous, intramuscular, suppositories, eye drops, eye ointments, transdermal solutions. , Ointment, transdermal patch, transmucosal liquid, transmucosal patch, parenteral administration by inhalation, etc. It may be a form.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch. , Polybulurpyrrolidone, and / or magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as carboxymethyl starch sodium, a stabilizer, and a solubilizing agent according to a conventional method. Good.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, etc., commonly used inert diluents such as purified Contains water or ethanol.
  • the liquid composition may contain solubilizers, wetting agents, suspending agents and other adjuvants, sweeteners, flavors, fragrances and preservatives.
  • Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • aqueous solvent include distilled water for injection or physiological saline.
  • water-insoluble solvent include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emollients, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a pacteria retention filter, blending of a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointment or lotion bases include: polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol Cole, cetyl alcohol, lauromacrogol, sorbitan sesquioleate and the like.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like can use a dry powder or a powder-containing capsule which can be used for single or multiple administrations.
  • a dry powder or a powder-containing capsule which can be used for single or multiple administrations.
  • it may be in the form of an appropriate propellant such as a pressurized aerosol spray using a suitable gas such as black mouth fluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Dosing once or in 2 to 4 divided doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and should be administered once to several times a day. As a transmucosal agent, administer about 0.001 to 100 mg / kg per body weight once or multiple times a day. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc.
  • the compound of the present invention can be used in combination with various therapeutic or preventive agents for diseases for which the compound of the present invention is considered effective.
  • the combination may be administered simultaneously, separately in succession, or at desired time intervals.
  • the co-administered product may be a combination drug or separately formulated.
  • Ethyl 5-[(2,3-dihydro-1H-indene-5-yloxy) methyl] thiophene-2-carboxylic acid was subjected to -trolation with acetic acid in concentrated acetic acid to give ethyl 5- ⁇ [(6- -Tro-2,3-dihydro-1H-indene-5-yl) oxy] methyl ⁇ thiophene-2-carboxylic acid was prepared.
  • the residue obtained by concentrating the reaction solution under reduced pressure was covered with 1M hydrochloric acid and chloroform, and the organic layer was separated using a Phase Separate-filter manufactured by Isotute. Hexane and ethyl acetate were added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration.
  • Example compounds shown in Tables 8 to 24 below were produced using the corresponding starting materials.
  • Tables 8 to 24 show the structures of the example compounds, and Tables 25 to 26 show the production methods and physicochemical data.
  • Tables 27 to 28 show NMR data of some example compounds.
  • Tables 29 to 32 show structures of other compounds of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in the Examples, methods obvious to those skilled in the art, or variations thereof.
  • the compound of the present invention has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urinary incontinence associated with overactive bladder, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial It is useful as a therapeutic agent for lower urinary tract diseases such as cystitis and prostatitis.

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Abstract

[PROBLEMS] To provide a compound which can be used as a therapeutic agent for a disease associated with an EP1 receptor, particularly a lower urinary tract disease such as frequent urination/strong urge to urinate or incontinence accompanied by overactive bladder, cystitis, interstitial cystitis or prostatitis. [MEANS FOR SOLVING PROBLEMS] Disclosed is a carboxylic acid derivative characterized in that it has a sulfonamide structure and also has a lower alkyl group substituted by a heterocyclic group which may be substituted as a substituent on an N-atom in the sulfonamide structure, or a salt of the derivative. It is found that the carboxylic acid derivative or salt thereof has a potent antagonistic activity on an EP1 receptor. Therefore, the compound is useful as a therapeutic agent for a lower urinary tract disease such as frequent urination/incontinence accompanied by overactive bladder, a lower urinary tract symptom accompanied by prostatism, interstitial cystitis or prostatitis.

Description

明 細 書  Specification
カルボン酸誘導体又はその塩  Carboxylic acid derivative or salt thereof
技術分野  Technical field
[0001] 本発明は、医薬、特に過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部 尿路症状、間質性膀胱炎、前立腺炎などの下部尿路疾患治療薬として有用な新規 なカルボン酸誘導体に関する。  [0001] The present invention is useful as a medicine, particularly as a therapeutic agent for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc. The present invention relates to a novel carboxylic acid derivative.
背景技術  Background art
[0002] 過活動膀胱は失禁の有無にかかわらず尿意切迫感を訴える病態であり、通常頻尿 および夜間頻尿を伴う（非特許文献 1)。現在その治療には主に抗コリン薬が使用さ れ、一定の治療成績を示している。しかし、一方でロ渴、便秘、かすみ目といった副 作用の発現も知られているほか、尿閉の危険性もあるため、前立腺肥大症患者や高 齢者には使いづらいことが報告されている。また、抗コリン薬治療で有効性を示さな い患者の存在も知られている。以上のことから、過活動膀胱に対する新規機序の薬 剤への期待は大きい。  [0002] Overactive bladder is a pathological condition complaining of urgency regardless of incontinence, and is usually accompanied by frequent urination and nocturia (Non-patent Document 1). Currently, anticholinergic drugs are mainly used for the treatment, and some treatment results have been shown. However, on the other hand, it has been reported that it is difficult to use for patients with benign prostatic hyperplasia and the elderly because of the known side effects such as rheumatoid arthritis, constipation, and blurred vision and the risk of urinary retention. . It is also known that there are patients who do not show efficacy with anticholinergic treatment. Based on the above, there are high expectations for drugs with a new mechanism for overactive bladder.
[0003] プロスタグランジン E (PGE )はァラキドン酸を前駆物質とする生体内活性物質であ  [0003] Prostaglandin E (PGE) is a bioactive substance with arachidonic acid as a precursor.
2 2  twenty two
り、 G蛋白共役型受容体である EP1、 EP2、 EP3および EP4の 4種類のサブタイプを介し て生体の機能調節に関与することが知られている。  In other words, it is known to be involved in the regulation of biological functions through four subtypes of EP1, EP2, EP3 and EP4, which are G protein-coupled receptors.
PGEの膀胱内注入がヒトで強 ヽ尿意切迫感と膀胱容量減少をきたすこと (非特許 Intravesical infusion of PGE causes urgency and decreased bladder capacity in humans (Non-patented
2 2
文献 2)、 PGEの膀胱内注入がラットの膀胱容量を減少させることが知られており（非  2) It is known that intravesical infusion of PGE reduces rat bladder capacity (non-
2  2
特許文献 3)、 PGEが下部尿路機能に影響する可能性が示唆されている。近年、脊  Patent Document 3) suggests that PGE may affect lower urinary tract function. In recent years, spine
2  2
髄損傷モデルラットに対する EP1受容体拮抗剤の投与が排尿機能改善に有用である との報告がなされて!/ヽること (非特許文献 4)、尿道狭窄モデルマウスの排尿機能異 常が EP1受容体 KOにより消失すること及び PGEの膀胱内注入により排尿機能異常  It has been reported that administration of an EP1 receptor antagonist to a spinal cord injury model rat is useful for improving urinary function! (Non-Patent Document 4), abnormal urinary function in urethral stricture model mice is EP1 receptor Disappeared by KO and abnormal urination due to intravesical injection of PGE
2  2
が亢進することが示されていることから (特許文献 1)、 EP1受容体拮抗剤は過活動膀 胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状、間質性膀胱炎、前立腺 炎などの下部尿路疾患治療薬として有用であると考えられる。  EP1 Receptor Antagonist is a frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis It is considered useful as a therapeutic agent for lower urinary tract diseases such as prostatitis.
[0004] 力！]えて、 EP1受容体拮抗剤は作用機序が異なるため、抗コリン薬に特有の副作用 の回避が期待できるほか、抗コリン薬治療で有効性を示さない患者に対しても効果 が期待できる。また、本剤は知覚神経に作用してより強い自覚症状の改善効果が期 待できる。更に脊髄損傷ラットの排尿効率を低下させることなく病態改善効果を示す ことが報告されており（非特許文献 5)、前立腺肥大症患者や高齢者にも安全に投与 できることが期待できる。 [0004] Power! ] Since EP1 receptor antagonists have different mechanisms of action, side effects unique to anticholinergic drugs This can be expected to be avoided, and it can be expected to be effective for patients who have not shown efficacy with anticholinergic treatment. In addition, this drug acts on sensory nerves and is expected to have a stronger effect of improving subjective symptoms. Furthermore, it has been reported that it has an effect of improving the pathological condition without lowering the urination efficiency of rats with spinal cord injury (Non-Patent Document 5), and it can be expected that it can be safely administered to patients with benign prostatic hyperplasia and the elderly.
[0005] また、 PGEは炎症や組織障害に伴い局所で産生され、炎症反応を増強すると共に [0005] In addition, PGE is produced locally with inflammation and tissue damage, and enhances the inflammatory response.
2  2
発痛 ·発熱にも関与することが広く知られている。近年 EP1受容体拮抗剤が、炎症性 疼痛 (非特許文献 6)、術後疼痛 (非特許文献 7)、神経因性疼痛 (非特許文献 8) t ヽ つた各種疼痛モデル動物において有効性を示すことが知られ、また酢酸誘発内臓痛 に対する EP1受容体拮抗剤投与の臨床効果についても報告されている (非特許文献 9)。以上から、 EP1受容体拮抗剤は、各種疼痛の治療薬としても有用であると考えら れる。  Pain · It is widely known that it is also involved in fever. In recent years, EP1 receptor antagonists have shown efficacy in inflammatory pain (Non-patent document 6), postoperative pain (Non-patent document 7), and neuropathic pain (Non-patent document 8). In addition, the clinical effect of EP1 receptor antagonist administration on acetic acid-induced visceral pain has also been reported (Non-patent Document 9). Based on the above, EP1 receptor antagonists are considered to be useful as therapeutic agents for various pains.
[0006] 更に、 EP1受容体拮抗剤は大腸粘膜異常腺窩および腸内ポリープ形成の抑制作 用を有することが知られており（特許文献 2)、 EP1受容体拮抗剤は、大腸癌、膀胱癌 、前立腺癌等の治療薬としても有用であると考えられる。  [0006] Furthermore, it is known that an EP1 receptor antagonist has an action of suppressing abnormal formation of colonic mucosa abnormal crypts and intestinal polyps (Patent Document 2), and EP1 receptor antagonists are used for colon cancer, bladder It is considered useful as a therapeutic agent for cancer, prostate cancer and the like.
[0007] EP1受容体拮抗剤としては、以下の特許文献 3〜6に示される化合物が報告されて いる。  [0007] As EP1 receptor antagonists, compounds shown in the following Patent Documents 3 to 6 have been reported.
特許文献 3には式 (A)で示される化合物が開示されて!ヽる。  Patent Document 3 discloses a compound represented by the formula (A)!
[化 1]  [Chemical 1]
Figure imgf000004_0001
Figure imgf000004_0001
(式中 ITは水素、 Cl〜8アルキル、 C2〜87ルケ-ル、 C2〜8アルキ -ル、 1個または 2個の COOZ8、 CONZ9Z1Q、
Figure imgf000004_0002
Cl〜4アルコキシからなる群から選ばれる基によつ て置換された Cl〜6アルキル、 C3〜7シクロアルキル、フエ-ルまたはじ3〜7シクロ アルキルで置換された Cl〜4アルキル、 C2〜47ルケ-ル、 C2〜4アルキ-ルを示す 。他の記号は当該公報参照。 ) (Where IT is hydrogen, Cl to 8 alkyl, C2 to 87, C2 to 8 alkyl, 1 or 2 COOZ 8 , CONZ 9 Z 1Q ,
Figure imgf000004_0002
Cl to 4 alkyl substituted with a group selected from the group consisting of Cl to 4 alkoxy, Cl to 6 alkyl, C3 to 7 cycloalkyl, ferrule or the same 3 to 7 cycloalkyl, Cl to 4 alkyl, C2 to 47 Luke, C2-4 Alkyel . For other symbols, see the publication. )
し力しながら、式 (A)の化合物において R4として、本発明化合物の特徴である置換 されて 、てもよ 、ヘテロ環基で置換された低級アルキルの開示はな!/、。 However, in the compound of the formula (A), as R 4 , there is no disclosure of a substituted lower alkyl substituted with a heterocyclic group, which is a feature of the compound of the present invention.
[0008] 特許文献 4には式 (B)で示される化合物が開示されている。 [0008] Patent Document 4 discloses a compound represented by the formula (B).
[化 2]  [Chemical 2]
Figure imgf000005_0001
Figure imgf000005_0001
(式中、 R1まイソプロピル、イソブチル、 2—メチルー 2—プロべ-ル、シクロプロピルメ チル、メチル、ェチル、プロピル、 2—プロぺニルまたは 2—ヒドロキシー 2—メチルプ 口ピルを示す。他の記号は当該公報参照。 )  (In the formula, R1 represents isopropyl, isobutyl, 2-methyl-2-propyl, cyclopropylmethyl, methyl, ethyl, propyl, 2-propenyl, or 2-hydroxy-2-methylpropyl. (See the official gazette for the symbol.)
し力しながら、式 (B)の化合物において R5として、本発明化合物の特徴である置換 されて 、てもよ 、ヘテロ環基で置換された低級アルキルの開示はな!/、。 However, in the compound of the formula (B), as R 5 , there is no disclosure of a substituted lower alkyl substituted with a heterocyclic group, which is a feature of the compound of the present invention.
[0009] 特許文献 5には広範な化合物を含む式 (C)で示される化合物が開示されているが 、 X又は Qとして、置換されていてもよいフエ-レン、置換されていてもよい単環式へ テロアリーレンのような環状構造を有していない点で、本発明化合物とは化学構造を 異にする。 [0009] Patent Document 5 discloses compounds represented by the formula (C) including a wide range of compounds. However, X or Q may be an optionally substituted phenylene or an optionally substituted single. The chemical structure is different from the compound of the present invention in that it does not have a cyclic structure such as cyclic heteroarylene.
[化 3]  [Chemical 3]
Ar1— W-Ar-X-Q (C) Ar 1 — W-Ar-XQ (C)
(式中の記号は当該公報参照。 ) (See the official gazette for symbols in the formula.)
[0010] 更に、本願の優先日後に公開された特許文献 6には式 (D)で示される化合物が開 示されている。 [0010] Furthermore, Patent Document 6 published after the priority date of the present application discloses a compound represented by the formula (D).
Figure imgf000006_0001
Figure imgf000006_0001
(式中、 A環は置換されていてもよい 5〜8員へテロ環を示す。他の記号は当該公報 参照。） (In the formula, ring A represents an optionally substituted 5- to 8-membered heterocycle. For other symbols, refer to this publication.)
し力しながら、式 (D)の化合物において、 A環が置換されていてもよい 5〜8員へテ 口環である点で、本発明化合物とは化学構造を異にする。  However, in the compound of the formula (D), the chemical structure is different from that of the compound of the present invention in that the ring A is a 5- to 8-membered heterocyclic ring which may be substituted.
非特許文献 1：「ニューロウロロジ^ ~ ·アンド ·ゥロダイナミクス（Neurourology and Urody namics)」、 (英国）、 2002年、第 21卷、 p.167-78 Non-Patent Document 1: “Neurourology and Urody namics” (UK), 2002, 21st pp.167-78
非特許文献 2 :「ゥロロジカル 'リサーチ（Urological Research)」、（米国）、 1990年、第 1 8卷、第 5号、 P.349- 52 Non-Patent Document 2: “Urological Research” (USA), 1990, No. 18 卷 No. 5, P.349- 52
非特許文献 3：「ザ ·ジャーナル ·ォブ ·ゥロロジー (The Journal of Urology)」、（米国）、 1995年 6月、第 153卷、第 6号、 p.2034-8 Non-Patent Document 3: “The Journal of Urology” (USA), June 1995, No. 153, No. 6, p.2034-8
非特許文献 4 :「日本泌尿器科学会雑誌」、 2001年 2月、第 92卷、第 2号、 p.304 非特許文献 5 :「第 89回日本泌尿器科学会総会予稿集」、神戸、 2001年、 MP-305 非特許文献 6 :「ァネシージオロジー（Anesthesiology)」、（米国）、 2002年 11月、第 97 卷、第 5号、 p.1254-62 Non-Patent Document 4: "Journal of the Japanese Urological Association", February 2001, No. 92, No. 2, p. 304 Non-Patent Document 5: "Proceedings of the 89th Annual Meeting of the Japanese Urological Association", Kobe, 2001 , MP-305 Non-Patent Document 6: “Anesthesiology”, (USA), November 2002, No. 97, No. 5, p.1254-62
非特許文献 7：「ァネシージァ ·アンド ·アナルジージァ (Anesthesia and Analgesia)」、（ 米国）、 2002年 12月、第 95卷、第 6号、 p.1708-12 Non-Patent Document 7: “Anesthesia and Analgesia” (USA), December 2002, No. 95, No. 6, p.1708-12
非特許文献 8：「ァネシージァ ·アンド ·アナルジージァ (Anesthesia and Analgesia)」、（ 米国）、 2001年 10月、第 93卷、第 4号、 p.1012-7 Non-Patent Document 8: “Anesthesia and Analgesia” (USA), October 2001, No. 93, No. 4, p.1012-7
非特許文献 9 :「ガストロェンテロロジー（Gastroenterology)」、 2003年 1月、第 124卷、 第 1号、 p.18-25 Non-Patent Document 9: “Gastroenterology”, January 2003, No. 124, No. 1, p.18-25
特許文献 1：米国特許出願公開第 2005Z0020646号明細書 Patent Document 1: US Patent Application Publication No. 2005Z0020646 Specification
特許文献 2：国際公開第 00Z069465号パンフレット Patent Document 2: Pamphlet of International Publication No. 00Z069465
特許文献 3：国際公開第 98Z027053号パンフレット 特許文献 4:国際公開第 02Z072564号パンフレット Patent Document 3: Pamphlet of International Publication No. 98Z027053 Patent Document 4: International Publication No. 02Z072564 Pamphlet
特許文献 5：国際公開第 00Z020371号パンフレット  Patent Document 5: Pamphlet of International Publication No. 00Z020371
特許文献 6 :国際公開第 06Z121097号パンフレット  Patent Document 6: International Publication No. 06Z121097 Pamphlet
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0012] 既存の過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状、間質 性膀胱炎、前立腺炎などの下部尿路疾患治療薬は、有効性、安全性等の点で満足 できるものではなぐ有効性、安全性に優れた下部尿路疾患の治療剤の提供が切望 されている。 [0012] Existing therapeutic drugs for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc. are effective, safe, etc. Therefore, there is an urgent need to provide a therapeutic agent for lower urinary tract disease that is superior in terms of efficacy and safety.
課題を解決するための手段  Means for solving the problem
[0013] EP1受容体拮抗剤は、ロ渴、尿閉等の副作用が少なぐ安全性の高い下部尿路疾 患治療剤となることが期待できる。そこで本発明者等は下部尿路疾患等の治療に有 用な新規化合物を提供することを目的として、 EP1受容体拮抗作用を有する化合物 にっき鋭意研究した。その結果、スルホンアミドの N原子上の置換基として、置換され て!、てもよ 、ヘテロ環基で置換された低級アルキル基を有することを構造上の特徴と する後記一般式 (I)で示される新規なカルボン酸誘導体が強力な EP1受容体拮抗作 用を有することを知見し、本発明を完成した。  [0013] An EP1 receptor antagonist can be expected to be a highly safe therapeutic agent for lower urinary tract disease with few side effects such as phlegm and urinary retention. Accordingly, the present inventors have intensively studied compounds having an EP1 receptor antagonistic activity for the purpose of providing novel compounds useful for the treatment of lower urinary tract diseases and the like. As a result, it can be substituted as a substituent on the N atom of the sulfonamide, but may have a lower alkyl group substituted with a heterocyclic group. The present invention was completed by discovering that the novel carboxylic acid derivative shown has a potent EP1 receptor antagonistic action.
[0014] 即ち、本発明は、  [0014] That is, the present invention provides
[1] 下記一般式 (I)で示されるカルボン酸誘導体又はその製薬学的に許容される塩  [1] Carboxylic acid derivatives represented by the following general formula (I) or pharmaceutically acceptable salts thereof
[化 5] [Chemical 5]
Figure imgf000007_0001
Figure imgf000007_0001
[式中の記号は以下の意味を示す。 R1及び R2:同一又は異なって、 H、ハロゲン、低級アルキル、ハロゲノ低級アルキル、 - OH、 -0-低級アルキル、或いは、 R1及び R2が結合している炭素原子と一体となつ て、 5〜8員シクロアルケン環、又はベンゼン環を形成してもよぐ [The symbols in the formula have the following meanings. R 1 and R 2 : the same or different, H, halogen, lower alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, or a carbon atom to which R 1 and R 2 are bonded. A 5- to 8-membered cycloalkene ring or a benzene ring may be formed.
R3:- OH、 -O-低級アルキル、又は- NH- SO - (-OHゝ及び- O- C(=0)—低級アル R 3 : —OH, —O-lower alkyl, or —NH—SO — (— OH ゝ and —O—C (= 0) —lower alkyl
2  2
キル力 選択される基で置換されて 、てもよ 、低級アルキル）、 Kill power substituted with a selected group, which may be lower alkyl),
A：置換されて!、てもよ 、ヘテロ環基、  A: substituted !, may be a heterocyclic group,
B：置換されて!、てもよ 、フエ-ル、又は置換されて 、てもよ 、単環式へテロァリール  B: substituted !, may, file, or substituted, may be monocyclic heteroaryl
C：置換されて!、てもよ 、フエ-レン、又は置換されて!、てもよ!/、単環式へテロァリー レン、 C: substituted !, may, phenylene, substituted !, may! /, Monocyclic heteroalkylene,
X：低級アルキレン、低級ァルケ-レン、 -0-低級アルキレン-、又は-低級アルキレン - o-、  X: lower alkylene, lower alkylene, -0-lower alkylene-, or -lower alkylene -o-,
Y:単結合、低級アルキレン、低級ァルケ-レン、又は- o-低級アルキレン-、 Y: a single bond, lower alkylene, lower alkylene, or -o-lower alkylene,
Z :低級アルキレン。以下同様。 ] Z: Lower alkylene. The same applies below. ]
[2] Aが含酸素 4〜6員飽和へテロ環基又は含窒素 5〜6員へテロアリールであって 、 Bがフエ-ル、又は N若しくは Oを必ず 1個含む 5〜6員へテロアリールである、 [1]記 載の化合物、ここで A及び Bにおける各環基は置換されていてもよぐ  [2] A is oxygen-containing 4- to 6-membered saturated heterocyclic group or nitrogen-containing 5- to 6-membered heteroaryl, and B is a ring, or N or O. The compound according to [1], wherein each ring group in A and B may be substituted.
[3] Aがォキセタ -ル、テトラヒドロフリル、テトラヒドロビラ-ル、ピリジル、ピラジュル、 イミダゾリル、及びビラゾリルカ なる群力 選択される環基であって、 Bがフエニル、 チアゾリル、フリル、及びピリジルから選択される環基である、 [2]記載の化合物、ここ で A及び Bにおける各環基は低級アルキル又はハロゲンで置換されていてもよぐ [4] Aがォキセタニル及びピリジルカもなる群力 選択される環基であって、 Bがフエ -ル及びチアゾリルカも選択される環基である、 [3]記載の化合物、ここで Aにおける 各環基は低級アルキルで置換されて ヽてもよく、 Bにおける各環基は低級アルキル 又はハロゲンで置換されていてもよぐ [3] A is a group selected from the group consisting of oxetal, tetrahydrofuryl, tetrahydrobiral, pyridyl, pyrajur, imidazolyl, and virazolylca, and B is selected from phenyl, thiazolyl, furyl, and pyridyl The compound according to [2], wherein each ring group in A and B may be substituted with lower alkyl or halogen. [4] A is selected from the group power in which A is also oxetanyl and pyridylca. The compound according to [3], wherein B is a cyclic group in which phenol and thiazolylca are also selected, wherein each cyclic group in A may be substituted with lower alkyl, Each ring group may be substituted with lower alkyl or halogen.
[5] Xカ O-低級アルキレン-である、 [1]〜[4]のいずれかに記載の化合物、  [5] The compound according to any one of [1] to [4], wherein X is O-lower alkylene-
[6] Yが単結合である、 [5]記載の化合物、 [6] The compound according to [5], wherein Y is a single bond,
[7] Zがメチレンである、 [6]記載の化合物、 [8] Cがフエ-レンである、 [7]記載の化合物、 [7] The compound according to [6], wherein Z is methylene, [8] The compound according to [7], wherein C is phenylene.
[9] R3が- OHであって、 R1及び R2が同一又は異なって、 H、ハロゲン、低級アルキ ル、ハロゲノ低級アルキル、 -0-低級アルキル、或いは、 R1及び R2が結合している炭 素原子と一体となって、シクロペンテン環を形成している、 [8]記載の化合物、 [9] R 3 is —OH, R 1 and R 2 are the same or different, and H, halogen, lower alkyl, halogeno lower alkyl, −0-lower alkyl, or R 1 and R 2 are bonded. The compound according to [8], which forms a cyclopentene ring together with the carbon atom
[10] 4-[({6-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ォキセタン- 2-ィルメチ ル)ァミノ] -2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、 [10] 4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (oxetane-2-ylmethyl) amino] -2,3-dihydro-1H -Inden-5-yl} oxy) methyl] benzoic acid,
4-{[(6-{[(3-メチルォキセタン- 3-ィル)メチル ][(4-メチル - 1,3-チアゾール -2-ィル)スル ホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸、 4-{[(6-{[(3-Methyloxetane-3-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2,3- Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid,
4-[({6-[[(3,5-ジフルオロフェ -ル)スルホ -ル] (ォキセタン- 2-ィルメチル)ァミノ] -2,3- ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、 4-[({6-[[(3,5-difluorophenyl) sulfol] (oxetane-2-ylmethyl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) Methyl] benzoic acid,
4-[({6-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ 4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino
1- 2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、 1- 2,3-dihydro-1H-indene-5-yl} oxy) methyl] benzoic acid,
4-[({6-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (テトラヒドロフラン- 3-ィルメ チル)ァミノ] -2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (tetrahydrofuran-3-ylmethyl) amino] -2,3-dihydro-1H-indene- 5-yl} oxy) methyl] benzoic acid,
4-[({6-[[(5-メチル - 2-フリル)スルホ -ル] (テトラヒドロフラン- 3-ィルメチル)ァミノ] -2,3- ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、 4-[({6-[[(5-Methyl-2-furyl) sulfol] (tetrahydrofuran-3-ylmethyl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) methyl ]benzoic acid,
4-[({6- [(ピリジン- 2-ィルメチル) (ピリジン- 3-ィルスルホ -ル)ァミノ] -2,3-ジヒドロ- 1H- インデン -5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[(pyridine-2-ylmethyl) (pyridine-3-ylsulfo-yl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) methyl] benzoic acid,
4-({4,5-ジメチル- 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィ ルメチル)ァミノ]フエノキシ }メチル)安息香酸、  4-({4,5-dimethyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) benzoic acid ,
4-({4-クロ口- 5-メチル - 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 4-({4-Chloro-5-methyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-
2-ィルメチル)ァミノ]フエノキシ }メチル)安息香酸、 2-ylmethyl) amino] phenoxy} methyl) benzoic acid,
4- {[2- [[(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -5- (トリフルォロメチル)フエノキシ]メチル }安息香酸、  4- {[2- [[(4-Methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] -5- (trifluoromethyl) phenoxy] methyl} benzoic acid,
4-({4,5-ジメチル- 2- [(ピリジン- 2-ィルメチル) (ピリジン- 3-ィルスルホ -ル)ァミノ]フエノ キシ }メチル)安息香酸、  4-({4,5-dimethyl-2-[(pyridine-2-ylmethyl) (pyridine-3-ylsulfoyl) amino] phenoxy} methyl) benzoic acid,
4-{[(6-{[(1-メチル -1H-ピラゾール -4-ィル)メチル ][(4-メチル - 1,3-チアゾール -2-ィ ル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸、 4-({5-メトキシ -4-メチル - 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン -2-ィルメチル)ァミノ]フエノキシ }メチル)安息香酸、 4-{[(6-{[(1-Methyl-1H-pyrazol-4-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2 , 3-Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid, 4-({5-methoxy-4-methyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) benzoic acid acid,
4-({4,5-ジメチル- 2- [(ピリジン- 2-ィルメチル) (ピリジン- 2-ィルスルホ -ル)ァミノ]フエノ キシ }メチル)安息香酸、  4-({4,5-dimethyl-2-[(pyridine-2-ylmethyl) (pyridine-2-ylsulfol) amino] phenoxy} methyl) benzoic acid,
4-[({6-[[(2-フルオロフェ -ル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -2,3-ジヒドロ -1H-インデン -5-ィル }ォキシ)メチル]安息香酸、及び  4-[({6-[[(2-Fluorophenyl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) methyl] benzoic acid Acid, and
4- {[(6- {[(1-メチル -1H-イミダゾール- 2-ィル)メチル ][(4-メチル -1,3-チアゾール -2-ィ ル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸、 力 なる群力 選択される [1]記載の化合物又はその製薬学的に許容される塩、 [11] [1]記載の化合物を有効成分とする医薬組成物、  4- {[(6- {[(1-Methyl-1H-imidazol-2-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2 , 3-Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid, powerful group power selected The compound according to [1] or a pharmaceutically acceptable salt thereof, [11] [1 ] A pharmaceutical composition comprising the compound as described above as an active ingredient,
[12] EP1受容体拮抗剤である [11]記載の医薬組成物、  [12] The pharmaceutical composition according to [11], which is an EP1 receptor antagonist,
[13] 過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状、間質性 膀胱炎、前立腺炎力もなる下部尿路疾患の治療薬である、 [11]記載の医薬組成物、 [14] EP1受容体拮抗剤、及び/又は過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症 に伴う下部尿路症状、間質性膀胱炎、前立腺炎からなる下部尿路疾患の治療薬の 製造のための、 [1]記載の化合物の使用、  [13] The drug according to [11], which is a therapeutic agent for frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptom associated with prostatic hypertrophy, interstitial cystitis, and prostatic inflammation. [14] EP1 receptor antagonist, and / or urinary frequency associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with benign prostatic hyperplasia, interstitial cystitis, prostatitis, lower urinary tract disease Use of a compound according to [1] for the manufacture of a therapeutic agent for
[15] [1]記載の化合物の治療有効量を患者に投与することを含む、過活動膀胱に伴 う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状、間質性膀胱炎、前立腺炎から なる下部尿路疾患の治療方法、  [15] The method includes administering to a patient a therapeutically effective amount of the compound according to [1], frequent urination with overactive bladder, urinary incontinence, lower urinary tract symptoms with prostatic hypertrophy, interstitial cystitis, A method for treating lower urinary tract disease comprising prostatitis,
に関する。  About.
発明の効果  The invention's effect
[0015] 本発明化合物は、強力な EP1受容体拮抗作用を有することから、 EP1受容体が関与 する疾患、特に過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状 、間質性膀胱炎、前立腺炎などの下部尿路疾患治療薬として有用である。  [0015] Since the compound of the present invention has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, It is useful as a therapeutic agent for lower urinary tract diseases such as interstitial cystitis and prostatitis.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0016] 以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本明細書中、「低級」なる語は、特に断らない限り炭素数 1〜6個（以下、 C と略す）  In this specification, the term “lower” means 1 to 6 carbon atoms (hereinafter abbreviated as C) unless otherwise specified.
1-6 の直鎖または分枝状の炭化水素鎖を意味する。 [0017] 「低級アルキル」とは、 C アルキルを意味する。具体的には、メチル、ェチル、 n-プ 1-6 linear or branched hydrocarbon chain. “Lower alkyl” means C alkyl. Specifically, methyl, ethyl, n-propyl
1-6  1-6
口ピル、イソプロピル、 n-ブチル、イソブチル、 sec-ブチル、 tert-ブチル、 n-ペンチル 、 n-へキシル等が挙げられる。好ましくは C アルキルであり、より好ましくはメチル、  Mouth pill, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like can be mentioned. Preferably it is C alkyl, more preferably methyl,
1-3  1-3
ェチルである。  Yetil.
「低級アルキレン」とは、 C アルキルの任意の位置の水素を 1個除去してなる 2価  “Lower alkylene” is a divalent group formed by removing one hydrogen from any position of C alkyl.
1-6  1-6
基を意味する。具体的にはメチレン、エチレン、メチルメチレン、ジメチルメチレン、トリ メチレン、テトラメチレン、プロピレン等が挙げられる。好ましくはメチレン、エチレン、ト リメチレンであり、より好ましくはメチレン、エチレンである。  Means group. Specific examples include methylene, ethylene, methylmethylene, dimethylmethylene, trimethylene, tetramethylene, and propylene. Preferred are methylene, ethylene and trimethylene, and more preferred are methylene and ethylene.
「低級ァルケ-レン」とは、 C ァルケ-ルの任意の位置の水素を 1個除去してなる 2  “Lower alkellene” is formed by removing one hydrogen atom at any position of the C alkell 2
2-6  2-6
価基を意味する。具体的にはビ-レン、プロべ-レン、 1 ブテ-レン、 2—ブテユレ ン等が挙げられる。好ましくはビ-レンである。  Means a valent group. Specific examples include beylene, probelene, 1-butylene, 2-butene. Biylene is preferred.
[0018] 「ハロゲン」とは、ハロゲン原子を意味する。具体的にはフルォロ、クロ口、ブロモ、ョ ードが挙げられる。好ましくはフルォロ、クロ口である。 “Halogen” means a halogen atom. Specific examples include fluoro, black mouth, bromo and iodine. Fluoro and black mouth are preferred.
「ハロゲノ低級アルキル」とは、前記「低級アルキル」の 1個以上の任意の水素原子 力 同一または異なって前記「ハロゲン」で置換された基を意味する。具体的には、ト リフルォロメチル、ペンタフルォロェチル等が挙げられる。好ましくはトリフルォロメチ ルである。  The “halogeno lower alkyl” means a group substituted with the above “halogen” in the same or different one or more arbitrary hydrogen atom forces of the “lower alkyl”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Trifluoromethyl is preferred.
「5〜8員シクロアルケン環」とは、環内に 1又は 2個の二重結合を有する C の炭化  “5- to 8-membered cycloalkene ring” means carbonization of C having 1 or 2 double bonds in the ring.
5-8 水素環を意味する。具体的には、シクロペンテン、シクロペンタジェン、シクロへキセ ン、シクロへキサジェン、シクロヘプテン、シクロオタテン等が挙げられる。好ましくは シクロペンテンである。  5-8 This means a hydrogen ring. Specific examples include cyclopentene, cyclopentagen, cyclohexene, cyclohexagen, cycloheptene, cyclootaten and the like. Cyclopentene is preferred.
[0019] 「単環式へテロァリール」とは、 0、 S及び N力 選択されるへテロ原子を 1〜4個含有 する単環 5〜6員芳香環基であり、環原子である S又は Nが酸ィ匕されォキシドゃジォキ シドを形成してもよい。具体的には、ピリジル、ピリダジ -ル、ピリミジ -ル、ピラジュル 、トリアジニル、フリル、チェニル、ピロリル、ォキサゾリル、イソォキサゾリル、ォキサジ ァゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、イミダゾリル、ピラゾリル、トリア ゾリル、テトラゾリル等が挙げられる。好ましくはピリジル、フリル、チアゾリルである。 「含窒素 5〜6員へテロアリール」とは、上記「単環式へテロァリール」の内、環の構 成原子として少なくとも 1個以上の Nを含有する環基を意味する。具体的には、ピリジ ル、ピリダジ -ル、ピリミジニル、ピラジ -ル、トリアジ-ル、ピロリル、ォキサゾリル、イソ ォキサゾリル、ォキサジァゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、イミダゾ リル、ピラゾリル、トリァゾリル、テトラゾリル等が挙げられる。好ましくはピリジル、ピラジ -ル、チアゾリル、イミダゾリル、ピラゾリル、ォキサジァゾリルであり、より好ましくはピリ ジル、ピラジニル、チアゾリル、イミダゾリル、ピラゾリルである。 [0019] "Monocyclic heteroaryl" is a monocyclic 5- to 6-membered aromatic ring group containing 1 to 4 heteroatoms selected from 0, S and N forces, and S or a ring atom N may be oxidized to form an oxide. Specific examples include pyridyl, pyridazyl, pyrimidyl, pyrajyl, triazinyl, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. . Pyridyl, furyl and thiazolyl are preferred. “Nitrogen-containing 5- to 6-membered heteroaryl” refers to the ring structure in the above “monocyclic heteroaryl”. It means a cyclic group containing at least one N as a constituent atom. Specific examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. Pyridyl, pyrazyl, thiazolyl, imidazolyl, pyrazolyl and oxadiazolyl are preferable, and pyridyl, pyrazinyl, thiazolyl, imidazolyl and pyrazolyl are more preferable.
「N若しくは 0を必ず 1個含む 5〜6員へテロアリール」とは、上記「単環式へテロァリ ール」の内、環の構成原子として必ず 1個の N及び/又は 0を含有し、更に 1個の Sを 含有してもよい環基を意味する。具体的には、ピリジル、ピロリル、ォキサゾリル、イソ ォキサゾリル、チアゾリル、イソチアゾリル、フリル等が挙げられる。好ましくはピリジル 、チアゾリル、フリルである。  “5- to 6-membered heteroaryl containing at least one N or 0” means that the above “monocyclic heteroaryl” always contains one N and / or 0 as a ring-constituting atom, Furthermore, it means a cyclic group which may contain one S. Specific examples include pyridyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl and the like. Pyridyl, thiazolyl and furyl are preferred.
「単環式へテロァリーレン」とは、上記「単環式へテロァリール」の環原子上の任意の 水素を 1個除去してなる 2価基を意味する。具体的には、ピリジンジィル、ピリダジンジ ィル、ピリミジンジィル、ピラジンジィル、トリアジンジィル、フランジィル、チォフェンジ ィル、ピロールジィル、ォキサゾールジィル、イソォキサゾールジィル、ォキサジァゾ ールジィル、チアゾールジィル、イソチアゾールジィル、チアジアゾールジィル、イミダ ゾールジィル、トリァゾールジィル、テトラゾールジィル等が挙げられる。好ましくはピリ ジンジィル、チォフェンジィルである。  The “monocyclic heteroarylene” means a divalent group formed by removing one arbitrary hydrogen on the ring atom of the “monocyclic heteroaryl”. Specifically, pyridine, pyridazine, pyrimidine, pyrazine, triazine, flanged, thiophene, pyrrole, oxazole, isoxazole, oxadiazol, thiazole, and thiadiazole Imidazole dil, triazole dil, tetrazol dil and the like. Pyridine diyl and thiophen diyl are preferable.
「ヘテロ環基」とは、 0、 S及び N力 選択されるへテロ原子を 1〜4個含有する飽和、 不飽和又は部分的に不飽和の 3〜8員単環へテロ環基、 8〜14員二環式へテロ環 基、 11〜20員三環式へテロ環基を意味する。環原子である S又は Nが酸ィヒされォキ シドゃジォキシドを形成してもよぐまた、架橋環ゃスピロ環を形成してもよい。単環へ テロ環基としては具体的には、ピリジル、ピリダジニル、ピリミジ -ル、ピラジュル、トリ アジニル、フリル、ジヒドロフリル、チェニル、ピロリル、ォキサゾリル、イソォキサゾリル 、ォキサジァゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、イミダゾリル、ピラゾ リル、トリァゾリル、テトラゾリル、ォキセタニル、テトラヒドロフリル、テトラヒドロビラニル 、ァゼチジニル、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、ァゼパニル 、ジァゼパニル等が挙げられる。二環式へテロ環基としては具体的には、インドリル、 ベンゾフラニル、ジヒドロベンゾフラニル、ベンゾチェニル、ベンゾ才キサゾリノレ、ベン ゾイミダゾリル、ベンゾチアゾリル、インダゾリル、キノリル、キナゾリニル、キノキサリニ ル、シンノリ-ル等が挙げられる。三環式へテロ環基としては具体的には、力ルバゾリ ル、アタリジ-ル等が挙げられる。好ましくは 4〜6員単環へテロ環基であり、より好ま しくはォキセタニル、テトラヒドロフリル、テトラヒドロビラニル、ピリジル、ピラジニル、ィ ミダゾリル、ピラゾリル、チアゾリル、ォキサジァゾリルであり、より更に好ましくはォキセ タニル、テトラヒドロフリル、ピリジル、ピラジュル、チアゾリル、イミダゾリル、ピラゾリル である。 “Heterocyclic group” means a saturated, unsaturated or partially unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N forces, 8 Means a 14-membered bicyclic heterocyclic group or an 11-20 membered tricyclic heterocyclic group. The ring atom S or N may be acidified to form an oxide or dioxide, or a bridged ring or spiro ring may be formed. Specific examples of the monocyclic heterocyclic group include pyridyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, furyl, dihydrofuryl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, and pyrazol. Examples include ryl, triazolyl, tetrazolyl, oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and the like. Specific examples of the bicyclic heterocyclic group include indolyl, Examples include benzofuranyl, dihydrobenzofuranyl, benzocenyl, benzoid oxazolinole, benzoimidazolyl, benzothiazolyl, indazolyl, quinolyl, quinazolinyl, quinoxalinyl, cinnoyl and the like. Specific examples of the tricyclic heterocyclic group include force rubazolyl and attalizyl. Preferably, it is a 4- to 6-membered monocyclic heterocyclic group, more preferably oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, and still more preferably oxetanyl, Tetrahydrofuryl, pyridyl, pyrajur, thiazolyl, imidazolyl, pyrazolyl.
[0021] 「含酸素 4〜6員飽和へテロ環基」とは、上記「ヘテロ環基」の内、環の構成原子とし て少なくとも 1個以上の 0を含有する 4〜6員飽和へテロ環基を意味する。具体的に は、  [0021] "Oxygen-containing 4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated hetero group containing at least one or more 0 as a ring constituent atom in the "heterocyclic group". Means a cyclic group. In particular,
ォキセタニル、テトラヒドロフリル、テトラヒドロビラニル、モルホリニル、ォキサゼパニル 、ジォキソラ -ル、ジォキサ-ル等が挙げられる。好ましくはォキセタ -ル、テトラヒドロ フリル、テトラヒドロビラ-ルであり、より好ましくはォキセタ -ル、テトラヒドロフリルであ る。  Examples include oxetanyl, tetrahydrofuryl, tetrahydrobiranyl, morpholinyl, oxazepanyl, dioxol, and dioxal. Preferred are oxetal, tetrahydrofuryl and tetrahydroviral, and more preferred are oxetal and tetrahydrofuryl.
[0022] 「置換されていてもよい」とは、「無置換」あるいは「同一又は異なる置換基を 1〜5個 有していること」を示す。なお、複数個の置換基を有する場合、それらの置換基は同 一でも互!ヽに異なって!/、てもよ!/、。  The term “which may be substituted” means “unsubstituted” or “having 1 to 5 substituents which are the same or different”. In the case of having a plurality of substituents, these substituents may be the same or different from each other! /, May! /.
Aの「置換されていてもよいへテロ環基」における置換基として、好ましくは低級アル キル、ハロゲン、ハロゲノ低級アルキル、 - OH、 -O-低級アルキル、 -O-ハロゲノ低級 アルキル、シァ入及び-トロカゝら選択される基であり、より好ましくは低級アルキル、 ハロゲン、 -O-低級アルキルであり、より更に好ましくは低級アルキルである。  As the substituent in the “optionally substituted heterocyclic group” of A, preferably lower alkyl, halogen, halogeno lower alkyl, —OH, —O-lower alkyl, —O-halogeno lower alkyl, -Troca and the like, more preferably lower alkyl, halogen, and -O-lower alkyl, still more preferably lower alkyl.
Bの「置換されて 、てもよ 、フエ-ル」、及びじの「置換されて!、てもよ!/、フエ-レン」 における置換基として、好ましくは低級アルキル、ハロゲン、ハロゲノ低級アルキル、 - OH、 -0-低級アルキル、 -0-ハロゲノ低級アルキル、シァ入及び-トロから選択さ れる基であり、より好ましくは低級アルキル、ハロゲン、 OH、 -O-低級アルキルであり 、より更に好ましくは低級アルキル、ハロゲンである。  As a substituent in B “substituted or phenyl” and the same “substituted !, may! /, Phenol”, preferably a lower alkyl, halogen, halogeno lower alkyl , -OH, -0-lower alkyl, -0-halogeno lower alkyl, sialed and -tro, more preferably lower alkyl, halogen, OH, -O-lower alkyl, and more Preferred are lower alkyl and halogen.
Bの「置換されて 、てもよ 、単環式へテロァリール」、及びじの「置換されて!、てもよ い単環式へテロァリーレン」における置換基として、好ましくは低級アルキル、ハロゲ ン、ハロゲノ低級アルキル、 -0-低級アルキル、 -o-ハロゲノ低級アルキル、シァ入 及び-トロ力 選択される基であり、より好ましくは低級アルキル、ハロゲン、 -0-低級 アルキルであり、より更に好ましくは低級アルキル、ハロゲンである。 B “Substituted, may be a monocyclic heteroaryl”, and the same “Substituted !, may be As a substituent in the `` monocyclic heteroarylene '', preferably a lower alkyl, a halogen, a halogeno lower alkyl, a -0-lower alkyl, a -o-halogeno lower alkyl, a cyanide and a -tro force, More preferred are lower alkyl, halogen and -0-lower alkyl, and even more preferred are lower alkyl and halogen.
本発明における好ま 、態様を以下に示す。  Preferred embodiments of the present invention are shown below.
(1) Aとして、好ましくは、それぞれ置換されていてもよいォキセタニル、テトラヒドロフ リル、テトラヒドロビラ-ル、ピリジル、ピラジュル、イミダゾリル、ピラゾリル、チアゾリル 、ォキサジァゾリルであり、より好ましくは、それぞれ置換されていてもよいォキセタ- ル、テトラヒドロフリル、ピリジル、ピラジュル、イミダゾリル、ピラゾリルであり、より更に 好ましくは、それぞれ置換されていてもよいォキセタニル、ピリジルである。ここに、 A 上の置換基としては、上記に記載の置換基が好まし 、。  (1) A is preferably an optionally substituted oxetanyl, tetrahydrofuryl, tetrahydroviral, pyridyl, pyrajyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, more preferably each substituted. May be oxetal, tetrahydrofuryl, pyridyl, pyrajyl, imidazolyl, pyrazolyl, and more preferably oxetanyl and pyridyl which may be substituted. Here, as the substituent on A, the substituents described above are preferable.
(2) Bとして、好ましくは、それぞれ置換されていてもよいチアゾリル、フリル、ピリジル 、フエ-ルであり、より好ましくは、それぞれ置換されていてもよいチアゾリル、フエ二 ルである。ここに、 B上の置換基としては、上記に記載の置換基が好ましい。  (2) B is preferably an optionally substituted thiazolyl, furyl, pyridyl, or phenol, and more preferably an optionally substituted thiazolyl or vinyl. Here, as the substituent on B, the substituents described above are preferable.
(3) Cとして、好ましくは、それぞれ置換されていてもよいフエ-レン、チォフェンジィ ル、ピリジンジィルであり、より好ましくは、置換されていてもよいフエ-レンである。こ こに、 C上の置換基としては、上記に記載の置換基又は無置換が好ましぐ無置換が より好まし 、。  (3) C is preferably an optionally substituted phenylene, thiopheneyl, or pyridinezyl, and more preferably an optionally substituted phenylene. Here, as the substituent on C, the substituent described above or unsubstituted is more preferable, and unsubstituted is more preferable.
(4) R2として、好ましくは、同一又は異なって、 H、低級アルキル、ハロゲン、 - O- 低級アルキル、ハロゲノ低級アルキルである。
Figure imgf000014_0001
R2の別の好ましい態様は、 R1及び R2が結合している炭素と一体となってシクロペンテン環を形成する場合である。(4) R 2 is preferably the same or different and is H, lower alkyl, halogen, —O-lower alkyl, or halogeno lower alkyl.
Figure imgf000014_0001
Another preferred embodiment of R 2 is the case of forming a cyclopentene ring together with the carbon to which R 1 and R 2 are attached.
(5) R3として、好ましくは、 - OH、 -NH-SO - (-OH,及び- O- C(=0)—低級アルキ (5) R 3 is preferably -OH, -NH-SO-(-OH, and -O-C (= 0) -lower alkyl.
2  2
ルカ 選択される基で置換されていてもよい低級アルキル)であり、より好ましくは、 -Luka, lower alkyl optionally substituted with a selected group), more preferably-
OHである。 OH.
(6) Xとして、好ましくは、 -0-低級アルキレン-であり、より好ましくは- 0-メチレン-で ある。  (6) X is preferably -0-lower alkylene-, more preferably -0-methylene-.
(7) Yとして、好ましくは、単結合である。  (7) Y is preferably a single bond.
(8) Zとして、好ましくは、メチレン、メチルメチレン、エチレンであり、より好ましくは、メ チレンである。 (8) Z is preferably methylene, methylmethylene, or ethylene, more preferably Tylene.
本発明の特に好ま 、態様としては、上記 (1)〜(8)に記載の各好まし 、基の組合わ せ力 なる化合物である。  A particularly preferred embodiment of the present invention is a compound capable of combining each preferred group described in the above (1) to (8).
[0024] 本発明の化合物は、置換基の種類によっては他の互変異性体や幾何異性体が存 在する場合もある。本明細書中、それら異性体の一形態のみで記載することがあるが 、本発明にはこれらの異性体も包含し、異性体の分離したもの、あるいは混合物も包 含する。 In the compound of the present invention, other tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, only one form of these isomers may be described, but the present invention includes these isomers, and also includes a separated isomer or a mixture thereof.
また、化合物 (I)は不斉炭素原子や軸不斉を有する場合があり、これに基づく (R)体 、（S)体などの光学異性体が存在しうる。本発明はこれらの光学異性体の混合物や単 離されたものを全て包含する。  In addition, compound (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers such as (R) and (S) isomers may exist based on this. The present invention includes all of these optical isomers and mixtures thereof.
更に、本発明には、化合物 (I)の薬理学的に許容されるプロドラッグも含まれる。薬 理学的に許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で本発 明のアミノ基、 OH、 CO H等に変換できる基を有する化合物である。プロドラッグを形  Furthermore, the present invention includes pharmacologically acceptable prodrugs of Compound (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, OH, COH, or the like of the present invention by solvolysis or under physiological conditions. Shape prodrug
2  2
成する基としては、例えば、 Prog. Med., 5, 2157-2161 (1985)や「医薬品の開発」（廣 川書店、 1990年)第 7卷 分子設計 163-198に記載の基が挙げられる。  Examples of the group to be formed include groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), No. 7 Molecular design 163-198. .
[0025] また、本発明化合物は、置換基の種類によっては酸付加塩若しくは塩基との塩を 形成する場合もあり、カゝかる塩が製薬学的に許容され得る塩である限りにおいて本発 明に包含される。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン 酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シユウ酸、マロン酸、コハク酸、フマル 酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クェン酸、メタンスルホン酸、エタンスルホン 酸、 P-トルエンスルホン酸、ァスパラギン酸、又はグルタミン酸等の有機酸との酸付カロ 塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチ ルァミン、ェチルァミン、エタノールァミン、リシン、オル-チン等の有機塩基との塩や アンモ-ゥム塩等が挙げられる。 [0025] Further, the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent. Explicitly included. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid , Lactic acid, Malic acid, Tartaric acid, Chenic acid, Methanesulfonic acid, Ethanesulfonic acid, P-Toluenesulfonic acid, Aspartic acid, Carboxylic acid with organic acids such as glutamic acid, sodium, potassium, magnesium, calcium, aluminum And inorganic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortho salts, and ammonium salts.
更に、本発明は、本発明化合物及びその製薬学的に許容される塩の各種の水和 物や溶媒和物、及び結晶多形の物質をも包含する。また、本発明は、種々の放射性 又は非放射性同位体でラベルされたィ匕合物も包含する。  Furthermore, the present invention also includes various hydrates and solvates of the compound of the present invention and pharmaceutically acceptable salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
[0026] (製造法） 本発明化合物及びその製薬学的に許容され得る塩は、その基本骨格あるいは置 換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することが できる。その際、官能基の種類によっては、当該官能基を原料乃至中間体の段階で 適当な保護基 (容易に当該官能基に転化可能な基)に置き換えておくことが製造技 術上効果的な場合がある。このような官能基としては例えばアミノ基、水酸基、カルボ キシル基等であり、それらの保護基としては例えばグリーン (Greene)及びウッツ (Wuts) 著、「Protective Groups in Organic Synthesis (第 3版、 1999年)」に記載の保護基等を 挙げることができ、これらを反応条件に応じて適宜選択して用いればよい。このような 方法では、当該保護基を導入して反応を行った後、必要に応じて保護基を除去する ことにより、所望の化合物を得ることができる。 [0026] (Production method) The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is a case. Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups, and examples of their protecting groups include Greene and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999). And the like, and these may be appropriately selected and used according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.
また、化合物 (I)のプロドラッグは上記保護基と同様、原料乃至中間体の段階で特 定の基を導入、あるいは得られた化合物 (I)を用い反応を行うことで製造できる。反応 は通常のエステル化、アミド化、脱水等、当業者により公知の方法を適用することによ り行うことができる。  Similarly to the above protecting group, the prodrug of compound (I) can be produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound (I). The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
以下、本発明化合物の代表的な製造法を説明する。各製法は、当該説明に付した 参考文献を参照して行うこともできる。なお、本発明の製造法は以下に示した例には 限定されない。  Hereafter, the typical manufacturing method of this invention compound is demonstrated. Each manufacturing method can also be performed with reference to the references attached to the description. The production method of the present invention is not limited to the examples shown below.
(製法 1) (Manufacturing method 1)
[化 6][Chemical 6]
Figure imgf000016_0001
Figure imgf000016_0001
(式中、 Lvは脱離基を示し、その他の記号は前記と同じ意味を表す。 ) (In the formula, Lv represents a leaving group, and other symbols have the same meaning as described above.)
本工程は化合物 (II)を脱離基を有する化合物 (III)を用いてアルキルィ匕することに より本発明化合物 (I)を製造する工程である。 Lvで示される脱離基は、求核置換反応 において常用される脱離基であればいずれでもよぐクロ口、ブロモ等のハロゲン、メ タンスルホニルォキシ、 p-トルエンスルホニルォキシ、トリフルォロメタンスルホニルォ キシ等のスルホ -ルォキシ、低級アルキルスルホ -ル、ァリールスルホ-ル等のスル ホニル等が好適に用いられる。本工程のアルキルィ匕反応は当業者が通常用いうるァ ルキルイ匕を採用することができる。例えば、無溶媒下、若しくはベンゼン、トルエン、 キシレン等の芳香族炭化水素類、酢酸ェチル等のエステル類、ジェチルエーテル、 テトラヒドロフラン（THF)、ジォキサン等のエーテル類、ジクロロメタン、 1,2-ジクロロェ タン、クロ口ホルム等のハロゲン化炭化水素類、 Ν,Ν-ジメチルホルムアミド（DMF)、 N, N-ジメチルァセトアミド（DMA)、 N-メチルピロリドン（NMP)、ジメチルスルホキシド（D MSO)、ァセトニトリル等の反応に不活性な溶媒、あるいはアルコール類等の溶媒中 、室温乃至加熱還流下に行うことができる。化合物によっては、有機塩基（トリェチル ァミン、ジイソプロピルェチルァミン、 N-メチルモルホリン、ピリジン、 4-(N,N-ジメチル ァミノ)ピリジン等が好適に用いられる）、又は金属塩塩基 (炭酸カリウム、炭酸セシゥ ム、水酸化ナトリウム、水酸ィ匕カリウム、水素化ナトリウム、 tert-ブトキシカリウム等が好 適に用いられる）の存在下に行うことが、反応を円滑に進行させる上で有利な場合が ある。 This step is a step for producing the compound (I) of the present invention by alkylating the compound (II) with the compound (III) having a leaving group. The leaving group represented by Lv can be any leaving group commonly used in nucleophilic substitution reactions. Sulfonoxy such as tansulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., sulfonyl such as lower alkyl sulfole, arylsulfol and the like are preferably used. For the alkylation reaction in this step, an alkyl iodide usually used by those skilled in the art can be employed. For example, in the absence of solvent, or aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane, dichloromethane, 1,2-dichloroethane , Halogenated hydrocarbons such as black mouth form, Ν, Ν-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), acetonitrile The reaction can be carried out in a solvent inert to the reaction, or a solvent such as alcohols at room temperature to heating under reflux. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, In the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy, etc.) may be advantageous for the smooth progress of the reaction. is there.
[0029] また、式（III)にお!/、て Lvカ OHである化合物を用いて、 THF、ジォキサン、ジェチ ルエーテル等のエーテル類、塩化メチレン、クロ口ホルム等のハロゲンィ匕炭化水素類 、トルエン、ベンゼン等の芳香族炭化水素類、 DMF等の溶媒中、トリフ ニルホスフィ ン、トリ- n-ブチルホスフィン、トリス（ジメチルァミノ）ホスフィン、トリフエ-ルホスファイト 、ジフエノキシフエ-ルホスフィン、ジフエ-ル（2-ピリジル）ホスフィン、 （4-ジメチルァ ミノ）ジフエ-ルホスフィン等のホスフィン及びジェチルァゾジカルボキシレート、ジイソ プロピルァゾジカルボキシレート、ジメチルァゾジカルボキシレート等のァゾジカルボ キシレートの存在下、冷却下乃至室温下にて行うこともできる。  [0029] In addition, by using a compound of formula (III)! /, Lv OH, ethers such as THF, dioxane, and diethyl ether, and halogenated hydrocarbons such as methylene chloride and black mouth form, Aromatic hydrocarbons such as toluene and benzene, triphenylphosphine, tri-n-butylphosphine, tris (dimethylamino) phosphine, triphenylphosphite, diphenoxyphenylphosphine, diphenyl (2-pyridyl) in solvents such as DMF ) In the presence of phosphine, phosphine such as (4-dimethylamino) diphenylphosphine, and azodicarboxylate such as jetylazodicarboxylate, diisopropylpropyl dicarboxylate, dimethylazodicarboxylate, etc. It can also be performed at room temperature.
[0030] (製法 2)  [0030] (Manufacturing method 2)
[化 7] [Chemical 7]
Figure imgf000018_0001
Figure imgf000018_0001
(式中、 Rは低級アルキルを示し、その他の記号は前記と同じ意味を表す。 ) (In the formula, R represents lower alkyl, and other symbols have the same meanings as described above.)
[0031] 本工程は、加水分解により R3カ ORである本発明化合物（I-a)より、 R3が- OHであ る本発明化合物 (I-b)を製造する工程である。本工程の加水分解反応は、例えば前 記の「Protective Groups in Organic Synthesis (第 3版、 1999年)」に記載の脱保護反応 に準じて行うことができる。 [0031] In this step, a compound of the invention which is R 3 months OR by hydrolysis from (Ia), R 3 is - a step for producing a OH der Ru present compound (Ib). The hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in “Protective Groups in Organic Synthesis (3rd edition, 1999)”.
[0032] 本発明化合物 (I)の製造に使用する原料化合物は、例えば下記の方法、公知の方 法、あるいはその変法を用いて容易に製造することができる。 [0032] The starting compound used for the production of the compound (I) of the present invention can be easily produced, for example, using the following method, a known method, or a modified method thereof.
(原料合成 1)  (Raw material synthesis 1)
[化 8]  [Chemical 8]
Figure imgf000018_0002
Figure imgf000018_0002
(VII) (VIII)  (VII) (VIII)
(式中、 Lvは脱離基を、 Akは低級アルキレンをそれぞれ示し、その他の記号は前記と 同じ意味を表す。 )  (In the formula, Lv represents a leaving group, Ak represents lower alkylene, and other symbols have the same meanings as described above.)
[0033] 第一工程 [0033] First step
本工程は化合物 (IV)を、脱離基を有する化合物 (V)を用いてアルキルィ匕すること により、化合物 (VI)を製造する工程である。本工程のアルキル化は製法 1と同様の方 法で行うことができる。 [0034] 第二工程 This step is a step for producing compound (VI) by alkylating compound (IV) with compound (V) having a leaving group. The alkylation in this step can be performed in the same manner as in Production Method 1. [0034] Second step
本工程は化合物 (VI)を-トロ化して化合物 (VII)を製造する工程である。ニトロ化は 当業者が通常採用しうる方法により行うことができる。例えば、酢酸、濃硫酸等の溶媒 中、濃硝酸をニトロ化剤として行うことができる。  This step is a step for producing compound (VII) by -trolation of compound (VI). Nitration can be carried out by a method that can be generally employed by those skilled in the art. For example, concentrated nitric acid can be used as a nitrating agent in a solvent such as acetic acid or concentrated sulfuric acid.
[0035] 第三工程  [0035] Third step
本工程はニトロ化合物 (νπ)を還元して化合物 (vm)を製造する工程である。本ェ 程のニトロ基の還元反応は当業者が通常採用しうるニトロ基の還元反応を用いること ができる。例えば、還元鉄、塩化スズ等の還元剤を用いた還元反応や、パラジウム- 炭素等を触媒とした水素添加反応が挙げられる。  This step is a step for producing the compound (vm) by reducing the nitro compound (νπ). A nitro group reduction reaction that can be generally employed by those skilled in the art can be used for the reduction reaction of the nitro group. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride, and a hydrogenation reaction using palladium-carbon or the like as a catalyst.
[0036] (原料合成 2)  [0036] (Raw material synthesis 2)
[化 9]  [Chemical 9]
Figure imgf000019_0001
Figure imgf000019_0001
(VIII)  (VIII)
(式中、 Lvは脱離基を、 Akは低級アルキレンをそれぞれ示し、その他の記号は前記と 同じ意味を表す。 ) (In the formula, Lv represents a leaving group, Ak represents lower alkylene, and other symbols have the same meanings as described above.)
[0037] 第一工程 [0037] First step
本工程は化合物 (IX)を脱離基を有する化合物 (V)を用いてアルキルィ匕することに より化合物 (VII)を製造する工程である。本工程のアルキル化は製法 1と同様の方法 で行うことができる。  This step is a step of producing compound (VII) by alkylating compound (IX) with compound (V) having a leaving group. The alkylation in this step can be carried out by the same method as Production method 1.
[0038] 第二工程  [0038] Second step
本工程はニトロ化合物 (νπ)を還元して化合物 (vm)を製造する工程である。本ェ 程の-トロ基の還元は原料合成 1の第三工程と同様の方法で行うことができる。 [0039] (原料合成 3) This step is a step for producing the compound (vm) by reducing the nitro compound (νπ). This reduction of the -tro group can be carried out in the same manner as in the third step of raw material synthesis 1. [0039] (Raw material synthesis 3)
[化 10]  [Chemical 10]
Figure imgf000020_0001
Figure imgf000020_0001
(X) (II)  (X) (II)
(式中、 Lvは脱離基を示し、その他の記号は前記と同じ意味を表す。 ) (In the formula, Lv represents a leaving group, and other symbols have the same meaning as described above.)
[0040] 本工程は化合物 (X)をィ匕合物 (XI)によりスルホ二ルイ匕することにより、化合物（II)を製 造する工程である。 Lvの脱離基としてはクロ口、ブロモ等のハロゲンが好適に用いら れる。反応は例えば、前記の「Protective Groups in Organic Synthesis (第 3版、 1999 年)」に記載のスルホ二ルイ匕の条件が適用できる。具体的には、無溶媒下、又はテトラ ヒドロフラン、塩化メチレン、ァセトニトリル等の溶媒中、必要によりトリェチルァミン、ピ リジン等の塩基の存在下、冷却下乃至加熱還流下にて行うことができる。 [0040] This step is a step of producing compound (II) by sulfonating compound (X) with compound (XI). As the leaving group for Lv, halogen such as black mouth and bromo is preferably used. For the reaction, for example, the conditions of sulfoniru 匕 described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” can be applied. Specifically, the reaction can be carried out in the absence of a solvent or in a solvent such as tetrahydrofuran, methylene chloride, and acetonitrile, in the presence of a base such as triethylamine and pyridine, if necessary, under cooling or under reflux with heating.
[0041] 本発明化合物は、遊離化合物、その製薬学的に許容される塩、水和物、溶媒和物 、あるいは結晶多形の物質として単離され、精製される。本発明化合物 (I)の製薬学 的に許容される塩は、常法の造塩反応に付すことにより製造することもできる。 [0041] The compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphic substance thereof. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to a conventional salt formation reaction.
単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等通常の化学操作 を適用して行われる。  Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
各種の異性体は、適当な原料化合物を選択することにより、あるいは異性体間の物 理ィ匕学的性質の差を利用して分離することができる。例えば、光学異性体は一般的 な光学分割法 (例えば、光学活性な塩基又は酸とのジァステレオマー塩に導く分別 結晶化やキラルカラム等を用いたクロマトグラフィー等)により、立体化学的に純粋な 異性体に導くことができる。また、適当な光学活性な原料ィ匕合物より製造することもで きる。  Various isomers can be separated by selecting an appropriate raw material compound or by utilizing the difference in physical and physical properties between isomers. For example, optical isomers can be obtained by stereochemically pure isomers by general optical resolution methods (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Can lead to. It can also be produced from a suitable optically active raw material compound.
[0042] 本発明化合物の薬理活性は以下の試験により確認した。  [0042] The pharmacological activity of the compound of the present invention was confirmed by the following test.
試験例 1 EP1受容体発現細胞を用いた受容体拮抗活性の測定実験  Test Example 1 Measurement of receptor antagonistic activity using EP1 receptor-expressing cells
ラット EP1受容体を安定的に発現させた HEK293細胞 (アメリカン ·タイプ ·カルチャー •コレクション社 (American Type Culture Collection) )を、実験前日に 2 X 104細胞/ ゥエルとなるように、 96ゥエル (well)ポリ- D-リジン-コートプレート（商品名：バイオコー ト PDL96Wブラック/クリア一、日本べタトンディッキンソン社）に分注し、 37°C、 5%二酸 化炭素（CO )下にて、 10%ゥシ胎児血清 (FBS)を含む培地（商品名： DMEM、インビト HEK293 cells stably expressing rat EP1 receptor (American type culture) • Collection (American Type Culture Collection), 96-well poly-D-lysine-coated plate (trade name: Biocoat PDL96W Black / Clear) to be 2 X 10 4 cells / well the day before the experiment First, it was dispensed to Nippon Betaton Dickinson Co., Ltd., and the medium containing 10% urinary fetal serum (FBS) at 37 ° C and 5% carbon dioxide (CO) (trade name: DMEM, Invito
2  2
ロジェン社）中、一晩培養する。培地をローデイングバッファー (蛍光標識試薬 (商品 名： Fluo3- AM、同仁堂社）、 4 μ Μを含む洗浄溶液:ノヽンタスバランス塩溶液（HBSS) 、 20mM 2-[4-(2-ヒドロキシェチル) - 1-ピペラジ -ル]エタンスルホン酸（HEPES) -水 酸化ナトリウム（NaOH)、 2.5mMプロベネシド、 0.1%ゥシ血清アルブミン（BSA) )に置き 換え、室温で 3時間静置した後、洗浄溶液をセットしたプレートウォッシャー（商品名： ELx405、バイオ-テック（BIO-TEK)インスツルメント社）にて細胞を洗浄する。洗浄溶 液であらかじめ溶解、希釈したィ匕合物を添加し、細胞内カルシウム (Ca)濃度測定シ ステム（商品名： FLIPR、モレキュラーデバイス社）にセットする。 5分後に最終濃度 100 nMとなるように PGEを添加し、細胞内 Ca濃度変化を測定する。細胞内 Ca濃度変化 Incubate overnight in Rogen). The culture medium was loaded with a loading buffer (fluorescent labeling reagent (trade name: Fluo3-AM, Dojindo), 4 μΜ of washing solution: Nontas balanced salt solution (HBSS), 20 mM 2- [4- (2-hydroxyl Chill) -1-piperadyl-ethane] sulfonic acid (HEPES) -sodium hydroxide (NaOH), 2.5 mM probenecid, 0.1% ushi serum albumin (BSA)) and left at room temperature for 3 hours, The cells are washed with a plate washer (trade name: ELx405, BIO-TEK Instruments, Inc.) in which a washing solution is set. Add the compound previously dissolved and diluted with the washing solution, and set it in the intracellular calcium (Ca) concentration measurement system (trade name: FLIPR, Molecular Devices). After 5 minutes, add PGE to a final concentration of 100 nM and measure the change in intracellular Ca concentration. Changes in intracellular Ca concentration
2  2
の最大値と最小値の差を算出し、測定データとして保存した。 100nMの PGE添カロ時 The difference between the maximum value and the minimum value was calculated and stored as measurement data. 100nM with PGE
2 を 0%、ノ ッファー添カ卩時の応答を 100%としたときに、 50%阻害する濃度を IC 値として  Assuming that 2 is 0% and the response when the noferer is added is 100%, the concentration that inhibits 50% is the IC value.
50 算出した。  50 calculated.
結果を下記表 1に示す。表中 Exは、後記実施例化合物番号を示す。  The results are shown in Table 1 below. In the table, Ex represents an Example compound number described later.
[表 1] [table 1]
Figure imgf000021_0001
Figure imgf000021_0001
対照化合物 J：特許文献 4、 実施例 2 ( 7 1 )に開示の化合物 試験例 2 EP1受容体発現細胞を用いた受容体結合実験  Control Compound J: Compound disclosed in Patent Document 4, Example 2 (71) Test Example 2 Receptor binding experiment using cells expressing EP1 receptor
ラット EP1受容体は、 N末端にシグナルペプチド（MKTIIALSYIFCLVFA:配列番号 1 )、および FLAG配列（DYKDDDDK:配列番号 2)を導入したうえ、発現ベクター（商品 名： pCEP4、インビトロジェン社）へサブクローユングした（当該シグナルペプチド及び 当該 FLAG配列のアミノ酸配列は特許文献 6 配列表を参照)。このラット EP1発現べ クタ一を、トランスフエクシヨン試薬（商品名： Fugene-6、ロシュ'ダイァグノスティックス 社）を用いて HEK293EBNA細胞（アメリカン ·タイプ ·カルチャ^ ~ ·コレクション社 (Ameri can Type Culture Collection) )にトランスフエクシヨンした後、 37°C、 5% CO下にて、 1 Rat EP1 receptor has a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) at the N-terminus. ) And a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) and subcloned into an expression vector (trade name: pCEP4, Invitrogen) (the amino acid sequences of the signal peptide and the FLAG sequence are described in Patent Document 6) See). This rat EP1 expression vector was transformed into HEK293EBNA cells (Ameri can Type) using a transfer reagent (trade name: Fugene-6, Roche Diagnostics). Culture Collection)), then 37 ° C, 5% CO, 1
2  2
0% FBSを含む培地（商品名： DMEM、インビトロジェン社）中、 2日間培養した。培養後 の細胞を回収し、細胞溶解液（20mMトリス（ヒドロキシメチル）ァミノメタン (Tris)緩衝 液 pH7.5、 5mMエチレンジァミン四酢酸（EDTA) )にて細胞を処置し、超遠心（23000 回転、 25分 X 2回）により膜標品を粗調整した。  The cells were cultured in a medium containing 0% FBS (trade name: DMEM, Invitrogen) for 2 days. The cultured cells are collected, treated with a cell lysate (20 mM Tris (hydroxymethyl) aminomethane (Tris) buffer pH 7.5, 5 mM ethylenediamine tetraacetic acid (EDTA)), and centrifuged (23000 rpm, 25 The membrane preparation was roughly adjusted by min x 2).
調整した膜標品（15 g)と3 H- PGEを含む反応液（150 μ 1、組成： 10mM 2- (N-モル Reaction solution containing prepared membrane preparation (15 g) and 3 H-PGE (150 μ1, composition: 10 mM 2- (N-mol)
2  2
ホリノ)エタンスルホン酸 (MES)/水酸化カリウム（KOH) pH6.0、 ImM EDTA, lOmM塩 化マグネシウム（MgCl )、 0.02% 3- [(3-コラミドプロピル)ジメチルアンモニォ]プロパン Horino) ethanesulfonic acid (MES) / potassium hydroxide (KOH) pH6.0, ImM EDTA, lOmM magnesium chloride (MgCl), 0.02% 3-[(3-Colamidopropyl) dimethylammonio] propane
2  2
スルホン酸 (CHAPS) )を、室温で 1時間インキュベートした。反応を氷冷バッファーで 停止し、減圧下、吸引ろ過して結合した3 H-PGEをガラスフィルター（商品名：ュ-フ Sulfonic acid (CHAPS)) was incubated for 1 hour at room temperature. The reaction was stopped with ice-cold buffer, and 3 H-PGE bound by suction filtration under reduced pressure was added to a glass filter (trade name: UF
2  2
ィルタ一- 96、 GF/B、パーキンエルマ一社）にトラップし、結合放射活性をマイクロシ ンチ（商品名：マイクロシンチ 20、パーキンエルマ一社）を用いてマイクロプレートシン チレーシヨンカウンター（商品名：トップカウント、ノ ッカード社)で測定した。 The filter is trapped on a filter 1-96, GF / B, Perkin Elma Co., Ltd., and the combined radioactivity is microplate (trade name: Micro Cinch 20, Perkin Elma Co.) using a microplate scintillation counter (product) Name: Top Count, Notcard Inc.).
解離定数 (Kd)値と最大結合量 (Bmax)値は、スキャッチヤードプロットから求めた（「 アナルス ·ォブ ·ザ ·ニュ' ~ ·ヨーク'アカデミ^ ~ ·ォブ ·サイエンス (Annals of the New Y ork Academy of Science)] , (米国）、 1949年、第 51卷、 p.660)。非特異的結合は過剰 量 (2.5 /z M)の非標識 PGEの存在下での結合として求めた。本発明化合物による3 H The dissociation constant (Kd) and maximum binding (Bmax) values were determined from the Scatchyard plot (“Annals of the Science”). New York Academy of Science)], (USA), 1949, 51, p.660). Nonspecific binding is determined as binding in the presence of an excess of unlabeled PGE (2.5 / z M). 3 H with the compound of the present invention
2  2
-PGE結合阻害作用の測定は、 3H-PGEを 2.5nM、および本発明化合物を添カ卩して-PGE binding inhibitory activity is measured by adding 2.5 nM 3 H-PGE and the compound of the present invention.
2 2 twenty two
行った。 went.
各化合物の阻害定数 Ki (nM)は次式により求めた： The inhibition constant Ki (nM) for each compound was determined by the following formula:
Ki=IC / (1 + ( [C]/Kd) ) Ki = IC / (1 + ([C] / Kd))
50  50
式中、 [C]は反応系に用いた3 H-PGE濃度を表す。 In the formula, [C] represents the 3 H-PGE concentration used in the reaction system.
2  2
結果を下記表 2に示す。 [0045] [表 2] The results are shown in Table 2 below. [0045] [Table 2]
Figure imgf000023_0001
Figure imgf000023_0001
[0046] 試験例 3 Sulprostone処置ラット膀胱内圧変化に対する化合物の作用 [0046] Test Example 3 Effects of compounds on changes in intravesical pressure in rats treated with sulprostone
静脈内投与時の in vivo EP1受容体拮抗作用を評価するために、 EP1/3作動薬であ る sulprostoneにより惹起される膀胱内圧曲線の変化と、それに対する被験化合物の 抑制作用について検討した。  In order to evaluate the in vivo EP1 receptor antagonism when administered intravenously, changes in the intravesical pressure curve caused by sulprostone, an EP1 / 3 agonist, and the inhibitory effect of test compounds on it were investigated.
実験には体重 150〜350gの Wistar系雌性ラット（チャールズリバ一社）を用いた。ゥ レタン (1.2g/kg、 i.p.)麻酔下に腹部を正中切開し膀胱を露出した。膀胱頂部に内圧 測定用のポリエチレンカテーテル (PE-50)を留置した。カテーテルに圧トランスデュ ーサ一とシリンジポンプを接続し、 6mL/hrの速度で生理食塩水を注入しながら膀胱 内圧を測定した。大腿静脈には被験化合物投与用のカテーテルを留置した。術後 1 時間以上の安定化期間をおき、その時の膀胱内圧曲線を sulprostone投与前値とし た。次に sulprostone (0.3mg/kg、 sc)をラットに投与し、その 1時間後の膀胱内圧曲線 を被験化合物投与前値とした。その後、大腿静脈へ被験化合物を投与し、最長 90分 間まで膀胱内圧を測定した。被験化合物投与前値と sulprostone投与前値の差を 100 %としたときの、被験化合物による抑制率を算出した。その結果、 sulprostone投与によ り排尿間隔の減少、基礎圧の上昇、最大排尿圧の上昇、コンプライアンスの低下など の膀胱過活動状態が認められた。一方、本発明化合物は膀胱過活動状態を良好に 改善した。  In the experiment, female Wistar rats (Charles River Inc.) weighing 150 to 350 g were used. Under anesthesia with urethane (1.2 g / kg, i.p.), a midline incision was made in the abdomen to expose the bladder. A polyethylene catheter (PE-50) for measuring internal pressure was placed at the top of the bladder. A pressure transducer and syringe pump were connected to the catheter, and the intravesical pressure was measured while injecting physiological saline at a rate of 6 mL / hr. A catheter for administering the test compound was placed in the femoral vein. A stabilization period of 1 hour or more after the operation was performed, and the intravesical pressure curve at that time was defined as the value before sulprostone administration. Next, sulprostone (0.3 mg / kg, sc) was administered to the rat, and the intravesical pressure curve 1 hour later was used as the pre-test compound administration value. Thereafter, the test compound was administered to the femoral vein, and the intravesical pressure was measured for up to 90 minutes. The inhibition rate by the test compound was calculated when the difference between the pre-test compound administration value and the sulprostone pre-administration value was 100%. As a result, sulprostone administration resulted in bladder overactivity such as decreased urination interval, increased basal pressure, increased maximum urinary pressure, and decreased compliance. On the other hand, the compound of the present invention improved the bladder overactivity.
[0047] 試験例 4 酢酸誘発頻尿ラットに対する化合物の作用  [0047] Test Example 4 Effects of compounds on acetic acid-induced frequent urination rats
化合物の抗頻尿作用を病態モデルを用いて検討した。酢酸のラット膀胱内処置に より膀胱粘膜が障害され、侵害刺激伝達求心性神経が活性化されることが知られて V、る（「ザ ·ジャーナノレ ·ォブ ·ニューロサイエンス (The Journal of Neuroscience)」、（ 米国）、 1992年 12月、第 12卷、第 12号、 p.4878-89)。酢酸の膀胱内処置により頻尿状 態が誘発されるため、これら症状に対する薬効評価が可能である。 The anti- frequent urination effect of the compound was examined using a disease state model. Intravesical treatment of acetic acid in rats is known to damage the bladder mucosa and activate nociceptive afferent afferents. V, “The Journal of Neuroscience” , ( USA), December 1992, No. 12, IV, p.4878-89). Since urinary frequency is induced by intravesical treatment with acetic acid, the efficacy of these symptoms can be evaluated.
実験には体重 200〜450gの Wistar系雄性ラット（チャールズリバ一社）を用いた。ぺ ントバルビタール (50mg/kg、 i.p.)麻酔下に腹部を正中切開して膀胱を露出し、 27G の注射針を装着したシリンジで膀胱内の残尿を除去した。その後 1%酢酸溶液 0.5〜0. 7mLを膀胱内に注射し、閉創した。その 2日後に実験を行った。ラットを代謝ケージに 入れ、 1時間馴化した後に、被験化合物を投与し、その直後から 6時間排尿重量変化 を連続的に測定した。総排尿量を総排尿回数で除することにより、有効膀胱容量を 算出した。その結果、酢酸膀胱内処置群においては偽手術群に比べて有効膀胱容 量が減少し、頻尿状態を呈した。一方、本発明化合物は頻尿状態を良好に改善した 試験例 5 チトクローム P450 (CYP) 3A4酵素阻害試験 (薬物間相互作用評価） Wistar male rats (Charles River Inc.) weighing 200 to 450 g were used for the experiment. Under anesthesia with pentobarbital (50 mg / kg, i.p.), a midline incision was made in the abdomen to expose the bladder, and residual urine in the bladder was removed with a syringe equipped with a 27G needle. Thereafter, 0.5% to 0.7 mL of 1% acetic acid solution was injected into the bladder and closed. Two days later, the experiment was conducted. Rats were placed in metabolic cages and acclimated for 1 hour, then the test compound was administered, and changes in urinary weight were measured continuously for 6 hours immediately thereafter. The effective bladder capacity was calculated by dividing the total urination volume by the total number of urinations. As a result, the effective bladder capacity decreased in the acetic acid intravesical treatment group compared with the sham operation group, and a frequent urination state was observed. On the other hand, the compound of the present invention successfully improved the frequent urination state Test Example 5 Cytochrome P450 (CYP) 3A4 enzyme inhibition test (drug interaction evaluation)
(1)阻害試験 I (阻害活性 Iの算出） (1) Inhibition test I (calculation of inhibitory activity I)
96穴プレートを用いて、基質 (ミダゾラム）、試験化合物およびヒト肝ミクロゾーム (0.1 mg protein/ml)を O.lmM EDTA、 ImM NADPHを含む lOOmMリン酸緩衝液中で 20分 間 37°Cでインキュベーションした。その後ァセトニトリル 80%含有水溶液を加えて反応 を停止した。その後サンプルを LC/MSで分析し、次式を用いて阻害活性 Iを算出した 阻害活性 1(%)= 100— V /V X 100  Incubate substrate (midazolam), test compound and human liver microsomes (0.1 mg protein / ml) in lOOmM phosphate buffer containing O.lmM EDTA and ImM NADPH for 20 minutes at 37 ° C using 96-well plates did. Thereafter, an aqueous solution containing 80% acetonitrile was added to stop the reaction. Samples were then analyzed by LC / MS, and inhibitory activity I was calculated using the following formula: Inhibitory activity 1 (%) = 100—V / V X 100
i,I 0,1  i, I 0,1
V ：阻害試験 Iで既知濃度の試験化合物存在下における基質の代謝速度  V: Metabolic rate of substrate in the presence of test compound at a known concentration in inhibition test I
i,I  i, I
V ：阻害試験 Iで試験化合物非存在下における基質の代謝速度  V: Metabolic rate of substrate in the absence of test compound in inhibition test I
0,1  0,1
(2)阻害試験 II (阻害活性 IIの算出）  (2) Inhibition test II (calculation of inhibitory activity II)
96穴プレートを用いて、試験化合物およびヒト肝ミクロゾーム（0.1 mg protein/ml)を O.lmM EDTA、 ImM NADPHを含む lOOmMリン酸緩衝液（pH=7.4)の総量 145 1中 で、 30分間 37°Cでインキュベーションした。その後、基質であるミダゾラムを添カ卩して 2 0分間 37°Cでインキュベーションした。インキュベーション後、ァセトニトリル 80%含有水 溶液を加えて反応停止した。その後サンプルを LC/MSで分析し、次式を用いて阻害 活性 IIを算出した。 阻害活性 Π(%) = 100— V /V /(100—阻害活性 1(%)) X 100 X 100 Using a 96-well plate, test compound and human liver microsome (0.1 mg protein / ml) in a total volume of 145 1 of lOOmM phosphate buffer (pH = 7.4) containing O.lmM EDTA and ImM NADPH for 30 minutes 37 Incubated at ° C. Thereafter, the substrate midazolam was added and incubated at 37 ° C. for 20 minutes. After the incubation, the reaction was stopped by adding an aqueous solution containing 80% acetonitrile. Samples were then analyzed by LC / MS and inhibitory activity II was calculated using the following formula. Inhibitory activity Π (%) = 100— V / V / (100—Inhibitory activity 1 (%)) X 100 X 100
i,II 0,11  i, II 0,11
V ：阻害試験 IIで既知濃度の試験化合物存在下における基質の代謝速度 i,II  V: Metabolic rate of substrate i, II in the presence of test compound at a known concentration in inhibition test II
V ：阻害試験 IIで試験化合物非存在下における基質の代謝速度  V: Metabolic rate of substrate in the absence of test compound in inhibition test II
0,11  0,11
その結果、対照化合物 J (特許文献 4、実施例 2(71)に開示の化合物）は阻害活性 I 力 S37%、阻害活性 IIが 71%であるのに対し、例えば、実施例 51の化合物は阻害活 性 Iが 6%、阻害活性 IIが 7%であった。このことより、本発明化合物の CYP3A4阻害作 用は弱いことが確認され、 CYP3A4が代謝に関与する薬剤との薬物相互作用を引き 起こす懸念が少な!、と考えられる。  As a result, the control compound J (the compound disclosed in Patent Document 4, Example 2 (71)) has an inhibitory activity I power of S37% and an inhibitory activity II of 71%, whereas for example the compound of Example 51 Inhibitory activity I was 6% and inhibitory activity II was 7%. This confirms that the CYP3A4 inhibitory action of the compound of the present invention is weak, and it is thought that there is little concern that CYP3A4 will cause drug interaction with drugs involved in metabolism.
[0049] 試験例 6 ヒト肝ミクロゾームでの代謝安定性試験 [0049] Test Example 6 Metabolic stability test in human liver microsomes
ガラス試験管にて、試験化合物、ヒト肝ミクロゾーム（0.2mg protein/ml)を O.lmM ED TA、 ImM NADPHを含む lOOmMリン酸緩衝液中（pH7.4)で 15分間 37°Cでインキュべ ーシヨンした。その後ァセトニトリル 80%含有水溶液を加えて反応を停止した。その後 サンプルを HPLCで分析 Untegration plotにより in vitroクリアランスを算出した。 その結果、本発明化合物はヒト肝臓における代謝に対する安定性が高ぐ肝初回 通過効果を受けにくいと考えられる。  In a glass test tube, incubate the test compound and human liver microsome (0.2 mg protein / ml) in lOOmM phosphate buffer (pH 7.4) containing O.lmM ED TA and ImM NADPH for 15 minutes at 37 ° C. -I took it. Thereafter, an aqueous solution containing 80% acetonitrile was added to stop the reaction. Samples were then analyzed by HPLC. In vitro clearance was calculated by untegration plot. As a result, it is considered that the compound of the present invention is less susceptible to the first-pass effect of liver due to its high metabolic stability in human liver.
上記の各試験の結果、本発明化合物は強力な EP1受容体拮抗作用を有すること、 及び、頻尿状態を良好に改善することが確認された。また、本発明化合物は薬物相 互作用を引き起こす懸念が少なぐ代謝安定性に優れるなど医薬品として好ましい 性質を有する。  As a result of the above tests, it was confirmed that the compound of the present invention has a strong EP1 receptor antagonistic action and satisfactorily improves frequent urination. In addition, the compound of the present invention has favorable properties as a pharmaceutical product, such as being excellent in metabolic stability and causing little drug interaction.
従って、本発明化合物は安全性の高い、過活動膀胱に伴う頻尿，尿失禁、前立腺 肥大症に伴う下部尿路症状、間質性膀胱炎、前立腺炎などの下部尿路疾患治療薬 として有用である。  Therefore, the compound of the present invention is highly safe and useful as a therapeutic agent for lower urinary tract diseases such as frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial cystitis, prostatitis, etc. It is.
[0050] 本発明化合物 (I)又はその塩の 1種又は 2種以上を有効成分として含有する製剤 は、当分野において通常用いられている薬剤用担体、賦形剤等を用いて通常使用さ れて 、る方法によって調製することができる。  [0050] A preparation containing one or more of the compounds (I) or a salt thereof of the present invention as an active ingredient is usually used using a pharmaceutical carrier, excipient, etc. that are usually used in the art. It can be prepared by this method.
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関 節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、 経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれ の形態であってもよい。 Administration is oral by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intraarticular, intravenous, intramuscular, suppositories, eye drops, eye ointments, transdermal solutions. , Ointment, transdermal patch, transmucosal liquid, transmucosal patch, parenteral administration by inhalation, etc. It may be a form.
[0051] 本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用 いられる。このような固体組成物においては、 1種又は 2種以上の有効成分を、少なく とも 1種の不活性な賦形剤、例えば乳糖、マン-トール、ブドウ糖、ヒドロキシプロピル セルロース、微結晶セルロース、デンプン、ポリビュルピロリドン、及び/又はメタケイ 酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添カロ 剤、例えばステアリン酸マグネシウムのような潤滑剤やカルボキシメチルスターチナト リウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸 剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよ 、。 経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、 シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例え ば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化 剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有してい てもよい。  [0051] Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch. , Polybulurpyrrolidone, and / or magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as carboxymethyl starch sodium, a stabilizer, and a solubilizing agent according to a conventional method. Good. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, etc., commonly used inert diluents such as purified Contains water or ethanol. In addition to the inert diluent, the liquid composition may contain solubilizers, wetting agents, suspending agents and other adjuvants, sweeteners, flavors, fragrances and preservatives.
非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳 濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含ま れる。非水溶性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール 又はオリーブ油のような植物油、エタノールのようなアルコール類、又はポリソルベー ト 80 (局方名）等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳 ィ匕剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばパクテリ ァ保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、 これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶 解又は懸濁して使用することもできる。  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of the water-insoluble solvent include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emollients, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a pacteria retention filter, blending of a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
[0052] 外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローシ ヨン剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤 、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏又はローション 基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミ ッロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアル コール、セチルアルコール、ラウロマクロゴール、セスキォレイン酸ソルビタン等が挙 げられる。 [0052] External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include: polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol Cole, cetyl alcohol, lauromacrogol, sorbitan sesquioleate and the like.
吸入剤や経鼻剤等の経粘膜剤は固体、液体又は半固体状のものが用いられ、従 来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、 pH調 整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよ い。投与は、適当な吸入又は吹送のためのデバイスを使用することができる。例えば 、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独で 又は処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせ て溶液又は懸濁液として投与することができる。乾燥粉末吸入器等は、単回又は多 数回の投与用のものであってもよぐ乾燥粉末又は粉末含有カプセルを利用すること ができる。あるいは、適当な駆出剤、例えば、クロ口フルォロアルカン、ヒドロフルォロ アルカン又は二酸ィ匕炭素等の好適な気体を使用した加圧エアゾールスプレー等の 形態であってもよい。  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like can use a dry powder or a powder-containing capsule which can be used for single or multiple administrations. Alternatively, it may be in the form of an appropriate propellant such as a pressurized aerosol spray using a suitable gas such as black mouth fluoroalkane, hydrofluoroalkane or carbon dioxide.
[0053] 通常経口投与の場合、 1日の投与量は、体重当たり約 0.001〜100 mg/kg、好ましく は 0.1〜30 mg/kg、更に好ましくは 0.1〜10 mg/kgが適当であり、これを 1回であるい は 2乃至 4回に分けて投与する。静脈内投与される場合は、 1日の投与量は、体重当 たり約 0.0001〜10 mg/kgが適当で、 1日 1回乃至複数回に分けて投与する。また、経 粘膜剤としては、体重当たり約 0.001〜100 mg/kgを 1日 1回乃至複数回に分けて投与 する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される  [0053] In normal oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Dosing once or in 2 to 4 divided doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and should be administered once to several times a day. As a transmucosal agent, administer about 0.001 to 100 mg / kg per body weight once or multiple times a day. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc.
[0054] 本発明化合物は、前述の本発明化合物が有効と考えられる疾患の種々の治療又 は予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続しても しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても 別個に製剤化されて 、てもよ 、。 [0054] The compound of the present invention can be used in combination with various therapeutic or preventive agents for diseases for which the compound of the present invention is considered effective. The combination may be administered simultaneously, separately in succession, or at desired time intervals. The co-administered product may be a combination drug or separately formulated.
実施例  Example
[0055] 以下、実施例に基づき本発明化合物 (I)の製法を更に詳細に説明する。本発明化 合物は下記実施例に記載の化合物に限定されるものではな 、。また原料化合物の 製法を参考例に示す。 [0056] また、参考例、実施例及び後記表中で以下の略号を用いる。 [0055] Hereinafter, the production method of the compound (I) of the present invention will be described in more detail based on Examples. The compounds of the present invention are not limited to the compounds described in the Examples below. The production method of the raw material compound is shown in the reference example. [0056] In addition, the following abbreviations are used in Reference Examples, Examples and Tables below.
Rf:参考例番号、 Ex:実施例番号、 No:化合物番号、 Str:構造式、 Dat :物理学的デー タ（EI:EI- MS ([M]+) ; EP: ESI- MS (Pos) (無記載である場合は [M+H ； EN: ESI- MS ( Neg) (無記載である場合は [Μ- ΗΓ)； API :API- MS (Pos) (無記載である場合は [Μ+Η]+ )； FP: FAB- MS (Pos) (無記載である場合は [M+H ； FN： FAB- MS (Neg) (無記載で ある場合は [M- ΗΓ)； NMRl : DMSO-d中の1!" I- NMRにおける特徴的なピークの δ (p Rf: Reference number, Ex: Example number, No: Compound number, Str: Structural formula, Dat: Physical data (EI: EI-MS ([M] +); EP: ESI-MS (Pos) (If not specified, [M + H; EN: ESI- MS (Neg) (If not specified, [Μ- ΗΓ); API: API- MS (Pos) (If not specified, [Μ FP: FAB- MS (Pos) (if not specified, [M + H; FN: FAB- MS (Neg) (if not specified, [M- ΗΓ)); NMRl: DMSO -d in 1 ! "I-NMR in -d
6  6
pm) ; NMR2 : CDC1中の1 H- NMRにおける特徴的なピークの δ (ppm))、 Me:メチル、 E pm); NMR2: δ (ppm) of the characteristic peak in 1 H-NMR in CDC1, Me: methyl, E
3  Three
t :ェチル、 Syn:製造方法 (数字は、その番号を実施例番号として有する実施例化合 物と同様に、対応する原料を用いて製造したことを示す。数字の前に Rが付いている 場合はその番号を参考例番号として有する参考例化合物と同様に、対応する原料を 用いて製造したことを示す。）。  t: Ethyl, Syn: Manufacturing method (Numbers indicate that they were manufactured using the corresponding raw materials in the same way as Example compounds having the number as the Example number. When the number is preceded by R. Indicates that the compound was produced using the corresponding starting material in the same manner as the reference compound having the reference number as the reference example).
[0057] 参考例 1 [0057] Reference Example 1
5-ヒドロキシインダンをジメチルホルムアミド中、炭酸カリウム存在下、ェチル 5- (ブ ロモメチル)チォフェン- 2-カルボン酸と反応させることにより、ェチル 5-[(2,3-ジヒドロ -1H-インデン -5-ィルォキシ)メチル]チォフェン- 2-カルボン酸を製造した。  By reacting 5-hydroxyindane with ethyl 5- (bromomethyl) thiophene-2-carboxylic acid in dimethylformamide in the presence of potassium carbonate, ethyl 5-[(2,3-dihydro-1H-indene-5- (Iloxy) methyl] thiophene-2-carboxylic acid was prepared.
参考例 2  Reference example 2
ェチル 5-[(2,3-ジヒドロ- 1H-インデン -5-ィルォキシ)メチル]チォフェン- 2-カルボン 酸を酢酸中、濃硝酸を用いて-トロ化を行い、ェチル 5- {[(6- -トロ- 2,3-ジヒドロ- 1H- インデン -5-ィル)ォキシ]メチル }チォフェン- 2-カルボン酸を製造した。  Ethyl 5-[(2,3-dihydro-1H-indene-5-yloxy) methyl] thiophene-2-carboxylic acid was subjected to -trolation with acetic acid in concentrated acetic acid to give ethyl 5- {[(6- -Tro-2,3-dihydro-1H-indene-5-yl) oxy] methyl} thiophene-2-carboxylic acid was prepared.
参考例 3  Reference example 3
2-ニトロ- 4- (トリフルォロメチル)フエノールをジメチルホルムアミド中、炭酸カリウム存 在下、メチル 4- (プロモメチル)安息香酸と反応させることにより、メチル 4-{[2-二トロ- 4- (トリフルォロメチル)フエニル]メチル }安息香酸を製造した。  By reacting 2-nitro-4- (trifluoromethyl) phenol in dimethylformamide with methyl 4- (promomethyl) benzoic acid in the presence of potassium carbonate, methyl 4-{[2-nitro-4- (Trifluoromethyl) phenyl] methyl} benzoic acid was prepared.
[0058] 参考例 4 [0058] Reference Example 4
ェチル 5-{[(6-ニトロ- ^-ジヒドロ-^-ィンデン^-ィルォキシ チルチォフェン- ？-カルボン酸を酢酸中、還元鉄を用いてニトロ基の還元を行い、ェチル 5-{[(6-ァミノ -2, 3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }チォフェン- 2-カルボン酸を製造し 参考例 5 Ethyl 5-{[(6-Nitro-^-dihydro-^-indene ^ -yloxy tilthiophene-?-Carboxylic acid in acetic acid and reduced iron with reduced iron, ethyl 5-{[(6- Amino-2,3-dihydro-1H-indene-5-yl) oxy] methyl} thiophene-2-carboxylic acid Reference Example 5
メチル 6-{[(6-ァミノ- 2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }ニコチン酸を ピリジン中、 4-メチル -1,3-チアゾール -2-スルホユルク口リドと反応させることにより、メ チル 6- {[(6- {[(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル]アミノト 2,3-ジヒドロ- 1H -インデン -5-ィル)ォキシ]メチル }ニコチン酸を製造した。  Methyl 6-{[(6-Amino-2,3-dihydro-1H-indene-5-yl) oxy] methyl} nicotinic acid in pyridine, 4-methyl-1,3-thiazole-2-sulfoluculide To give methyl 6- {[((6- {[(4-methyl-1,3-thiazol-2-yl) sulfoyl] aminoto 2,3-dihydro-1H-indene-5- Yl) oxy] methyl} nicotinic acid was prepared.
[0059] 上記参考例 1〜5の方法と同様にして、後記表 3〜7に示す参考例化合物をそれぞ れ対応する原料を使用して製造した。表 3〜7に参考例化合物の構造、製造方法、 及び物理化学的データを示す。  [0059] In the same manner as in Reference Examples 1 to 5 described above, Reference Example compounds shown in Tables 3 to 7 below were produced using the corresponding raw materials. Tables 3 to 7 show the structures, production methods, and physicochemical data of Reference Example compounds.
[0060] 実施例 1  [0060] Example 1
メチル 4- {[(6- {[(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル]アミノト 2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸 2.00g、（3-メチルォキセタン- 3-ィル)メ タノール 445mg、トリフエ-ルホスフィン 2.29gをテトラヒドロフラン 8.00mLに溶解し、これ に氷冷下、ジェチルァゾジカルボキシレートの 40%トルエン溶液 3.97mLを滴下し、室 温にて 12時間攪拌した。反応液に炭酸水素ナトリウム水溶液を加え、酢酸ェチルで 抽出し、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。溶媒を減圧留去 して得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル = 2 : 1 )により精製を行い、メチル 4- {[(6- {[(3-メチルォキセタン- 3-ィル)メチル ][(4-メチル -1 ,3-チアゾール -2-ィル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ] メチル }安息香酸 2.36gを製造した。  Methyl 4- {[(6- {[(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydro-1H-indene-5-yl) oxy] methyl} Dissolve 2.00 g of benzoic acid, 445 mg of (3-methyloxetane-3-yl) methanol, and 2.29 g of triphenylphosphine in 8.00 mL of tetrahydrofuran. 3.97 mL of the solution was added dropwise and stirred at room temperature for 12 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain methyl 4-{[(6-{[(3-methyloxetane-3-yl. L) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2,3-dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid 2.36 g was produced.
実施例 2  Example 2
メチル 4- {[(6- {[(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル]アミノト 2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸 459mgを DMFlO.Omlに溶解し、これに 2 - (ブロモメチル）テトラヒドロフラン 198mg、炭酸カリウム 166mg、ヨウ化カリウム 166mgを 加え、 100°Cにて 7時間攪拌した。反応液を減圧濃縮して得られた残渣に水を加え、 酢酸ェチルで抽出し、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。溶 媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸 ェチル = 3 : 1)により精製を行い、メチル 4-[({6-[[(4-メチル -1,3-チアゾール -2-ィル) スルホ -ル] (テトラヒドロフラン- 2-ィルメチル)ァミノ] -2,3-ジヒドロ- 1H-インデン -5-ィ ル}ォキシ)メチル]安息香酸 286mgを得た。 Methyl 4- {[(6- {[(4-Methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydro-1H-indene-5-yl) oxy] methyl} Benzoic acid (459 mg) was dissolved in DMFlO.Oml, and 2- (bromomethyl) tetrahydrofuran (198 mg), potassium carbonate (166 mg) and potassium iodide (166 mg) were added thereto, and the mixture was stirred at 100 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and methyl 4-[({6-[[(4-methyl-1, 3-thiazol-2-yl) sulfoyl] (tetrahydrofuran-2-ylmethyl) amino] -2,3-dihydro-1H-indene-5- Ru} oxy) methyl] benzoic acid 286 mg was obtained.
実施例 3 Example 3
メチル 4-[({6-[[(4-メチル - 1 ,3-チアゾール -2-ィル)スルホ -ル] (テトラヒドロフラン- 2 -ィルメチル)ァミノ] -2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸 260mg をテトラヒドロフラン 5.00mlとメタノール 5.00mlに溶解し、これに 1M水酸化ナトリウム水 溶液 2.00mlを加え、室温にて終夜攪拌した。反応液を減圧濃縮して得られた残渣に 1M塩酸とクロ口ホルムをカ卩え、有機層を Isotute社製 Phase Separate- filterを用いて分 離した。溶媒を減圧留去して得られた残渣にへキサンと酢酸ェチルを加え、析出した 結晶を濾取した。得られた粗製物をへキサン/酢酸ェチルカゝら再結晶し、 4-[({6-[[(4- メチル -1,3-チアゾール -2-ィル)スルホ -ル] (テトラヒドロフラン- 2-ィルメチル)ァミノ]- 2 , 3-ジヒドロ- 1 H-インデン -5-ィル }ォキシ)メチル]安息香酸 219mgを得た。  Methyl 4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (tetrahydrofuran-2-ylmethyl) amino] -2,3-dihydro-1H-indene- 5-yl} oxy) methyl] benzoic acid (260 mg) was dissolved in tetrahydrofuran (5.00 ml) and methanol (5.00 ml), and 1M aqueous sodium hydroxide solution (2.00 ml) was added thereto, followed by stirring at room temperature overnight. The residue obtained by concentrating the reaction solution under reduced pressure was covered with 1M hydrochloric acid and chloroform, and the organic layer was separated using a Phase Separate-filter manufactured by Isotute. Hexane and ethyl acetate were added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration. The obtained crude product was recrystallized from hexane / ethyl acetate to give 4-[({6-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (tetrahydrofuran-2 219 mg of -ylmethyl) amino] -2,3-dihydro-1 H-indene-5-yl} oxy) methyl] benzoic acid was obtained.
実施例 4 Example 4
メチル 4-{[(6-{[(3-メチルォキセタン- 3-ィル)メチル ][(4-メチル - 1 ,3-チアゾール -2- ィル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸 1. Methyl 4-{[(6-{[(3-methyloxetane-3-yl) methyl] [(4-methyl-1,3, thiazol-2-yl) sulfol] amino} -2,3- Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid 1.
64gをメタノール 15.00mlに溶解し、これに 1M水酸化ナトリウム水溶液 3.10mlを加え、 室温にて 30分攪拌した。反応液を減圧濃縮して得られた粗結晶をエタノール/イソプ 口ピルエーテル力も再結晶し、 4-{[(6-{[(3-メチルォキセタン- 3-ィル)メチル ][(4-メチ ル- 1,3-チアゾール -2-ィル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォ キシ]メチル }安息香酸ナトリウム 1.7水和物 1.51gを得た。 64 g was dissolved in 15.00 ml of methanol, and 3.10 ml of 1M aqueous sodium hydroxide solution was added thereto and stirred at room temperature for 30 minutes. The crude crystals obtained by concentrating the reaction solution under reduced pressure were recrystallized from ethanol / isopropyl pill ether force, and 4 -{[( 6 -{[(3-methyloxetane- 3 -yl) methyl] [( 4 -methyl Ru-1,3-thiazol-2-yl) sulfol] amino} -2,3-dihydro-1H-indene-5-yl) oxy] methyl} sodium benzoate 1.7hydrate 1.51 g Obtained.
実施例 153 Example 153
4-({4,5-ジメチル- 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィ ルメチル)ァミノ]フエノキシ }メチル)安息香酸 250mgを DMF 5.0mLに溶解し、これに C DI lOlmgをカ卩え、室温にて 3時間攪拌した。反応液にメタンスルホンアミド 59.0mgと 1, 8-ジァザビシクロ [5.4.0]ゥンデ力- 7-ェン 94.5mgをカ卩え、室温にて終夜攪拌した。反 応液を 1.0M HC1で pHを 3にした後、析出した結晶を濾取し、水とイソプロパノールで 洗浄後減圧乾燥し、 4-({4,5-ジメチル -2-[[(4-メチル -1 ,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ]フエノキシ }メチル) -N- (メチルスルホ -ル)ベンズァ ミド 80mgを得た。 [0062] 実施例 165 4-({4,5-dimethyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) benzoic acid 250 mg was dissolved in 5.0 mL of DMF, and CDI lOlmg was added thereto and stirred at room temperature for 3 hours. To the reaction solution, 59.0 mg of methanesulfonamide and 94.5 mg of 1,8-diazabicyclo [5.4.0] unde-7-ene were added and stirred at room temperature overnight. The reaction solution was adjusted to pH 3 with 1.0M HC1, and the precipitated crystals were collected by filtration, washed with water and isopropanol, and dried under reduced pressure to give 4-({4,5-dimethyl-2-[[(4- 80 mg of methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) -N- (methylsulfol) benzamide were obtained. [0062] Example 165
3-({[4-({4,5-ジメチル- 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン -2-ィルメチル)ァミノ]フエノキシ }メチル)ベンゾィル]アミノ}スルホ -ル)プロピル酢酸 34 2mgをメタノール 5.51mLに溶解し、これに 1M水酸化ナトリウム水溶液 0.548mLをカロえ 、室温にて終夜攪拌した。反応液を 1M塩酸水で中和した後、減圧乾燥した。得られ た残渣を、シリカゲルカラムクロマトグラフィー（クロ口ホルム：メタノール =99 : 1〜95:5) で精製し、得られた粗成物をへキサンと酢酸ェチルの混合溶媒から再結晶し、 4-({4, 5-ジメチル- 2-[[(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチ ル)ァミノ]フエノキシ }メチル) -N- [(3-ヒドロキシプロピル)スルホ -ル]ベンズアミド 87mg を得た。  3-({[4-({4,5-dimethyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} Methyl) benzoyl] amino} sulfol) propylacetic acid 34 (2 mg) was dissolved in methanol (5.51 mL). The reaction solution was neutralized with 1M aqueous hydrochloric acid and then dried under reduced pressure. The obtained residue was purified by silica gel column chromatography (black form: methanol = 99: 1 to 95: 5), and the resulting crude product was recrystallized from a mixed solvent of hexane and ethyl acetate. -({4,5-dimethyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) -N- 87 mg of [(3-hydroxypropyl) sulfol] benzamide was obtained.
[0063] 上記実施例 1〜4、 153、及び 165の方法と同様にして、後記表 8〜24に示す実施 例化合物をそれぞれ対応する原料を使用して製造した。表 8〜24に実施例化合物 の構造を、表 25〜26に製造方法、及び物理化学的データを示す。また、表 27〜28 にいくつかの実施例化合物の NMRデータを示す。  [0063] In the same manner as in the above Examples 1 to 4, 153, and 165, Example compounds shown in Tables 8 to 24 below were produced using the corresponding starting materials. Tables 8 to 24 show the structures of the example compounds, and Tables 25 to 26 show the production methods and physicochemical data. Tables 27 to 28 show NMR data of some example compounds.
[0064] また、表 29〜32に本発明の別の化合物の構造を示す。これらは、上記の製造法や 実施例に記載の方法及び当業者にとって自明である方法、又はこれらの変法を用い ることにより、容易に合成することができる。  [0064] Tables 29 to 32 show structures of other compounds of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in the Examples, methods obvious to those skilled in the art, or variations thereof.
[0065] [表 3] [0065] [Table 3]
Figure imgf000032_0001
4]
Figure imgf000033_0001
5]
Figure imgf000034_0001
6]
Figure imgf000035_0001
Figure imgf000032_0001
Four]
Figure imgf000033_0001
Five]
Figure imgf000034_0001
6]
Figure imgf000035_0001
Figure imgf000035_0002
.6TSZC/900Zdf/X3d εε Z8LZL0/L00Z OAV [8挲] [OZOO]
Figure imgf000035_0002
.6TSZC / 900Zdf / X3d εε Z8LZL0 / L00Z OAV [8 挲] [OZOO]
Figure imgf000036_0001
Figure imgf000036_0001
/.6ISZC/900Zdf/X3d ZSLZLO/LOOl ΟΛΧ
Figure imgf000037_0001
9]
Figure imgf000038_0001
10] /.6ISZC/900Zdf/X3d ZSLZLO / LOOl ΟΛΧ
Figure imgf000037_0001
9]
Figure imgf000038_0001
Ten]
Figure imgf000039_0001
11]
Figure imgf000039_0001
11]
Figure imgf000040_0001
12]
Figure imgf000040_0001
12]
Figure imgf000041_0001
表 13]
Figure imgf000042_0001
14]
Figure imgf000041_0001
Table 13]
Figure imgf000042_0001
14]
Figure imgf000043_0001
15]
Figure imgf000043_0001
15]
Figure imgf000044_0001
Figure imgf000044_0001
[0079] [表 17]
Figure imgf000045_0001
18]
Figure imgf000046_0001
19]
Figure imgf000047_0001
20]
Figure imgf000048_0001
21]
Figure imgf000049_0001
22]
Figure imgf000050_0001
[0079] [Table 17]
Figure imgf000045_0001
18]
Figure imgf000046_0001
19]
Figure imgf000047_0001
20]
Figure imgf000048_0001
twenty one]
Figure imgf000049_0001
twenty two]
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0002
Figure imgf000051_0001
Figure imgf000051_0001
[0086] [表 24] [0086] [Table 24]
Figure imgf000052_0001
Figure imgf000052_0001
[0087] [表 25] [0087] [Table 25]
Ex Syn Dat Ex Syn Dat Ex Syn DatEx Syn Dat Ex Syn Dat Ex Syn Dat
1 1 EP 543 39 1 FP 531 77 4 FP 5521 1 EP 543 39 1 FP 531 77 4 FP 552
2 2 EP 543 40 1 FP 551 78 3 FP 5032 2 EP 543 40 1 FP 551 78 3 FP 503
3 3 FP 527 41 1 FP 535 79 4 FP 5233 3 FP 527 41 1 FP 535 79 4 FP 523
4 4 FP 529 42 1 FP 571 80 4 FP 5074 4 FP 529 42 1 FP 571 80 4 FP 507
5 1 EP 529 43 1 FP 538 81 4 FP 5435 1 EP 529 43 1 FP 538 81 4 FP 543
6 1 EP 557 44 1 FP 558 82 4 FP 5236 1 EP 557 44 1 FP 558 82 4 FP 523
7 1 EP 558 45 1 FP 542 83 4 FP 5367 1 EP 558 45 1 FP 542 83 4 FP 536
8 1 FP 544 46 1 FP 578 84 4 FP 5218 1 FP 544 46 1 FP 578 84 4 FP 521
9 1 FP 512 47 4 FP 515 85 4 FP 5579 1 FP 512 47 4 FP 515 85 4 FP 557
10 1 FP 526 48 3 FP 543 86 4 FP 52410 1 FP 526 48 3 FP 543 86 4 FP 524
11 1 FP 533 49 4 FP 551 87 4 FP 54311 1 FP 533 49 4 FP 551 87 4 FP 543
12 1 FP 550 50 4 FP 544 88 4 FP 52812 1 FP 550 50 4 FP 544 88 4 FP 528
13 1 EP 543 51 4 FP 530 89 4 FP 56413 1 EP 543 51 4 FP 530 89 4 FP 564
14 1 EP 526 52 4 EP 498 90 1 FP 56514 1 EP 526 52 4 EP 498 90 1 FP 565
15 1 FP 557 53 4 FP 512 91 1 FP 54015 1 FP 557 53 4 FP 512 91 1 FP 540
16 1 FP 564 54 4 FP 519 92 1 FP 54016 1 FP 564 54 4 FP 519 92 1 FP 540
17 1 FP 540 55 4 FP 536 93 1 FP 55817 1 FP 540 55 4 FP 536 93 1 FP 558
18 1 FP 547 56 4 EN 510 94 1 FP 57418 1 FP 547 56 4 EN 510 94 1 FP 574
19 1 FP 579 57 4 FN 510 95 1 FP 52319 1 FP 579 57 4 FN 510 95 1 FP 523
20 1 FP 579 58 4 EP 543 96 1 FP 55820 1 FP 579 58 4 EP 543 96 1 FP 558
21 1 FP 547 59 4 EP 550 97 1 FP 59021 1 FP 547 59 4 EP 550 97 1 FP 590
22 1 FP 547 60 3 FP 526 98 1 EP 53122 1 FP 547 60 3 FP 526 98 1 EP 531
23 1 FP 565 61 4 FP 533 99 1 EP 52323 1 FP 565 61 4 FP 533 99 1 EP 523
24 1 FP 581 62 4 FP 558 100 1 FP 55824 1 FP 581 62 4 FP 558 100 1 FP 558
25 1 FP 530 63 4 FP 565 101 1 FP 55725 1 FP 530 63 4 FP 565 101 1 FP 557
26 2 FP 550 64 4 FP 533 102 1 FP 55726 2 FP 550 64 4 FP 533 102 1 FP 557
27 2 FP 556 65 4 FP 533 103 1 FP 52127 2 FP 556 65 4 FP 533 103 1 FP 521
28 2 FP 551 66 4 FP 551 104 1 FP 56228 2 FP 551 66 4 FP 551 104 1 FP 562
29 2 FP 555 67 4 FP 567 105 1 FP 55829 2 FP 555 67 4 FP 567 105 1 FP 558
30 1 EP 569 68 4 EP 516 106 1 AP I : 57830 1 EP 569 68 4 EP 516 106 1 AP I: 578
31 1 EP 544 69 4 EP 536 107 1 FP 55831 1 EP 544 69 4 EP 536 107 1 FP 558
32 1 EP 551 70 4 EP 542 108 1 FP 53232 1 EP 551 70 4 EP 542 108 1 FP 532
33 1 EP 559 71 4 EP 537 109 1 FP 51833 1 EP 559 71 4 EP 537 109 1 FP 518
34 1 EP 556 72 3 FP 541 110 1 FP 51834 1 EP 556 72 3 FP 541 110 1 FP 518
35 1 FP 517 73 4 EP 541 111 1 EP 55335 1 FP 517 73 4 EP 541 111 1 EP 553
36 1 FP 537 74 4 FP 530 112 1 EP 552 [M] + 36 1 FP 537 74 4 FP 530 112 1 EP 552 [M] +
37 1 FP 521 75 4 EP 537 113 1 FP 54237 1 FP 521 75 4 EP 537 113 1 FP 542
38 1 FP 557 76 4 FP 545 114 1 FP 524 ] Ex Syn Dat Ex Syn Dat38 1 FP 557 76 4 FP 545 114 1 FP 524] Ex Syn Dat Ex Syn Dat
115 1 EP 524 144 4 FP 543 [ ]+ 115 1 EP 524 144 4 FP 543 [] +
116 1 FP 551 145 4 FP 518116 1 FP 551 145 4 FP 518
117 1 FP 538 146 4 FP 503 [ ] + 117 1 FP 538 146 4 FP 503 [] +
118 1 FP 554 147 4 FP 504118 1 FP 554 147 4 FP 504
119 1 FP 539 148 3 FP 539119 1 FP 539 148 3 FP 539
120 1 FP 518 149 3 FP 539120 1 FP 518 149 3 FP 539
121 1 FP 518 150 3 EP 528121 1 FP 518 150 3 EP 528
122 1 FP 544 151 4 FP 510122 1 FP 544 151 4 FP 510
123 1 FP 559 152 4 FP 510123 1 FP 559 152 4 FP 510
124 1 FP 538 153 153 FP 601124 1 FP 538 153 153 FP 601
125 1 FP 558 154 4 FP 537125 1 FP 558 154 4 FP 537
126 1 FP 552 155 4 FP 524126 1 FP 552 155 4 FP 524
127 1 FP 538 156 4 FP 540127 1 FP 538 156 4 FP 540
128 4 EP 526 157 3 EN 523128 4 EP 526 157 3 EN 523
129 4 FP 526 158 4 FP 504129 4 FP 526 158 4 FP 504
130 4 FP 544 159 4 FP 504130 4 FP 544 159 4 FP 504
131 4 EP 560 160 3 EP 530131 4 EP 560 160 3 EP 530
132 4 FP 509 161 153 EP 613132 4 FP 509 161 153 EP 613
133 4 FP 544 162 3 EP 545133 4 FP 544 162 3 EP 545
134 4 FP 576 163 4 EP 524134 4 FP 576 163 4 EP 524
135 3 EP 516 164 153 FP 687135 3 EP 516 164 153 FP 687
136 3 EP 509 165 165 EP 645136 3 EP 509 165 165 EP 645
137 4 FP 544 166 3 FP 544137 4 FP 544 166 3 FP 544
138 4 FP 543 167 153 FP 606138 4 FP 543 167 153 FP 606
139 4 FP 543 168 153 FP 692139 4 FP 543 168 153 FP 692
140 4 FP 507 169 165 FP 649140 4 FP 507 169 165 FP 649
141 3 EP 548 170 4 FP 538141 3 EP 548 170 4 FP 538
142 4 EP 544 171 3 FP 524142 4 EP 544 171 3 FP 524
143 4 FP 564 143 4 FP 564
Figure imgf000055_0001
S¾2
Figure imgf000055_0002
Figure imgf000055_0001
S¾2
Figure imgf000055_0002
S〔〕¾00912 S [] ¾00912
Figure imgf000056_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000057_0001
[0092] [表 30] [0092] [Table 30]
Figure imgf000058_0001
Figure imgf000058_0001
[0093] [表 31]
Figure imgf000059_0001
[0093] [Table 31]
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0001
産業上の利用可能性 Industrial applicability
本発明化合物は、強力な EP1受容体拮抗作用を有することから、 EP1受容体が関与 する疾患、特に過活動膀胱に伴う頻尿'尿失禁、前立腺肥大症に伴う下部尿路症状 、間質性膀胱炎、前立腺炎などの下部尿路疾患治療薬として有用である。  Since the compound of the present invention has a strong EP1 receptor antagonism, diseases involving the EP1 receptor, particularly frequent urinary incontinence associated with overactive bladder, lower urinary tract symptoms associated with prostatic hypertrophy, interstitial It is useful as a therapeutic agent for lower urinary tract diseases such as cystitis and prostatitis.

Claims

請求の範囲  The scope of the claims
下記一般式 (I)で示されるカルボン酸誘導体又はその製薬学的に許容される塩。 A carboxylic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
[化 11] [Chemical 11]
Figure imgf000061_0001
Figure imgf000061_0001
{ EMBED ISISServer , } {EMBED ISISServer,}
[式中の記号は以下の意味を示す。  [The symbols in the formula have the following meanings.
R1及び R2:同一又は異なって、 Η、ハロゲン、低級アルキル、ハロゲノ低級アルキル、 - ΟΗ、 -0-低級アルキル、或いは、 R1及び R2が結合している炭素原子と一体となつ て、 5〜8員シクロアルケン環、又はベンゼン環を形成してもよぐ R 1 and R 2 : the same or different, Η, halogen, lower alkyl, halogeno lower alkyl, -ΟΗ, -0-lower alkyl, or a carbon atom to which R 1 and R 2 are bonded. A 5- to 8-membered cycloalkene ring or a benzene ring may be formed.
R3:- ΟΗ、 -Ο-低級アルキル、又は- NH- SO 2 - (-OHゝ及び- O- C(=0)—低級アル キル力 選択される基で置換されて 、てもよ 、低級アルキル）、 R 3 : -ΟΗ, -Ο-lower alkyl, or -NH-SO 2-(-OH ゝ and -O-C (= 0) -lower alkyl force may be substituted with a selected group, Lower alkyl),
A：置換されて!、てもよ 、ヘテロ環基、  A: substituted !, may be a heterocyclic group,
B：置換されて!、てもよ 、フエ-ル、又は置換されて 、てもよ 、単環式へテロァリール  B: substituted !, may, file, or substituted, may be monocyclic heteroaryl
C：置換されて!、てもよ 、フエ-レン、又は置換されて!、てもよ!/、単環式へテロァリー レン、 C: substituted !, may, phenylene, substituted !, may! /, Monocyclic heteroalkylene,
X：低級アルキレン、低級ァルケ-レン、 -0-低級アルキレン-、又は-低級アルキレン - o-、  X: lower alkylene, lower alkylene, -0-lower alkylene-, or -lower alkylene -o-,
Y:単結合、低級アルキレン、低級ァルケ-レン、又は- o-低級アルキレン-、  Y: a single bond, lower alkylene, lower alkylene, or -o-lower alkylene,
Z :低級アルキレン。]  Z: Lower alkylene. ]
Aが含酸素 4〜6員飽和へテロ環基又は含窒素 5〜6員へテロアリールであって、 B がフエ-ル、又は N若しくは Oを必ず 1個含む 5〜6員へテロアリールである、請求の 範囲 1記載の化合物。ここで A及び Bにおける各環基は置換されていてもよい。 [3] Aがォキセタ -ル、テトラヒドロフリル、テトラヒドロビラ-ル、ピリジル、ピラジュル、イミ ダゾリル、及びビラゾリルカもなる群力 選択される環基であって、 Bがフエニル、チア ゾリル、フリル、及びピリジルカ 選択される環基である、請求の範囲 2記載の化合物 。ここで A及び Bにおける各環基は低級アルキル又はハロゲンで置換されて 、てもよ い。 A is an oxygen-containing 4- to 6-membered saturated heterocyclic group or nitrogen-containing 5- to 6-membered heteroaryl, and B is a 5- to 6-membered heteroaryl containing at least one of N or O. A compound according to claim 1. Here, each ring group in A and B may be substituted. [3] The group power of which A is oxetal, tetrahydrofuryl, tetrahydroviral, pyridyl, pyrajur, imidazolyl, and virazolylca, and B is phenyl, thiazolyl, furyl, and pyridylca The compound according to claim 2, which is a selected cyclic group. Here, each ring group in A and B may be substituted with lower alkyl or halogen.
[4] Aがォキセタ-ル及びピリジルカ なる群力 選択される環基であって、 Bがフエ-ル 及びチアゾリルカも選択される環基である、請求の範囲 3記載の化合物。ここで Aに おける各環基は低級アルキルで置換されて ヽてもよく、 Bにおける各環基は低級アル キル又はハロゲンで置換されて 、てもよ！/、。  [4] The compound according to claim 3, wherein A is a ring group selected from the group power of oxetal and pyridylca, and B is a ring group also selected from phenol and thiazolylca. Here, each ring group in A may be substituted with lower alkyl, and each ring group in B may be substituted with lower alkyl or halogen! /.
[5] Xカ 0-低級アルキレン-である、請求の範囲 1〜4のいずれかに記載の化合物。  [5] The compound according to any one of claims 1 to 4, wherein X is 0-lower alkylene-.
[6] Yが単結合である、請求の範囲 5記載の化合物。  [6] The compound according to claim 5, wherein Y is a single bond.
[7] Zがメチレンである、請求の範囲 6記載の化合物。  [7] The compound according to claim 6, wherein Z is methylene.
[8] Cがフエ-レンである、請求の範囲 7記載の化合物。  [8] The compound according to claim 7, wherein C is phenylene.
[9] R3が- OHであって、 R1及び R2が同一又は異なって、 H、ハロゲン、低級アルキル、ハ ロゲノ低級アルキル、 -0-低級アルキル、或いは、 R1及び R2が結合している炭素原 子と一体となって、シクロペンテン環を形成している、請求の範囲 8記載の化合物。 [9] R 3 is —OH, R 1 and R 2 are the same or different, and H, halogen, lower alkyl, halogeno lower alkyl, −0-lower alkyl, or R 1 and R 2 are bonded. 9. The compound according to claim 8, which forms a cyclopentene ring together with the carbon atom.
[10] 4-[({6-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ォキセタン- 2-ィルメチル)ァ ミノ] -2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、  [10] 4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (oxetane-2-ylmethyl) amino] -2,3-dihydro-1H -Inden-5-yl} oxy) methyl] benzoic acid,
4-{[(6-{[(3-メチルォキセタン- 3-ィル)メチル ][(4-メチル - 1,3-チアゾール -2-ィル)スル ホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸、  4-{[(6-{[(3-Methyloxetane-3-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2,3- Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid,
4-[({6-[[(3,5-ジフルオロフェ -ル)スルホ -ル] (ォキセタン- 2-ィルメチル)ァミノ] -2,3- ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[[(3,5-difluorophenyl) sulfol] (oxetane-2-ylmethyl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) Methyl] benzoic acid,
4-[({6-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ ]-2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1H-indene-5 -Yl} oxy) methyl] benzoic acid,
4-[({6-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (テトラヒドロフラン- 3-ィルメ チル)ァミノ] -2,3-ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (tetrahydrofuran-3-ylmethyl) amino] -2,3-dihydro-1H-indene- 5-yl} oxy) methyl] benzoic acid,
4-[({6-[[(5-メチル - 2-フリル)スルホ -ル] (テトラヒドロフラン- 3-ィルメチル)ァミノ] -2,3- ジヒドロ- 1H-インデン -5-ィル }ォキシ)メチル]安息香酸、 4-[({6- [(ピリジン- 2-ィルメチル) (ピリジン- 3-ィルスルホ -ル)ァミノ] -2,3-ジヒドロ- 1H- インデン -5-ィル }ォキシ)メチル]安息香酸、 4-[({6-[[(5-Methyl-2-furyl) sulfol] (tetrahydrofuran-3-ylmethyl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) methyl ]benzoic acid, 4-[({6-[(pyridine-2-ylmethyl) (pyridine-3-ylsulfo-yl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) methyl] benzoic acid,
4-({4,5-ジメチル- 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィ ルメチル)ァミノ]フエノキシ }メチル)安息香酸、  4-({4,5-dimethyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) benzoic acid ,
4-({4-クロ口- 5-メチル - 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ]フエノキシ }メチル)安息香酸、  4-({4-chrome-5-methyl-2-[[(4-methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] phenoxy} methyl) benzoic acid,
4- {[2- [[(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -5- (トリフルォロメチル)フエノキシ]メチル }安息香酸、  4- {[2- [[(4-Methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] -5- (trifluoromethyl) phenoxy] methyl} benzoic acid,
4-({4,5-ジメチル- 2- [(ピリジン- 2-ィルメチル) (ピリジン- 3-ィルスルホ -ル)ァミノ]フエノ キシ }メチル)安息香酸、  4-({4,5-dimethyl-2-[(pyridine-2-ylmethyl) (pyridine-3-ylsulfoyl) amino] phenoxy} methyl) benzoic acid,
4-{[(6-{[(1-メチル -1H-ピラゾール -4-ィル)メチル ][(4-メチル - 1,3-チアゾール -2-ィ ル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸、 4-({5-メトキシ -4-メチル - 2-[[(4-メチル - 1,3-チアゾール -2-ィル)スルホ -ル] (ピリジン -2-ィルメチル)ァミノ]フエノキシ }メチル)安息香酸、  4-{[(6-{[(1-Methyl-1H-pyrazol-4-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2 , 3-Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid, 4-({5-methoxy-4-methyl-2-[[(4-methyl-1,3-thiazole-2- Yl) sulfoyl] (pyridine-2-ylmethyl) amino] phenoxy} methyl) benzoic acid,
4-({4,5-ジメチル- 2- [(ピリジン- 2-ィルメチル) (ピリジン- 2-ィルスルホ -ル)ァミノ]フエノ キシ }メチル)安息香酸、  4-({4,5-dimethyl-2-[(pyridine-2-ylmethyl) (pyridine-2-ylsulfol) amino] phenoxy} methyl) benzoic acid,
4-[({6-[[(2-フルオロフェ -ル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -2,3-ジヒドロ -1H-インデン -5-ィル }ォキシ)メチル]安息香酸、及び  4-[({6-[[(2-Fluorophenyl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1H-indene-5-yl} oxy) methyl] benzoic acid Acid, and
4- {[(6- {[(1-メチル -1H-イミダゾール- 2-ィル)メチル ][(4-メチル -1,3-チアゾール -2-ィ ル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1H-インデン -5-ィル)ォキシ]メチル }安息香酸、 力 なる群力 選択される請求の範囲 1記載の化合物又はその製薬学的に許容され る塩。  4- {[(6- {[(1-Methyl-1H-imidazol-2-yl) methyl] [(4-methyl-1,3-thiazol-2-yl) sulfol] amino} -2 , 3-Dihydro-1H-indene-5-yl) oxy] methyl} benzoic acid, powerful group force The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
[11] 請求の範囲 1記載の化合物を有効成分とする医薬組成物。  [11] A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient.
[12] EP1受容体拮抗剤である請求の範囲 11記載の医薬組成物。 [12] The pharmaceutical composition according to claim 11, which is an EP1 receptor antagonist.
[13] 過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状、間質性膀胱炎 、前立腺炎力もなる下部尿路疾患の治療薬である、請求の範囲 11記載の医薬組成 物。  [13] The method according to claim 11, which is a therapeutic agent for frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with benign prostatic hyperplasia, interstitial cystitis, and lower urinary tract disease that also has prostatitis power. Pharmaceutical composition.
[14] EP1受容体拮抗剤、及び/又は過活動膀胱に伴う頻尿，尿失禁、前立腺肥大症に伴 う下部尿路症状、間質性膀胱炎、前立腺炎からなる下部尿路疾患の治療薬の製造 のための、請求の範囲 1記載の化合物の使用。 [14] EP1 receptor antagonist and / or accompanying frequent urination, urinary incontinence, and prostatic hypertrophy associated with overactive bladder Use of the compound according to claim 1 for the manufacture of a therapeutic agent for lower urinary tract disease consisting of lower urinary tract symptoms, interstitial cystitis, and prostatitis.
請求の範囲 1記載の化合物の治療有効量を患者に投与することを含む、過活動膀 胱に伴う頻尿，尿失禁、前立腺肥大症に伴う下部尿路症状、間質性膀胱炎、前立腺 炎からなる下部尿路疾患の治療方法。 Claims 1, comprising administering to a patient a therapeutically effective amount of frequent urination associated with overactive bladder, urinary incontinence, lower urinary tract symptoms associated with benign prostatic hyperplasia, interstitial cystitis, prostatitis A method of treating lower urinary tract disease comprising:
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