WO2006121097A1 - Bicyclic heterocyclic derivative or salt thereof - Google Patents

Bicyclic heterocyclic derivative or salt thereof Download PDF

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Publication number
WO2006121097A1
WO2006121097A1 PCT/JP2006/309447 JP2006309447W WO2006121097A1 WO 2006121097 A1 WO2006121097 A1 WO 2006121097A1 JP 2006309447 W JP2006309447 W JP 2006309447W WO 2006121097 A1 WO2006121097 A1 WO 2006121097A1
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Prior art keywords
methyl
dihydro
oxy
benzofuran
lower alkylene
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PCT/JP2006/309447
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French (fr)
Japanese (ja)
Inventor
Hideki Kubota
Issei Tsukamoto
Daisuke Suzuki
Hiroyuki Koshio
Kazunori Kamijo
Kei Ohnuki
Koji Kato
Yuta Fukuda
Yusuke Hirano
Toru Watanabe
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Astellas Pharma Inc.
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Publication of WO2006121097A1 publication Critical patent/WO2006121097A1/en

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    • 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
    • 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
    • A61P13/10—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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a bicyclic heterocycle useful as a therapeutic agent for lower urinary tract diseases such as urinary incontinence, cystitis, interstitial cystitis, and prostatitis, which is associated with urinary frequency associated with overactive bladder.
  • urinary tract diseases such as urinary incontinence, cystitis, interstitial cystitis, and prostatitis, which is associated with urinary frequency associated with overactive bladder.
  • 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.
  • side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people.
  • side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people.
  • side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people.
  • there are patients who do not show efficacy with anticholinergic treatment Based on the above, there are great expectations for
  • 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
  • EP1 receptor antagonists are frequently used in overactive bladder, It is thought to be useful as a therapeutic agent for lower urinary tract diseases such as urgency, urinary incontinence, cystitis, interstitial cystitis, and prostatitis.
  • EP1 receptor antagonists have different mechanisms of action, they can be expected to avoid the side effects peculiar to anticholinergic drugs, and can also be expected to be effective in patients who do not show efficacy with anticholinergic treatment. In addition, this drug is expected to improve the subjective symptoms by acting on sensory nerves. it can. Furthermore, it has been reported that the effect of improving the pathological condition is exhibited without reducing the urination efficiency of rats with spinal cord injury (Non-patent Document 5), and it can be expected to 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.
  • Non-patent Document 9 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).
  • EP1 receptor antagonists are known to have an inhibitory effect on colonic mucosal abnormal crypts and intestinal polyp formation (Patent Document 1). EP1 receptor antagonists are used for colon cancer, bladder cancer, It is considered useful as a therapeutic agent for prostate cancer and the like.
  • Patent Document 2 discloses a compound represented by the formula (A)!
  • B represents a C5-15 carbocyclic ring, or a 5- to 7-membered heterocyclic ring having one or two oxygen, sulfur, or nitrogen atoms.
  • B represents a C5-15 carbocyclic ring, or a 5- to 7-membered heterocyclic ring having one or two oxygen, sulfur, or nitrogen atoms.
  • Patent Document 3 discloses a compound represented by the formula (B).
  • R 3 and R 4 are (1) methyl and methyl, (2) methyl and black mouth, (3) black mouth and methyl, (4) a combination of trifluoromethyl and hydrogen, or R 3 and R 4 is bonded to V and carbon atoms to form (5) cyclopentene or (6) a benzene ring.
  • Patent Document 4 discloses a compound represented by the formula (C) including a wide range of compounds!
  • 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, 97th Sakai, 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 International Publication No. 00Z69465 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 98Z27053
  • Patent Document 3 Pamphlet of International Publication No. 02Z72564
  • Patent Document 4 Pamphlet of International Publication No. 00Z20371
  • the 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 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 was found that a novel bicyclic heterocycle derivative represented by the following general formula (I) has a strong EP1 receptor antagonistic action, and the present invention was completed.
  • Ring B cycloalkyl, benzene ring, or hetero ring
  • R 1 substituted, optionally lower alkyl, or heterocyclic group
  • R 2 C alkyl, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloa
  • R 3 - OH, - C (O) - OR °, - C (O) - NR 5 R 5a, 1H- tetrazol - 5 I le, or 5 Okiso 4,5-dihydro - 1,2, 4-oxadiazol-3-yl,
  • R ° and R °° the same or different, H or lower alkyl
  • R 5 and R 5a the same or different, -R °, -lower alkylene-NR ° R °°, -lower alkylene-C 0 R °, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloalkyl -Low
  • R 4 nanogen, lower alkyl, halogeno lower alkyl, nitro-nitro, -0R °, -0-halogeno lower alkyl, -C (0) R °, or -NR ° C (0) R °°,
  • J lower alkylene, lower alkylene, -0-lower alkylene-, -lower alkylene-0-,- 0-lower alkylene, -lower alkylene-0-, -C (0) NR °-, or -NR ° C (0)-
  • X single bond, lower alkylene, lower alkylene, -0-lower alkylene-, -0-lower alkylene-, -NR ° -lower alkylene-, -S (O) -lower alkylene-, or- S (O) -lower alkenylene-,
  • n 0, 1, or 2.
  • R 3 is —CO 2 H or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl
  • a 1 ring: substituted with lower alkyl! May be 2,3-dihydrofuran, 2,3-dihydrothiophene, or 2,3-dihydrothiophene 1,1-dioxide,
  • B 1 ring benzene ring or thiophene ring
  • R 1A (1) -OH, (2) halogen, (3) lower alkyl, -O-lower alkyl, or halogen substituted
  • the pyridylca group force may be substituted with a selected group, which may be a lower alkyl,
  • R 2A (1) halogen, (2) lower alkyl, (3) 0-lower alkyl group power is also selected
  • R 3A -CO H, or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
  • R 4A H, halogen, lower alkyl, or -0-lower alkyl.
  • a pharmaceutical composition comprising the compound according to [1] as an active ingredient,
  • 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.
  • the compound of the present invention showed a strong EP1 receptor antagonistic activity.
  • Table 1 shows the test results of the representative compounds. Ex represents an Example compound number described later.
  • the rat EP1 receptor was introduced into the expression vector (trade name: pCEP4, Invitrogen) after introducing a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) and a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) at the N-terminus. .
  • This rat EP1 expression vector was transformed into HEK293EBNA cells (American's type culture ⁇ ⁇ ⁇ American Type Culture) using transfection reagent (trade name: Fugene-6, Roche Diagnostics). Collection)), then 10% FB at 37 ° C, 5% CO
  • the cells were cultured in a medium containing S (trade name: DMEM, Invitrogene) 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 ultracentrifuged (23,000 rpm, 25 The membrane preparation was roughly adjusted by min x 2).
  • MES ethanesulfonic acid
  • KOH potassium hydroxide
  • ImM EDTA ImM EDTA
  • MgCl lOmM salt ⁇ magnesium
  • 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.
  • the compound of the present invention showed strong EP1 receptor binding activity.
  • Table 2 The test results of representative compounds are shown in Table 2 below.
  • 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. The experiment was conducted two days later. Rats were placed in metabolic cages and acclimated for 1 hour, then the test drug 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.
  • the effective bladder capacity decreased in the acetic acid intravesical treatment group compared to the sham-operated group, resulting in frequent urination.
  • the compound of the present invention improved the frequent urination state well.
  • 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 excellent metabolic stability with few concerns about drug interaction, etc. It is preferred as a medicine and has properties.
  • the compound of the present invention is expected as a therapeutic agent for lower urinary tract diseases such as frequent urination, urinary incontinence, cystitis, interstitial cystitis, prostatitis power associated with overactive bladder with less side effects.
  • lower urinary tract diseases such as frequent urination, urinary incontinence, cystitis, interstitial cystitis, prostatitis power associated with overactive bladder with less side effects.
  • lower means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms unless otherwise specified.
  • “Lower alkyl” means C alkyl. Specifically, methyl, ethyl,
  • Examples include normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like. Preferred are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl and tert-butyl.
  • “Lower ark” means a C alkell. Double bond can be at any position
  • it may have a plurality of double bonds.
  • Specific examples include ethenyl, probe, butyr, pentale, hexyl, butagel and the like.
  • Preferred are etule, 1-probe, and 2-probe.
  • “Lower alkylene” is formed by removing one hydrogen at any position of alkyl of C 2
  • Means a valent group means methylene, ethylene, methylmethylene, dimethylmethylene, propylene and the like. Preferred are methylene, ethylene and propylene.
  • “Lower alkylene” refers to the removal of one hydrogen atom at any position of the C alkenyl.
  • Means a divalent group means a divalent group. Specific examples include beylene, probelene, 1-butylene, 2-butylene. Biylene is preferred.
  • Cycloalkyl means a non-aromatic hydrocarbon ring of C, and the bridged ring is a spiro ring.
  • Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexenole, cycloheptinole, cyclooctyl, cyclohexenyl, cyclooctanegel, adamantyl and norbol.
  • Halogen means a halogen atom. Specific examples include fluoro, black mouth, bromo and iodine. Fluoro and black mouth are preferred.
  • halogeno lower alkyl means one or more arbitrary hydrogen atoms of the “lower alkyl” which are the same or different from each other and substituted with the “halogen”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Preferred is trifluoromethyl.
  • Aryl means a monocyclic to tricyclic C aromatic hydrocarbon ring group, specifically
  • the 5-8 cycloalkyl ring may be condensed.
  • indanyl or tetrahydronaphthyl may be formed.
  • Heterocyclic group means a saturated or unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N forces, and 8 to 14 It means a membered bicyclic heterocyclic group or an 11-20 membered tricyclic heterocyclic group.
  • the ring atom S or N may be oxidized to form an oxide or a bridged ring or a spiro ring.
  • the monocyclic heterocyclic group examples include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazinyl, furyl, dihydrofuryl, chenyl, dihydrochenyl, pyrrolinole, pyrrolinyl, oxazolinole, isoxazolyl, oxadiazolyl , Thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, virazolinyl, virazolidinyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidyl, piperazil, morpholinyl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl -Le.
  • bicyclic heterocyclic group examples include indolyl, indolyl, benzofuran, dihydrobenzofuranore, benzocenore, dihydrobenzocenore, indazolinole, benzoxazolyl, benzoimidazolyl, benzothiazolyl, Examples include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, cinnolinyl and the like.
  • tricyclic heterocyclic group examples include carbazolyl and attalidinyl.
  • Heterocycle means the above “heterocyclic group” as a ring.
  • the heterocyclic groups pyridyl, chenyl, dihydrofuryl and pyrrolinyl are pyridine, thiophene, Corresponds to dihydrofuran and pyrroline (2,3-dihydro-1H-pyrrole).
  • all of the above “heterocyclic groups” may be divalent or higher polyvalent groups depending on the force structure described as a monovalent group for convenience.
  • the present invention includes those structures. Specific embodiments of the divalent group correspond to those obtained by converting the above-mentioned “heterocyclic group” suffix into a dil according to the organic compound nomenclature.
  • the permissible substituent of the word “substituted or may be used” is usually used in the art as a substituent of each group. Any substituent may be used. In addition, each group may have at least one identical or different substituent.
  • the substituent in the “substituted or lower alkyl” of R 1 is preferably a group selected from the following G group forces.
  • cycloalkyl, aryl, and heterocyclic groups in Group G may be substituted with halogen, lower alkyl, halogeno lower alkyl, -OR ° or -0-norogeno lower alkyl!
  • R 2 may preferably be a substituent in “C alkyl”.
  • p group neurogen, -OR 0 ,-0- SiR ° R °° (Areel), -NR ° R °°, -CO R. And -C (0) NR ° R. .
  • Lower alkyl optionally substituted by a group selected from the group consisting of halogen, sirene-to, -OR °, -0-halogeno lower alkyl, -C (0) R °, -CO R °,- NR ° C (0) R °°,-C (0) NR ° R °
  • a ring is preferably furan, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3-dihydrothiophene 1,1-dioxide, pyrroline, 3,4-dihydro-2H-pyran, 1,3 -Dioxol or 2,3-dihydro-1,4-dioxin, which are fused together!
  • the ring B is preferably benzene, thiophene, pyridine or thiazole, more preferably benzene, thiophene or thiazole, and still more preferably benzene or thiophene.
  • R 1 is preferably halogen, -OR 0 , cycloalkyl, aryl, or lower alkyl optionally substituted with a heterocyclic group, and more preferably halogen, -OR °, or heterocyclic.
  • Lower alkyl which may be substituted with a group, more preferably isobutyl, 2-fluoropropyl, 3-hydroxy-2-methylpropyl or (pyridin-2-yl) methyl.
  • R 2 is preferably each independently substituted or unsubstituted or more preferably a heterocyclic group, and more preferably one or more lower alkyl, -0-lower alkyl or halogen each being the same or different.
  • a aryl group or a heterocyclic group more preferably Each is the same or different phenyl, pyridyl, furyl or thiazolyl substituted with one or more lower alkyl or halogen.
  • R 3 is preferably -C (0) -OR °, 1H-tetrazol-5-yl or 5-oxo-4,5-dihydride-1,2,4-oxadiazol-3-yl, More preferably, -CO H or 5-oxo-4,5-
  • R 4 is preferably halogen, lower alkyl, halogeno lower alkyl, -0-lower alkyl, or -0-nitrogeno lower alkyl, and more preferably halogen or lower alkyl.
  • m is 0 or 1.
  • X is preferably a single bond, lower alkylene, lower alkylene, or 0-lower alkylene-, more preferably a single bond or lower alkylene, and still more preferably a single bond.
  • J is preferably -0-lower alkylene-, more preferably -0-methylene-.
  • L is preferably -S (O)-.
  • a particularly preferred embodiment of the present invention is a compound comprising a combination of each preferred group described above.
  • the compound of the present invention may have a geometric isomer or a tautomer depending on the kind of the substituent, but the present invention includes a separated or a mixture of these isomers.
  • the compound of the present invention may have an asymmetric carbon atom, and optical isomers such as (R) isomer and (S) isomer based on this may exist.
  • optical isomers such as (R) isomer and (S) isomer based on this may exist.
  • the present invention includes all of these optical isomers and isolated ones.
  • the compounds of the present invention include pharmacologically acceptable prodrugs.
  • a pharmacologically acceptable prodrug is a compound having a group that can be converted to NH, OH, COH or the like of the present invention by solvolysis or under physiological conditions. Form a prodrug
  • the compound of the present invention may form a salt with a base depending on the type of acid addition salt or substituent.
  • strong salts are pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propion.
  • Acid addition salts with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid
  • organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid
  • Inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum
  • salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortin, and ammonium salts.
  • the present invention includes various hydrates and solvates of the compound (I) and salts thereof, and crystalline polymorphic substances.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent.
  • a suitable protecting group at the raw material or intermediate stage, or replace it with a group that can be easily transferred to the functional group. May be effective.
  • Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups, and examples of protective groups for these functional groups include “Protective”, “Groups”, “In” and “Organic” by TW Greene and PGM Wuts. 'Protective Groups in Organic Synthesis', (USA), 3rd edition, John' Wiley & Sons, Inc. What is necessary is just to select suitably according to reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
  • R la and R 2a represent groups that are converted into R 1 and R 2 , respectively, by the reductive amination reaction described later.
  • the first step is a step of producing the compound (V) from the compound (II) by alkylation.
  • This step is a step of producing the compound (V) by reductive alkylation of the compound (II) and the carbonyl compound (III).
  • the reaction for example, the method described in “Chemical Experiment Course (20) Organic Synthesis 2” edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, p. Specifically, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, etc.
  • Ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane, alcohols such as methanol and ethanol, and solvents inert to the reaction such as acetic acid It is preferable to carry out the reaction at room temperature to reflux with heating using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • This step is a step for producing compound (V) by alkylating compound (II) with compound (IV) having a leaving group.
  • the leaving group represented by Lv may be any leaving group that is commonly used in nucleophilic substitution reactions, such as halogen, halogen such as bromo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonylo. Sulfoloxy such as xy, sulfone such as lower alkyl sulphone, aryl sulol and the like are preferably used.
  • an alkylation commonly used by those skilled in the art can be employed.
  • reaction in the absence of solvent or inert to reactions such as the aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, dimethylsulfoxide (DMSO), and acetonitrile.
  • the reaction can be carried out in a solvent or a solvent such as alcohols at room temperature or under reflux.
  • organic bases triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.
  • metal salt bases are preferably used) or metal salt bases (potassium carbonate, In the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxypotassium, etc.), it may be advantageous for the reaction to proceed smoothly.
  • compound (V) is treated with compound (VI) by sulfo-louis, so that L is -S (O)-
  • Lv halogen such as black mouth and bromo
  • the conditions of sulfoniru ⁇ described in “Protective Groups in Organic Synthesis” can be applied. Specifically, it can be carried out in a solvent such as tetrahydrofuran, dichloromethane or acetonitrile, in the presence of a base such as triethylamine or pyridine, if necessary, under cooling to heating under reflux.
  • This step is a step for producing the compound (I-b) of the present invention in which L is —C (O) — by subjecting compound (V) to carboxylic acid (VII) or a reactive derivative thereof.
  • reactive derivatives include acid salts, logogens (acid chlorides, acid bromides, etc.), acid anhydrides (black ester carbonate, benzyl carbonate, chloroform carbonate, P-toluenesulfonic acid, isoforms).
  • the reaction is carried out by using an equimolar amount or an excess of one of the carboxylic acid compound (VII) or its reactive derivative and compound (V), aromatic hydrocarbons, halogenated hydrocarbons, ethers,
  • the reaction can be carried out under cooling to heating in a solvent inert to the reaction such as DMF, DMA, NMP, ethyl acetate or acetonitrile.
  • a solvent inert such as DMF, DMA, NMP, ethyl acetate or acetonitrile.
  • the reaction may be carried out in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.) In some cases, the reaction proceeds smoothly.
  • a base preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N
  • a condensing agent ⁇ , ⁇ '-dicyclohexyl carpositimide, (DCC), 1- [3- (dimethylamino) propyl] -3-ethyl carbodiimide (WSC), 1,1 , -Carbo-rubbisimidazole (CDI), ⁇ , ⁇ '-Disuccinimidyl carbonate, Bop reagent (Aldrich, USA), 2- (1 ⁇ -benzotriazol-1-yl) -1,1, 3,3-tetramethylu-mu-tetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1,1, 3,3-tetramethylu mouth -Umhexafluorophosphate (HBTU), diphenylphosphoric acid azide (DPPA), phosphorus oxychloride, phosphorus trichloride, triphenylphosphine ZN-bromosuccinimi
  • This step is a step for producing a compound (I-c) of the present invention in which L is a single bond by alkylating compound (V) with compound (VIII) or compound (IX).
  • the alkylation in this step can be performed in the same manner as the alkylation in the first step.
  • This step is a step of producing compound (X) from compound (II) by sulfonylation, acylation or alkylation.
  • the sulfonylation, the acylation, and the alkylation can be carried out in the same manner as in the second step 1 to the second step 3 of production method 1, respectively.
  • This step is a step for producing the present compound (I) from the compound (X) by alkylation.
  • the alkylation reaction in this step can be produced in the same manner as in the first step 2 of production method 1.
  • R represents lower alkyl
  • R 3 is —CO 2 H from the compound (Id) of the present invention in which R 3 is —CO 2 R by hydrolysis.
  • the hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in the above-mentioned “Protective Groups Inorganic Organic Synthesis”.
  • R 3 is —CONR 5a from the compound (Ie) of the present invention in which R 3 is —CO 2 H by amido.
  • the amidation reaction in this step can be carried out in the same manner as in the second step 1 and 2 of production method 1.
  • the starting compound used for the production of the compound (I) of the present invention can be produced, for example, using the following method, a known method, or a modified method thereof.
  • This step is a step for producing compound (XIII) by nitration of compound (XII).
  • Nitration can be produced by a method usually 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 ( ⁇ ) by reducing the nitro compound ( ⁇ ).
  • a -tro group reduction reaction that can be usually employed by those skilled in the art can be used. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride and a hydrogenation reaction using palladium-carbon as a catalyst.
  • J 1 and / represent groups that can be converted to J.
  • compound (XVI) and compound (XV) are condensed to produce compound (XVI). It is.
  • This step can be produced by amidation, alkylation or the like that can be usually employed by those skilled in the art depending on the structure of J.
  • a compound (XVI) in which J is -0-lower alkylene- is a compound (XIV) in which J 1 OH is a -lower alkylene-Lv (Lv represents a leaving group).
  • the alkylation can be carried out in the same manner as in the first step 2 of production method 1.
  • reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate.
  • the salt can be produced by subjecting it to normal salt formation treatment.
  • Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
  • optical isomers can be isolated by a conventional method using physical and physical differences between isomers.
  • optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography.
  • An optical isomer can be produced from an appropriate optically active raw material compound.
  • a preparation containing one or more of the compounds of the present invention or a salt thereof as an active ingredient is usually prepared using carriers, excipients, and other additives used for formulation.
  • Administration is oral by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral by injections such as intravenous and intramuscular injections, suppositories, transdermal, nasal or inhalants. Either form may be sufficient.
  • the dosage is appropriately determined according to the individual case, taking into account the symptoms, age of the subject, sex, etc., but in the case of oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per day for an adult. This should be administered once or in 2 to 4 divided doses.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substances are less potent. It is mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybulurpyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. Tablets or pills may be coated with sugar coating or gastric or enteric coatings if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and are generally used inert solvents such as purified water, ethanol. including.
  • the composition may contain solubilizers, wetting agents, suspending agents and other auxiliary agents, sweeteners, corrigents, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solvent include distilled water for injection and physiological saline.
  • Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can be prepared by preparing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
  • 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.
  • an excipient and as Ratatosu Ya starch furthermore, P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate.
  • 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 as a solution or suspension alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier be able to.
  • the dry powder inhaler or the like can use a dry powder or a capsule containing a powder, which may be for single or multiple administrations.
  • a suitable propellant such as black mouth fluo It may be in the form of a caloric pressure aerosol spray using a suitable gas such as loalkane, hydrofluoroalkane or carbon dioxide.
  • Syn production method (numbers indicate that the product was produced using the corresponding raw material in the same manner as the example compound having the number as the example number. R is attached before the number)
  • the reference example number in the case of the reference example, it indicates that it was produced using the corresponding raw material in the same manner as the reference example compound.
  • reaction solution was cooled to room temperature and then concentrated under reduced pressure to about 100 ml.
  • the precipitate deposited by ice cooling was collected by filtration and dried under reduced pressure to obtain 3.49 g of 5-hydroxy-6-nitro-1,3-benzodioxole.
  • Example 13 4- ⁇ [(5- ⁇ [(5-Methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl ⁇ methyl benzoate 300 mg into 4 ml of pyridine Dissolved, 196 mg of propylene oxide was added thereto, and the mixture was stirred overnight at 100 ° C in a sealed tube. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with 1M hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate.
  • N- ⁇ 6-[(4-Cyanobenzyl) oxy] -2,3-dihydro-1-benzofuran-5-yl ⁇ -N-isobutyl-5-methylfuran-2-sulfonamide 300 mg suspended in 6 mL toluene It became cloudy and 331 mg of trimethyltin azide was added. The reaction was heated to reflux for 8 hours, then returned to room temperature and stirred overnight. To the reaction solution, 12 mL of MeOH and 16 mL of 1M hydrochloric acid were added and stirred at room temperature for 2 hours.
  • the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate.
  • the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate.
  • Example 192 4- ⁇ [(5- ⁇ Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl ⁇
  • benzoic acid was dissolved in 4.0 mL of THF, and 1.19 mL of a 1M THF solution of borane-THF complex was added thereto under ice cooling, followed by stirring at room temperature for 2 hours. A water-acetic acid mixture was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate.
  • Example compounds shown in Tables 19 to 82 to be described later were produced using the corresponding raw materials.
  • Tables 19 to 82 show the structures and physicochemical data of the example compounds.
  • Table 83 shows the structure of another compound 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 is excellent in EP1 receptor antagonistic activity.
  • Diseases involving EP1 receptor particularly frequent urination associated with overactive bladder, urinary urgency, urinary incontinence, cystitis, interstitial cystitis, prostate It is useful as a therapeutic agent for lower urinary tract diseases such as adenitis. Sequence listing free text
  • the numerical heading ⁇ 223> in the sequence listing below describes the “Artificial Sequence”. Specifically, the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing is an artificially synthesized signal peptide sequence. The amino acid sequence represented by SEQ ID NO: 2 in the sequence listing is an artificially synthesized FLAG sequence.

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Abstract

[PROBLEMS] To provide a compound which can be used as a therapeutic agent for a disease in which an EP1 receptor is involved, particularly a lower urinary tract disease such as pollakiuria/urinary urgency and incontinence associated with overactive bladder, cystitis, interstitial cystitis and prostatitis. [MEANS FOR SOLVING PROBLEMS] It is found that a bicyclic heterocyclic derivative in which benzene rings are fused or a salt thereof has a potent EP1 receptor-antagonistic effect. The bicyclic heterocyclic derivative or salt thereof can be used as a therapeutic agent for a disease in which an EP1 receptor is involved, particularly a lower urinary tract disease such as pollakiuria/urinary urgency and incontinence associated with overactive bladder, cystitis, interstitial cystitis and prostatitis.

Description

明 細 書  Specification
二環式へテロ環誘導体又はその塩  Bicyclic hetero ring 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、膀胱炎、間質性膀胱炎、 前立腺炎力 なる下部尿路疾患の治療薬として有用な二環式へテロ環誘導体に関 する。  [0001] The present invention relates to a bicyclic heterocycle useful as a therapeutic agent for lower urinary tract diseases such as urinary incontinence, cystitis, interstitial cystitis, and prostatitis, which is associated with urinary frequency associated with overactive bladder. Regarding derivatives.
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 side effects such as rheumatoid arthritis, constipation and blurred vision are known, and there is a risk of urinary retention, which makes it difficult to use for patients with enlarged prostate and elderly people. It is also known that there are patients who do not show efficacy with anticholinergic treatment. Based on the above, there are great 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いることから (非特許文献 4)、 EP1受容体拮抗剤は過活動膀胱に 伴う頻尿，尿意切迫感や尿失禁、膀胱炎、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。  Since it has been reported that administration of EP1 receptor antagonists to medullary injury model rats is useful in improving urinary function (Non-patent Document 4), EP1 receptor antagonists are frequently used in overactive bladder, It is thought to be useful as a therapeutic agent for lower urinary tract diseases such as urgency, urinary incontinence, cystitis, interstitial cystitis, and 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! In addition, since EP1 receptor antagonists have different mechanisms of action, they can be expected to avoid the side effects peculiar to anticholinergic drugs, and can also be expected to be effective in patients who do not show efficacy with anticholinergic treatment. In addition, this drug is expected to improve the subjective symptoms by acting on sensory nerves. it can. Furthermore, it has been reported that the effect of improving the pathological condition is exhibited without reducing the urination efficiency of rats with spinal cord injury (Non-patent Document 5), and it can be expected to 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)。  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).
[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 1)、 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有用であると考えられる。  [0006] Furthermore, EP1 receptor antagonists are known to have an inhibitory effect on colonic mucosal abnormal crypts and intestinal polyp formation (Patent Document 1). EP1 receptor antagonists are used for colon cancer, bladder cancer, It is considered useful as a therapeutic agent for prostate cancer and the like.
[0007] EP1受容体拮抗剤としては、以下の特許文献 2〜4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 2 to 4 have been reported.
特許文献 2には式 (A)で示される化合物が開示されて!ヽる。  Patent Document 2 discloses a compound represented by the formula (A)!
[化 1]  [Chemical 1]
Figure imgf000004_0001
Figure imgf000004_0001
(式中 Bは C5〜15の炭素環、または 1個または 2個の酸素、硫黄または窒素原子を有 する 5〜7員複素環を示す。他の記号は当該公報参照。 )  (In the formula, B represents a C5-15 carbocyclic ring, or a 5- to 7-membered heterocyclic ring having one or two oxygen, sulfur, or nitrogen atoms. For other symbols, refer to this publication.)
し力しながら、式 (A)の化合物の B環部分としては本発明化合物の特徴であるベン ゼン環が縮合した二環式へテロ環の開示はない。  However, there is no disclosure of a bicyclic heterocycle in which the benzene ring, which is a feature of the compound of the present invention, is condensed as the B ring portion of the compound of the formula (A).
特許文献 3には式 (B)で示される化合物が開示されている。 Patent Document 3 discloses a compound represented by the formula (B).
Figure imgf000005_0001
Figure imgf000005_0001
(式中、 R3及び R4は (1)メチルおよびメチル、（2)メチルおよびクロ口、（3)クロ口およびメ チル、（4)トリフルォロメチルおよび水素の組み合わせ、または R3および R4が結合して V、る炭素原子と一体となって (5)シクロペンテンまたは (6)ベンゼン環を示す。他の記号 は当該公報参照。 ) Wherein R 3 and R 4 are (1) methyl and methyl, (2) methyl and black mouth, (3) black mouth and methyl, (4) a combination of trifluoromethyl and hydrogen, or R 3 and R 4 is bonded to V and carbon atoms to form (5) cyclopentene or (6) a benzene ring.
し力しながら、式 (B)の化合物において R3および R4がベンゼン環と一体となって形 成する二環式環としては、本発明化合物の特徴である二環式へテロ環の開示はない However, as the bicyclic ring in which R 3 and R 4 are formed integrally with the benzene ring in the compound of the formula (B), the disclosure of the bicyclic hetero ring that characterizes the compound of the present invention is disclosed. No
[0009] 特許文献 4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!ヽる。 [0009] Patent Document 4 discloses a compound represented by the formula (C) including a wide range of compounds!
[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.)
式 (C)の化合物の Ar2で実際に合成されているのは置換フエニルのみであり本発明 化合物の特徴であるベンゼン環が縮合した二環式へテロ環の実施例はない。 Only the substituted phenyl is actually synthesized with Ar 2 of the compound of the formula (C), and there is no example of a bicyclic heterocycle having a condensed benzene ring, which is a feature of the compound of the present invention.
[0010] 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 [0010] 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, 97th Sakai, 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：国際公開第 00Z69465号パンフレット  Patent Document 1: International Publication No. 00Z69465 Pamphlet
特許文献 2：国際公開第 98Z27053号パンフレット  Patent Document 2: Pamphlet of International Publication No. 98Z27053
特許文献 3：国際公開第 02Z72564号パンフレット  Patent Document 3: Pamphlet of International Publication No. 02Z72564
特許文献 4 :国際公開第 00Z20371号パンフレット  Patent Document 4: Pamphlet of International Publication No. 00Z20371
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
[0011] 上述のように既存の抗コリン薬等の過活動膀胱に伴う頻尿'尿意切迫感や尿失禁、 膀胱炎、間質性膀胱炎、前立腺炎などの下部尿路疾患治療剤は有効性、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。 [0011] As described above, therapeutic agents for lower urinary tract diseases such as frequent urinary urinary urgency and urinary incontinence, cystitis, interstitial cystitis, prostatitis such as existing anticholinergic drugs are effective Therefore, there is an urgent need to provide a therapeutic agent for lower urinary tract disease that is superior in efficacy and safety, and is not satisfactory in terms of safety and safety.
課題を解決するための手段  Means for solving the problem
[0012] 上述のように、 EP1受容体拮抗剤は、ロ渴、尿閉等の副作用が少なく安全性の高い 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受容体拮抗活性を有 する化合物につき鋭意研究した。その結果、後記一般式 (I)で示される新規な二環 式へテロ環誘導体が強力な 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。  [0012] As described above, the 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 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 was found that a novel bicyclic heterocycle derivative represented by the following general formula (I) has a strong EP1 receptor antagonistic action, and the present invention was completed.
[0013] 即ち、本発明は、  [0013] That is, the present invention provides
[1]式 (I)で示される二環式へテロ環誘導体又はその製薬学的に許容される塩、 [1] A bicyclic heterocyclic derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000007_0001
Figure imgf000007_0001
[式中の記号は以下の意味を示す。 [The symbols in the formula have the following meanings.
A環：置換されて!、てもよ 、5〜8員へテロ環、  Ring A: Substituted! Maybe a 5- to 8-membered heterocycle,
B環：シクロアルキル、ベンゼン環、又はへテロ環、  Ring B: cycloalkyl, benzene ring, or hetero ring,
R1:置換されて 、てもよ 、低級アルキル、又はへテロ環基、 R 1 : substituted, optionally lower alkyl, or heterocyclic group,
R2:C アルキル、シクロアルキル、ァリール、ヘテロ環基、 -低級アルキレン-シクロアR 2 : C alkyl, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloa
1-12 1-12
ルキル、 -低級アルキレン-ァリール、又は-低級アルキレン-ヘテロ環基、 Alkyl, -lower alkylene-aryl, or -lower alkylene-heterocyclic group,
(ただし、 R2における C アルキル、シクロアルキル、ァリール、及びへテロ環基は置 (However, C alkyl, cycloalkyl, aryl, and heterocyclic groups in R 2 are not substituted.
1-12  1-12
換されていてもよい。 ) It may be replaced. )
R3:- OH、 - C(O)- OR°、 - C(O)- NR5R5a、 1H-テトラゾール- 5-ィル、又は 5-ォキソ -4,5- ジヒドロ- 1,2,4-ォキサジァゾール -3-ィル、 R 3: - OH, - C (O) - OR °, - C (O) - NR 5 R 5a, 1H- tetrazol - 5 I le, or 5 Okiso 4,5-dihydro - 1,2, 4-oxadiazol-3-yl,
R°、及び R°°:同一又は異なって、 H、又は低級アルキル、  R ° and R °°: the same or different, H or lower alkyl,
R5、及び R5a:同一又は異なって、 - R°、 -低級アルキレン- NR°R°°、 -低級アルキレン- C 0 R°、シクロアルキル、ァリール、ヘテロ環基、 -低級アルキレン-シクロアルキル、 -低R 5 and R 5a : the same or different, -R °, -lower alkylene-NR ° R °°, -lower alkylene-C 0 R °, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloalkyl -Low
2 2
級アルキレン-ァリール、 -低級アルキレン-ヘテロ環基、 -so -低級アルキル、 -so ≡ Secondary alkylene-aryl, -lower alkylene-heterocyclic group, -so -lower alkyl, -so ≡
2 2 低級アルキレン- 0R°、又は- SO≡低級アルキレン- 0- C(0)-低級アルキル、  2 2 lower alkylene-0R °, or-SO≡lower alkylene-0-C (0) -lower alkyl,
2  2
(ただし、 R5、 R5aにおけるシクロアルキル、ァリール、及びへテロ環基は置換されてい てちよい。 ) (However, the cycloalkyl, aryl, and heterocyclic groups in R 5 and R 5a may be substituted.)
R4:ノヽロゲン、低級アルキル、ハロゲノ低級アルキル、シァ入ニトロ、 - 0R°、 - 0-ハロ ゲノ低級アルキル、 -C(0)R°、又は- NR°C(0)R°°、 R 4 : nanogen, lower alkyl, halogeno lower alkyl, nitro-nitro, -0R °, -0-halogeno lower alkyl, -C (0) R °, or -NR ° C (0) R °°,
m : 0、 1、又は 2、 m: 0, 1, or 2,
(ただし、 mが 2である場合、 2つの R4は同一又は互いに異なっていてもよい。 ) J：低級アルキレン、低級ァルケ-レン、 -0-低級アルキレン-、 -低級アルキレン- 0-、 -0-低級ァルケ-レン-、 -低級ァルケ-レン- 0-、 - C(0)NR°-、又は- NR°C(0)-、 X:単結合、低級アルキレン、低級ァルケ-レン、 -0-低級アルキレン-、 -0-低級アル ケ-レン-、 - NR°-低級アルキレン-、 -S(O) -低級アルキレン-、又は- S(O) -低級アル ケニレン-、 (However, when m is 2, two R 4 s may be the same or different from each other.) J: lower alkylene, lower alkylene, -0-lower alkylene-, -lower alkylene-0-,- 0-lower alkylene, -lower alkylene-0-, -C (0) NR °-, or -NR ° C (0)-, X: single bond, lower alkylene, lower alkylene, -0-lower alkylene-, -0-lower alkylene-, -NR ° -lower alkylene-, -S (O) -lower alkylene-, or- S (O) -lower alkenylene-,
n: 0、 1、又は 2。 n: 0, 1, or 2.
L:単結合、 - C(O)-、又は- S(O) -。以下同様。 ]  L: single bond, -C (O)-, or -S (O)-. The same applies below. ]
2  2
[2] Jが- 0-低級アルキレン-である [1]記載の化合物、  [2] The compound according to [1], wherein J is -0-lower alkylene-;
[3] Xが単結合、低級アルキレン、又は低級ァルケ-レンである [2]記載の化合物、 [4] B環がベンゼン、チォフェン、チアゾール、又はピリジンである [3]記載の化合物、 [5] A環がフラン、 2, 3-ジヒドロフラン、 2,3-ジヒドロチォフェン、 2,3-ジヒドロチォフェン 1,1-ジォキシド、ピロリン、 3,4-ジヒドロ- 2H-ピラン、 1,3-ジォキノール、又は 2,3-ジヒ ドロ- 1,4-ジォキシンである [4]記載の化合物、  [3] The compound according to [2], wherein X is a single bond, lower alkylene, or lower alkylene; [4] the compound according to [3], wherein the B ring is benzene, thiophene, thiazole, or pyridine; ] Ring A is furan, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3-dihydrothiophene 1,1-dioxide, pyrroline, 3,4-dihydro-2H-pyran, 1,3- The compound according to [4], which is diquinol or 2,3-dihydro-1,4-dioxin,
[6] Lが- S(O) -である [5]記載の化合物、 [6] The compound according to [5], wherein L is -S (O)-,
2  2
[7] R2が置換されていてもよいァリール、又は置換されていてもよいへテロ環基である [6]記載の化合物、 [7] The compound according to [6], wherein R 2 is an optionally substituted aryl, or an optionally substituted heterocyclic group,
[8] R3が- CO H、又は 5-ォキソ -4,5-ジヒドロ- 1,2,4-ォキサジァゾール -3-ィルである [ [8] R 3 is —CO 2 H or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl [
2  2
7]記載の化合物、  7] the compound according to the above,
[9]式 (I-A)で示される二環式へテロ環誘導体又はその製薬学的に許容される塩、 [化 5]  [9] A bicyclic heterocyclic derivative represented by the formula (I-A) or a pharmaceutically acceptable salt thereof, [Chemical Formula 5]
R4A R4A
Figure imgf000008_0001
Figure imgf000008_0001
[式中の記号は以下の意味を示す。 [The symbols in the formula have the following meanings.
A1環：低級アルキルで置換されて!、てもよ 、2,3-ジヒドロフラン、 2,3-ジヒドロチォフエ ン、又は 2,3-ジヒドロチォフェン 1,1-ジォキシド、 A 1 ring: substituted with lower alkyl! May be 2,3-dihydrofuran, 2,3-dihydrothiophene, or 2,3-dihydrothiophene 1,1-dioxide,
B1環：ベンゼン環、又はチォフェン環、 R1A: (1)- OH、（2)ハロゲン、（3)低級アルキル、 -O-低級アルキル、又はハロゲンで置 換さ B 1 ring: benzene ring or thiophene ring, R 1A : (1) -OH, (2) halogen, (3) lower alkyl, -O-lower alkyl, or halogen substituted
れて 、てもよ 、ピリジルカもなる群力も選択される基で置換されて 、てもよ 、低級 アルキル、 Also, the pyridylca group force may be substituted with a selected group, which may be a lower alkyl,
R2A: (1)ハロゲン、（2)低級アルキル、（3)- 0-低級アルキル力もなる群力も選択される基 で R 2A : (1) halogen, (2) lower alkyl, (3) 0-lower alkyl group power is also selected
置換されていてもよいフエ-ル、フリル、又はチアゾリル、 Optionally substituted phenol, furyl, or thiazolyl,
R3A:-CO H、又は 5-ォキソ -4,5-ジヒドロ- 1,2,4-ォキサジァゾール -3-ィル、 R 3A : -CO H, or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
2  2
R4A: H、ハロゲン、低級アルキル、又は- 0-低級アルキル。 ] R 4A : H, halogen, lower alkyl, or -0-lower alkyl. ]
[10] 4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾ フラン- 6-ィル)ォキシ]メチル }安息香酸、  [10] 4- {[(5- {isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4-{[(5-{イソブチル [(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 口- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、  4-{[(5- {Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl }benzoic acid,
4- {[(5- {[(2S)- 3-ヒドロキシ- 2-メチルプロピル] [(5-メチル -2-フリル)スルホニル]アミノト 4- {[(5- {[(2S) -3-Hydroxy-2-methylpropyl] [(5-methyl-2-furyl) sulfonyl] aminoto
2, 3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4- {[(6- {[(2R)- 3-ヒドロキシ- 2-メチルプロピル] [(5-メチル -2-フリル)スルホニル]ァミノ)- 4- {[(6- {[(2R)-3-Hydroxy-2-methylpropyl] [(5-methyl-2-furyl) sulfonyl] amino)-
2, 3-ジヒドロ- 1-ベンゾフラン- 5-ィル)ォキシ]メチル }安息香酸、 2,3-dihydro-1-benzofuran-5-yl) oxy] methyl} benzoic acid,
4- {[(5- {(2-フルォロプロピル) [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1- ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、  4- {[(5- {(2-fluoropropyl) [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4- [({6- [[(3-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 -1-ベンゾフラン- 5-ィル }ォキシ)メチル]安息香酸、  4-[({6- [[(3-Fluorophenyl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzofuran-5-yl} oxy) methyl] benzoic acid Acid,
4-[({6-[[(3,5-ジフルオロフェ -ル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -2,3-ジヒ ドロ- 1-ベンゾフラン- 5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[[(3,5-Difluorophenyl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzofuran-5-yl} oxy ) Methyl] benzoic acid,
N-イソブチル -5-メチル - N- (6-{[4-(5-ォキソ - 4,5-ジヒドロ- 1,2,4-ォキサジァゾ一ル- N-isobutyl-5-methyl-N- (6-{[4- (5-oxo- 4,5-dihydro-1,2,4-oxadiazole-
3-ィル)ベンジル]ォキシ }-2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル)フラン- 2-スルホンアミ ド、 3-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-5-yl) furan-2-sulfonamide,
4- {[(6-{イソブチル [(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 口- 1-ベンゾフラン- 5-ィル)ォキシ]メチル }安息香酸、 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- 1-ベンゾフラン- 5-ィル }ォキシ)メチル]安息香酸、 4- {[(6- {Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto-2,3-dihydric 1-benzofuran-5-yl) oxy] methyl }benzoic acid, 4-[({6-[[(4-Methyl-1,3-thiazol-2-yl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzofuran-5 -Yl} oxy) methyl] benzoic acid,
5- {[(5-{イソブチル [(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラ ン -6-ィル)ォキシ]メチル }チォフェン- 2-カルボン酸、  5- {[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} thiophene-2- carboxylic acid,
3-クロ口- 4-{[(5-{イソブチル [(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル]アミノト 2, 3-black mouth 4-{[(5- {isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,
3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、 3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾチェ ン -6-ィル)ォキシ]メチル }安息香酸、  4- {[(5- {isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzochen-6-yl) oxy] methyl} benzoic acid,
5- {[(5-{イソブチル [(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 口- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }チォフェン- 2-カルボン酸、  5- {[(5- {Isobutyl [(4-Methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl } Thiophene-2-carboxylic acid,
4-[({5-[[(5-メチル - 2-フリル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -2,3-ジヒドロ- 1-ベンゾチェン- 6-ィル }ォキシ)メチル]安息香酸、 4-[({5-[[(5-Methyl-2-furyl) sulfoyl] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzochen-6-yl} oxy) methyl ]benzoic acid,
及び as well as
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノ}- 1,1-ジォキシド- 2,3-ジヒド 口- 1-ベンゾチェン- 6-ィル)ォキシ]メチル }安息香酸、  4- {[(5- {Isobutyl [(5-methyl-2-furyl) sulfoyl] amino}-1,1-dioxide-2,3-dihydrin 1-benzochen-6-yl) oxy] Methyl} benzoic acid,
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、 Group power selected as described in [1] or a pharmaceutically acceptable salt thereof,
[11] [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 [1] 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、膀胱炎、間質性膀胱炎、前立腺炎からなる下 部尿路疾患の治療薬である [12]記載の医薬組成物、  [13] A pharmaceutical composition according to [12], which is a therapeutic agent for lower urinary tract disease comprising frequent urination, urinary incontinence, cystitis, interstitial cystitis, prostatitis associated with overactive bladder,
[14] EP1受容体拮抗剤、過活動膀胱に伴う頻尿，尿失禁、膀胱炎、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、  [14] As described in [1] for producing a therapeutic agent for lower urinary tract disease consisting of EP1 receptor antagonist, frequent urination with overactive bladder, urinary incontinence, cystitis, interstitial cystitis, prostatitis Use of compounds,
[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、膀胱炎、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] Lower urinary tract consisting of frequent urination with urinary bladder, urinary incontinence, cystitis, interstitial cystitis, prostatitis, comprising administering to a patient a therapeutically effective amount of the compound according to [1] How to treat the disease,
に関する。 About.
発明の効果 The invention's effect
本発明化合物 (I)の有用性は以下の試験により確認した。 (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 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 The usefulness of the compound (I) of the present invention was confirmed by the following test. (1) Measurement of receptor antagonistic activity using EP1 receptor-expressing cells Experiments with HEK293 cells (American Type Culture Collection) stably expressing rat EP1 receptor Dispense into 96-well poly-D-lysine-coated plates (trade name: Biocoat PDL96W Black / Clear, Nippon Betaton Dickinson) so that 2 x 10 4 cells / well the day before Medium containing 10% urinary fetal serum (FBS) at 37 ° C under 5% carbon dioxide (CO 2) (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 Rogen), overnight culture. 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 changes 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.
その結果、本発明化合物は強力な EP1受容体拮抗活性を示した。代表化合物の試 験結果を下記表 1に示す。また、 Exは後記実施例化合物番号を示す。  As a result, the compound of the present invention showed a strong EP1 receptor antagonistic activity. Table 1 shows the test results of the representative compounds. Ex represents an Example compound number described later.
[表 1] [table 1]
Ex ICs(nM) Ex IC s (nM)
1 2.5  1 2.5
28 3.6  28 3.6
79 3.1  79 3.1
93 1 1 (2) EP1受容体発現細胞を用いた受容体結合実験 93 1 1 (2) Receptor binding experiments using EP1 receptor-expressing cells
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。このラット EP1発現ベクター 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 、て HEK293EBNA細胞（アメリカン'タイプ ·カルチャ^ ~ ·コレクシヨン社 (American T ype Culture Collection) )にトランスフエクシヨンした後、 37°C、 5% CO下にて、 10% FB  The rat EP1 receptor was introduced into the expression vector (trade name: pCEP4, Invitrogen) after introducing a signal peptide (MKTIIALSYIFCLVFA: SEQ ID NO: 1) and a FLAG sequence (DYKDDDDK: SEQ ID NO: 2) at the N-terminus. . This rat EP1 expression vector was transformed into HEK293EBNA cells (American's type culture ^ ~ · American Type Culture) using transfection reagent (trade name: Fugene-6, Roche Diagnostics). Collection)), then 10% FB at 37 ° C, 5% CO
2  2
Sを含む培地（商品名： DMEM、インビトロジヱン社）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 pH 7.5、 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 S (trade name: DMEM, Invitrogene) 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 ultracentrifuged (23,000 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 ィ匕マグネシウム（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 salt 匕 magnesium (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。 その結果、本発明化合物は強力な EP1受容体結合活性を示した。代表化合物の試 験結果を下記表 2に示す。 In the formula, [C] represents the 3 H-PGE concentration used in the reaction system. As a result, the compound of the present invention showed strong EP1 receptor binding activity. The test results of representative compounds are shown in Table 2 below.
[表 2] [Table 2]
Figure imgf000013_0001
(3)酢酸誘発頻尿ラットに対する化合物の作用
Figure imgf000013_0001
(3) 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 nerves. (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、被検薬を投与し、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。  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. The experiment was conducted two days later. Rats were placed in metabolic cages and acclimated for 1 hour, then the test drug 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.
その結果、酢酸膀胱内処置群にお!、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。  As a result, the effective bladder capacity decreased in the acetic acid intravesical treatment group compared to the sham-operated group, resulting in frequent urination. On the other hand, the compound of the present invention improved the frequent urination state well.
以上の試験（1)〜（3)の結果より、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できた。  From the results of the above tests (1) to (3), it was confirmed that the compound of the present invention has a strong EP1 receptor antagonistic action and satisfactorily improves frequent urination.
また、本発明化合物は薬物相互作用の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 、性質を有する。 In addition, the compound of the present invention has excellent metabolic stability with few concerns about drug interaction, etc. It is preferred as a medicine and has properties.
従って、本発明化合物は副作用の懸念が少ない過活動膀胱に伴う頻尿，尿失禁、 膀胱炎、間質性膀胱炎、前立腺炎力 なる下部尿路疾患の治療薬として期待される 発明を実施するための最良の形態  Therefore, the compound of the present invention is expected as a therapeutic agent for lower urinary tract diseases such as frequent urination, urinary incontinence, cystitis, interstitial cystitis, prostatitis power associated with overactive bladder with less side effects. Best form for
[0019] 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個の直鎖又は分枝状 の炭化水素鎖を意味する。  In the present specification, the term “lower” means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms unless otherwise specified.
[0020] 「低級アルキル」とは、 C のアルキルを意味する。具体的には、メチル、ェチル、ノ [0020] "Lower alkyl" means C alkyl. Specifically, methyl, ethyl,
1-6  1-6
ルマルプロピル、イソプロピル、ノルマルブチル、イソブチル、 sec-ブチル、 tert-ブチ ル、ノルマルペンチル、ノルマルへキシル等が挙げられる。好ましくはメチル、ェチル 、ノルマルプロピル、イソプロピル、ノルマルブチル、イソブチル、 sec-ブチル、 tert-ブ チルである。  Examples include normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl, tert-butyl, normal pentyl, normal hexyl and the like. Preferred are methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, sec-butyl and tert-butyl.
「低級ァルケ-ル」とは、 C のァルケ-ルを意味する。二重結合は任意の位置でよ  “Lower ark” means a C alkell. Double bond can be at any position
2-6  2-6
くまた、複数の二重結合を有していてもよい。具体的には例えば、ェテニル、プロべ -ル、ブテュル、ペンテ-ル、へキセ -ル、ブタジェ-ル等が挙げられる。好ましくは 、ェテュル、 1 -プロべ-ル、 2-プロぺ-ルである。  Further, it may have a plurality of double bonds. Specific examples include ethenyl, probe, butyr, pentale, hexyl, butagel and the like. Preferred are etule, 1-probe, and 2-probe.
[0021] 「低級アルキレン」とは、 C のアルキルの任意の位置の水素を 1個除去してなる 2 “Lower alkylene” is formed by removing one hydrogen at any position of alkyl of C 2
1-6  1-6
価基を意味する。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、 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、プロピレンである。  Means a valent group. Specific examples include methylene, ethylene, methylmethylene, dimethylmethylene, propylene and the like. Preferred are methylene, ethylene and propylene.
「低級ァルケ-レン」とは、 C のァルケ-ルの任意の位置の水素を 1個除去してな  “Lower alkylene” refers to the removal of one hydrogen atom at any position of the C alkenyl.
2-6  2-6
る 2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- レン等が挙げられる。好ましくはビ-レンである。  Means a divalent group. Specific examples include beylene, probelene, 1-butylene, 2-butylene. Biylene is preferred.
「シクロアルキル」とは、 C の非芳香族の炭化水素環を意味し、架橋環ゃスピロ環  “Cycloalkyl” means a non-aromatic hydrocarbon ring of C, and the bridged ring is a spiro ring.
3-15  3-15
を形成していてもよぐまた部分的に不飽和結合を有していてもよい。具体的には、シ クロプロピノレ、シクロブチノレ、シクロペンチノレ、シクロへキシノレ、シクロへプチノレ、シクロ ォクチル、シクロへキセニル、シクロオクタンジェ -ル、ァダマンチル及びノルボル- ル等が挙げられる。好ましくはシクロブチル、シクロペンチル若しくはシクロへキシル である。 May be formed or may have a partially unsaturated bond. Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexenole, cycloheptinole, cyclooctyl, cyclohexenyl, cyclooctanegel, adamantyl and norbol. Preferably cyclobutyl, cyclopentyl or cyclohexyl It is.
[0022] 「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 同一または互いに異なって前記「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 one or more arbitrary hydrogen atoms of the “lower alkyl” which are the same or different from each other and substituted with the “halogen”. Specific examples include trifluoromethyl, pentafluoroethyl and the like. Preferred is trifluoromethyl.
「ァリール」とは、単環〜 3環式の C の芳香族の炭化水素環基を意味し、具体的に  “Aryl” means a monocyclic to tricyclic C aromatic hydrocarbon ring group, specifically
6-14  6-14
は例えば、フエ-ル、ナフチル等が挙げられる。好ましくはフエ-ルである。また、 C  For example, there can be mentioned a film, naphthyl and the like. A ferrule is preferred. C
5-8 のシクロアルキル環が縮環していてもよぐ例えば、インダニル、テトラヒドロナフチル を形成していてもよい。  The 5-8 cycloalkyl ring may be condensed. For example, indanyl or tetrahydronaphthyl may be formed.
[0023] 「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、 又は不飽和の 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が酸化されて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。単環式へテロ環基とし ては具体的には、ピリジル、ピリダジ -ル、ピリミジニル、ピラジ -ル、トリアジニル、フリ ル、ジヒドロフリル、チェニル、ジヒドロチェニル、ピロリノレ、ピロリニル、ォキサゾリノレ、 イソキサゾリル、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、イミダゾリニル、イミダゾリジニル、ピラゾリル、ビラゾリニル、ビラゾリジニル、トリ ァゾリル、テトラゾリル、ピロリジニル、ピペリジル、ピぺラジュル、モルホリニル、ォキセ タ -ル、テトラヒドロフリル、テトラヒドロチェ-ル、テトラヒドロビラ-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、インドリ-ル、ベンゾフラ -ル、ジ ヒドロべンゾフラ-ノレ、ベンゾチェ-ノレ、ジヒドロべンゾチェ-ノレ、インダゾリノレ、ベンゾ ォキサゾリル、ベンゾイミダゾリル、ベンゾチアゾリル、キノリル、イソキノリル、キナゾリ -ル、キノキサリニル、フタラジニル、シンノリニル等が挙げられる。三環式へテロ環基 としては具体的には、カルバゾリル、アタリジニル等が挙げられる。好ましくは、ピリジ ル、フリル、ジヒドロフリル、チェニル、ジヒドロチェニル、チアゾリル、ォキセタニル、テ トラヒドロフリル、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、ベンゾフラ二 ル、ジヒドロベンゾフラニル、ベンゾチェニル、ジヒドロべンゾチェニル、インドリニル等 が挙げられる。 [0023] "Heterocyclic group" means a saturated or unsaturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from 0, S and N forces, and 8 to 14 It means a membered bicyclic heterocyclic group or an 11-20 membered tricyclic heterocyclic group. The ring atom S or N may be oxidized to form an oxide or a bridged ring or a spiro ring. Specific examples of the monocyclic heterocyclic group include pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, triazinyl, furyl, dihydrofuryl, chenyl, dihydrochenyl, pyrrolinole, pyrrolinyl, oxazolinole, isoxazolyl, oxadiazolyl , Thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, virazolinyl, virazolidinyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidyl, piperazil, morpholinyl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl -Le. Specific examples of the bicyclic heterocyclic group include indolyl, indolyl, benzofuran, dihydrobenzofuranore, benzocenore, dihydrobenzocenore, indazolinole, benzoxazolyl, benzoimidazolyl, benzothiazolyl, Examples include quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, cinnolinyl and the like. Specific examples of the tricyclic heterocyclic group include carbazolyl and attalidinyl. Preferably, pyridyl, furyl, dihydrofuryl, chenyl, dihydrochenyl, thiazolyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, benzofurani , Dihydrobenzofuranyl, benzocenyl, dihydrobenzozenyl, indolinyl and the like.
[0024] 「ヘテロ環」とは、上記の「ヘテロ環基」を環として表したものを意味し、例えば、へテ 口環基であるピリジル、チェニル、ジヒドロフリル及びピロリニルはそれぞれピリジン、 チォフェン、ジヒドロフラン及びピロリン（2,3-ジヒドロ- 1H-ピロール)に相当する。ただ し、上記の「ヘテロ環基」はすべて、便宜上一価基として記載してある力 構造によつ ては二価基以上の多価基である場合がある。本発明はそれらの構造を包含するもの である。二価基の具体的な態様としては、有機化合物命名法に従って上記の「へテ 口環基」の接尾辞をジィルに変換したものが対応する。  [0024] "Heterocycle" means the above "heterocyclic group" as a ring. For example, the heterocyclic groups pyridyl, chenyl, dihydrofuryl and pyrrolinyl are pyridine, thiophene, Corresponds to dihydrofuran and pyrroline (2,3-dihydro-1H-pyrrole). However, all of the above “heterocyclic groups” may be divalent or higher polyvalent groups depending on the force structure described as a monovalent group for convenience. The present invention includes those structures. Specific embodiments of the divalent group correspond to those obtained by converting the above-mentioned “heterocyclic group” suffix into a dil according to the organic compound nomenclature.
[0025] 「置換されていてもよい」とは、「置換されていない」又は「同一又は異なる 1〜5個の 置換基で置換された」ことを意味する。  The term “which may be substituted” means “not substituted” or “substituted with 1 to 5 substituents which are the same or different”.
[0026] 本明細書にぉ 、て、「置換されて 、てもよ 、」の語の許容される置換基としては、そ れぞれの基の置換基として、当該技術分野で通常用いられる置換基であれば 、ず れでもよい。また、それぞれの基に同一又は異なった置換基カ^つ以上存在していて ちょい。  In the present specification, the permissible substituent of the word “substituted or may be used” is usually used in the art as a substituent of each group. Any substituent may be used. In addition, each group may have at least one identical or different substituent.
A環の「置換されていてもよい 5〜8員へテロ環」における置換基として好ましくは、ハ ロゲン、低級アルキル、ハロゲノ低級アルキル、ォキソ（ = 0)、 - C(0)R°、 - OR。又は- 0-ハロゲノ低級アルキルである。  The substituent in the “optionally substituted 5- to 8-membered hetero ring” of the A ring is preferably halogen, lower alkyl, halogeno lower alkyl, oxo (= 0), −C (0) R °, − OR. Or -0-halogeno lower alkyl.
R1の「置換されて 、てもよ 、低級アルキル」における置換基として好ましくは、以下 の G群力 選択される基である。 The substituent in the “substituted or lower alkyl” of R 1 is preferably a group selected from the following G group forces.
G群：ノヽロゲン、 - OR°、 -0-ハロゲノ低級アルキル、 - 0- SiR°R°° (ァリール)、ォキソ（= 0)、 - NR°R°°、 - C(0)R°、 -CO R°、 - NR°C(0)R°°、 - C(0)NR°R°°、シクロアルキル、ァリ  Group G: neurogen, -OR °, -0-halogeno lower alkyl, -0- SiR ° R °° (Areel), oxo (= 0), -NR ° R °°, -C (0) R °, -CO R °, -NR ° C (0) R °°, -C (0) NR ° R °°, cycloalkyl, aryl
2  2
ール及びへテロ環基。ただし、 G群におけるシクロアルキル、ァリール及びへテロ環 基はハロゲン、低級アルキル、ハロゲノ低級アルキル、 - OR°又は- 0-ノヽロゲノ低級ァ ルキルで置換されて!、てもよ!/、。  And heterocyclic groups. However, the cycloalkyl, aryl, and heterocyclic groups in Group G may be substituted with halogen, lower alkyl, halogeno lower alkyl, -OR ° or -0-norogeno lower alkyl!
R2における置換されて 、てもよ 、「C アルキル」における置換基として好ましくは、 Substituted in R 2 may preferably be a substituent in “C alkyl”.
1-12  1-12
ハロゲン、 -OR0, - NR°R°°、 -CO R。又は- C(0)NR°R。。である。 Halogen, -OR 0 , -NR ° R °°, -CO R. Or -C (0) NR ° R. . It is.
2  2
R2におけるそれぞれ置換されて!/、てもよ!/、「シクロアルキル」、「ァリール」及び「へテ 口環基」における置換基として好ましくは、以下の P群から選択される基である。 Each substituted in R 2 ! /, May! /, “Cycloalkyl”, “aryl” and “het The substituent in the “ring group” is preferably a group selected from the following group P.
p群:ノヽロゲン、 -OR0, - 0- SiR°R°° (ァリール)、 - NR°R°°、 -CO R。及び- C(0)NR°R。。から p group: neurogen, -OR 0 ,-0- SiR ° R °° (Areel), -NR ° R °°, -CO R. And -C (0) NR ° R. . From
2  2
なる群より選択される基で置換されていてもよい低級アルキル、ハロゲン、シァ入 -ト 口、 - OR°、 -0-ハロゲノ低級アルキル、 - C(0)R°、 -CO R°、 - NR°C(0)R°°、 - C(0)NR°R°  Lower alkyl optionally substituted by a group selected from the group consisting of halogen, sirene-to, -OR °, -0-halogeno lower alkyl, -C (0) R °, -CO R °,- NR ° C (0) R °°,-C (0) NR ° R °
2  2
0  0
R5、 R5aにおけるそれぞれ置換されて!、てもよ!/、「シクロアルキル」、「ァリール」及び「 ヘテロ環基」における置換基として好ましくは、ハロゲン、低級アルキル、ハロゲノ低 級アルキル、 -OR°または- 0-ハロゲノ低級アルキルである。 Substituted in R 5 and R 5a !, May ! /, As a substituent in “cycloalkyl”, “aryl” and “heterocyclic group”, preferably halogen, lower alkyl, halogeno lower alkyl, − OR ° or -0-halogeno lower alkyl.
[0027] 本発明における好ま 、態様を以下に示す。 [0027] Preferred embodiments in the present invention are described below.
A環として好ましくは、フラン、 2,3-ジヒドロフラン、 2, 3-ジヒドロチォフェン、 2,3-ジヒド ロチォフェン 1,1-ジォキシド、ピロリン、 3,4-ジヒドロ- 2H-ピラン、 1,3-ジォキソール又 は 2,3-ジヒドロ- 1,4-ジォキシンであって、それぞれ縮環して!/、るベンゼン環と一体と なって、ベンゾフラン、 2, 3-ジヒドロ- 1-ベンゾフラン、 2,3-ジヒドロ- 1-ベンゾチォフェン 、 2,3-ジヒドロ- 1-ベンゾチォフェン 1,1-ジォキシド、インドリン、クロマン、 1,3-ベンゾ ジォキソール又は 2,3-ジヒドロ- 1,4-ベンゾジォキシンを形成する環である。より好まし くは、フラン、 2,3-ジヒドロフラン、 2,3-ジヒドロチォフェン、 2,3-ジヒドロチォフェン 1,1 -ジォキシド又はピロリンであり、更に好ましくは、 2,3-ジヒドロフラン、 2,3-ジヒドロチォ フェン又は 2, 3-ジヒドロチォフェン 1,1-ジォキシドである。  A ring is preferably furan, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3-dihydrothiophene 1,1-dioxide, pyrroline, 3,4-dihydro-2H-pyran, 1,3 -Dioxol or 2,3-dihydro-1,4-dioxin, which are fused together! /, Together with the benzene ring, benzofuran, 2,3-dihydro-1-benzofuran, 2, In the ring to form 3-dihydro-1-benzothiophene, 2,3-dihydro-1-benzothiophene 1,1-dioxide, indoline, chroman, 1,3-benzodioxol or 2,3-dihydro-1,4-benzodioxin is there. More preferably, it is furan, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3-dihydrothiophene 1,1-dioxide or pyrroline, and more preferably 2,3-dihydrofuran. 2,3-dihydrothiophene or 2,3-dihydrothiophene 1,1-dioxide.
B環として好ましくは、ベンゼン、チォフェン、ピリジン又はチアゾールであり、より好 ましくは、ベンゼン、チォフェン又はチアゾールであり、更に好ましくは、ベンゼン又は チォフェンである。  The ring B is preferably benzene, thiophene, pyridine or thiazole, more preferably benzene, thiophene or thiazole, and still more preferably benzene or thiophene.
[0028] R1として好ましくは、ハロゲン、 -OR0,シクロアルキル、ァリール又はへテロ環基で置 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、ハロゲン、 - OR°又はへテロ 環基で置換されていてもよい低級アルキルであり、更に好ましくは、イソブチル、 2-フ ルォロプロピル、 3-ヒドロキシ -2-メチルプロピル又は（ピリジン- 2-ィル)メチルである。 [0028] R 1 is preferably halogen, -OR 0 , cycloalkyl, aryl, or lower alkyl optionally substituted with a heterocyclic group, and more preferably halogen, -OR °, or heterocyclic. Lower alkyl which may be substituted with a group, more preferably isobutyl, 2-fluoropropyl, 3-hydroxy-2-methylpropyl or (pyridin-2-yl) methyl.
R2として好ましくは、それぞれ置換されて 、てもよ 、ァリール又はへテロ環基であり、 より好ましくは、それぞれ同一又は異なる 1個以上の低級アルキル、 -0-低級アルキ ル又はハロゲンで置換されたァリール又はへテロ環基であり、更に好ましくは、それ ぞれ同一又は異なる 1個以上の低級アルキル又はハロゲンで置換されたフエ-ル、 ピリジル、フリル又はチアゾリルである。 R 2 is preferably each independently substituted or unsubstituted or more preferably a heterocyclic group, and more preferably one or more lower alkyl, -0-lower alkyl or halogen each being the same or different. A aryl group or a heterocyclic group, more preferably Each is the same or different phenyl, pyridyl, furyl or thiazolyl substituted with one or more lower alkyl or halogen.
R3として好ましくは、 - C(0)-OR°、 1H-テトラゾール -5-ィル又は 5-ォキソ -4,5-ジヒド 口- 1,2,4-ォキサジァゾール -3-ィルであり、より好ましくは、 -CO H又は 5-ォキソ -4,5-R 3 is preferably -C (0) -OR °, 1H-tetrazol-5-yl or 5-oxo-4,5-dihydride-1,2,4-oxadiazol-3-yl, More preferably, -CO H or 5-oxo-4,5-
2 2
ジヒドロ- 1,2,4-ォキサジァゾール -3-ィルである。  Dihydro-1,2,4-oxadiazol-3-yl.
R4として好ましくは、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 キル又は- 0-ノヽロゲノ低級アルキルであり、より好ましくはハロゲン又は低級アルキル である。 R 4 is preferably halogen, lower alkyl, halogeno lower alkyl, -0-lower alkyl, or -0-nitrogeno lower alkyl, and more preferably halogen or lower alkyl.
[0029] mとして好ましくは、 0又は 1である。  [0029] Preferably, m is 0 or 1.
Xとして好ましくは、単結合、低級アルキレン、低級ァルケ-レン又は- 0-低級アル キレン-であり、より好ましくは、単結合又は低級ァルケ-レンであり、更に好ましくは、 単結合である。  X is preferably a single bond, lower alkylene, lower alkylene, or 0-lower alkylene-, more preferably a single bond or lower alkylene, and still more preferably a single bond.
J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。 Lとして好ましくは、 - S(O) -である。  J is preferably -0-lower alkylene-, more preferably -0-methylene-. L is preferably -S (O)-.
2  2
本発明の特に好ま 、態様としては、上記に記載の各好ま 、基の組み合わせか らなる化合物である。  A particularly preferred embodiment of the present invention is a compound comprising a combination of each preferred group described above.
[0030] 本発明化合物は置換基の種類によっては幾何異性体や互変異性体が存在する場 合があるが、本発明にはこれらの異性体の分離したもの、あるいは混合物が包含され る。  The compound of the present invention may have a geometric isomer or a tautomer depending on the kind of the substituent, but the present invention includes a separated or a mixture of these isomers.
また、本発明化合物は不斉炭素原子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, the compound of the present invention may have an asymmetric carbon atom, and optical isomers such as (R) isomer and (S) isomer based on this may exist. The present invention includes all of these optical isomers and isolated ones.
[0031] 更に、本発明化合物には、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、加溶媒分解によりまたは生理学的条件下で本発明 の NH、 OH、 CO H等に変換できる基を有する化合物である。プロドラッグを形成する[0031] Furthermore, the compounds of the present invention include pharmacologically acceptable prodrugs. A pharmacologically acceptable prodrug is a compound having a group that can be converted to NH, OH, COH or the like of the present invention by solvolysis or under physiological conditions. Form a prodrug
2 2 twenty two
基としては、「プログレス'イン'メディシン（Progress in Medicine)」、ライフサイエンス' メデイカ社、 1985年、 5卷、 P.2157-2161や「医薬品の開発 (第 7卷)分子設計」、廣川 書店、 1990年、 p.163-198に記載の基が挙げられる。 [0032] 本発明化合物は、酸付加塩または置換基の種類によっては塩基との塩を形成する 場合もある。力かる塩としては、製薬学的に許容される塩であり、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、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、マイレン酸、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、ァスパラギン酸、グルタミン酸等の有機 酸との酸付加塩、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、リジン、オル-チン等の有機 塩基との塩やアンモニゥム塩等が挙げられる。 Based on "Progress in Medicine", Life Science Medica, 1985, May 5, P.2157-2161 and "Development of Drugs (Part 7) Molecular Design", Yodogawa Shoten 1990, pages 163-198. The compound of the present invention may form a salt with a base depending on the type of acid addition salt or substituent. Examples of strong salts are pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propion. Acid addition salts with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid Inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortin, and ammonium salts.
さらに、本発明は、化合物 (I)及びその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。  Furthermore, the present invention includes various hydrates and solvates of the compound (I) and salts thereof, and crystalline polymorphic substances.
[0033] (製造法）  [0033] (Production method)
本発明化合物 (I)及びその製薬学的に許容される塩は、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 適当な保護基で保護、又は当該官能基に容易に転ィヒ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 (T. W. Greene )及びウッツ（P. G. M. Wuts)著、「プロテクティブ'グループス'イン'オーガニック'シ ンセシス（Protective Groups in Organic Synthesis)」、（米国）、第 3版、ジョン'ウイレイ •アンド ·サンズ (John Wiley & Sons)社、 1999年に記載の保護基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、あるいは所望の基に 転化することにより、所望の化合物を得ることができる。  The compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. At that time, depending on the type of functional group, it is possible to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or replace it with a group that can be easily transferred to the functional group. May be effective. Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups, and examples of protective groups for these functional groups include “Protective”, “Groups”, “In” and “Organic” by TW Greene and PGM Wuts. 'Protective Groups in Organic Synthesis', (USA), 3rd edition, John' Wiley & Sons, Inc. What is necessary is just to select suitably according to reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
[0034] 以下に本発明化合物の代表的な製造法を説明する。 [0034] A typical production method of the compound of the present invention will be described below.
(製法 1)  (Manufacturing method 1)
[化 6]
Figure imgf000020_0001
[Chemical 6]
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0002
(式中、 Lvは脱離基を意味する。以下同様。また、 Rla及び R2aは後述する還元的ァミノ 化反応によりそれぞれ R1及び R2に変換される基を示す。） (In the formula, Lv represents a leaving group. The same applies hereinafter. R la and R 2a represent groups that are converted into R 1 and R 2 , respectively, by the reductive amination reaction described later.)
第一工程 First step
第一工程はアルキルィ匕によりィ匕合物 (II)より化合物 (V)を製造する工程である。 (1)第一工程 1  The first step is a step of producing the compound (V) from the compound (II) by alkylation. (1) First step 1
本工程は化合物 (II)とカルボ二ルイ匕合物 (III)とを還元的アルキルィ匕することによりィ匕 合物 (V)を製造する工程である。反応は、例えば日本化学会編「実験化学講座 (20 卷)有機合成 2」、第 4版、丸善、 1992年、 P.300等に記載の方法が適用できる。具 体的には、無溶媒中またはジクロロメタン、 1,2-ジクロロエタン、クロ口ホルム等のハロ ゲン化炭化水素類、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)、ジォキサン等のェ 一テル類、メタノール、エタノール等のアルコール類、酢酸等の反応に不活性な溶媒 中、水素化ホウ素ナトリウム、ナトリウムシァノボロヒドリド、トリァセトキシ水素化ホウ素 ナトリウム等の還元剤を用い冷却下、室温下乃至加熱還流下に行うのが好適であるThis step is a step of producing the compound (V) by reductive alkylation of the compound (II) and the carbonyl compound (III). For the reaction, for example, the method described in “Chemical Experiment Course (20) Organic Synthesis 2” edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, p. Specifically, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, etc. , Ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane, alcohols such as methanol and ethanol, and solvents inert to the reaction such as acetic acid It is preferable to carry out the reaction at room temperature to reflux with heating using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
。化合物によっては硫酸、塩酸、臭化水素酸等の鉱酸、ギ酸、酢酸等の有機酸等の 酸、あるいは四塩ィ匕チタン等のルイス酸存在下反応を行うことが有利な場合がある。 また、例えば触媒として、パラジウム一炭素、ラネーニッケル、白金等を用い、常圧乃 至加圧の水素雰囲気下、前述の芳香族炭化水素類、エステル類、エーテル類、ハロ ゲン化炭化水素類、 Ν,Ν-ジメチルホルムアミド（DMF)、 Ν,Ν-ジメチルァセトアミド（D ΜΑ)、 Ν-メチルピロリドン (ΝΜΡ)、ァセトニトリル、酢酸等反応に不活性な溶媒中、室 温乃至加熱還流下に行うことができる。化合物によっては酸 (好ましくは、塩酸、酢酸 等)の存在下に反応させることが、反応を円滑に進行させる上で有利な場合がある。 (2)第一工程 2 . Depending on the compound, it may be advantageous to carry out the reaction in the presence of a mineral acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, an acid such as an organic acid such as formic acid or acetic acid, or a Lewis acid such as tetrasalt-titanium. Further, for example, as a catalyst, palladium monocarbon, Raney nickel, platinum or the like is used, and the above-mentioned aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, , Ν-dimethylformamide (DMF), Ν, Ν-dimethylacetamide (D ΜΑ), Ν-methylpyrrolidone (ΝΜΡ), acetonitrile, acetic acid, etc. be able to. Depending on the compound, it may be advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid, etc.) to facilitate the reaction. (2) First step 2
本工程は化合物 (II)を脱離基を有する化合物 (IV)によりアルキルィ匕することにより 化合物 (V)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-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アルキルィ匕を 採用することができる。例えば、無溶媒下、若しくは前述の芳香族炭化水素類、エス テル類、エーテル類、ハロゲン化炭化水素類、 DMF、 DMA, NMP、ジメチルスルホキ シド (DMSO)、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 セシウム、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 compound (V) by alkylating compound (II) with compound (IV) having a leaving group. The leaving group represented by Lv may be any leaving group that is commonly used in nucleophilic substitution reactions, such as halogen, halogen such as bromo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonylo. Sulfoloxy such as xy, sulfone such as lower alkyl sulphone, aryl sulol and the like are preferably used. For the alkylation reaction in this step, an alkylation commonly used by those skilled in the art can be employed. For example, in the absence of solvent or inert to reactions such as the aromatic hydrocarbons, esters, ethers, halogenated hydrocarbons, DMF, DMA, NMP, dimethylsulfoxide (DMSO), and acetonitrile. The reaction can be carried out in a solvent or a solvent such as alcohols at room temperature or 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, tert-butoxypotassium, etc.), it may be advantageous for the reaction to proceed smoothly.
第二工程 1 Second step 1
本工程は化合物 (V)を化合物 (VI)によりスルホ-ルイ匕することにより、 Lが- S(O) -で ある本発明化合物（I-a)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「プロテクティブ'グループス 'イン'オーガニック 'シンセシス (Protective Groups in Organic Synthesis)」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、テトラヒドロフラン、ジクロロメタン、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。 In this step, compound (V) is treated with compound (VI) by sulfo-louis, so that L is -S (O)- This is a process for producing a compound of the present invention (Ia). 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” can be applied. Specifically, it can be carried out in a solvent such as tetrahydrofuran, dichloromethane or acetonitrile, in the presence of a base such as triethylamine or pyridine, if necessary, under cooling to heating under reflux.
第二工程 2 Second step 2
本工程は化合物 (V)をカルボン酸 (VII)またはその反応性誘導体とァシルイヒすること により、 Lが- C(O)-である本発明化合物 (I-b)を製造する工程である。反応性誘導体と しては酸ノ、ロゲンィ匕物（酸クロリド、酸ブロミド等）、酸無水物（クロ口炭酸ェチル、クロ 口炭酸ベンジル、クロ口炭酸フ -ル、 P-トルエンスルホン酸、イソ吉草酸等との反応 で得られる混合酸無水物、或いは対称酸無水物）、活性エステル (ニトロ基あるいは フッ素原子などの電子吸弓 I基で置換して 、てもよ 、フエノール、 1-ヒドロキシベンゾト リアゾール (HOBt)、 N-ヒドロキシスクシンイミド（HONSu)等を用いて調製できるエス テル）、低級アルキルエステル、酸アジド等が挙げられる。これらの反応性誘導体は 常法により製造することができる。反応はカルボン酸ィ匕合物 (VII)またはその反応性誘 導体と化合物 (V)とを等モルあるいは一方を過剰量用いて、芳香族炭化水素類、ハ ロゲン化炭化水素類、エーテル類、 DMF、 DMA, NMP、酢酸ェチル又はァセトニトリ ル等の反応に不活性な溶媒中、冷却下〜加熱下で行うことができる。反応性誘導体 の種類によっては、塩基 (好ましくは、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）の存在下に反応さ せるのが、反応を円滑に進行させる上で有利な場合がある。ピリジンは溶媒を兼ねる ことちでさる。  This step is a step for producing the compound (I-b) of the present invention in which L is —C (O) — by subjecting compound (V) to carboxylic acid (VII) or a reactive derivative thereof. Examples of reactive derivatives include acid salts, logogens (acid chlorides, acid bromides, etc.), acid anhydrides (black ester carbonate, benzyl carbonate, chloroform carbonate, P-toluenesulfonic acid, isoforms). Mixed acid anhydride or symmetric acid anhydride obtained by reaction with valeric acid, etc., active ester (substituted with electron arch I group such as nitro group or fluorine atom, phenol, 1-hydroxy Examples thereof include benzotriazole (HOBt), esters prepared using N-hydroxysuccinimide (HONSu), lower alkyl esters, acid azides and the like. These reactive derivatives can be produced by conventional methods. The reaction is carried out by using an equimolar amount or an excess of one of the carboxylic acid compound (VII) or its reactive derivative and compound (V), aromatic hydrocarbons, halogenated hydrocarbons, ethers, The reaction can be carried out under cooling to heating in a solvent inert to the reaction such as DMF, DMA, NMP, ethyl acetate or acetonitrile. Depending on the type of reactive derivative, the reaction may be carried out in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.) In some cases, the reaction proceeds smoothly. Pyridine is also used as a solvent.
遊離カルボン酸を用いる場合には、縮合剤 (Ν,Ν' -ジシクロへキシルカルポジイミド、( DCC)、 1- [3- (ジメチルァミノ)プロピル]- 3-ェチルカルボジイミド (WSC)、 1,1， -カルボ -ルビスイミダゾール (CDI)、 Ν,Ν' -ジスクシンィミジルカルボナート、 Bop試薬 (Aldrich 社、米国)、 2-(1Η-ベンゾトリアゾール -1-ィル) -1,1, 3,3-テトラメチルゥ口-ゥムテトラフ ルォロボラート (TBTU)、 2- (1H-ベンゾトリアゾール -1-ィル) -1,1, 3,3-テトラメチルゥ口 -ゥムへキサフルオロフォスフェート (HBTU)、ジフエ-ルリン酸アジド (DPPA)、ォキシ 塩化リン、三塩化リン、トリフエ-ルホスフィン ZN-ブロモスクシンイミド等）、場合によ つては、更に添加剤（例えば、 HONSu、 HOBt等）を用いるのが好ましい。 When a free carboxylic acid is used, a condensing agent (Ν, Ν'-dicyclohexyl carpositimide, (DCC), 1- [3- (dimethylamino) propyl] -3-ethyl carbodiimide (WSC), 1,1 , -Carbo-rubbisimidazole (CDI), Ν, Ν'-Disuccinimidyl carbonate, Bop reagent (Aldrich, USA), 2- (1Η-benzotriazol-1-yl) -1,1, 3,3-tetramethylu-mu-tetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1,1, 3,3-tetramethylu mouth -Umhexafluorophosphate (HBTU), diphenylphosphoric acid azide (DPPA), phosphorus oxychloride, phosphorus trichloride, triphenylphosphine ZN-bromosuccinimide, etc.), and in some cases, additional additives ( For example, HONSu, HOBt, etc.) are preferably used.
[0038] 第二工程 3  [0038] Second step 3
本工程は化合物 (V)を化合物 (VIII)または化合物（IX)とアルキルィ匕することにより、 Lが単結合である本発明化合物 (I-c)を製造する工程である。本工程のアルキル化は 第一工程のアルキル化と同様にして行うことができる。  This step is a step for producing a compound (I-c) of the present invention in which L is a single bond by alkylating compound (V) with compound (VIII) or compound (IX). The alkylation in this step can be performed in the same manner as the alkylation in the first step.
[0039] (製法 2)  [0039] (Manufacturing method 2)
[化 7]  [Chemical 7]
Figure imgf000023_0001
Figure imgf000023_0001
( T T ) ( X )
Figure imgf000023_0002
(TT) (X)
Figure imgf000023_0002
[0040] 第一工程 [0040] First step
本工程はスルホニル化、ァシルイ匕またはアルキルィ匕により化合物（II)より化合物（X )を製造する工程である。スルホニル化、ァシル化、アルキルィ匕はそれぞれ製法 1の 第二工程— 1乃至第二工程— 3と同様にして行うことができる。  This step is a step of producing compound (X) from compound (II) by sulfonylation, acylation or alkylation. The sulfonylation, the acylation, and the alkylation can be carried out in the same manner as in the second step 1 to the second step 3 of production method 1, respectively.
[0041] 第二工程 [0041] Second step
本工程はアルキル化により化合物 (X)より本発明化合物 (I)を製造する工程である 。本工程のアルキル化反応は製法 1の第一工程 2と同様の方法で製造できる。ま た、 Lvカ OHである化合物（IV)を用いて、テトラヒドロフラン、ジクロロメタン等の溶媒 中、トリフエ-ルホスフィン及びジェチル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ができる。 This step is a step for producing the present compound (I) from the compound (X) by alkylation. The alkylation reaction in this step can be produced in the same manner as in the first step 2 of production method 1. In addition, using the compound (IV) which is Lv OH, in a solvent such as tetrahydrofuran or dichloromethane, in the presence of triphenylphosphine and jetylazodicarboxylate, under cooling. It can be performed at room temperature.
(製法 3)  (Manufacturing method 3)
[化 8]  [Chemical 8]
Figure imgf000024_0001
Figure imgf000024_0001
( i-f )  (i-f)
(式中、 Rは低級アルキルを示す。 ) (In the formula, R represents lower alkyl.)
[0043] 第一工程 [0043] First step
本工程は加水分解により R3が- CO Rである本発明化合物（I-d)より R3が- CO Hであ In this process, R 3 is —CO 2 H from the compound (Id) of the present invention in which R 3 is —CO 2 R by hydrolysis.
2 2 る本発明化合物 (I-e)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「プロテクティブ ·グノレープス 'イン'オーガニック ·シンセシス (Protective Groups i n Organic Synthesis)」に記載の脱保護反応に準じて行うことができる。  This is a process for producing the present compound (I-e). The hydrolysis reaction in this step can be performed, for example, according to the deprotection reaction described in the above-mentioned “Protective Groups Inorganic Organic Synthesis”.
[0044] 第二工程 [0044] Second step
本工程はアミドィ匕により R3が- CO Hである本発明化合物（I-e)より R3が- CONR 5aで In this step, R 3 is —CONR 5a from the compound (Ie) of the present invention in which R 3 is —CO 2 H by amido.
2  2
ある本発明化合物 (I-f)を製造する工程である。本工程のアミド化反応は製法 1の第 二工程一 2と同様にして行うことができる。  This is a process for producing a compound (I-f) of the present invention. The amidation reaction in this step can be carried out in the same manner as in the second step 1 and 2 of production method 1.
[0045] 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製造することができる。 [0045] The starting compound used for the production of the compound (I) of the present invention can be 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 9] [Chemical 9]
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0002
( I I )  (I I)
[0046] 第一工程  [0046] First step
本工程は化合物 (XII)をニトロ化して化合物 (XIII)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製造することができる。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 (XIII) by nitration of compound (XII). Nitration can be produced by a method usually 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.
[0047] 第二工程  [0047] Second step
本工程はニトロ化合物 (ΧΙΠ)を還元して化合物（Π)を製造する工程である。本工程 の-トロの還元反応は当業者が通常採用しうる-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 (ΧΙΠ) by reducing the nitro compound (ΧΙΠ). As the -tro reduction reaction in this step, a -tro group reduction reaction that can be usually employed by those skilled in the art can be used. Examples thereof include a reduction reaction using a reducing agent such as reduced iron and tin chloride and a hydrogenation reaction using palladium-carbon as a catalyst.
[0048] (原料合成 2)  [0048] (Raw material synthesis 2)
[化 10]  [Chemical 10]
Figure imgf000025_0003
Figure imgf000025_0003
( XIV ) ( VI )  (XIV) (VI)
(式中、 J1及び/は Jに変換しうる基を示す。 ) (In the formula, J 1 and / represent groups that can be converted to J.)
第一工程  First step
本工程は化合物 (XIV)及び化合物 (XV)を縮合して化合物 (XVI)を製造する工程 である。本工程は Jの構造に応じて当業者が通常採用しうるアミド化、アルキル化等に より製造することができる。例えば、 Jが- 0-低級アルキレン-である化合物 (XVI)は、 J1 カ OHである化合物 (XIV)と が-低級アルキレン - Lv(Lvは脱離基を示す。 )である 化合物 (XV)を用いてアルキルィ匕により製造することができる。当該アルキル化は製 法 1の第一工程— 2と同様の方法で行うことができる。 In this step, compound (XVI) and compound (XV) are condensed to produce compound (XVI). It is. This step can be produced by amidation, alkylation or the like that can be usually employed by those skilled in the art depending on the structure of J. For example, a compound (XVI) in which J is -0-lower alkylene- is a compound (XIV) in which J 1 OH is a -lower alkylene-Lv (Lv represents a leaving group). ) Can be used to produce an alkyl group. The alkylation can be carried out in the same manner as in the first step 2 of production method 1.
[0050] 上記各製法により得られた反応生成物は、遊離化合物、その塩あるいは水和物な ど各種の溶媒和物として単離、精製することができる。塩は通常の造塩処理に付すこ とにより製造できる。 [0050] The reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced by subjecting it to normal salt formation treatment.
単離、精製は、抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー 等通常の化学操作を適用して行うことができる。  Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
各種異性体は異性体間の物理ィ匕学的な差を利用して常法により単離できる。例え ば、光学異性体は一般的な光学分割法、例えば分別結晶化またはクロマトグラフィ 一等により分離できる。また、光学異性体は、適当な光学活性な原料ィ匕合物より製造 することちでさる。  Various isomers can be isolated by a conventional method using physical and physical differences between isomers. For example, optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. An optical isomer can be produced from an appropriate optically active raw material compound.
[0051] 本発明化合物またはその塩の 1種または 2種以上を有効成分として含有する製剤 は通常製剤化に用いられる担体ゃ賦形剤、その他の添加剤を用いて調製される。 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、あるいは 静注、筋注等の注射剤、坐剤、経皮剤、経鼻剤あるいは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。投与量は症状、投与対象の年齢、性別等を考慮し て個々の場合に応じて適宜決定されるが、通常、経口投与の場合、成人 1日当たり 0. 001 mg/kg乃至 100 mg/kg程度であり、これを 1回で、あるいは 2〜4回に分けて投与 する。また、静脈投与される場合は、通常、成人 1回当たり 0.0001 mg/kg乃至 10 mg/ kgの範囲で 1日に 1回乃至複数回投与される。また、経鼻投与の場合、通常、成人 1 回当たり 0.0001 mg/kg乃至 10 mg/kgの範囲で 1日に 1回乃至複数回投与される。ま た、吸入の場合は、通常、成人 1回当たり 0.0001 mg/kg乃至 1 mg/kgの範囲で 1日に 1回乃至複数回投与される。  [0051] A preparation containing one or more of the compounds of the present invention or a salt thereof as an active ingredient is usually prepared using carriers, excipients, and other additives used for formulation. Administration is oral by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral by injections such as intravenous and intramuscular injections, suppositories, transdermal, nasal or inhalants. Either form may be sufficient. The dosage is appropriately determined according to the individual case, taking into account the symptoms, age of the subject, sex, etc., but in the case of oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per day for an adult. This should be administered once or in 2 to 4 divided doses. When administered intravenously, it is usually administered once or multiple times per day in the range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of nasal administration, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of inhalation, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 1 mg / kg per adult.
[0052] 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、一つまたはそれ以上の活性物質力 少 なくとも一つの不活性な賦形剤、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、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、不活性な添加剤、例え ばステアリン酸マグネシウム等の滑沢剤やカルボキシメチルスターチナトリウム等の崩 壊剤、溶解補助剤を含有していてもよい。錠剤または丸剤は必要により糖衣または胃 溶性若しくは腸溶性コーティング剤で被膜してもよ 、。 [0052] Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, one or more active substances are less potent. It is mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybulurpyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. Tablets or pills may be coated with sugar coating or gastric or enteric coatings if necessary.
経口投与のための液体組成物は、薬剤的に許容される乳剤、液剤、懸濁剤、シロッ プ剤、エリキシル剤等を含み、一般的に用いられる不活性な溶剤、例えば精製水、ェ タノールを含む。この組成物は不活性な溶剤以外に可溶化剤、湿潤剤、懸濁化剤の ような補助剤、甘味剤、矯味剤、芳香剤、防腐剤を含有していてもよい。  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and are generally used inert solvents such as purified water, ethanol. including. In addition to the inert solvent, the composition may contain solubilizers, wetting agents, suspending agents and other auxiliary agents, sweeteners, corrigents, fragrances and preservatives.
非経口投与のための注射剤としては、無菌の水性または非水性の液剤、懸濁剤、 乳剤を含む。水性の溶剤としては、例えば注射用蒸留水及び生理食塩水が含まれる 。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール、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、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、乳化剤、分散剤、 安定化剤、溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを 通す濾過、殺菌剤の配合また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、使用前に無菌水または無菌の注射用溶媒に溶解、懸濁して使 用することちでさる。  Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can be prepared by preparing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
吸入剤や経鼻剤等の経粘膜剤は固体、液体、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、ラタトースゃ澱粉のような賦形剤や 、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、適当な吸入また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、 化合物を単独でまた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また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、単回または多数回の投与用のものであってもよぐ乾燥粉末または粉末含 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または二酸ィ匕炭素等の好適な気体を使用したカロ 圧エアゾールスプレー等の形態であってもよ 、。 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, an excipient and as Ratatosu Ya starch, furthermore, P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate. 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 as a solution or suspension alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier be able to. The dry powder inhaler or the like can use a dry powder or a capsule containing a powder, which may be for single or multiple administrations. Alternatively, a suitable propellant such as black mouth fluo It may be in the form of a caloric pressure aerosol spray using a suitable gas such as loalkane, hydrofluoroalkane or carbon dioxide.
実施例  Example
[0054] 以下、本発明化合物の製造例を挙げ、本発明化合物の製造方法を具体的に説明 するが本発明はこれらの実施例により何ら制限されるものではない。なお、本発明化 合物の原料化合物には新規な化合物も含まれており、これらの化合物の製造方法を 参考例として説明する。  [0054] Hereinafter, production examples of the compound of the present invention will be given and the production method of the compound of the present invention will be specifically described. However, the present invention is not limited to these examples. Note that the raw material compounds of the compounds of the present invention include novel compounds, and the production methods of these compounds will be described as reference examples.
[0055] なお、参考例、実施例中の記号は以下の意味を示す (以下同様)。  [0055] The symbols in the reference examples and examples have the following meanings (the same applies hereinafter).
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) ([M+H]^; EN : ESI— MS (Neg) ([M— H]—)； AP I： API-MS (Pos) (無記載である場合は [M+H]+); 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-H]—) ; NMR1 : DMS0- d  Rf: Reference number, Ex: Example number, No: Compound number, Str: Structural formula, DAT: Physical data ((EI: EI—MS ([M] +); EP: ESI-MS ( Pos) ([M + H] ^; EN: ESI—MS (Neg) ([M—H] —); AP I: API-MS (Pos) ([M + H] + if not specified) ; FP: FAB-MS (Pos) (if not stated [M + H] +); FN: FAB- MS (Neg) (if not stated [MH] —); NMR1: DMS0- d
6 中の1 HNMRにおける特徴的なピークの S (ppm) ; NMR2 : CDC1中の1!" INMRにおける S (ppm) of the characteristic peak in 1 HNMR in 6; NMR2: 1 ! "In CDC1 in I NMR
3  Three
特徴的なピークの δ (ppm) ; Sal:塩 (無記載はフリー体であることを示し、例えば HC1 が記載されている場合、その化合物が塩酸塩であることを示す。））、 Me :メチル、 Et : ェチル、 cPr:シクロプロピル、 iPr:イソプロピル、 nBu:ノルマルブチル、 cBu:シクロブ チル、 iBu:イソブチル、 cPen:シクロペンチル、 cHex:シクロへキシル、 nOct:ノルマル ォクチル、 CF：トリフルォロメチル、 Ph:フエニル、 Bn:ベンジル、 Ac:ァセチル、 Py:ピリ  Δ (ppm) of the characteristic peak; Sal: salt (unshown indicates free form, for example, when HC1 is described, the compound indicates hydrochloride)), Me: Methyl, Et: Ethyl, cPr: Cyclopropyl, iPr: Isopropyl, nBu: Normal butyl, cBu: Cyclobutyl, iBu: Isobutyl, cPen: Cyclopentyl, cHex: Cyclohexyl, nOct: Normal octyl, CF: Trifluoromethyl , Ph: phenyl, Bn: benzyl, Ac: acetyl, Py: pyri
3  Three
ジル、 Fur:フリル、 Thi:チェ-ル、 BFur:ベンゾフラ -ル、 Thia:チアゾリル、 Im:イミダゾリ ル、 THFur:テトラヒドロフリル、 Pyra:ピラジ -ル、 Pyrimi:ピリミジ -ル、 Pyrida:ピリダジ -ル、 TBDPS:tert-ブチルジフエ-ルシリル。置換基の前の数字は置換位置を示し、 従って、例えば 2,4- diF-Phは 2,4-ジフルオロフェ-ルを、 5- Me- 2Furは 5-メチル - 2- フリル、すなわち、 5-メチルフラン- 2-ィルを示す。）、 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が着 、て 、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。 ) o  Jill, Fur: Furyl, Thi: Chael, BFur: Benzofuryl, Thia: Thiazolyl, Im: Imidazol, THFur: Tetrahydrofuryl, Pyra: Pyrazyl, Pyrimi: Pyrimidyl, Pyrida: Pyridazil TBDPS: tert-butyldiphenylsilyl. The number before the substituent indicates the substitution position, for example 2,4-diF-Ph is 2,4-difluorophenol, 5-Me-2Fur is 5-methyl-2-furyl, ie 5 -Methylfuran-2-yl is shown. ), Syn: production method (numbers indicate that the product was produced using the corresponding raw material in the same manner as the example compound having the number as the example number. R is attached before the number) In the case of the reference example number in the case of the reference example, it indicates that it was produced using the corresponding raw material in the same manner as the reference example compound.
[0056] 参考例 1 [0056] Reference Example 1
2,3-ジヒドロ- 6-ヒドロキシベンゾフラン 12.6gの酢酸（90.0ml)溶液を 15°Cに冷却し、 攪拌下濃硝酸 (69%) 7.17mlを滴下した。滴下終了後、反応液を 35°Cまで昇温し、 10 分間攪拌した。反応液に水を加えた後、混合物を減圧濃縮し、析出した粗製物を濾 取した。得られた粗製物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 = 5 : 1)で精製し、 5 - -トロ- 2 , 3-ジヒドロ - 1 -ベンゾフラン- 6 -オール 9.00gを得た。 2,3-dihydro-6-hydroxybenzofuran 12.6g acetic acid (90.0ml) solution was cooled to 15 ° C, 7.17 ml of concentrated nitric acid (69%) was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was heated to 35 ° C and stirred for 10 minutes. After adding water to the reaction solution, the mixture was concentrated under reduced pressure, and the precipitated crude product was collected by filtration. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 9.00 g of 5--tro-2,3-dihydro-1-benzofuran-6-ol.
[0057] 参考例 2 [0057] Reference Example 2
濃硝酸（69%) 11.7mlと酢酸 25.0mlの混合物に、氷冷下 1,3-ベンゾジォキソール -5- ィル 酢酸 17.5gの酢酸 (20.0ml)溶液を滴下した。氷冷下 30分間攪拌した後、反応液 を氷水に注ぎ、析出した沈殿物を濾取し、 6-ニトロ- 1,3-ベンゾジォキソール -5-ィル 酢酸 19.7gを淡黄色固体として得た。 6-ニトロ- 1,3-ベンゾジォキソール -5-ィル酢酸 4 .50gのメタノール溶液（160ml)に、 3M塩酸 80.0mlを加え、 4.5時間加熱還流した。反 応液を室温まで冷却した後、約 100mlまで減圧濃縮した。氷冷により析出した沈殿物 を濾取、減圧下乾燥し、 5-ヒドロキシ -6-ニトロ- 1,3-ベンゾジォキソール 3.49gを得た。  To a mixture of 11.7 ml of concentrated nitric acid (69%) and 25.0 ml of acetic acid, a solution of 17.5 g of 1,3-benzodioxol-5-yl acetic acid in acetic acid (20.0 ml) was added dropwise. After stirring for 30 minutes under ice-cooling, the reaction solution is poured into ice water, and the deposited precipitate is collected by filtration. Got as. To a methanol solution (160 ml) of 4.50 g of 6-nitro-1,3-benzodioxol-5-ylacetic acid was added 80.0 ml of 3M hydrochloric acid, and the mixture was heated to reflux for 4.5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to about 100 ml. The precipitate deposited by ice cooling was collected by filtration and dried under reduced pressure to obtain 3.49 g of 5-hydroxy-6-nitro-1,3-benzodioxole.
[0058] 参考例 3 [0058] Reference Example 3
2,3-ジヒドロ- 5-ヒドロキシベンゾフラン 4.04gを DMF 50mlに溶解し、これに 4- (ブロモ メチル)安息香酸メチル 7.47gと炭酸カリウム 2.75gを加え、 80°Cにて終夜攪拌した。反 応液を室温まで冷却した後、水を加え、酢酸ェチルで抽出した。有機層を水と食塩 水で洗浄し、無水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（トルエン：酢酸ェチル =30 : 1)で精製し、 4-[(2,3-ジ ヒドロ- 1-ベンゾフラン- 5-ィルォキシ)メチル]安息香酸メチル 5.62gを得た。  4.04 g of 2,3-dihydro-5-hydroxybenzofuran was dissolved in 50 ml of DMF, 7.47 g of methyl 4- (bromomethyl) benzoate and 2.75 g of potassium carbonate were added thereto, and the mixture was stirred at 80 ° C. overnight. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 30: 1) to give 4-[(2,3-dihydro-1-benzofuran-5-yloxy). 5.62 g of methyl] methyl benzoate were obtained.
[0059] 参考例 4 [0059] Reference Example 4
5-ニトロ- 2,3-ジヒドロ- ベンゾフラン- 6-オール 3.00gを DMF 30mlに溶解し、これに 4- (ブロモメチル)安息香酸メチル 4.17gと炭酸カリウム 2.75gをカ卩え、 60°Cにて終夜攪 拌した。反応液を室温まで冷却した後、水と酢酸ェチルを加え、析出した沈殿物を濾 取、減圧下乾燥し、 4-{[(5-ニトロ- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル } 安息香酸メチル 5.40gを得た。  Dissolve 3.00 g of 5-nitro-2,3-dihydro-benzofuran-6-ol in 30 ml of DMF and add 4.17 g of methyl 4- (bromomethyl) benzoate and 2.75 g of potassium carbonate to 60 ° C. Stir all night. After cooling the reaction solution to room temperature, water and ethyl acetate were added, and the deposited precipitate was collected by filtration and dried under reduced pressure to give 4-{[((5-nitro-2,3-dihydro-1-benzofuran-6- Yl) oxy] methyl} 5.40 g of methyl benzoate was obtained.
[0060] 参考例 5 [0060] Reference Example 5
4-[(2,3-ジヒドロ- 1-ベンゾフラン- 5-ィルォキシ)メチル]安息香酸メチル l.OOgを酢酸 10mlに溶解し、攪拌下濃硝酸 (69%) 0.245mlを滴下した。滴下終了後、室温にて 10分 間攪拌した。析出した沈殿物を濾取し、水で洗浄した後、減圧下乾燥し、 4-{[(6-ニト 口- 2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル)ォキシ]メチル }安息香酸メチル 1.16gを得た。 Methyl 4-[(2,3-dihydro-1-benzofuran-5-yloxy) methyl] benzoate l.OOg was dissolved in 10 ml of acetic acid, and 0.245 ml of concentrated nitric acid (69%) was added dropwise with stirring. 10 minutes at room temperature after dropping Stir for a while. The deposited precipitate was collected by filtration, washed with water, and dried under reduced pressure. 4-{[(6-Nitto-2,3-dihydro-1-benzofuran-5-yl) oxy] methyl} benzoic acid 1.16 g of methyl acid was obtained.
[0061] 参考例 6 [0061] Reference Example 6
4-{[(5-ニトロ- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 5. 50gを酢酸 60mlと水 15mlに溶解し、 60°Cまで昇温した後、還元鉄 4.64gを加え、 60°C にて 3時間攪拌した。反応液をセライト濾過した後、濾液を減圧濃縮した。残渣に酢 酸ェチルと水を加えた後、炭酸水素ナトリウムで溶液を中和した後、セライト濾過した 。濾液を、酢酸ェチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシ ゥムで乾燥した。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（トルエン：酢酸ェチル =4: 1)で精製し、 4-{[(5-ァミノ- 2,3-ジヒドロ- 1-ベンゾフラ ン -6-ィル)ォキシ]メチル }安息香酸メチル 4.47gを得た。  4-{[(5-Nitro-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 5. Dissolve 50 g in 60 ml acetic acid and 15 ml water and warm to 60 ° C After that, 4.64 g of reduced iron was added and stirred at 60 ° C for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, the solution was neutralized with sodium bicarbonate, and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 4: 1) to give 4-{[(5-amino-2,3-dihydro-1-benzofuran. N-6-yl) oxy] methyl} 4.47 g of methyl benzoate was obtained.
[0062] 参考例 7 [0062] Reference Example 7
4- {3- [(5-二トロ- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]プロピル }安息香酸メチ ル 507mgをメタノール 10mlと THF 5mlに溶解し、これに 10% w/wパラジウム炭素（50% 含水）を 232mg加え、水素雰囲気下 2時間攪拌した。反応液をセライト濾過した後、濾 液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢 酸ェチル =3： 1)で精製し、 4— {3— [(5—ァミノ— 2,3—ジヒドロ— 1—ベンゾフラン— 6—ィル)ォキ シ]プロピル }安息香酸メチル 412mgを得た。  4- {3- [(5-Nitro-2,3-dihydro-1-benzofuran-6-yl) oxy] propyl} Methyl benzoate 507 mg was dissolved in 10 ml of methanol and 5 ml of THF. 232 mg of w / w palladium carbon (containing 50% water) was added and stirred for 2 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 4- {3 — [(5-amino-2,3-dihydro-1-benzofuran-6-yl. ) Oxy] propyl} 412 mg of methyl benzoate was obtained.
[0063] 参考例 8 [0063] Reference Example 8
4-{[(5-ァミノ- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 4. 46gをピリジン 60mlに溶解し、これに 5-メチルフラン- 2-スルホユルクロリド 3.50gを加え 、室温にて終夜攪拌した。反応液を減圧濃縮した後、残渣に 1M塩酸を加え、酢酸ェ チルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した 。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（トルエン： 酢酸ェチル =9 : 1)で精製し、 4-{[(5-{[(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジ ヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 6.14gを得た。  4-{[(5-Amino-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 4. Dissolve 46 g in 60 ml pyridine and add 5-methylfuran-2- Sulfoyl chloride (3.50 g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 9: 1) to give 4-{[(5-{[(5-methyl-2-furyl) sulfo- [Lu] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate, 6.14 g.
[0064] 参考例 9 [0064] Reference Example 9
4- {[(5- {[(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル )ォキシ]メチル }安息香酸メチル l.OOgをトルエン 10mlに溶解し、これに 2,3-ジクロロ- 5, 6-ジシァノ- 1,4-ベンゾキノン 512mgを加え、 100°Cにて 3時間攪拌した。反応液を室 温まで冷却した後、炭酸水素ナトリウム水溶液を加え、酢酸ェチルで抽出した。有機 層を炭酸水素ナトリウム水溶液と食塩水で洗浄後、無水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： 1〜1： 1)で精製し、 4- {[(5- {[(5-メチル -2-フリル)スルホ -ル]アミノト 1- ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 852mgを得た。 4- {[(5- {[(5-Methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl ) Oxy] methyl} Methyl benzoate l.OOg was dissolved in 10 ml of toluene, and 512 mg of 2,3-dichloro-5,6-disiano-1,4-benzoquinone was added thereto and stirred at 100 ° C. for 3 hours. . The reaction solution was cooled to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine, and then dried over anhydrous 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 to 1: 1) to give 4-{[(5-{[(5-methyl- 2-Furyl) sulfol] aminoto 1-benzofuran-6-yl) oxy] methyl} methyl benzoate (852 mg) was obtained.
[0065] 参考例 10 [0065] Reference Example 10
4-{[(5-ァミノ- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 3. 49gを 1,2-ジクロロェタン 100mlに溶解し、これにイソブチルアルデヒド 1.17mlとトリァセ トキシ水素化ホウ素ナトリウム 3.21gを加え、室温にて終夜攪拌した。反応液に炭酸水 素ナトリウム水溶液を加えた後、クロ口ホルムで抽出し、有機層を無水硫酸ナトリウム 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 = 10： 1〜5： 1)で精製し、 4-({[5- (イソブチルァミノ) -2,3-ジヒドロ -1-ベンゾフラン- 6-ィル]ォキシ }メチル)安息香酸メチル 3.60gを得た。  4-{[(5-Amino-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 3. 49 g was dissolved in 100 ml of 1,2-dichloroethane, and isobutyraldehyde 1.17 ml and 3.21 g of sodium triacetoxyborohydride were added and stirred at room temperature overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with black mouth form, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to give 4-({[5- (isobutylamino) -2, 3.60 g of methyl 3-dihydro-1-benzofuran-6-yl] oxy} methyl) benzoate was obtained.
[0066] 参考例 11 [0066] Reference Example 11
水素化ナトリウム 133mg(60% in oil)を DMF 3.0mLに懸濁し、これに 4- (ヒドロキシメチ ル)安息香酸 252mgをカ卩ぇ室温にて 15分攪拌した後、 6-フルォロ- 5-ニトロ- 2,3-ジヒド 口- 1-ベンゾチォフェン 300mgを加え 100°Cにて 2時間攪拌した。反応液を室温まで冷 却した後、反応液を 1M塩酸水にあけ、析出した沈殿物を濾取した。得られた沈殿物 を水で洗い、減圧下乾燥し、 4-{[(5-ニトロ- 2,3-ジヒドロ- 1-ベンゾチェン- 6-ィル)ォキ シ]メチル }安息香酸 384mgを得た。  Sodium hydride 133 mg (60% in oil) was suspended in DMF 3.0 mL, and 4- (hydroxymethyl) benzoic acid 252 mg was stirred at room temperature for 15 minutes and then 6-fluoro-5-nitro. -2,3-dihydrone-1-benzothiophene (300 mg) was added, and the mixture was stirred at 100 ° C for 2 hr. After cooling the reaction solution to room temperature, the reaction solution was poured into 1M aqueous hydrochloric acid, and the deposited precipitate was collected by filtration. The obtained precipitate was washed with water and dried under reduced pressure to obtain 384 mg of 4-{[(5-nitro-2,3-dihydro-1-benzochen-6-yl) oxy] methyl} benzoic acid. It was.
[0067] 参考例 12 [0067] Reference Example 12
4- {[(5-二トロ- 2,3-ジヒドロ- 1-ベンゾチェン- 6-ィル)ォキシ]メチル }安息香酸 2.50gを THF 25mLとメタノール 12.5mLに溶解し、これに塩化チォ -ル 2.75mLを滴下し、 60°C にて 3時間攪拌した。反応液を減圧濃縮し、得られた残渣に水を加え、クロ口ホルム で抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィ 一（へキサン：クロ口ホルム：酢酸ェチル =20:20: 1〜トルエン：酢酸ェチル =10: 1)で精 製し、 4- {[(5- -トロ- 2,3-ジヒドロ- 1-ベンゾチェン- 6-ィル)ォキシ]メチル }安息香酸メ チル 1.40gを得た。 4- {[(5-Nitro-2,3-dihydro-1-benzochen-6-yl) oxy] methyl} benzoic acid 2.50g was dissolved in THF 25mL and methanol 12.5mL, 2.75 mL was added dropwise and stirred at 60 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with black mouth form. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: chloroform: ethyl acetate = 20: 20: 1 to toluene: ethyl acetate = 10: 1). To obtain 1.40 g of methyl 4-{[(5--tro-2,3-dihydro-1-benzochen-6-yl) oxy] methyl} benzoate.
参考例 13 Reference Example 13
4- {[(5- -トロ- 2,3-ジヒドロ- 1-ベンゾチェン- 6-ィル)ォキシ]メチル }安息香酸メチル 8 70mgをジクロロメタン 30mLに溶解し、これに m-クロ口過安息香酸 956mgをカ卩え、室温 にて 4時間攪拌した。反応液に m-クロ口過安息香酸 435mgを加え、さらに室温にて 3 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、クロ口ホルムで抽出した。 有機層を減圧濃縮し、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：酢酸ェチル =40:1で精製し、 4- {[(5-二トロ- 1,1-ジォキシド- 2,3-ジヒドロ- 1-ベンゾ チェン- 6-ィル)ォキシ]メチル }安息香酸メチル 767mgを得た。  4- {[(5--Tro-2,3-dihydro-1-benzochen-6-yl) oxy] methyl} methyl benzoate 8 Dissolve 70 mg in 30 mL dichloromethane and add m-cloperbenzoic acid to this 956 mg was added and stirred at room temperature for 4 hours. To the reaction solution, 435 mg of m-chloroperbenzoic acid was added, and the mixture was further stirred at room temperature for 3 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with black mouth form. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 40: 1, 4-{[(5-nitro-1,1-dioxide-2, 767 mg of methyl 3-dihydro-1-benzochen-6-yl) oxy] methyl} benzoate was obtained.
参考例 14 Reference Example 14
5-ァミノ- 2-クロ口ベンゼンスルホン酸 4.04gを水に懸濁させ、これに 5°Cにて濃塩酸 4 .82mLをカ卩えた後、亜硝酸ナトリウム 1.47gの水溶液を 0〜5°Cにて滴下した。反応液を 5〜10°Cにて 30分間攪拌し、ジァゾ -ゥム塩を調整した。 6-ヒドロキシ-トァセチルイ ンドール 3.28gを水 450mLと 1M水酸化ナトリウム水溶液 18.5mLに溶解し、これに先に 調整したジァゾ -ゥム塩の水溶液を 0〜10°Cにて滴下した。 5°Cにて 1時間攪拌した後 、炭酸ナトリウム 2.94g、メタノール、 4- (ブロモメチル)安息香酸メチル 9.33gのァセトニト リル溶液 (20mL)を加え、 80°Cにて 2時間攪拌した。反応液を室温まで冷却した後、 1 M塩酸水にあけ、析出した沈殿物を濾取した。得られた沈殿物を水で洗い減圧下乾 燥し、 5-[(1-ァセチル -6-{[4- (メトキシカルボ-ル)ベンジル]ォキシ }-2,3-ジヒドロ- 1H- インドール- 5-ィル)ジァゼ -ル] -2-クロ口ベンゼンスルホン酸 7.44gを得た。  Suspend 4.04 g of 5-amino-2-chlorobenzene sulfonic acid in water, add 4.82 mL of concentrated hydrochloric acid at 5 ° C, and then add 1.47 g of an aqueous solution of sodium nitrite to 0 to 5 °. Added dropwise at C. The reaction solution was stirred at 5 to 10 ° C. for 30 minutes to prepare diazo-um salt. 6.28 g of 6-hydroxy-tocetylindole was dissolved in 450 mL of water and 18.5 mL of 1M aqueous sodium hydroxide solution, and the previously prepared aqueous solution of diazo-um salt was added dropwise at 0 to 10 ° C. After stirring at 5 ° C for 1 hour, 2.94 g of sodium carbonate, methanol, 9.33 g of methyl 4- (bromomethyl) benzoate in acetonitrile (20 mL) were added, and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was cooled to room temperature, poured into 1 M aqueous hydrochloric acid, and the deposited precipitate was collected by filtration. The obtained precipitate was washed with water and dried under reduced pressure to give 5-[(1-acetyl-6-{[4- (methoxycarbol) benzyl] oxy} -2,3-dihydro-1H-indole- 5-yl) diazyl] -2-44 g benzenesulfonic acid 7.44 g was obtained.
5-[(1-ァセチル -6-{[4- (メトキシカルボ-ル)ベンジル]ォキシ }-2,3-ジヒドロ- 1H-イン ドール- 5-ィル)ジァゼ -ル] -2-クロ口ベンゼンスルホン酸 7.44gを DMF 40mLに懸濁さ せ、これにラネーニッケル l.OOgを加え、水素雰囲気下 (3atm)、室温にて終夜攪拌し た。反応液をセライト濾過し、濾液を水にあけ、クロ口ホルムで抽出した。有機層を食 塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧濃縮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 =2:1〜1:1で精製し、 4-{[(1-ァセ チル- 5-ァミノ- 2,3-ジヒドロ- 1H-インドール- 6-ィル)ォキシ]メチル }安息香酸メチル 1.8 2gを得た。 5-[(1-Acetyl-6-{[4- (methoxycarbol) benzyl] oxy} -2,3-dihydro-1H-indole-5-yl) diazel] -2-black mouth 7.44 g of benzenesulfonic acid was suspended in 40 mL of DMF, Raney nickel l.OOg was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere (3 atm). The reaction solution was filtered through Celite, and the filtrate was poured into water and extracted with black mouth form. The organic layer was washed with brine and dried over sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to give 4-{[(1-acetyl-5-amino-2 , 3-Dihydro-1H-indole-6-yl) oxy] methyl} methyl benzoate 1.8 2g was obtained.
参考例 125  Reference Example 125
N-{6-[(4-シァノベンジル)ォキシ ]- 2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル }-N-イソブチ ル -5-メチルフラン- 2-スルホンアミド 400mgをエタノール 4mlに溶解し、これにヒドロキ シルァミン'塩酸塩 119mgとトリエチルァミン 0.239mlを加え 6時間加熱還流した。反応 液を室温まで冷却した後、酢酸ェチルで抽出し、有機層を水、食塩水で洗浄後、無 水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、 Ν'-ヒドロキシ -4-{[(5-{ィソブ チル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォ キシ]メチル }ベンゼンカルボキシイミドアミド 507mgを得た。  N- {6-[(4-Cyanobenzyl) oxy] -2,3-dihydro-1-benzofuran-5-yl} -N-isobutyl-5-methylfuran-2-sulfonamide 400 mg dissolved in 4 ml ethanol To this was added 119 mg of hydroxylamine hydrochloride and 0.239 ml of triethylamine, and the mixture was heated to reflux for 6 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and Ν'-hydroxy-4-{[(5- {isobutyryl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6- 507 mg of (l) oxy] methyl} benzenecarboximidamide was obtained.
[0069] 上記参考例 1〜14の方法と同様にして、後記表 3〜18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 3〜18に参考例化合物の構造及び物理 化学的データを示す。  [0069] In the same manner as in the above Reference Examples 1 to 14, the Reference Example compounds shown in Tables 3 to 18 below were produced using the corresponding starting materials. Tables 3 to 18 show the structures and physicochemical data of Reference Example compounds.
[0070] 実施例 1  [0070] Example 1
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフ ラン- 6-ィル)ォキシ]メチル }安息香酸メチル 385mgをメタノール 5mlと THF 10mlに溶解 し、これに 1M水酸ィ匕ナトリウム水溶液 3mlを加え、室温にて 3.5時間攪拌した。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加え、有機層をフェイズ'セ パレート 'フィルター（Phase Separate- filter,アイソテユート (Isotute)社製）を用いて分 離した。溶媒を減圧留去して得られた残渣に酢酸ェチルを加え、析出した結晶を濾 取した。得られた粗製物を酢酸ェチルカゝら再結晶し、 4-{[(5-{イソブチル [(5-メチル -2 -フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息 香酸 294mgを得た。  4-{[(5- {Isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 385 mg in methanol Dissolved in 5 ml and 10 ml of THF, 3 ml of 1M sodium hydroxide aqueous solution was added thereto and stirred at room temperature for 3.5 hours. To the residue obtained by concentrating the reaction solution under reduced pressure, 1M hydrochloric acid and chloroform were added, and the organic layer was separated using a phase “separate” filter (manufactured by Isotute). Ethyl acetate was added to the residue obtained by distilling off the solvent under reduced pressure, and the precipitated crystals were collected by filtration. The obtained crude product was recrystallized from ethyl acetate, 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran- 6-yl) oxy] methyl} benzoic acid 294 mg was obtained.
[0071] 実施例 2 [0071] Example 2
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフ ラン- 6-ィル)ォキシ]メチル }安息香酸メチル 4.67gを 1,4-ジォキサン 60mlとメタノール 6 0mlに溶解し、これに 1M水酸ィ匕ナトリウム水溶液 40mlを加え、 60°C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塩酸を加え、酢酸ェチルで抽出した。 有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。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（酢酸ェチル)で精製した。 得られた粗製物をエタノールに溶解し、 1M水酸ィ匕ナトリウム水溶液を加えた後、減圧 濃縮した。得られた粗結晶を水から再結晶し、 4-{[(5-{イソブチル [(5-メチル -2-フリル )スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸ナト リウム 1水和物 3.25gを得た。 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 4.67 g Dissolved in 60 ml of 1,4-dioxane and 60 ml of methanol, 40 ml of 1M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid 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 anhydrous magnesium sulfate. Remove the solvent under reduced pressure The residue obtained was purified by silica gel column chromatography (ethyl acetate). The obtained crude product was dissolved in ethanol, 1M aqueous sodium hydroxide solution was added, and the mixture was concentrated under reduced pressure. The obtained crude crystals were recrystallized from water to give 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6- Yl) oxy] methyl} sodium benzoate monohydrate 3.25 g was obtained.
[0072] 実施例 3 [0072] Example 3
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフ ラン- 6-ィル)ォキシ]メチル }安息香酸 220mgを DMF 5mlに溶解し、これに炭酸アンモ -ゥム 216mg、 WSC '塩酸塩 104mg及び HOBt 73mgを加え、室温にて終夜攪拌した。 反応液に水を加え、酢酸ェチルで抽出した。有機層を水と食塩水で洗浄した後、無 水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に、トルエンを加え、 析出した結晶を濾取した。得られた粗製物をエタノール力 再結晶することにより、 4- {[(5-{イソブチル [(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }ベンズァミド lOOmgを得た。  4-{[(5- {Isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 220 mg in DMF 5 ml Ammonium carbonate (216 mg), WSC ′ hydrochloride (104 mg) and HOBt (73 mg) were added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. Toluene was 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 with ethanol to give 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran- 6-yl) oxy] methyl} benzamide lOOmg was obtained.
[0073] 実施例 4 [0073] Example 4
4- {[(5- {[(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル )ォキシ]メチル }安息香酸メチル 209mgを DMF 5mlに溶解し、これにヨウ化イソブチル 1 30mgと炭酸セシウム 459mgをカ卩え、 100°Cにて 3時間攪拌した。反応液を室温まで冷 却した後、水を加え、酢酸ェチルで抽出した。有機層を水と食塩水で洗浄した後、無 水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 =5： 1)で精製した。得られた粗製物をエタ ノールから再結晶することにより、 4-{[(5-{イソブチル [(5-メチル -2-フリル)スルホ -ル] アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 140mgを 得た。  4- {[(5- {[(5-Methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 209 mg into DMF 5 ml This was dissolved, and 30 mg of isobutyl iodide and 459 mg of cesium carbonate were added thereto and stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). The crude product obtained was recrystallized from ethanol to give 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran. 140 mg of methyl 6-yl) oxy] methyl} benzoate was obtained.
[0074] 実施例 5 [0074] Example 5
4-({[5- (イソブチルァミノ) -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル]ォキシ }メチル)安息 香酸メチル 380mgを 1,2-ジクロロェタン 10mlに溶解し、 5-メチル -2-フルアルデヒド 0.2 9mlとトリァセトキシ水素化ホウ素ナトリウム 750mgを加え、室温にて終夜攪拌した。反 応液に炭酸水素ナトリウム水溶液を加え、クロ口ホルムで抽出した。有機層を無水硫 酸ナトリウムで乾燥した後、溶媒を留去し、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 = 5 : 1)で精製し、 4- {[(5- {イソブチル [(5-メチル -2-フ リル)メチル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチ ル 478mgを得た。 4-({[5- (Isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) methyl) benzoate 380 mg is dissolved in 10 ml of 1,2-dichloroethane, 0.29 ml of methyl-2-furaldehyde and 750 mg of sodium triacetoxyborohydride were added and stirred overnight at room temperature. Anti A sodium hydrogen carbonate aqueous solution was added to the reaction solution, and the mixture was extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4-{[(5- { 478 mg of methyl isobutyl [(5-methyl-2-furyl) methyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoate was obtained.
[0075] 実施例 6 [0075] Example 6
4- {[(5- {[(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル )ォキシ]メチル }安息香酸メチル 4.54gを DMF 50mlに溶解し、これにヨウ化イソブチル 3 .77gと炭酸セシウム 9.97gを加え、 100°Cにて 2時間攪拌した。反応液を室温まで冷却 した後、水を加え、酢酸ェチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫 酸マグネシウムで乾燥した。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 口マトグラフィー（トルエン：酢酸ェチル = 19： 1)で精製し、 4- {[(5- {イソブチル [(5-メチ ル- 2-フリル)スルホニル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル } 安息香酸メチル 4.68gを得た。  4-{[(5- {[(5-Methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 4.54 g in DMF 50 ml Then, 3.77 g of isobutyl iodide and 9.97 g of cesium carbonate were added thereto, and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 19: 1) to give 4-{[(5- {isobutyl [(5-methyl-2- Furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} 4.68 g of methyl benzoate was obtained.
[0076] 実施例 7 [0076] Example 7
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフ ラン- 6-ィル)ォキシ]メチル }桂皮酸メチル 160mgと塩化ニッケル (Π) · 6水和物 14mgを、 メタノール 5mlと THF 1mlに溶解し、これに氷冷下、水素化ホウ素ナトリウム 28mgをカロ えた。室温にて 3時間攪拌した後、反応液に 1M塩酸を加え、酢酸ェチルで抽出し、 有機層を無水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 =4: 1)で精製し、 3-(4-{[(5-{イソ ブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル） ォキシ]メチル }フエ二ル)プロピオン酸メチル 155mgを得た。  4- {[(5- {Isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} 14 mg of nickel (·) hexahydrate was dissolved in 5 ml of methanol and 1 ml of THF, and 28 mg of sodium borohydride was added thereto under ice cooling. After stirring at room temperature for 3 hours, 1M hydrochloric acid was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3- (4-{[(5- {isobutyl [(5-methyl -2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} phenyl) methyl propionate 155 mg was obtained.
[0077] 実施例 8 [0077] Example 8
4- {[(5- {((2R)- 3- {[tert-ブチルジフエニル)シリル]ォキシ }- 2-メチルプロピル) [(5-メチ ル- 2-フリル)スルホニル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル } 安息香酸メチル 453mgを THF 6mlに溶解し、これに 1Mテトラプチルアンモ -ゥムフル オリド THF溶液 0.9mlを加え、室温にて 1時間攪拌した。反応液に炭酸水素ナトリウ ム水溶液を加えた後、酢酸ェチルで抽出し、有機層を無水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： 1〜1： 1)で精製し、 4- {[(5- {[(2R)- 3-ヒドロキシ- 2-メチルプロピル] [(5 -メチル- 2-フリル)スルホニル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メ チル }安息香酸メチル 296mgを得た。 4- {[(5- {((2R)-3- {[tert-Butyldiphenyl) silyl] oxy}-2-methylpropyl) [(5-methyl-2-furyl) sulfonyl] amino} -2,3 -Dihydro-1-benzofuran-6-yl) oxy] methyl} 453 mg of methyl benzoate was dissolved in 6 ml of THF, 0.9 ml of 1M tetraptylammo-um fluoride THF solution was added thereto, and the mixture was stirred at room temperature for 1 hour. . Sodium bicarbonate in the reaction solution Aqueous solution was added, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous 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 to 1: 1) to give 4-{[(5- {[(2R) -3- Hydroxy-2-methylpropyl] [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate (296 mg) was obtained.
実施例 9 Example 9
4-({[5- (イソブチルァミノ) -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル]ォキシ }メチル)安息 香酸メチル 360mgをピリジン 10mlに溶解し、これにベンゼンスルホユルクロリド 231mg を加え、室温にて終夜攪拌した。反応液を減圧濃縮した後、残渣に食塩水を加え、 酢酸ェチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を留去 し、得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン：酢酸ェチル =3 : 1) で精製し、 4- [({5- [イソブチル (フエ-ルスルホ -ル)ァミノ]- 2,3-ジヒドロ- 1-ベンゾフラ ン -6-ィル }ォキシ)メチル]安息香酸メチル 477mgを得た。  4-({[5- (Isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) methyl benzoate 360 mg is dissolved in 10 ml of pyridine and dissolved in benzenesulfuryl chloride. 231 mg was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (toluene: ethyl acetate = 3: 1) to give 4-[({5- [isobutyl ( 477 mg of phenylsulfol) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoate were obtained.
実施例 10 Example 10
tert-ブチル (2-フリルメトキシ)ジフエ-ルシラン 16.5gを 1,2-ジクロロェタン 100mlに溶 解し、これに SO -ピリジン複合体 27.3gを加え、 80°Cにて 6日間攪拌した。室温まで冷  16.5 g of tert-butyl (2-furylmethoxy) diphenylsilane was dissolved in 100 ml of 1,2-dichloroethane, 27.3 g of SO-pyridine complex was added thereto, and the mixture was stirred at 80 ° C. for 6 days. Cool to room temperature
3  Three
却した後、反応液に DMF 1mlと塩ィ匕ォキサリル 25.3mlをカ卩え、室温にて 4時間攪拌し た。反応液を減圧濃縮し、残渣に酢酸ェチルと炭酸水素ナトリウム水溶液を加えた後 、酢酸ェチルで抽出し、有機層を無水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 =5： 1)で 精製し、 5-({[tert-ブチル (ジフエ-ル)シリル]ォキシ }メチル)フラン- 2-スルホユルクロリ ド 10.9gを得た。 After the reaction, 1 ml of DMF and 25.3 ml of salt oxalyl were added to the reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the residue, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and 5-({[tert-butyl (diphenyl) silyl] oxy} methyl) 10.9 g of furan-2-sulfoyl chloride was obtained.
4-({[5- (イソブチルァミノ) -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル]ォキシ }メチル)安息 香酸メチル 300mgをピリジン 8mlに溶解し、これに 5-({[tert-ブチル (ジフエ-ル)シリル] ォキシ }メチル)フラン- 2_スルホユルクロリド 1.84gをカ卩え、室温にて終夜攪拌した。反 応液を減圧濃縮し、残渣に炭酸水素ナトリウム水溶液を加えた後、酢酸ェチルで抽 出し、有機層を無水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 =5 : 1)で精製し、 4-[({5-[{[ 5-({[tert-ブチル (ジフエ-ル)シリル]ォキシ }メチル )-2-フリル]スルホ-ル } (イソブチル） ァミノ] -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチル 537mgを 得た。 4-({[5- (isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) methyl) benzoate 300 mg is dissolved in 8 ml of pyridine, and 5-({ [tert-Butyl (diphenyl) silyl] oxy} methyl) furan-2-sulfuryl chloride 1.84 g was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4-[({5-[{[ 5-({[tert-butyl (diphenyl) silyl] oxy} methyl) -2-furyl] sulfol} (isobutyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy ) Methyl] methyl benzoate 537 mg was obtained.
[0079] 実施例 11 [0079] Example 11
4- [({5- [{[5- ({[tert-ブチル (ジフエ-ル)シリル]ォキシ }メチル )-2-フリル]スルホ-ル }( イソブチル)ァミノ] -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチ ル 537mgを THF 10mlに溶解し、これに 1Mテトラプチルアンモ -ゥムフルオリド THF 溶液 1.42mlを加え、室温にて 1時間攪拌した。反応液に炭酸水素ナトリウム水溶液を 加えた後、酢酸ェチルで抽出し、有機層を無水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)で精製し、 4- [({5- [{[5- (ヒドロキシメチル) -2-フリル]スルホ-ル }(イソブチル)アミ ノ] -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチル 334mgを得た  4- [({5- [{[5- ({[tert-butyl (diphenyl) silyl] oxy} methyl) -2-furyl] sulfol} (isobutyl) amino] -2,3-dihydro- 537 mg of 1-benzofuran-6-yl} oxy) methyl] benzoic acid was dissolved in 10 ml of THF, and 1.42 ml of 1M tetraptylammonium-fluoride THF solution was added thereto, followed by stirring at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous 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) to give 4-[({5-[{[5- (hydroxymethyl) -2 -Furyl] sulfol} (isobutyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] methyl benzoate 334 mg was obtained.
[0080] 実施例 12 [0080] Example 12
4-{[(5-ァミノ- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 45 Omgを 1,2-ジクロロェタン 7mlと酢酸 3.5mlに溶解し、これに 2-ァセチルビリジン 0.18ml とトリァセトキシ水素化ホウ素ナトリウム 413mgをカ卩え、室温にて 5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た後、クロ口ホルムで抽出し、有機層を無水硫 酸ナトリウムで乾燥した。溶媒を減圧留去して得られた 4-[({5-[α_ピリジン- 2-ィルェ チル)ァミノ] -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチルの粗 製物を、をピリジン 15mlに溶解し、これに 5-メチルフラン- 2-スルホユルクロリド 406mg を加え、室温にて終夜攪拌した。反応液を減圧濃縮した後、残渣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た。有機層を無水硫酸ナトリウムで乾燥した後 、溶媒を留去し、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)で精製し、 4- [({5- [[(5-メチル -2-フリル)スルホ -ル] (1-ピリジン- 2-ィル ェチル)ァミノ] -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチル 54 7mgを得た。  4-{[(5-Amino-2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 45 Omg was dissolved in 7 ml 1,2-dichloroethane and 3.5 ml acetic acid. 2-Acetylviridine (0.18 ml) and sodium triacetoxyborohydride (413 mg) were added and stirred at room temperature for 5 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. 4-[({{5- [α_Pyridin-2-ylethyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid obtained by distilling off the solvent under reduced pressure The crude methyl acid was dissolved in 15 ml of pyridine, and 406 mg of 5-methylfuran-2-sulfururyl chloride was added thereto, followed by stirring at room temperature overnight. After the reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 4-[({5-[[ (5-Methyl-2-furyl) sulfol] (1-pyridine-2-ylethyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] methyl benzoate 54 7 mg was obtained.
[0081] 実施例 13 4- {[(5- {[(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル )ォキシ]メチル }安息香酸メチル 300mgをピリジン 4mlに溶解し、これにプロピレンォキ シド 196mgを加え、封管中 100°Cにて終夜攪拌した。反応液を室温まで冷却した後、 減圧濃縮した。残渣に酢酸ェチルを加え、有機層を 1M塩酸、飽和食塩水で洗浄後 、無水硫酸マグネシウムで乾燥した。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（トルエン:酢酸ェチル =4: 1)で精製し、 4-{[(5-{(2-ヒドロキシ プロピル) [(5-メチル -2-フリル)スルホ -ル]アミノ}- 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィ ル)ォキシ]メチル }安息香酸メチル 333mgを得た。 [0081] Example 13 4- {[(5- {[(5-Methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 300 mg into 4 ml of pyridine Dissolved, 196 mg of propylene oxide was added thereto, and the mixture was stirred overnight at 100 ° C in a sealed tube. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the organic layer was washed with 1M hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: ethyl acetate = 4: 1) to give 4-{[(5-{(2-hydroxypropyl) [(5-methyl- 2-Furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate (333 mg) was obtained.
[0082] 実施例 14 [0082] Example 14
4- {[(5- {(2-ヒドロキシプロピル) [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシプロピル }安息香酸メチル 433mgを DMF 4mlに溶解し、 これに水素化ナトリウム（55%) 165mgとヨウ化メチル 0.82mlをカ卩え、封管中 80°Cにて 2 日間攪拌した。反応液を室温まで冷却した後、減圧濃縮した。残渣に炭酸水素ナトリ ゥム水溶液を加え、酢酸ェチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した 後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン： 酢酸ェチル =3： 1)で精製し、 4- {[(5- {(2-メトキシプロピル) [(5-メチル -2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 281 mgを得た。  4- {[(5- {(2-hydroxypropyl) [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxypropyl} methyl benzoate 433 mg Was dissolved in 4 ml of DMF, and 165 mg of sodium hydride (55%) and 0.82 ml of methyl iodide were added thereto and stirred at 80 ° C for 2 days in a sealed tube. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene: ethyl acetate = 3: 1) to give 4-{[(5- {( 2-Methoxypropyl) [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate (281 mg) was obtained.
[0083] 実施例 15 [0083] Example 15
4- {[(5- {[(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル )ォキシ]メチル }安息香酸メチル 222mgを THF 5mlに溶解し、これに 2- (ジメチルァミノ） エタノール 53mg、トリフエ-ルホスイン 262mg及びァゾカルボン酸ジェチル（40%トルェ ン溶液) 0.458mlをカ卩え、室温にて 5時間攪拌した。反応液に水を加え、酢酸ェチルで 抽出した。有機層を食塩水で洗浄後、無水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〜クロ口ホルム：メタノール = 100： 1)で精製し、 4-{[(5-{[2- (ジメチルァミノ)ェチル ][(5 -メチル- 2-フリル)スルホニル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メ チル }安息香酸メチル 188mgを得た。 [0084] 実施例 16 4- {[(5- {[(5-Methyl-2-furyl) sulfoyl] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methyl benzoate 222 mg into THF 5 ml After dissolution, 53 mg of 2- (dimethylamino) ethanol, 262 mg of triphenylphosphine and 0.458 ml of jetyl azocarboxylate (40% toluene solution) were added and stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous 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 to blackform: methanol = 100: 1) to give 4-{[(5-{[ 2- (Dimethylamino) ethyl] [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} methylbenzoate (188 mg) was obtained. [0084] Example 16
4-({[5- (イソブチルァミノ) -2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル]ォキシ }メチル)安息 香酸メチル 250mgを 1,2-ジクロロェタン 10mlに溶解し、これにトリェチルァミン 0.29mlと 塩ィ匕ベンゾィル 231mgを加え、室温にて終夜攪拌した。反応液に炭酸水素ナトリウム 水溶液をを加え、クロ口ホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した後 、溶媒を留去し、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 =5： 1〜3： 1)で精製し、 4- [({5- [ベンゾィル (イソブチル)ァミノ]- 2,3-ジヒドロ- 1- ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチル 318mgを得た。  4-({[5- (isobutylamino) -2,3-dihydro-1-benzofuran-6-yl] oxy} methyl) methyl) benzoate 250 mg was dissolved in 1,2-dichloroethane 10 ml, 0.29 ml of triethylamine and 231 mg of salt benzoyl were added and stirred overnight at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 3: 1) to give 4-[({ There were obtained 318 mg of methyl 5- [benzoyl (isobutyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoate.
[0085] 実施例 188 [0085] Example 188
Ν'-ヒドロキシ- 4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒド 口- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }ベンゼンカルボキシイミドアミド 507mgを DM F5mlに溶解し、これに氷冷下ピリジンと 0.107mLとクロロギ酸 2-ェチルへキシル 196mg を加え、 5°Cにて 1時間攪拌した。反応液を酢酸ェチルで抽出し、有機層を水、飽和 食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた 残渣を、キシレン lO.OmLに溶解し、 13時間加熱還流した。反応液に酢酸ェチルとへ キサンを加え、析出した不溶物を濾取した。得られた不溶物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 =50:1〜20:1)で精製し、得られた粗製物を酢酸 ェチルから再結晶し、 N-イソブチル -5-メチル - N- (6-{[4-(5-ォキソ - 4,5-ジヒドロ- 1,2, 4-ォキサジァゾール -3-ィル)ベンジル]ォキシ }-2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル） フラン- 2-スルホンアミド 364mgを得た。  Ν'-Hydroxy-4- {[(5- {Isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl} benzene Carboxymidamide (507 mg) was dissolved in DM F (5 ml), and pyridine, 0.107 mL and 2-ethylhexyl chloroformate (196 mg) were added to the solution under ice cooling, and the mixture was stirred at 5 ° C for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in xylene 10 mL and heated to reflux for 13 hours. Ethyl acetate and hexane were added to the reaction solution, and the precipitated insoluble material was collected by filtration. The obtained insoluble matter was purified by silica gel column chromatography (black mouth form: methanol = 50: 1 to 20: 1), and the resulting crude product was recrystallized from ethyl acetate to give N-isobutyl-5-methyl. -N- (6-{[4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-5 -Yl) Furan-2-sulfonamide 364 mg was obtained.
[0086] 実施例 189 [0086] Example 189
N-{6-[(4-シァノベンジル)ォキシ ]- 2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル }-N-イソブチ ル -5-メチルフラン- 2-スルホンアミド 300mgをトルエン 6mLに懸濁し、アジ化トリメチル スズ 331mgを加えた。反応液を 8時間加熱還流した後、室温に戻し、終夜攪拌した。 反応液に MeOH12mL、 1M塩酸 16mLをカ卩え、室温にて 2時間攪拌した。反応液を水 にあけて、酢酸ェチルで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸 マグネシウムで乾燥した。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（クロ口ホルム:メタノール =95:1〜90:10)で精製し、得られた粗製物を 水とエタノールの混合溶媒を用いて結晶化し、 N-イソブチル -5-メチル -N— (6-{[4-(1 H-テトラゾール -5-ィル)ベンジル]ォキシ }-2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル)フラ ン- 2-スルホンアミド 115mgを得た。 N- {6-[(4-Cyanobenzyl) oxy] -2,3-dihydro-1-benzofuran-5-yl} -N-isobutyl-5-methylfuran-2-sulfonamide 300 mg suspended in 6 mL toluene It became cloudy and 331 mg of trimethyltin azide was added. The reaction was heated to reflux for 8 hours, then returned to room temperature and stirred overnight. To the reaction solution, 12 mL of MeOH and 16 mL of 1M hydrochloric acid were added and stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (black mouth form: methanol = 95: 1 to 90:10), and the resulting crude product was purified. N-isobutyl-5-methyl-N— (6-{[4- (1 H-tetrazol-5-yl) benzyl] oxy} -2,3-dihydro 115 mg of 1-benzofuran-5-yl) furan-2-sulfonamide was obtained.
[0087] 実施例 190 [0087] Example 190
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾフ ラン- 6-ィル)ォキシ]メチル }安息香酸 500mgを DMF 7.5mLに溶解し、これに CDI 183 mgを加え、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と 1,8-ジァザビシ クロ [5.4.0]ゥンデ力- 7-ェンをカ卩え、室温にて 15時間攪拌した後、 60°Cで 3時間攪拌 した。反応液を室温まで放冷した後、 0.2M HC1で pHを 3にした後、酢酸ェチルで抽 出した。有機層を水、食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。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（クロ口ホルム:メ タノール =100:0〜90:10)で精製し、得られた粗製物を 2-プロノ V—ルカも再結晶し、 4-{[(5-{イソブチル [(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラ ン -6-ィル)ォキシ]メチル }-N- (メチルスルホ -ル)ベンズアミド 120mgを得た。  4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid 500 mg DMF 7.5 It melt | dissolved in mL, CDI 183 mg was added to this, and it stirred at room temperature for 3 hours. Methanesulfonamide and 1,8-diazabicyclo [5.4.0] unde force-7-en were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours and then stirred at 60 ° C for 3 hours. The reaction solution was allowed to cool to room temperature, adjusted to pH 3 with 0.2M HC1, and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 90:10), and the resulting crude product was purified with 2-prono V-Luca. 4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} 120 mg of -N- (methylsulfol) benzamide was obtained.
[0088] 実施例 191 [0088] Example 191
3- {[(4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベン ゾフラン- 6-ィル)ォキシ]メチル }ベンゾィル)ァミノ]スルホ-ル }プロピル酢酸 668mgをメ タノール 10mLに溶解し、これに 1M水酸化ナトリウム水溶液 5.1mLを加え、室温にて 30 分間攪拌した。反応液を 1M塩酸水で中和した後、酢酸ェチルで抽出した。有機層を 水、食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。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（クロ口ホルム：メタノール：酢酸 =9 0:5:5)で精製し、得られた残渣に重曹水を加え塩基性 (pH=8)にした後、酢酸ェチル で抽出した。有機層を水、食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。 溶媒を減圧留去して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、 N- [(3-ヒドロキシプロピル)スルホ -ル] -4-{[(5-{イソブチル [(5-メチル - 2-フリル） スルホニル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }べンズアミド 54 3mgを得た。  3- {[(4- {[(5- {Isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoyl ) Amino] sulfol} propyl acetic acid (668 mg) was dissolved in methanol (10 mL), and 1 M aqueous sodium hydroxide solution (5.1 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: acetic acid = 90: 5: 5), and sodium bicarbonate water was added to the resulting residue to give a basic (pH = 8), followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from a mixed solvent of hexane and ethyl acetate, and N-[(3-hydroxypropyl) sulfol] -4-{[(5- { 3 mg of isobutyl [(5-methyl-2-furyl) sulfonyl] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzamide 54 was obtained.
[0089] 実施例 192 4-{[(5-{イソブチル [(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 口- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸 300mgを THF4.0mLに溶解し、こ れに氷冷下、ボラン- THF錯体の 1M THF溶液 1.19mLをカ卩え、室温にて 2時間攪拌し た。反応液に水-酢酸混合液を加えた後、減圧濃縮した。得られた残渣に水を加え 酢酸ェチルで抽出した。有機層を水、食塩水で洗浄した後、無水硫酸マグネシウム 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 一（へキサン：酢酸ァチル =1:2)で精製し、得られた粗成物をジェチルエーテルを用 いて結晶化し、 N- (6-{[4- (ヒドロキシメチル)ベンジル]ォキシ }-2,3-ジヒドロ- 1-ベンゾ フラン- 5-ィル) -N-イソブチル -4-メチル -1,3-チアゾール -2-スルホンアミド 162mgを 得た。 [0089] Example 192 4-{[(5- {Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl } 300 mg of benzoic acid was dissolved in 4.0 mL of THF, and 1.19 mL of a 1M THF solution of borane-THF complex was added thereto under ice cooling, followed by stirring at room temperature for 2 hours. A water-acetic acid mixture was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2), and the resulting crude product was crystallized using jetyl ether. (6-{[4- (hydroxymethyl) benzyl] oxy} -2,3-dihydro-1-benzofuran-5-yl) -N-isobutyl-4-methyl-1,3-thiazole-2-sulfone 162 mg of amide was obtained.
[0090] 実施例 193 [0090] Example 193
4- [({5- [[(5-メチル -2-フリル)スルホ -ル] (2-ォキソプロピル)ァミノ]- 2,3-ジヒドロ- 1- ベンゾフラン- 6-ィル }ォキシ)メチル]安息香酸メチル 212mgを 1,2-ジクロロェタン 3.0m Lに溶解し、これに氷冷下三フッ化ジェチルァミノ硫黄 685mgをカ卩え、室温にて 6日間 攪拌した。反応液を氷水にあけ、これに飽和炭酸水素ナトリウム水溶液を加えた後、 酢酸ェチルで抽出した。有機層を食塩水で洗浄後、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 ァチル =3:2)で精製し、 4-{[(5-{(2,2-ジフルォロプロピル) [(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸メチル 168 mgを得た。  4-[({5-[[(5-Methyl-2-furyl) sulfol] (2-oxopropyl) amino] -2,3-dihydro-1-benzofuran-6-yl} oxy) methyl] benzoic acid Methyl acid (212 mg) was dissolved in 1,2-dichloroethane (3.0 mL). Under ice-cooling, 685 mg of cetylaminosulfur trifluoride was added thereto, and the mixture was stirred at room temperature for 6 days. The reaction mixture was poured into ice water, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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: 2) to give 4-{[(5-{(2,2-difluoropropyl) 168 mg of methyl [(5-methyl-2-furyl) sulfo] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoate was obtained.
[0091] 上記実施例 1〜16及び実施例 188〜193の方法と同様にして、後記表 19〜82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 19〜82に実施 例化合物の構造及び物理化学的データを示す。  [0091] In the same manner as in the above Examples 1 to 16 and Examples 188 to 193, Example compounds shown in Tables 19 to 82 to be described later were produced using the corresponding raw materials. Tables 19 to 82 show the structures and physicochemical data of the example compounds.
[0092] また、表 83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、また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。 [0092] Table 83 shows the structure of another compound 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.
[0093] [表 3] [S挲] [S600]
Figure imgf000042_0001
[0093] [Table 3] [S 挲] [S600]
Figure imgf000042_0001
[權] 600]
Figure imgf000042_0002
[權] 600]
Figure imgf000042_0002
.M760C/900Zdf/X3d 017 .60ΪΖΪ/900Ζ OAV n 6oo]
Figure imgf000043_0002
.M760C / 900Zdf / X3d 017 .60ΪΖΪ / 900Ζ OAV n 6oo]
Figure imgf000043_0002
[9挲] [9600]
Figure imgf000043_0003
[9 挲] [9600]
Figure imgf000043_0003
Figure imgf000043_0001
Figure imgf000043_0001
L 60£/900ZdT/13d VP .60ΪΖΪ/900Ζ OAV [8挲] [8600] L 60 £ / 900ZdT / 13d VP .60ΪΖΪ / 900Ζ OAV [8 挲] [8600]
Figure imgf000044_0001
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000044_0002
.M760C/900Zdf/X3d 317 .60ΪΖΪ/900Ζ OAV [e [6600] .M760C / 900Zdf / X3d 317 .60ΪΖΪ / 900Ζ OAV [e [6600]
Figure imgf000045_0002
Figure imgf000045_0002
Figure imgf000045_0001
Figure imgf000045_0001
L 60£/900ZdT/13d .60ΪΖΪ/900Ζ OAV
Figure imgf000046_0001
Figure imgf000046_0003
L 60 £ / 900ZdT / 13d .60ΪΖΪ / 900Ζ OAV
Figure imgf000046_0001
Figure imgf000046_0003
[0100] [表 10]
Figure imgf000046_0002
Figure imgf000046_0004
[0100] [Table 10]
Figure imgf000046_0002
Figure imgf000046_0004
[0101] [表 11] βοιο] [0101] [Table 11] βοιο]
Figure imgf000047_0002
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0001
L 60£/900Zd /lDd 9P .60ΪΖΪ/900Ζ OAV L 60 £ / 900Zd / lDd 9P .60ΪΖΪ / 900Ζ OAV
[£i [εοτο] [£ i [εοτο]
Figure imgf000048_0001
Figure imgf000048_0001
w\ [雨 o] w \ [rain o]
Figure imgf000049_0002
Figure imgf000049_0002
Figure imgf000049_0001
Figure imgf000049_0001
L 60£/900ZdT/13d IP .60ΪΖΪ/900Ζ OAV ¾-dip-s'e 8Ή 611 L 60 £ / 900ZdT / 13d IP .60ΪΖΪ / 900Ζ OAV ¾-dip-s'e 8Ή 611
- da 811  -da 811
： N3 L\\  : N3 L \\
ινα u m ινα u m
Figure imgf000050_0001
Figure imgf000050_0001
[91挲] [9010]
Figure imgf000050_0004
[91 挲] [9010]
Figure imgf000050_0004
Figure imgf000050_0002
Figure imgf000050_0002
[SI挲] [SOTO]
Figure imgf000050_0005
[SI 挲] [SOTO]
Figure imgf000050_0005
Figure imgf000050_0003
Figure imgf000050_0003
,tf60£/900Zdf/13d L60TZI/900I OAV , tf60 £ / 900Zdf / 13d L60TZI / 900I OAV
Figure imgf000051_0001
Figure imgf000051_0004
Figure imgf000051_0001
Figure imgf000051_0004
Figure imgf000051_0002
Figure imgf000051_0002
[81挲] [8010]
Figure imgf000051_0005
[81 挲] [8010]
Figure imgf000051_0005
Figure imgf000051_0003
Figure imgf000051_0003
m 010] m 010]
L 60£/900ZdT/13d 6 .60ΪΖΪ/900Ζ OAV [oz [οπο] L 60 £ / 900ZdT / 13d 6.60ΪΖΪ / 900Ζ OAV [oz [οπο]
Figure imgf000052_0002
Figure imgf000052_0002
Figure imgf000052_0001
Figure imgf000052_0001
L 60£/900ZdT/13d 09 .60ΪΖΪ/900Ζ OAV //:/ O /- 60ε900ί1£-60m900iAV L 60 £ / 900ZdT / 13d 09 .60ΪΖΪ / 900Ζ OAV //: / O /-60ε900ί1 £ -60m900iAV
Figure imgf000053_0001
Figure imgf000053_0001
FP： 500； NMRl ： 2.10 (3H, s), 2.28-2.54 (2H, m).3.10 (2H.1. J = 8.3 Hz).3.62-3.95 (2H. m), 4.28-4.36 (】H. m). 4.40-4.46 (IH, m), 4.55 (2H, t, J = 8.3 Hz), 4.62-4.80 (1H，FP: 500; NMRl: 2.10 (3H, s), 2.28-2.54 (2H, m) 3.10 (2H.1. J = 8.3 Hz). 3.62-3.95 (2H. M), 4.28-4.36 (】 H. m). 4.40-4.46 (IH, m), 4.55 (2H, t, J = 8.3 Hz), 4.62-4.80 (1H,
1 m), 4.85-4.95 (IH, m), 5.06-5.19 (III, m), 6.13 (IH. d, J = 1 m), 4.85-4.95 (IH, m), 5.06-5.19 (III, m), 6.13 (IH.d, J =
3.5 Hz).6.58 (IH, s)， 6.85 (IH, d, J 3.0 Hz).6.92-7.00 (1H， m), 7.43 (2H, brs), 7.94 (2H, d, J = 8.3 Hz), 12.96 (IH, brs) 3.5 Hz) .6.58 (IH, s), 6.85 (IH, d, J 3.0 Hz) .6.92-7.00 (1H, m), 7.43 (2H, brs), 7.94 (2H, d, J = 8.3 Hz), 12.96 (IH, brs)
FN： 486； NMRl ： 1.40-1.92 (411, m).2.10 (3H, d， J = 2.7 Hz), 3.11 (2H， t, J = 8.3 Hz), 2.80-3.80 (5H, m), 4.56 (2H, t, J = 8.3 Hz), 4.86-4.93 (IH, m), 5.12 (IH, d, .1 = 3.2 Hz), 6.14FN: 486; NMRl: 1.40-1.92 (411, m) .2.10 (3H, d, J = 2.7 Hz), 3.11 (2H, t, J = 8.3 Hz), 2.80-3.80 (5H, m), 4.56 ( 2H, t, J = 8.3 Hz), 4.86-4.93 (IH, m), 5.12 (IH, d, .1 = 3.2 Hz), 6.14
1 -CH2-2THFur (IH, brs), 6.58 (IH, s), 6.83 (IH, d, J = 3.0 Hz), 7.01 (IH, s). 1 -CH 2 -2THFur (IH, brs), 6.58 (IH, s), 6.83 (IH, d, J = 3.0 Hz), 7.01 (IH, s).
7.41 (2H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.8 Hz).12.97 (1ΗΓ brs) 7.41 (2H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.8 Hz) 12.97 (1Η Γ brs)
Sal： HC1； FP： 527； NMRl： 1.54-1.98 (3H, m), 2.09 (3H. s). 2.12-2.24 (IH, m), 2.70 (1.5H. s), 2.85 (1.5H, s). Sal: HC1; FP: 527; NMRl: 1.54-1.98 (3H, m), 2.09 (3H. S). 2.12-2.24 (IH, m), 2.70 (1.5H. S), 2.85 (1.5H, s) .
Me 3.00-3.16 (3H, m), 3.30-3.58 (2H, m). 3.76-4.20 (2H, m), 4.52-4.62 (2H, m), 4.86 (IH, t, J = 3.2 IIz), 5.13 (IH, t. J =Me 3.00-3.16 (3H, m), 3.30-3.58 (2H, m). 3.76-4.20 (2H, m), 4.52-4.62 (2H, m), 4.86 (IH, t, J = 3.2 IIz), 5.13 (IH, t. J =
1 3.1 Hz), 6.12-6.19 (IH, m), 6.61 (IH, d, J 9.8 Hz), 1 3.1 Hz), 6.12-6.19 (IH, m), 6.61 (IH, d, J 9.8 Hz),
6.85-6.90 (IH, m)， 7.08 (IH, d. J = 9.3 IIz).7.47 (2H, dd, J = 19.1, 8.3 Hz).7.96 (2H, d, J = 7.8 Hz), 10.55-10.90 (IH, m), 12.97 (IH, brs).  6.85-6.90 (IH, m), 7.08 (IH, d. J = 9.3 IIz) .7.47 (2H, dd, J = 19.1, 8.3 Hz) .7.96 (2H, d, J = 7.8 Hz), 10.55-10.90 (IH, m), 12.97 (IH, brs).
Sal： HC1； FP： 527； NMRl： 1.78-2.00 (4H, m), 2.08 (3H, s).2.92-3.06 (211, m), 3.08-3.18 (2H. m), 3.26-3.34 (2H, m), 3.50-3.58 (2H, m), 3.80-3.90 (IH, m). 3.98-4.10 (1H， m), Sal: HC1; FP: 527; NMRl: 1.78-2.00 (4H, m), 2.08 (3H, s) .2.92-3.06 (211, m), 3.08-3.18 (2H.m), 3.26-3.34 (2H, m), 3.50-3.58 (2H, m), 3.80-3.90 (IH, m). 3.98-4.10 (1H, m),
1 4.52-4.63 (2H, m)， 4.86 (IH, d. J = 3.1 Hz), 5.12 (III, d. J = 1 4.52-4.63 (2H, m), 4.86 (IH, d. J = 3.1 Hz), 5.12 (III, d. J =
3.2 Hz), 6.14 (IH, d， J = 3.4 Hz), 6.62 (IH, s), 6.89 (IH. d, J - 3.4 Hz), 7.14 (IH, s), 7.44 (2H, d. J = 8.3 Hz), 7.95 (2H, d, J = 8.3 Hz),】0.50 (IH, brs), 12.98 (IH, brs).  3.2 Hz), 6.14 (IH, d, J = 3.4 Hz), 6.62 (IH, s), 6.89 (IH. D, J-3.4 Hz), 7.14 (IH, s), 7.44 (2H, d. J = 8.3 Hz), 7.95 (2H, d, J = 8.3 Hz),] 0.50 (IH, brs), 12.98 (IH, brs).
Sal： HC1； FF： 543； NMRl： 2.09 (3H, s), 3.04-3.18 (411, m), 3.24-3.44 (4H, m)， 3.66-3.81 (2H, m), 3.82-3.98 (3H, m), 4.00-4.19 (IH, m).4.50-4.64 (2H. m), 4.88 (1H， d. J = 13.2 Sal: HC1; FF: 543; NMRl: 2.09 (3H, s), 3.04-3.18 (411, m), 3.24-3.44 (4H, m), 3.66-3.81 (2H, m), 3.82-3.98 (3H, m), 4.00-4.19 (IH, m) .4.50-4.64 (2H.m), 4.88 (1H, d.J = 13.2
1 Hz), 5.13 (IH, d, J = 13.2 Hz), 6.11-6.17 (IH, m). 6.62 。 (IH, s).6.90 (IH, d， J = 3.4 Hz), 7.09 (IH, s).7.75 (2H, d. J = 8.3 IIz), 7.95 (211, d, J = 8.3 Hz), 10.87 (IH, brs), 12.98 (IH, brs) 1 Hz), 5.13 (IH, d, J = 13.2 Hz), 6.11-6.17 (IH, m). 6.62. (IH, s) .6.90 (IH, d, J = 3.4 Hz), 7.09 (IH, s) .7.75 (2H, d. J = 8.3 IIz), 7.95 (211, d, J = 8.3 Hz), 10.87 (IH, brs), 12.98 (IH, brs)
Figure imgf000055_0001
Figure imgf000055_0001
〔〕0114 [] 0114
Figure imgf000056_0001
Figure imgf000056_0001
〔 [
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000058_0001
/7:60£900ifc1>d ZS/ O.6S2900ZAV. / 7: 60 £ 900ifc1> d ZS / O.6S2900ZAV.
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0001
Figure imgf000059_0002
/60f/:9002Tl£ 89/ /-60S90 O0ZAV. / 60f /: 9002Tl £ 89 / / -60S90 O0ZAV.
Figure imgf000060_0001
Figure imgf000060_0001
〔〕∞πο /7: 0£900zfc>d 6S O.6sziAV [] ∞πο / 7: 0 £ 900zfc> d 6S O.6sziAV
Figure imgf000061_0001
Figure imgf000061_0001
〔¾u〔s66n Ex Syn Str DAT [¾u [s66n Ex Syn Str DAT
FN： 484； NMRl ： 1.02-1.28 (611, m), 2.16 (3H, s). 2.92-3.11 (2H, m), 3.12-3.26 (III, m), 4.35-4.53 (IH, m), 4.52 (2H,し J = 8.3 Hz), 4.62-4.84 (IH, FN: 484; NMRl: 1.02-1.28 (611, m), 2.16 (3H, s). 2.92-3.11 (2H, m), 3.12-3.26 (III, m), 4.35-4.53 (IH, m), 4.52 (2H, then J = 8.3 Hz), 4.62-4.84 (IH,
81 1 m), 5.17 (2H, s)， 5.86-5.93 (IH, m), 81 1 m), 5.17 (2H, s), 5.86-5.93 (IH, m),
5.93-6.00 (IH, m), 6.63 (IH. s). 6.86 (1H， s), 7.61 (2H, d, J = 8.3 Hz), 7.97
Figure imgf000062_0001
(2H, d, J = 8.3 Hz), 12.98 (IH. brs) 5.93-6.00 (IH, m), 6.63 (IH. S). 6.86 (1H, s), 7.61 (2H, d, J = 8.3 Hz), 7.97
Figure imgf000062_0001
(2H, d, J = 8.3 Hz), 12.98 (IH.brs)
[0120] [表 30] [0120] [Table 30]
Figure imgf000062_0002
Figure imgf000062_0002
Figure imgf000062_0003
Figure imgf000062_0003
[0121] [表 31]
Figure imgf000063_0001
[0121] [Table 31]
Figure imgf000063_0001
Figure imgf000063_0002
32]
Figure imgf000063_0002
32]
Figure imgf000064_0001
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0002
3] m [ssio]
Figure imgf000065_0002
3] m [ssio]
Figure imgf000065_0002
Figure imgf000065_0001
Figure imgf000065_0001
m [^το]
Figure imgf000065_0003
m [^ το]
Figure imgf000065_0003
L 60£/900Zdr/13d 89 .60ΪΖΐ/900ί ΟΛ\ 〕92ΐο
Figure imgf000066_0002
Figure imgf000066_0003
L 60 £ / 900Zdr / 13d 89 .60ΪΖΐ / 900ί ΟΛ \ ] 92ΐο
Figure imgf000066_0002
Figure imgf000066_0003
Figure imgf000066_0001
Figure imgf000066_0001
〕0 X— R ] 0 X—R
11
COつ Na CO-Na
( (
101 ( 1 101 (1
COつ Na CO-Na
( 1 ( (1 (
COつ H I CO HI
103 3  103 3
(
Figure imgf000067_0001
(
Figure imgf000067_0001
[0128] [表 38] [0128] [Table 38]
Figure imgf000068_0001
Figure imgf000068_0001
Figure imgf000068_0002
39]
Figure imgf000068_0002
39]
Figure imgf000069_0001
Figure imgf000069_0001
Figure imgf000069_0002
40]
Figure imgf000070_0001
Figure imgf000070_0003
Figure imgf000069_0002
40]
Figure imgf000070_0001
Figure imgf000070_0003
41]
Figure imgf000070_0002
41]
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000071_0001
Figure imgf000071_0003
Figure imgf000071_0003
Figure imgf000071_0002
Figure imgf000071_0002
Ltt60£/900Zd£/∑Jd 69 Ζ.60ΪΖΐ/900ί OAV Ltt60 £ / 900Zd £ / ∑Jd 69 Ζ.60ΪΖΐ / 900ί OAV
Figure imgf000072_0001
Figure imgf000072_0001
Figure imgf000072_0003
Figure imgf000072_0003
Figure imgf000072_0002
Figure imgf000072_0002
L 60£/900Zd /lDd 01 .60ΪΖΪ/900Ζ OAV
Figure imgf000073_0001
L 60 £ / 900Zd / lDd 01 .60ΪΖΪ / 900Ζ OAV
Figure imgf000073_0001
Ex Syn R1 DATEx Syn R 1 DAT
8 8 EP ： 516(1VT) 8 8 EP: 516 (1VT)
Me  Me
] 40 6 Me EP ： 457( +)] 40 6 Me EP ： 457 ( + )
141 6 iPr EP ： 486(M+)141 6 iPr EP: 486 (M + )
142 6 nBu EP ： 500(M+)142 6 nBu EP: 500 (M + )
143 6 -CH2- cPr EP ： 498(M+)143 6 -CH 2 -cPr EP: 498 (M + )
144 6 -CH2-cBu EP ： 535(MNa+)144 6 -CH 2 -cBu EP: 535 (MNa + )
145 6 -CH2-cPen EP ： 526(M+)145 6 -CH 2 -cPen EP ： 526 (M + )
146 6 -CH2-cHex EP ： 540146 6 -CH 2 -cHex EP: 540
147 6 Bn EP ： 556(MNa+)147 6 Bn EP: 556 (MNa + )
148 6 -(CH2)2OH FP ： 488148 6-(CH 2 ) 2 OH FP: 488
149 6 -(CH2)3OH EP ： 503149 6-(CH 2 ) 3 OH EP ： 503
150 6 -(CH2)2OMe FP ： 501(M+)150 6-(CH 2 ) 2 OMe FP: 501 (M + )
151 6 -(CH2)3OMe EP ： 516(M+)151 6-(CH 2 ) 3 OMe EP ： 516 (M + )
152 6 -CH2-2THFur FP ： 528 152 6 -CH 2 -2THFur FP: 528
153 6 〜 EP ： 557(M+) 153 6-EP: 557 (M + )
Z o Z o
154 6 ~"Y^ 丁 BDPS  154 6 ~ "Y ^ Ding BDPS
API ： 777(MNa+) Me API: 777 (MNa + ) Me
Z\^、o丁 BDPS  Z \ ^, o BDPS
155 6 CP ： 754(M+) 155 6 CP: 754 (M + )
Me  Me
156 8 EP ： 516(M+) 156 8 EP: 516 (M + )
Me 5] [9ε TO] Me 5] [9ε TO]
Figure imgf000074_0002
Figure imgf000074_0002
Figure imgf000074_0001
Figure imgf000074_0001
L 60£/900ZdT/13d ZL .60ΪΖΪ/900Ζ OAV
Figure imgf000075_0003
Figure imgf000075_0001
Figure imgf000075_0002
L 60 £ / 900ZdT / 13d ZL .60ΪΖΪ / 900Ζ OAV
Figure imgf000075_0003
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000076_0001
Figure imgf000076_0001
Figure imgf000076_0002
9]
Figure imgf000077_0001
Figure imgf000076_0002
9]
Figure imgf000077_0001
Ex Syn R1 R2 R5 DATEx Syn R 1 R 2 R 5 DAT
220 2 iBu 3-F-Ph Na FP:501 220 2 iBu 3-F-Ph Na FP: 501
221 1 4-Mc-2Thia H FP:520 221 1 4-Mc-2Thia H FP: 520
Et  Et
222 1 iBu 4-Me-2Thia H FP:503(M')  222 1 iBu 4-Me-2Thia H FP: 503 (M ')
223 1 4-Me-2Thia H FP:520 223 1 4-Me-2Thia H FP: 520
Et  Et
224 1 5-Me-2Fur H FP:502(M+) 224 1 5-Me-2Fur H FP: 502 (M + )
Et  Et
225 1 5-Me-2Fur H FP:502(M+) 225 1 5-Me-2Fur H FP: 502 (M + )
Et  Et
226 2 -CH2-2Py 5-Me-2Fur Na FP:521(M+)226 2 -CH 2 -2Py 5-Me-2Fur Na FP: 521 (M + )
227 2 -CH2-2Py 4-Me-2Thia Na FP:539227 2 -CH 2 -2Py 4-Me-2Thia Na FP: 539
228 2 -CH2-2Py 3,5-diF-Ph Na FP:553(M+)228 2 -CH 2 -2Py 3,5-diF-Ph Na FP: 553 (M + )
229 2 iBu 3,5-diF-Ph Na FP:519 50] 229 2 iBu 3,5-diF-Ph Na FP: 519 50]
Figure imgf000078_0001
51] Ex Syn R1 R5 DAT
Figure imgf000078_0001
51] Ex Syn R 1 R 5 DAT
242 2 -CH2CH(Me)-Et Na FP : 499(M+)242 2 -CH2CH (Me) -Et Na FP: 499 (M + )
243 1 -CH2CH(OH)-iPr H FP 516 h 243 1 -CH 2 CH (OH) -iPr H FP 516 h
244 1 -CH2C XH(OH)-nPr H FP 516244 1 -CH 2 C XH (OH) -nPr H FP 516
245 1 -CH2CI I(O HH)-nBu H FP 530245 1 -CH 2 CI I (O HH) -nBu H FP 530
246 1 H FP 516 246 1 H FP 516
Me  Me
247 1 H FP 516  247 1 H FP 516
Me  Me
248 1 -CH2CH(Mc)-CH2OMe H FP 516248 1 -CH 2 CH (Mc) -CH 2 OMe H FP 516
249 2 Na FP 500 249 2 Na FP 500
Me  Me
250 1 -(CH2)4OH H FP 502250 1-(CH 2 ) 4 OH H FP 502
25 1 2 -CH2CONH2 Na FP 48725 1 2 -CH2CONH2 Na FP 487
252 2 -CII2-4Py Na FP 521252 2 -CII 2 -4Py Na FP 521
253 1 -(CH2)2CH(OH)-Me H FP 502253 1-(CH 2 ) 2 CH (OH) -Me H FP 502
254 2 Na FP 526254 2 Na FP 526
255 2 -CI I2- 3 Fur Na FP 510 255 2 -CI I 2 - 3 Fur Na FP 510
256 2 -CH2-3 I hi Na FN •524256 2 -CH 2 -3 I hi Na FN • 524
257 1 -(CH2)C(Me)2-OMe H FP 530257 1-(CH 2 ) C (Me) 2-OMe H FP 530
258 2 -CH2-3Pyrida Na FP 522258 2 -CH 2 -3 Pyrida Na FP 522
259 2 -CH2-2Pyra Na FP 522259 2 -CH 2 -2 Pyra Na FP 522
260 2 - CH2CONMe2 Na FP 515260 2-CH 2 CONMe 2 Na FP 515
261 2 -CH2-(6-Me-2Py) Na FP 535261 2 -CH 2- (6-Me-2Py) Na FP 535
262 2 3THFur Na FP : 522(MNa")262 2 3THFur Na FP: 522 (MNa ")
263 2 -CH2-4Thia Na FP 527263 2 -CH 2 -4Thia Na FP 527
264 2 -C - 2Pyrimi Na FP 522264 2 -C-2Pyrimi Na FP 522
265 2 Et Na FP 458 66 2 -CH2C( )2-Mc Na FP： 507(M+) 67 2 Na FN 488 265 2 Et Na FP 458 66 2 -CH 2 C () 2 -Mc Na FP: 507 (M + ) 67 2 Na FN 488
F 52]
Figure imgf000080_0001
F 52]
Figure imgf000080_0001
Ex Syn R1 R5 DAT Ex Syn R 1 R 5 DAT
268 1 H FP:519 268 1 H FP: 519
Et  Et
269 1 H FP:519  269 1 H FP: 519
Et  Et
270 1 -(CH2)3OMe Na FP:519270 1-(CH 2 ) 3 OMe Na FP: 519
271 2 -CH2-2Py Na FP:538 271 2 -CH 2 -2Py Na FP: 538
Me  Me
272 2 Na EP:531 ヒ〇  272 2 Na EP: 531
273 2 -CH2CH(F)-Me Na FP:507273 2 -CH 2 CH (F) -Me Na FP: 507
274 2 -CII2C(F)2-Me Na FP:525274 2 -CII 2 C (F) 2 -Me Na FP: 525
275 1 H FP:519 275 1 H FP: 519
Me  Me
276 1 H FP:519  276 1 H FP: 519
Me 53] Me 53]
Figure imgf000081_0001
Figure imgf000081_0001
Figure imgf000081_0002
54]
Figure imgf000081_0002
54]
Figure imgf000082_0001
55] FN：605 ； NMRl ： 0.85 (6H, br)， 1.55
Figure imgf000082_0001
55] FN: 605; NMRl: 0.85 (6H, br), 1.55
(IH, m), 1.85 (2H, m), 2.14 (3H. s), 3.10 (2H, t. J = 8.5 Hz), 3.35 (2H, m), 3.49 (2H, d， J = 6.1 Hz). 3.56 (2H， m)， (IH, m), 1.85 (2H, m), 2.14 (3H.s), 3.10 (2H, t. J = 8.5 Hz), 3.35 (2H, m), 3.49 (2H, d, J = 6.1 Hz) 3.56 (2H, m),
191 191 4.55 (2H, m), 4.91 (I H. d. J = 13.2 Hz), 191 191 4.55 (2H, m), 4.91 (I H.d.J = 13.2 Hz),
5.14 (IH, d, J = 13.2 Hz), 6.16 (I H, d, J
Figure imgf000083_0001
= 3.3 Hz), 6.56 ( IH. s), 6.82 (I H, d， J = 5.14 (IH, d, J = 13.2 Hz), 6.16 (IH, d, J
Figure imgf000083_0001
= 3.3 Hz), 6.56 (IH.s), 6.82 (IH, d, J =
3.3 Hz), 6.99 (1 H， s), 7.44 (211. d, J = 8.2 Hz), 7.93 (2H, d, J = 8.2 Hz)  3.3 Hz), 6.99 (1 H, s), 7.44 (211.d, J = 8.2 Hz), 7.93 (2H, d, J = 8.2 Hz)
[0146] [表 56] [0146] [Table 56]
Figure imgf000083_0003
Figure imgf000083_0003
[0147] [表 57]  [0147] [Table 57]
Figure imgf000083_0002
Figure imgf000083_0002
Figure imgf000083_0004
Figure imgf000083_0004
[0148] [表 58] =
Figure imgf000084_0001
[0148] [Table 58] =
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000085_0001
Ex Syn R1 R5 DAT Ex Syn R 1 R 5 DAT
FP:503 ； NMRl ： 0.83 (3H, s)， 0.85 (3H, s), 1.48-1.60 (IH. m)， 2.26 (3H. d. J = 0.7 Hz), 3.17 (2H, t， J = 8.7 Hz), 3.45 (2H, d, J = 7.1 Hz).4.51 FP: 503; NMRl: 0.83 (3H, s), 0.85 (3H, s), 1.48-1.60 (IH. M), 2.26 (3H. D. J = 0.7 Hz), 3.17 (2H, t, J = 8.7 Hz), 3.45 (2H, d, J = 7.1 Hz) .4.51
313 2 iBu Na (2H, t, J = 8.4 Hz), 4.60-4.74 (111, br). 4.83-5.00 313 2 iBu Na (2H, t, J = 8.4 Hz), 4.60-4.74 (111, br). 4.83-5.00
(IH, br), 6.59 (IH, s)， 7.06 (IH, s), 7.13 (2H. d, J = 8.1 Hz), 7.55 (IH, d. J = 1.1 Hz), 7.84 (2H， d, .1 = 8.0 Hz) (IH, br), 6.59 (IH, s), 7.06 (IH, s), 7.13 (2H.d, J = 8.1 Hz), 7.55 (IH, d.J = 1.1 Hz), 7.84 (2H, d, .1 = 8.0 Hz)
P： 538； NMRl： 2.25 (3H, d, J = 0.7 Hz), 3.12 (2H, t, J = 8.5 Hz), 4.46 (2H， t, J 8.7 Hz), 4.62-5.22 (4H, br), 6.63 (1H， s), 7.02 (III, s), 7.15 (2H, d, J = P: 538; NMRl: 2.25 (3H, d, J = 0.7 Hz), 3.12 (2H, t, J = 8.5 Hz), 4.46 (2H, t, J 8.7 Hz), 4.62-5.22 (4H, br), 6.63 (1H, s), 7.02 (III, s), 7.15 (2H, d, J =
314 2 -CII2-2Py Na 314 2 -CII 2 -2Py Na
8.0 Hz), 7.21-7.27 (IH, m)， 7.51-7.59 (2H, m), 7.69-7.76 (IH, m), 7.87 (2H, d. J = 8.3 IIz), 8.39-8.45 (IH, m)  8.0 Hz), 7.21-7.27 (IH, m), 7.51-7.59 (2H, m), 7.69-7.76 (IH, m), 7.87 (2H, d. J = 8.3 IIz), 8.39-8.45 (IH, m )
315 1 H FP:519 315 1 H FP: 519
Et  Et
316 1 H FP:519 316 1 H FP: 519
Et  Et
317 2 -CH2CH(F)-Me Na EN :505 60] 317 2 -CH 2 CH (F) -Me Na EN: 505 60]
Figure imgf000086_0001
Figure imgf000086_0001
Figure imgf000086_0002
61] s
Figure imgf000086_0002
61] s
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000087_0001
Figure imgf000087_0001
ε9εΐο9 ε9εΐο9
[ 9 [SSTOj
Figure imgf000088_0003
[9 [SSTOj
Figure imgf000088_0003
Figure imgf000088_0001
Figure imgf000088_0001
[晦] [ I0]
Figure imgf000088_0004
[晦] [I0]
Figure imgf000088_0004
Figure imgf000088_0002
Figure imgf000088_0002
L 60£/900ZdT/13d 98 .60ΪΖΪ/900Ζ OAV
Figure imgf000089_0001
Figure imgf000089_0002
L 60 £ / 900ZdT / 13d 98 .60ΪΖΪ / 900Ζ OAV
Figure imgf000089_0001
Figure imgf000089_0002
[0156] [表 66] [0156] [Table 66]
Figure imgf000089_0003
Figure imgf000089_0003
[0157] [表 67]
Figure imgf000090_0001
[0157] [Table 67]
Figure imgf000090_0001
Figure imgf000090_0002
68]
Figure imgf000090_0002
68]
[69挲] [63 TO] [69 挲] [63 TO]
Figure imgf000091_0002
Figure imgf000091_0002
Figure imgf000091_0001
Figure imgf000091_0001
L 60£/900ZdT/13d 68 .60ΪΖΪ/900Ζ OAV
Figure imgf000092_0001
L 60 £ / 900ZdT / 13d 68 .60ΪΖΪ / 900Ζ OAV
Figure imgf000092_0001
Ex Syn R1 R2 DATEx Syn R 1 R 2 DAT
387 4 iBu 5-Me-2Fur EP:542(MNa+)387 4 iBu 5-Me-2Fur EP: 542 (MNa + )
388 15 5-Me-2Fur EP:534388 15 5-Me-2Fur EP: 534
389 4 iBu 4-Me-2Thia EP:537389 4 iBu 4-Me-2Thia EP: 537
390 4 iBu 3,5-diF-Ph EP:574(MNa")390 4 iBu 3,5-diF-Ph EP: 574 (MNa ")
391 13 3,5-diF-Ph EP:550(MNa+) 391 13 3,5-diF-Ph EP: 550 (MNa + )
OH  OH
Me  Me
392 15 5-Me-2Fur EP:548 ヒ 0  392 15 5-Me-2Fur EP: 548 HI 0
Me  Me
393 15 3,5-diF-Ph EP:548 し O  393 15 3,5-diF-Ph EP: 548 Shi O
394 15 -CH2CH(F)-Me 5-Me-2Fur EP： 546(MNa^)394 15 -CH 2 CH (F) -Me 5-Me-2Fur EP: 546 (MNa ^)
395 15 -CH2CH(F)-Me 3,5-diF-Ph EP:578(MNa+)395 15 -CH 2 CH (F) -Me 3,5-diF-Ph EP: 578 (MNa + )
396 15 -CH2CH(F)-Me 4-Me-2Thia EP: 541 (MNa396 15 -CH 2 CH (F) -Me 4-Me-2Thia EP: 541 (MNa
397 15 5-Me-2Fur API：555397 15 5-Me-2Fur API: 555
398 15 -CH2-2Py 3,5-diF-Ph API：587 398 15 -CH 2 -2Py 3,5-diF-Ph API: 587
[表 70] [Table 70]
^〔〕〔u016071 ^ [] [U016071
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000094_0001
Ex Syn R' DAT  Ex Syn R 'DAT
425 13 EP:533 425 13 EP: 533
Et  Et
n  n
426 13 ，, EP:533 ェ  426 13,, EP: 533
427 13 -(CII2)3OMe EP:555(MNa— )427 13-(CII 2 ) 3 OMe EP: 555 (MNa—)
428 15 -CH2-2Py EP:552 428 15 -CH 2 -2Py EP: 552
Me  Me
429 15 P:545 し〇  429 15 P: 545
430 15 -CH2CH(F)-Mc FP:521430 15 -CH 2 CH (F) -Mc FP: 521
431 4 -CH2C(0)-Me FP:517431 4 -CH 2 C (0) -Me FP: 517
432 193 -CH2C(F)2-Me FP:539 432 193 -CH 2 C (F) 2 -Me FP: 539
433 6 EP:533 433 6 EP: 533
Me  Me
434 6 ^^ ^OTBDPS  434 6 ^^ ^ OTBDPS
EP:533 Me  EP: 533 Me
435 8 EP:533  435 8 EP: 533
Me  Me
436 8 EP:533  436 8 EP: 533
Me 2] Me 2]
Figure imgf000095_0001
Figure imgf000095_0001
Figure imgf000095_0002
73]
Figure imgf000095_0002
73]
Figure imgf000096_0001
Figure imgf000096_0003
74]
Figure imgf000096_0002
[0164] [表 75]
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000096_0001
Figure imgf000096_0003
74]
Figure imgf000096_0002
[0164] [Table 75]
Figure imgf000097_0001
Figure imgf000097_0002
[0165] [表 76] [0165] [Table 76]
Figure imgf000098_0001
Figure imgf000098_0001
Figure imgf000098_0004
Figure imgf000098_0004
77] 77]
Figure imgf000098_0002
Figure imgf000098_0002
Ex Syn R' DAT  Ex Syn R 'DAT
492 13 EP:514 492 13 EP: 514
Et  Et
493 13 EP:514 493 13 EP: 514
Et  Et
494 4 -(CH2)3OMe FP:514494 4-(CH 2 ) 3 OMe FP: 514
495 15
Figure imgf000098_0003
FP:533 [0167] [表 78]495 15
Figure imgf000098_0003
FP: 533 [0167] [Table 78]
Figure imgf000099_0001
Figure imgf000099_0004
Figure imgf000099_0001
Figure imgf000099_0004
[0168] [表 79] [0168] [Table 79]
Figure imgf000099_0002
Figure imgf000099_0005
Figure imgf000099_0002
Figure imgf000099_0005
[0169] [表 80] [0169] [Table 80]
Figure imgf000099_0003
Figure imgf000099_0003
Ex Syn R' R2 DATEx Syn R 'R 2 DAT
505 4 3,5-diF-Ph FP:545(M+)505 4 3,5-diF-Ph FP: 545 (M + )
506 4 iBu 5-Me-2Fur FP:513(M+)506 4 iBu 5-Me-2Fur FP: 513 (M + )
507 4 4-Me-2Thia FP:531507 4 4-Me-2Thia FP: 531
508 15 3,5-diF-Ph FP:549( +)508 15 3,5-diF-Ph FP: 549 ( + )
509 15 -CH2CH(F)-Me 5-Me-2Fur FN:515509 15 -CH 2 CH (F) -Me 5-Me-2Fur FN: 515
510 15 4-Me-2Thia FP:535 510 15 4-Me-2Thia FP: 535
Figure imgf000100_0002
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0001
[18挲] [ΟΖΐΟ] [18 挲] [ΟΖΐΟ]
Z.^^60£/900Zdf/X3d 86 .60ΪΖΙ/900Ζ OAV
Figure imgf000101_0001
83] Z. ^^ 60 £ / 900Zdf / X3d 86 .60ΪΖΙ / 900Ζ OAV
Figure imgf000101_0001
83]
Figure imgf000102_0001
産業上の利用可能性
Figure imgf000102_0001
Industrial applicability
本発明化合物は、 EP1受容体拮抗活性に優れており、 EP1受容体が関与する疾患 、特に過活動膀胱に伴う頻尿 ·尿意切迫感や尿失禁，膀胱炎，間質性膀胱炎，前立 腺炎などの下部尿路疾患の治療薬として有用である。 配列表フリーテキスト The compound of the present invention is excellent in EP1 receptor antagonistic activity. Diseases involving EP1 receptor, particularly frequent urination associated with overactive bladder, urinary urgency, urinary incontinence, cystitis, interstitial cystitis, prostate It is useful as a therapeutic agent for lower urinary tract diseases such as adenitis. Sequence listing free text
以下の配列表の数字見出し < 223 >には、「Artificial Sequence」の説明を記載す る。具体的には、配列表の配列番号 1の配列で表されるアミノ酸配列は、人工的に合 成したシグナルペプチド配列である。また、配列表の配列番号 2の配列で表されるァ ミノ酸配列は、人工的に合成した FLAG配列である。  The numerical heading <223> in the sequence listing below describes the “Artificial Sequence”. Specifically, the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing is an artificially synthesized signal peptide sequence. The amino acid sequence represented by SEQ ID NO: 2 in the sequence listing is an artificially synthesized FLAG sequence.

Claims

請求の範囲 The scope of the claims
式 (I)で示される二環式へテロ環誘導体又はその製薬学的に許容される塩。 A bicyclic heterocyclic derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
[化 11] [Chemical 11]
Figure imgf000104_0001
Figure imgf000104_0001
[式中の記号は以下の意味を示す。 [The symbols in the formula have the following meanings.
A環：置換されて!、てもよ 、5〜8員へテロ環、  Ring A: Substituted! Maybe a 5- to 8-membered heterocycle,
B環：シクロアルキル、ベンゼン環、又はへテロ環、  Ring B: cycloalkyl, benzene ring, or hetero ring,
R1:置換されて 、てもよ 、低級アルキル、又はへテロ環基、 R 1 : substituted, optionally lower alkyl, or heterocyclic group,
R2:C アルキル、シクロアルキル、ァリール、ヘテロ環基、 -低級アルキレン-シクロアR 2 : C alkyl, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloa
1-12 1-12
ルキル、 -低級アルキレン-ァリール、又は-低級アルキレン-ヘテロ環基、 Alkyl, -lower alkylene-aryl, or -lower alkylene-heterocyclic group,
(ただし、 R2における C アルキル、シクロアルキル、ァリール、及びへテロ環基は置 (However, C alkyl, cycloalkyl, aryl, and heterocyclic groups in R 2 are not substituted.
1-12  1-12
換されていてもよい。 ) It may be replaced. )
R3:- OH、 - C(O)- OR°、 - C(O)- NR5R5a、 1H-テトラゾール- 5-ィル、又は 5-ォキソ -4,5- ジヒドロ- 1,2,4-ォキサジァゾール -3-ィル、 R 3: - OH, - C (O) - OR °, - C (O) - NR 5 R 5a, 1H- tetrazol - 5 I le, or 5 Okiso 4,5-dihydro - 1,2, 4-oxadiazol-3-yl,
R°、及び R°°:同一又は異なって、 H、又は低級アルキル、  R ° and R °°: the same or different, H or lower alkyl,
R5、及び R5a:同一又は異なって、 - R°、 -低級アルキレン- NR°R°°、 -低級アルキレン- C 0 R°、シクロアルキル、ァリール、ヘテロ環基、 -低級アルキレン-シクロアルキル、 -低R 5 and R 5a : the same or different, -R °, -lower alkylene-NR ° R °°, -lower alkylene-C 0 R °, cycloalkyl, aryl, heterocyclic group, -lower alkylene-cycloalkyl -Low
2 2
級アルキレン-ァリール、 -低級アルキレン-ヘテロ環基、 -so -低級アルキル、 -so≡ Secondary alkylene-aryl, -lower alkylene-heterocyclic group, -so -lower alkyl, -so≡
2 2 低級アルキレン- 0R°、又は- SO≡低級アルキレン- 0- C(0)-低級アルキル、  2 2 lower alkylene-0R °, or-SO≡lower alkylene-0-C (0) -lower alkyl,
2  2
(ただし、 R5、 R5aにおけるシクロアルキル、ァリール、及びへテロ環基は置換されてい てちよい。 ) (However, the cycloalkyl, aryl, and heterocyclic groups in R 5 and R 5a may be substituted.)
R4:ノヽロゲン、低級アルキル、ハロゲノ低級アルキル、シァ入ニトロ、 - 0R°、 - 0-ハロ ゲノ低級アルキル、 -C(0)R°、又は- NR°C(0)R°°、 R 4 : nanogen, lower alkyl, halogeno lower alkyl, nitro-nitro, -0R °, -0-halogeno lower alkyl, -C (0) R °, or -NR ° C (0) R °°,
m : 0、 1、又は 2、 (ただし、 mが 2である場合、 2つの R4は同一又は互いに異なっていてもよい。 ) J：低級アルキレン、低級ァルケ-レン、 -0-低級アルキレン-、 -低級アルキレン- 0-、 -0-低級ァルケ-レン-、 -低級ァルケ-レン- 0-、 - C(0)NR°-、又は- NR°C(0)-、 X：単結合、低級アルキレン、低級ァルケ-レン、 -0-低級アルキレン-、 -0-低級アル ケ-レン-、 - NR°-低級アルキレン-、 -S(O) -低級アルキレン-、又は- S(O) -低級アル ケニレン-、 m: 0, 1, or 2, (However, when m is 2, two R 4 s may be the same or different from each other.) J: lower alkylene, lower alkylene, -0-lower alkylene-, -lower alkylene-0-,- 0-lower alkylene-, -lower alkylene- 0-, -C (0) NR °-, or -NR ° C (0)-, X: single bond, lower alkylene, lower alkylene,- 0-lower alkylene-, -0-lower alkylene-, -NR ° -lower alkylene-, -S (O) -lower alkylene-, or -S (O) -lower alkenylene-,
n: 0、 1、又は 2。  n: 0, 1, or 2.
L:単結合、 - C(O)-、又は- S(O) -。 ]  L: single bond, -C (O)-, or -S (O)-. ]
2  2
[2] Jが- 0-低級アルキレン-である請求の範囲第 1項記載の化合物。  [2] The compound according to claim 1, wherein J is -0-lower alkylene-.
[3] Xが単結合、低級アルキレン、又は低級ァルケ-レンである請求の範囲第 2項記載の 化合物。 [3] The compound according to claim 2, wherein X is a single bond, lower alkylene, or lower alkylene.
[4] B環がベンゼン、チォフェン、チアゾール、又はピリジンである請求の範囲第 3項記載 の化合物。  [4] The compound according to claim 3, wherein the ring B is benzene, thiophene, thiazole, or pyridine.
[5] A環がフラン、 2,3-ジヒドロフラン、 2,3-ジヒドロチォフェン、 2, 3-ジヒドロチォフェン 1,1 -ジォキシド、ピロリン、 3,4-ジヒドロ- 2H-ピラン、 1,3-ジォキノール、又は 2,3-ジヒドロ- 1 ,4-ジォキシンである請求の範囲第 4項記載の化合物。  [5] Ring A is furan, 2,3-dihydrofuran, 2,3-dihydrothiophene, 2,3-dihydrothiophene 1,1-dioxide, pyrroline, 3,4-dihydro-2H-pyran, 1, The compound according to claim 4, which is 3-dioquinol or 2,3-dihydro-1,4-dioxin.
[6] Lが- S(O) -である請求の範囲第 5項記載の化合物。  [6] The compound according to claim 5, wherein L is —S (O) 2 —.
2  2
[7] R2が置換されて 、てもよ 、ァリール、又は置換されて 、てもよ 、ヘテロ環基である請 求の範囲第 6項記載の化合物。 [7] The compound according to claim 6, wherein R 2 is substituted, aryl, or substituted, and is a heterocyclic group.
[8] R3が- CO H、又は 5-ォキソ -4,5-ジヒドロ- 1,2,4-ォキサジァゾール -3-ィルである請求 [8] A claim wherein R 3 is —CO 2 H or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl
2  2
の範囲第 7項記載の化合物。  A compound according to claim 7, wherein
[9] 式 (I-A)で示される二環式へテロ環誘導体又はその製薬学的に許容される塩。 [9] A bicyclic heterocyclic derivative represented by the formula (I-A) or a pharmaceutically acceptable salt thereof.
[化 12]  [Chemical 12]
R4A R 4A
(I-A)
Figure imgf000105_0001
[式中の記号は以下の意味を示す。 (IA)
Figure imgf000105_0001
[The symbols in the formula have the following meanings.
A1環：低級アルキルで置換されて!、てもよ 、2,3-ジヒドロフラン、 2,3-ジヒドロチォフエ ン、又は 2,3-ジヒドロチォフェン 1,1-ジォキシド、 A 1 ring: substituted with lower alkyl! May be 2,3-dihydrofuran, 2,3-dihydrothiophene, or 2,3-dihydrothiophene 1,1-dioxide,
B1環：ベンゼン環、又はチォフェン環、 B 1 ring: benzene ring or thiophene ring,
R1A: (1)- OH、（2)ハロゲン、（3)低級アルキル、 -0-低級アルキル、又はハロゲンで置 換さ R 1A : (1) -OH, (2) halogen, (3) lower alkyl, -0-lower alkyl, or halogen substituted
れて 、てもよ 、ピリジルカもなる群力も選択される基で置換されて 、てもよ 、低級 アルキル、 Also, the pyridylca group force may be substituted with a selected group, which may be a lower alkyl,
R2A: (1)ハロゲン、（2)低級アルキル、（3)- 0-低級アルキル力もなる群力も選択される基 で R 2A : (1) halogen, (2) lower alkyl, (3) 0-lower alkyl group power is also selected
置換されていてもよいフエ-ル、フリル、又はチアゾリル、 Optionally substituted phenol, furyl, or thiazolyl,
R3A:-CO H、又は 5-ォキソ -4,5-ジヒドロ- 1,2,4-ォキサジァゾール -3-ィル、 R 3A : -CO H, or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,
2  2
R4A: H、ハロゲン、低級アルキル、又は- 0-低級アルキル。 ] R 4A : H, halogen, lower alkyl, or -0-lower alkyl. ]
4-{[(5-{イソブチル [(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラ ン -6-ィル)ォキシ]メチル }安息香酸、  4-{[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4-{[(5-{イソブチル [(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 口- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、  4-{[(5- {Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl }benzoic acid,
4- {[(5- {[(2S)- 3-ヒドロキシ- 2-メチルプロピル] [(5-メチル -2-フリル)スルホニル]アミノト 4- {[(5- {[(2S) -3-Hydroxy-2-methylpropyl] [(5-methyl-2-furyl) sulfonyl] aminoto
2, 3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4- {[(6- {[(2R)- 3-ヒドロキシ- 2-メチルプロピル] [(5-メチル -2-フリル)スルホニル]ァミノ)- 4- {[(6- {[(2R)-3-Hydroxy-2-methylpropyl] [(5-methyl-2-furyl) sulfonyl] amino)-
2, 3-ジヒドロ- 1-ベンゾフラン- 5-ィル)ォキシ]メチル }安息香酸、 2,3-dihydro-1-benzofuran-5-yl) oxy] methyl} benzoic acid,
4- {[(5- {(2-フルォロプロピル) [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1- ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、  4- {[(5- {(2-fluoropropyl) [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4- [({6- [[(3-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 -1-ベンゾフラン- 5-ィル }ォキシ)メチル]安息香酸、  4-[({6- [[(3-Fluorophenyl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzofuran-5-yl} oxy) methyl] benzoic acid Acid,
4-[({6-[[(3,5-ジフルオロフェ -ル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -2,3-ジヒ ドロ- 1-ベンゾフラン- 5-ィル }ォキシ)メチル]安息香酸、  4-[({6-[[(3,5-Difluorophenyl) sulfol] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzofuran-5-yl} oxy ) Methyl] benzoic acid,
N-イソブチル -5-メチル - N- (6-{[4-(5-ォキソ - 4,5-ジヒドロ- 1,2,4-ォキサジァゾール- 3-ィル)ベンジル]ォキシ }-2,3-ジヒドロ- 1-ベンゾフラン- 5-ィル)フラン- 2-スルホンアミ ド、、 N-isobutyl-5-methyl-N- (6-{[4- (5-oxo- 4,5-dihydro-1,2,4-oxadiazole- 3-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-5-yl) furan-2-sulfonamide,
4- {[(6-{イソブチル [(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 口- 1-ベンゾフラン- 5-ィル)ォキシ]メチル }安息香酸、  4- {[(6- {Isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto-2,3-dihydric 1-benzofuran-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- 1-ベンゾフラン- 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-1-benzofuran-5 -Yl} oxy) methyl] benzoic acid,
5- {[(5-{イソブチル [(5-メチル - 2-フリル)スルホ -ル]アミノ}-2,3-ジヒドロ- 1-ベンゾフラ ン -6-ィル)ォキシ]メチル }チォフェン- 2-カルボン酸、  5- {[(5- {isobutyl [(5-methyl-2-furyl) sulfol] amino} -2,3-dihydro-1-benzofuran-6-yl) oxy] methyl} thiophene-2- carboxylic acid,
3-クロ口- 4-{[(5-{イソブチル [(4-メチル -1,3-チアゾール -2-ィル)スルホ -ル]アミノト 2, 3-black mouth 4-{[(5- {isobutyl [(4-methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,
3-ジヒドロ- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }安息香酸、 3-dihydro-1-benzofuran-6-yl) oxy] methyl} benzoic acid,
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノト 2,3-ジヒドロ- 1-ベンゾチェ ン -6-ィル)ォキシ]メチル }安息香酸、  4- {[(5- {isobutyl [(5-methyl-2-furyl) sulfol] aminoto 2,3-dihydro-1-benzochen-6-yl) oxy] methyl} benzoic acid,
5- {[(5-{イソブチル [(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 口- 1-ベンゾフラン- 6-ィル)ォキシ]メチル }チォフェン- 2-カルボン酸、  5- {[(5- {Isobutyl [(4-Methyl-1,3-thiazol-2-yl) sulfol] aminoto 2,3-dihydrido-1-benzofuran-6-yl) oxy] methyl } Thiophene-2-carboxylic acid,
4-[({5-[[(5-メチル - 2-フリル)スルホ -ル] (ピリジン- 2-ィルメチル)ァミノ] -2,3-ジヒドロ- 1-ベンゾチェン- 6-ィル }ォキシ)メチル]安息香酸、  4-[({5-[[(5-Methyl-2-furyl) sulfoyl] (pyridine-2-ylmethyl) amino] -2,3-dihydro-1-benzochen-6-yl} oxy) methyl ]benzoic acid,
及び  as well as
4- {[(5- {イソブチル [(5-メチル -2-フリル)スルホ -ル]アミノ}- 1,1-ジォキシド- 2,3-ジヒド 口- 1-ベンゾチェン- 6-ィル)ォキシ]メチル }安息香酸、  4- {[(5- {Isobutyl [(5-methyl-2-furyl) sulfoyl] amino}-1,1-dioxide-2,3-dihydrin 1-benzochen-6-yl) oxy] Methyl} benzoic acid,
力 なる群力 選択される請求の範囲第 1項記載の化合物又はその製薬学的に許容 される塩。  Power of group power The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected.
[11] 請求の範囲第 1項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第 11項記載の医薬組成物。  [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、膀胱炎、間質性膀胱炎、前立腺炎力 なる下部尿 路疾患の治療薬である請求の範囲第 12項記載の医薬組成物。  13. The pharmaceutical composition according to claim 12, which is a therapeutic agent for lower urinary tract disease such as frequent urination, urinary incontinence, cystitis, interstitial cystitis and prostatitis associated with overactive bladder.
[14] EP1受容体拮抗剤、過活動膀胱に伴う頻尿，尿失禁、膀胱炎、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第 1項記載の化合 物の使用。 請求の範囲第 1項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、膀胱炎、間質性膀胱炎、前立腺炎力 なる下部尿路疾 患の治療方法。 [14] Claims for the manufacture of a therapeutic agent for lower urinary tract disease consisting of EP1 receptor antagonist, frequent urination with overactive bladder, urinary incontinence, cystitis, interstitial cystitis, prostatitis Use of the compounds described in Section 1. Lower urinary tract disease comprising: frequent urination with overactive bladder, urinary incontinence, cystitis, interstitial cystitis, prostatitis power, comprising administering to a patient a therapeutically effective amount of the compound of claim 1 How to treat the patient.
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