JPH09208570A - Benzylpiperazine derivative - Google Patents
Benzylpiperazine derivativeInfo
- Publication number
- JPH09208570A JPH09208570A JP8171924A JP17192496A JPH09208570A JP H09208570 A JPH09208570 A JP H09208570A JP 8171924 A JP8171924 A JP 8171924A JP 17192496 A JP17192496 A JP 17192496A JP H09208570 A JPH09208570 A JP H09208570A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- piperazinyl
- phenylacetic acid
- acceptable salt
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical class C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 title claims description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- -1 4-halogenated methylphenylacetic acid ester Chemical class 0.000 claims abstract description 31
- 125000005843 halogen group Chemical group 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000004885 piperazines Chemical class 0.000 claims abstract description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 5
- QSOJNPXWLAPPPQ-UHFFFAOYSA-N methyl 2-[4-[(4-benzhydrylpiperazin-1-yl)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1CN1CCN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 QSOJNPXWLAPPPQ-UHFFFAOYSA-N 0.000 claims abstract 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 229960003424 phenylacetic acid Drugs 0.000 claims description 13
- 239000003279 phenylacetic acid Substances 0.000 claims description 13
- 239000000043 antiallergic agent Substances 0.000 claims description 12
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 10
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 10
- GLYCKDFIGYHRDR-UHFFFAOYSA-N 2-[4-[[4-(carboxymethyl)phenyl]methyl]piperazin-1-yl]benzoic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1CCN(C=2C(=CC=CC=2)C(O)=O)CC1 GLYCKDFIGYHRDR-UHFFFAOYSA-N 0.000 claims description 7
- CKZAYHUBOGNVDE-UHFFFAOYSA-N 2-[4-[(4-benzhydrylpiperazin-1-yl)methyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1CCN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 CKZAYHUBOGNVDE-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- YAORPZDQWBTFIW-UHFFFAOYSA-N 2-[4-[[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1CCN(C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1 YAORPZDQWBTFIW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- HOHZAJYRISBYPV-UHFFFAOYSA-N 2-[4-[(4-phenylpiperazin-1-yl)methyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1CCN(C=2C=CC=CC=2)CC1 HOHZAJYRISBYPV-UHFFFAOYSA-N 0.000 claims 1
- IFISWXYXUNVCPJ-UHFFFAOYSA-N 2-[4-[(4-pyridin-1-ium-2-ylpiperazin-1-yl)methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)O)=CC=C1CN1CCN(C=2N=CC=CC=2)CC1 IFISWXYXUNVCPJ-UHFFFAOYSA-N 0.000 claims 1
- LMYMAYHRJCQLHF-UHFFFAOYSA-N 2-[4-[[4-(2,5-dimethylphenyl)piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound CC1=CC=C(C)C(N2CCN(CC=3C=CC(CC(O)=O)=CC=3)CC2)=C1 LMYMAYHRJCQLHF-UHFFFAOYSA-N 0.000 claims 1
- CMWNOTLHGKJMCQ-UHFFFAOYSA-N 2-[4-[[4-(2-methylphenyl)piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound CC1=CC=CC=C1N1CCN(CC=2C=CC(CC(O)=O)=CC=2)CC1 CMWNOTLHGKJMCQ-UHFFFAOYSA-N 0.000 claims 1
- MIRGPFGMCOAASY-UHFFFAOYSA-N 2-[4-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound COC1=CC=CC(N2CCN(CC=3C=CC(CC(O)=O)=CC=3)CC2)=C1 MIRGPFGMCOAASY-UHFFFAOYSA-N 0.000 claims 1
- NVVMULLZXCKPHG-UHFFFAOYSA-N 2-[4-[[4-(4-methoxyphenyl)piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound C1=CC(OC)=CC=C1N1CCN(CC=2C=CC(CC(O)=O)=CC=2)CC1 NVVMULLZXCKPHG-UHFFFAOYSA-N 0.000 claims 1
- JBZRYOGBOFSLJK-UHFFFAOYSA-N 2-[4-[[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CN1CCN(C=2C=C(C=CC=2)C(F)(F)F)CC1 JBZRYOGBOFSLJK-UHFFFAOYSA-N 0.000 claims 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- BJTSGUUOTZVJRP-UHFFFAOYSA-N methyl 2-[4-[[4-[phenyl(pyridin-2-yl)methyl]piperazin-1-yl]methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1CN1CCN(C(C=2C=CC=CC=2)C=2N=CC=CC=2)CC1 BJTSGUUOTZVJRP-UHFFFAOYSA-N 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 51
- 238000006243 chemical reaction Methods 0.000 abstract description 37
- 239000000243 solution Substances 0.000 abstract description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 12
- 230000003266 anti-allergic effect Effects 0.000 abstract description 11
- 239000007924 injection Substances 0.000 abstract description 9
- 238000002347 injection Methods 0.000 abstract description 9
- 150000001412 amines Chemical class 0.000 abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
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- 229910052736 halogen Inorganic materials 0.000 abstract description 2
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- 239000012442 inert solvent Substances 0.000 abstract description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 abstract description 2
- 208000005801 spondylosis Diseases 0.000 abstract description 2
- 206010048908 Seasonal allergy Diseases 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 241000700159 Rattus Species 0.000 description 33
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 28
- 230000000694 effects Effects 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 206010030113 Oedema Diseases 0.000 description 23
- 239000000126 substance Substances 0.000 description 21
- 238000012360 testing method Methods 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 229960001340 histamine Drugs 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000003889 eye drop Substances 0.000 description 10
- 230000006698 induction Effects 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 8
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 8
- 229920001525 carrageenan Polymers 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 8
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 7
- 235000010418 carrageenan Nutrition 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229960000905 indomethacin Drugs 0.000 description 6
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- 206010002091 Anaesthesia Diseases 0.000 description 4
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 206010010726 Conjunctival oedema Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
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- WCOCCXZFEJGHTC-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(CBr)C=C1 WCOCCXZFEJGHTC-UHFFFAOYSA-N 0.000 description 3
- VPEJAZQEYWICME-UHFFFAOYSA-N 2-[4-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]phenyl]acetic acid Chemical compound COC1=CC=CC=C1N1CCN(CC=2C=CC(CC(O)=O)=CC=2)CC1 VPEJAZQEYWICME-UHFFFAOYSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
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- 108010058846 Ovalbumin Proteins 0.000 description 3
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- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
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- DFOZOWZBUMYFDD-UHFFFAOYSA-N 1-[phenyl(pyridin-2-yl)methyl]piperazine Chemical compound C1CNCCN1C(C=1N=CC=CC=1)C1=CC=CC=C1 DFOZOWZBUMYFDD-UHFFFAOYSA-N 0.000 description 1
- DTTOVSVQDLDGMW-UHFFFAOYSA-N 1-piperazin-2-ylpiperazine Chemical compound C1NCCNC1N1CCNCC1 DTTOVSVQDLDGMW-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- QTYBZIKZNLAJBO-UHFFFAOYSA-N 2-[4-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]phenyl]acetic acid;dihydrochloride Chemical compound Cl.Cl.COC1=CC=CC(N2CCN(CC=3C=CC(CC(O)=O)=CC=3)CC2)=C1 QTYBZIKZNLAJBO-UHFFFAOYSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
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- 238000010931 ester hydrolysis Methods 0.000 description 1
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000022760 infectious otitis media Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
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- APXOMRFLJBRHNX-UHFFFAOYSA-N methyl 2-[4-(bromomethyl)phenyl]acetate Chemical compound COC(=O)CC1=CC=C(CBr)C=C1 APXOMRFLJBRHNX-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、新規かつ有用なベ
ンジルピペラジン誘導体、その製造法並びにそれを有効
成分として含有してなる抗アレルギー剤および抗炎症剤
に関する。TECHNICAL FIELD The present invention relates to a novel and useful benzylpiperazine derivative, a method for producing the same, and an antiallergic agent and an antiinflammatory agent containing the same as an active ingredient.
【０００２】[0002]
【従来の技術】従来、種々の抗アレルギー剤が知られて
いるが、これらのうち抗アレルギー作用を有するピペラ
ジン誘導体として、オキサトミド（セルテクト）などが
既に市販されている。さらに、抗アレルギー作用を有す
るピペラジン誘導体として、セチリジンなどが知られて
いる（特公昭６３−１１３５３号公報）。しかしなが
ら、これら化合物の抗アレルギー作用は未だ充分満足す
べきものではなく、さらに強力な抗アレルギー作用を有
する化合物が求められている。2. Description of the Related Art Conventionally, various antiallergic agents have been known, and among them, oxatomide (Certect) and the like have already been marketed as piperazine derivatives having an antiallergic effect. Further, cetirizine and the like are known as piperazine derivatives having an antiallergic effect (Japanese Patent Publication No. 63-11353). However, the antiallergic effect of these compounds is not yet satisfactory, and there is a demand for compounds having a stronger antiallergic effect.
【０００３】[0003]
【発明が解決しようとする課題】このような状況下、本
発明者らは、これらの関連化合物の合成および薬効に関
して、鋭意研究を進めてきた。その結果、新規のベンジ
ルピペラジン誘導体の合成に成功し、しかもそれら化合
物が強力な抗アレルギー作用および抗炎症作用を有する
ことを見い出した。これら新知見に基づきさらに検討を
重ね、本発明を完成したものである。Under such circumstances, the present inventors have conducted earnest research on the synthesis and drug efficacy of these related compounds. As a result, they have succeeded in synthesizing novel benzylpiperazine derivatives, and found that these compounds have strong antiallergic and antiinflammatory effects. The present invention has been completed through further studies based on these new findings.
【０００４】[0004]
【課題を解決するための手段】本発明は、 （１）次の式（Ｉ）The present invention provides (1) the following formula (I):
【０００５】[0005]
【化４】 Embedded image
【０００６】［式（Ｉ）中、Ｒ1 は、ピリジン環あるい
は次の式（ＩＶ）または式（Ｖ）で表される基を示し、
Ｒ2 は水素原子または低級アルキル基を示す。[In the formula (I), R 1 represents a pyridine ring or a group represented by the following formula (IV) or formula (V),
R 2 represents a hydrogen atom or a lower alkyl group.
【０００７】[0007]
【化５】 Embedded image
【０００８】式（ＩＶ）中、Ｒ3 は水素原子、低級アル
キル基、ピリジン環またはハロゲン原子で置換されてい
てもよいベンゼン環を示し、Ｘはハロゲン原子を示す。
式（Ｖ）中、Ｒ4 およびＲ5 は、同一または異なって、
水素原子、低級アルキル基、低級アルコキシ基、ハロゲ
ン原子またはカルボキシル基を示す。］で表されるベン
ジルピペラジン誘導体またはその薬理学的に許容できる
塩（以下、本化合物という。）、In the formula (IV), R 3 represents a hydrogen atom, a lower alkyl group, a pyridine ring or a benzene ring which may be substituted with a halogen atom, and X represents a halogen atom.
In formula (V), R 4 and R 5 are the same or different,
It represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a carboxyl group. ] The benzyl piperazine derivative represented by these, or its pharmacologically acceptable salt (henceforth this compound),
【０００９】（２）上記（１）記載の化合物の製造法、
並びに(2) A method for producing the compound described in (1) above,
And
【００１０】（３）上記（１）記載のピペラジン誘導体
またはその薬理学的に許容できる塩を有効成分として含
有してなる抗アレルギー剤および抗炎症剤に関する。(3) An anti-allergic agent and an anti-inflammatory agent containing the piperazine derivative or the pharmaceutically acceptable salt thereof described in (1) above as an active ingredient.
【００１１】本化合物として、具体的には、下記の化合
物またはその薬理学的に許容できる塩が例示される。 （１）４−［（４−ジフェニルメチル−１−ピペラジニ
ル）メチル］フェニル酢酸メチルエステル （２）４−［（４−ジフェニルメチル−１−ピペラジニ
ル）メチル］フェニル酢酸 （３）４−［［４−（２−メトキシフェニル）−１−ピ
ペラジニル］メチル］フェニル酢酸 （４）４−［［４−（２−カルボキシフェニル）−１−
ピペラジニル］メチル］フェニル酢酸 （５）４−［［４−（２−ピリジル）−１−ピペラジニ
ル］メチル］フェニル酢酸 （６）４−［［４−（２−トリル）−１−ピペラジニ
ル］メチル］フェニル酢酸 （７）４−［（４−フェニル−１−ピペラジニル）メチ
ル］フェニル酢酸 （８）４−［［４−（２−フルオロフェニル）−１−ピ
ペラジニル］メチル］フェニル酢酸 （９）４−［［４−（２，５−ジメチルフェニル）−１
−ピペラジニル］メチル］フェニル酢酸 （１０）４−［［４−（４−メトキシフェニル）−１−
ピペラジニル］メチル］フェニル酢酸 （１１）４−［［４−（３−メトキシフェニル）−１−
ピペラジニル］メチル］フェニル酢酸 （１２）４−［［４−（３−トリフルオロメチルフェニ
ル）−１−ピペラジニル］メチル］フェニル酢酸 （１３）４−［［４−［フェニル−（２−ピリジル）メ
チル］−１−ピペラジニル］メチル］フェニル酢酸メチ
ルエステル （１４）４−［［４−［フェニル−（２−ピリジル）メ
チル］−１−ピペラジニル］メチル｝フェニル酢酸 （１５）４−［［４−［（４−クロロフェニル）フェニ
ルメチル］−１−ピペラジニル］メチル］フェニル酢酸
メチルエステル （１６）４−［［４−［（４−クロロフェニル）フェニ
ルメチル］−１−ピペラジニル］メチル］フェニル酢酸Specific examples of the present compound include the following compounds and pharmaceutically acceptable salts thereof. (1) 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid methyl ester (2) 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid (3) 4-[[4 -(2-Methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid (4) 4-[[4- (2-carboxyphenyl) -1-
Piperazinyl] methyl] phenylacetic acid (5) 4-[[4- (2-pyridyl) -1-piperazinyl] methyl] phenylacetic acid (6) 4-[[4- (2-tolyl) -1-piperazinyl] methyl] Phenylacetic acid (7) 4-[(4-phenyl-1-piperazinyl) methyl] phenylacetic acid (8) 4-[[4- (2-Fluorophenyl) -1-piperazinyl] methyl] phenylacetic acid (9) 4- [[4- (2,5-dimethylphenyl) -1
-Piperazinyl] methyl] phenylacetic acid (10) 4-[[4- (4-methoxyphenyl) -1-
Piperazinyl] methyl] phenylacetic acid (11) 4-[[4- (3-methoxyphenyl) -1-
Piperazinyl] methyl] phenylacetic acid (12) 4-[[4- (3-trifluoromethylphenyl) -1-piperazinyl] methyl] phenylacetic acid (13) 4-[[4- [phenyl- (2-pyridyl) methyl] ] -1-Piperazinyl] methyl] phenylacetic acid methyl ester (14) 4-[[4- [Phenyl- (2-pyridyl) methyl] -1-piperazinyl] methyl} phenylacetic acid (15) 4-[[4- [ (4-Chlorophenyl) phenylmethyl] -1-piperazinyl] methyl] phenylacetic acid methyl ester (16) 4-[[4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] methyl] phenylacetic acid
【００１２】式（Ｉ）中のＲ2 、式（ＩＶ）中のＲ3 お
よび式（Ｖ）中のＲ4 、Ｒ5 の低級アルキル基として
は、直鎖状、分岐状または環状であって、炭素数が１乃
至６のものが好ましい。具体的には、メチル基、エチル
基、ｎ−プロピル基、ｉｓｏ−プロピル基、シクロプロ
ピル基、ｎ−ブチル基、ｔｅｒｔ−ブチル基、ｓｅｃ−
ブチル基、ｎ−ペンチル基、１−エチルプロピル基およ
びｉｓｏ−ペンチル基などが挙げられる。[0012] R 2 in formula (I), examples of the lower alkyl group R 4, R 5 in R 3 and wherein in formula (IV) (V), a straight-chain, branched or cyclic Those having 1 to 6 carbon atoms are preferable. Specifically, methyl group, ethyl group, n-propyl group, iso-propyl group, cyclopropyl group, n-butyl group, tert-butyl group, sec-
Examples thereof include a butyl group, an n-pentyl group, a 1-ethylpropyl group and an iso-pentyl group.
【００１３】式（Ｖ）中のＲ4 およびＲ5 の低級アルコ
キシ基としては、直鎖状、分岐状または環状であって、
炭素数が１乃至６のものが好ましい。具体的には、メト
キシ基、エトキシ基、プロポキシ基、ｉｓｏ−プロポキ
シ基、ｎ−ブトキシ基、ｉｓｏ−ブトキシ基、ｔｅｒｔ
−ブトキシ基、ｎ−ペンチルオキシ基、ネオペンチルオ
キシ基、２−メチルブトキシ基、１，２−ジメチルプロ
ポキシ基および１−エチルプロポキシ基などが挙げられ
る。The lower alkoxy group represented by R 4 and R 5 in the formula (V) is linear, branched or cyclic,
Those having 1 to 6 carbon atoms are preferable. Specifically, methoxy group, ethoxy group, propoxy group, iso-propoxy group, n-butoxy group, iso-butoxy group, tert.
Examples include -butoxy group, n-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group and 1-ethylpropoxy group.
【００１４】式（ＩＶ）中、Ｒ3 はベンゼン環の場合環
上がハロゲン原子で置換されていてもよい。ハロゲン原
子としては、フッ素原子、塩素原子、臭素原子およびヨ
ウ素原子が挙げられる。式（Ｖ）中のＲ4 およびＲ5 の
ハロゲン原子も前記と同義である。In the formula (IV), when R 3 is a benzene ring, the ring may be substituted with a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The halogen atom of R 4 and R 5 in the formula (V) has the same meaning as described above.
【００１５】式（Ｉ）で表される本化合物は、式（Ｉ
Ｉ）［式中、Ｒ1 は、前記と同義である。］で表される
ピペラジン誘導体および式（ＩＩＩ）［式中、Ｒ2 は前
記と同義であり、Ｘはハロゲン原子を示し、そのハロゲ
ン原子は前記と同義である。］で表される４−ハロゲン
化メチルフェニル酢酸エステルを反応させることにより
合成することができる。以下、本化合物の製造法を詳細
に説明する。The compound represented by the formula (I) has the formula (I
I) [In the formula, R 1 has the same meaning as described above. ] The piperazine derivative represented by these, and Formula (III) [In formula, R < 2 > is synonymous with the above, X shows a halogen atom, and the halogen atom is synonymous with the above. ] It can synthesize | combine by making 4-halogenated methylphenylacetic acid ester represented by these react. Hereinafter, the method for producing the present compound will be described in detail.
【００１６】[0016]
【化６】 [Chemical 6]
【００１７】原料物質である式（ＩＩ）で表されるピペ
ラジン誘導体は、市販されたものを入手するか、または
公知の方法により、たとえば次の２つの方法のいずれか
により合成することができる。すなわち、下記の式で表
されるように、ハロゲン化ベンゼン誘導体とピペラジン
あるいはＮ−ベンジルピペラジンを炭酸アルカリ存在
下、有機溶媒中または無溶媒にて加熱することにより、
Ｎ−ベンジルピペラジンの場合はさらにパラジウムカー
ボン（Pd-C) により接触還元させることにより、化合物
（ＩＩ）を得ることができる。式中、Ｒ4 、Ｒ5 および
Ｘは前記と同義である。The starting material, the piperazine derivative represented by the formula (II), may be commercially available or may be synthesized by a known method, for example, one of the following two methods. That is, as represented by the following formula, by heating a halogenated benzene derivative and piperazine or N-benzylpiperazine in the presence of an alkali carbonate in an organic solvent or without a solvent,
In the case of N-benzylpiperazine, compound (II) can be obtained by catalytic reduction with palladium carbon (Pd-C). In the formula, R 4 , R 5 and X are as defined above.
【００１８】[0018]
【化７】 Embedded image
【００１９】または、下記の式で表されるように、アニ
リン誘導体とビス（ジハロゲンエチル）アミンのハロゲ
ン塩とを有機溶媒中または無溶媒にて加熱することによ
り、化合物（ＩＩ）を得ることができる。式中、Ｒ4 、
Ｒ5 およびＸは前記と同義である。Alternatively, as represented by the following formula, compound (II) can be obtained by heating an aniline derivative and a halogen salt of bis (dihalogenethyl) amine in an organic solvent or without solvent. it can. Where R 4 ,
R 5 and X are as defined above.
【００２０】[0020]
【化８】 Embedded image
【００２１】もう一方の原料物質である式（ＩＩＩ）で
表される４−ハロゲン化メチルフェニル酢酸エステル
は、市販されたものを入手するか、または公知の方法に
より、たとえば次のようにして合成することができる。
すなわち、ハロゲン化メチルフェニル酢酸と低級アルコ
ールを、硫酸または塩化水素存在下、ジクロロエタン中
で加熱することにより得ることができる。式中、Ｒ2 お
よびＸは前記と同義である。The 4-halogenated methylphenylacetic acid ester represented by the formula (III), which is the other starting material, is commercially available or is synthesized by a known method, for example, as follows. can do.
That is, it can be obtained by heating halogenated methylphenylacetic acid and a lower alcohol in dichloroethane in the presence of sulfuric acid or hydrogen chloride. In the formula, R 2 and X are as defined above.
【００２２】[0022]
【化９】 Embedded image
【００２３】このようにして得られた化合物（ＩＩ）お
よび化合物（ＩＩＩ）を、トリエチルアミンなどの有機
アミンの存在下、ジオキサンなどの不活性溶媒中で室温
で数時間反応させることによって、本化合物（Ｉ）を得
ることができる。本反応に用いられる溶媒としては、ジ
オキサンなどが好ましいが、その他本反応を阻害しない
ものであればいずれものであっても使用することができ
る。有機アミンとしては、特にトリエチルアミンやトリ
ブチルアミンなどが好ましい。次に、溶媒を減圧下で留
去した後、残渣を酢酸エチルなどで抽出して得られた結
晶をメチルアルコールなどの適宜の溶媒から再結晶し
て、本化合物のエステル体を高収率で得ることができ
る。The compound (II) and compound (III) thus obtained are reacted in the presence of an organic amine such as triethylamine in an inert solvent such as dioxane at room temperature for several hours to give the present compound ( I) can be obtained. The solvent used in this reaction is preferably dioxane or the like, but any solvent that does not inhibit this reaction can be used. As the organic amine, triethylamine and tributylamine are particularly preferable. Then, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate and the obtained crystals were recrystallized from an appropriate solvent such as methyl alcohol to give the ester compound of the present compound in high yield. Obtainable.
【００２４】このようにして得られたエステル体を、ア
ルコール中またはアルコール水溶液中で、水酸化ナトリ
ウムまたは水酸化カリウムなどのアルカリ化合物で、室
温または加温下で数時間ケン化（エステル加水分解反
応）した後、溶媒を留去し、残渣に水を加えて溶解し、
さらに酢酸などの酸を加えて中性とし、析出する結晶を
濾取する。これをメチルアルコール−水などの適宜の溶
媒から再結晶して、本化合物のフリー体を高収率で得る
ことができる。The ester thus obtained is saponified in an alcohol or an aqueous alcohol solution with an alkali compound such as sodium hydroxide or potassium hydroxide at room temperature or under heating for several hours (ester hydrolysis reaction). After that, the solvent was distilled off, and water was added to the residue to dissolve it.
Further, an acid such as acetic acid is added to make it neutral, and the precipitated crystals are collected by filtration. This can be recrystallized from an appropriate solvent such as methyl alcohol-water to obtain the free form of the compound in high yield.
【００２５】このようにして得られた本化合物（Ｉ）
は、公知の方法により、薬理学的に許容できる塩として
得てもよい。たとえば、得られた本化合物を適当な溶媒
中で、水酸化物、炭酸塩や炭酸水素塩などのアルカリ金
属イオンやアルカリ土類金属イオンを与える物質を添加
することにより目的の塩を得ることができる。塩への変
換は、本化合物を一旦反応液から単離した後行ってもよ
く、反応液から単離することなく行ってもよい。The present compound (I) thus obtained
May be obtained as a pharmacologically acceptable salt by a known method. For example, the desired salt can be obtained by adding a substance that gives an alkali metal ion or an alkaline earth metal ion such as hydroxide, carbonate or hydrogen carbonate to the obtained compound in a suitable solvent. it can. The conversion to a salt may be performed after the compound is once isolated from the reaction solution, or may be performed without isolation from the reaction solution.
【００２６】このようにして得られる本化合物は、文献
未載の新規化合物であって、優れた抗アレルギー作用お
よび抗炎症作用を有しているので、極めて有用な化合物
である。The present compound thus obtained is a novel compound which has not been published in the literature and has an excellent anti-allergic action and anti-inflammatory action, and is therefore an extremely useful compound.
【００２７】本発明の抗アレルギー剤および抗炎症剤に
用いられる本化合物は、遊離のものであっても、その薬
理学的に許容できる塩であっても、本発明の目的のため
適宜に使用することができる。その薬理学的に許容でき
る塩としては、たとえばナトリウム塩、カリウム塩など
のアルカリ金属塩およびカルシウム塩、マグネシウム塩
などのアルカリ土類塩などが例示される。また、塩酸
塩、硫酸塩や硝酸塩などの無機塩または酢酸塩、マレイ
ン酸塩や酒石酸などの有機塩などが例示される。これら
以外の塩であっても薬理学的に許容できる塩であればい
ずれのものであっても適宜に使用することができる。The present compound used for the antiallergic agent and antiinflammatory agent of the present invention, whether it is a free compound or a pharmacologically acceptable salt thereof, is appropriately used for the purpose of the present invention. can do. Examples of the pharmacologically acceptable salt include alkali metal salts such as sodium salt and potassium salt and alkaline earth salts such as calcium salt and magnesium salt. Further, inorganic salts such as hydrochlorides, sulfates and nitrates or acetates, and organic salts such as maleates and tartaric acid are exemplified. Any salt other than these may be appropriately used as long as it is a pharmacologically acceptable salt.
【００２８】本発明の抗アレルギー剤によって治療され
るアレルギー性疾患としては、たとえば気管支性喘息、
花粉症、アレルギー性鼻炎、食事性アレルギー性胃炎、
アレルギー性下痢、潰瘍性大腸炎、口内炎、結節性動脈
周囲炎、閉塞性動脈内膜炎、心内膜炎、蕁麻疹、湿疹、
接触性皮膚炎、フリクテン、交感性眼炎、アレルギー性
結膜炎およびアレルギー性角膜炎などが挙げられる。Examples of allergic diseases treated by the antiallergic agent of the present invention include bronchial asthma,
Hay fever, allergic rhinitis, dietary allergic gastritis,
Allergic diarrhea, ulcerative colitis, stomatitis, periarteritis nodosa, endocarditis obliterans, endocarditis, urticaria, eczema,
Examples include contact dermatitis, fructene, sympathetic ophthalmitis, allergic conjunctivitis and allergic keratitis.
【００２９】本発明の抗炎症剤によって治療される炎症
性疾患としては、たとえば痔疾、慢性関節リウマチ、変
形性リウマチ、変形性脊椎症、変形性関節症、腰痛症、
痛風症発作、急性中耳炎、膀胱炎、前立腺炎、歯痛、葡
萄膜炎、副鼻腔炎などが挙げられる。Examples of inflammatory diseases to be treated by the anti-inflammatory agent of the present invention include hemorrhoids, rheumatoid arthritis, rheumatoid arthritis, degenerative spondylosis, osteoarthritis, low back pain,
Such as gout attack, acute otitis media, cystitis, prostatitis, toothache, uveitis, sinusitis and the like.
【００３０】本発明の抗アレルギー剤および抗炎症剤
は、上記のような種々の疾患の治療のため、経口的にま
たは非経口的に適宜に使用される。製剤の形態として
は、たとえば錠剤、顆粒剤、散剤、カプセル剤、軟膏剤
などの固形製剤、または点眼剤、点鼻剤、点耳剤、シロ
ップ剤などの液剤のいずれの形にも公知の方法により適
宜調製することができる。これらの製剤には、通常用い
られる賦形剤、結合剤、崩壊剤、増粘剤、分散剤、再吸
収促進剤、緩衝剤、界面活性剤、保存剤、等張化剤、安
定化剤やｐＨ調節剤などの各種添加剤を適宜使用しても
よい。The anti-allergic agent and anti-inflammatory agent of the present invention are appropriately used orally or parenterally for the treatment of various diseases as described above. The form of the preparation is, for example, a known method in the form of any of solid preparations such as tablets, granules, powders, capsules and ointments, or liquid preparations such as eye drops, nose drops, ear drops and syrups. Can be appropriately prepared by. These formulations include commonly used excipients, binders, disintegrants, thickeners, dispersants, reabsorption promoters, buffers, surfactants, preservatives, isotonic agents, stabilizers and Various additives such as a pH adjuster may be used as appropriate.
【００３１】本化合物を抗アレルギー剤および抗炎症剤
として使用する場合の本化合物の用量は、使用する化合
物の種類、対象とする疾患の種類、患者の体重、年齢や
適応症状および投与方法などによっても異なるが、たと
えば注射剤の場合は、成人１日１回約０．１mg〜約３０
mg、内服剤の場合は、成人１日数回、１回量約１mg〜約
１００mg程度投与するのがよい。点眼剤として使用する
場合には、濃度約０．０１（ｗ／ｖ）％〜０．５（ｗ／
ｖ）％程度のものを１回数滴、１日数回程度点眼するの
がよい。When the present compound is used as an anti-allergic agent and anti-inflammatory agent, the dose of the present compound depends on the kind of the compound used, the kind of target disease, the weight of the patient, the age and the indication symptoms and the administration method. For example, in the case of an injection, an adult once a day about 0.1 mg to about 30
In the case of oral administration in mg, it is advisable to administer a dose of about 1 mg to about 100 mg once daily for adults. When used as an eye drop, the concentration is about 0.01 (w / v)% to 0.5 (w /
v) It is advisable to instill about 1% of the substance once a few times and several times a day.
【００３２】本発明の抗アレルギー剤および抗炎症剤に
は、目的と必要に応じて、本化合物のうち１種または２
種以上を適宜組み合せて用いることもできる。The anti-allergic agent and anti-inflammatory agent of the present invention include one or two of the present compounds depending on the purpose and need.
It is also possible to use a combination of two or more species as appropriate.
【００３３】[0033]
【実施例】以下、実施例および製剤実施例を挙げて、本
発明をさらに詳細に説明する。The present invention will be described in more detail below with reference to Examples and Formulation Examples.
【００３４】［実施例１］４−［（４−ジフェニルメチ
ル−１−ピペラジニル）メチル］フェニル酢酸 ２００mlのナス型フラスコに４−ブロモメチルフェニル
酢酸メチルエステル５．３８ｇ、１−ベンズヒドリルピ
ぺラジン６．０６ｇおよびトリエチルアミン６．１mlに
ジオキサン１００mlを加えて室温で５時間攪拌する。次
に、溶媒を留去し、残渣を酢酸エチルエステルにて抽出
し、水で洗浄し、溶媒を留去後、残渣をメタノールから
再結晶して、融点１２４℃〜１２５℃の４−［（４−ジ
フェニルメチル−１−ピペラジニル）メチル］フェニル
酢酸メチルエステル８．３３ｇを得る。[Example 1] 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid 5.38 g of 4-bromomethylphenylacetic acid methyl ester, 5.38 g of 1-benzhydrylpiperazine in a 200 ml eggplant type flask. 100 ml of dioxane was added to 06 g and 6.1 ml of triethylamine, and the mixture was stirred at room temperature for 5 hours. Next, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with water, the solvent was distilled off, and the residue was recrystallized from methanol to give 4-[(melting point of 124 to 125 ° C. There is obtained 8.33 g of 4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid methyl ester.
【００３５】 元素分析 Ｃ27Ｈ30Ｎ2 Ｏ2 として 理論値（％）：Ｃ，７８．２３； Ｈ，７．２９； Ｎ，６．７６ 実測値（％）：Ｃ，７７．９８； Ｈ，７．１３； Ｎ，６．６０Elemental analysis As C 27 H 30 N 2 O 2 theoretical value (%): C, 78.23; H, 7.29; N, 6.76 measured value (%): C, 77.98; H , 7.13; N, 6.60
【００３６】このようにして得られた化合物２ｇをメチ
ルアルコール１０mlと２Ｎ水酸化ナトリウム５０mlの混
液を加えて３時間加熱還流する。反応混合液の溶媒を留
去し、残渣を水に溶解させ、不溶物を濾過する。濾液を
酢酸にて中性にし、析出した結晶を濾取する。さらに、
この結晶を２Ｎ塩酸に溶解させ不溶物を濾過する。濾液
を水酸化ナトリウム水溶液にて中性とし、析出した結晶
を濾取し、メタノール、水から再結晶し、融点１８３℃
〜１８５℃の目的化合物１．２５ｇを得る。そのＩＲを
図１に示す。A mixture of 10 ml of methyl alcohol and 50 ml of 2N sodium hydroxide is added to 2 g of the compound thus obtained, and the mixture is heated under reflux for 3 hours. The solvent of the reaction mixture is distilled off, the residue is dissolved in water, and the insoluble matter is filtered. The filtrate is neutralized with acetic acid, and the precipitated crystals are collected by filtration. further,
The crystals are dissolved in 2N hydrochloric acid and the insoluble matter is filtered. The filtrate was neutralized with an aqueous sodium hydroxide solution, the precipitated crystals were collected by filtration, recrystallized from methanol and water, and had a melting point of 183 ° C.
1.25 g of the desired compound are obtained at ˜185 ° C. The IR is shown in FIG.
【００３７】 元素分析 Ｃ26Ｈ28Ｎ2 Ｏ2 として 理論値（％）：Ｃ，７７．９７； Ｈ，７．０５； Ｎ，６．９９ 実測値（％）：Ｃ，７７．８０； Ｈ，６．９７； Ｎ，６．９６Elemental analysis As C 26 H 28 N 2 O 2 theoretical value (%): C, 77.97; H, 7.05; N, 6.99 actual measurement value (%): C, 77.80; H , 6.97; N, 6.96.
【００３８】［実施例２］４−［［４−（２−メトキシ
フェニル）−１−ピペラジニル］メチル］フェニル酢酸 ４−ブロモメチルフェニル酢酸メチルエステル２．４
ｇ、１−（２−メトキシフェニル）ピぺラジン１．９ｇ
に、トリエチルアミン３mlおよびジオキサン８０mlを加
えて溶かし、室温で４時間攪拌する。次に、溶媒を留去
し、残渣を酢酸エチルエステルにて抽出した。抽出液を
水洗した後、無水硫酸ナトリウムで乾燥し、溶媒を留去
した。得られた残渣をカラムクロマトグラフィー〔シリ
カゲル、ヘキサン−酢酸エチル（２：１）〕で処理し、
得られた油状物を２Ｎ水酸化ナトリウム３０ml、メタノ
ール１０mlの混合物を３時間加熱還流した後、溶媒を留
去した。残渣を水に溶解させ不溶物を濾別した後、濾液
を酢酸で中性としクロロホルムで抽出した。抽出液を留
去した残渣をメタノール−エチルエーテルから再結晶し
て、融点８７℃〜９０℃の目的化合物２．０ｇを得る。
そのＩＲを図２に示す。[Example 2] 4-[[4- (2-methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid 4-bromomethylphenylacetic acid methyl ester 2.4
g, 1.9 g of 1- (2-methoxyphenyl) piperazine
To the above, 3 ml of triethylamine and 80 ml of dioxane are added and dissolved, and the mixture is stirred at room temperature for 4 hours. Then, the solvent was distilled off, and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was treated by column chromatography [silica gel, hexane-ethyl acetate (2: 1)],
A mixture of 30 ml of 2N sodium hydroxide and 10 ml of methanol was heated under reflux for 3 hours, and the solvent was distilled off. The residue was dissolved in water and the insoluble material was filtered off. The filtrate was neutralized with acetic acid and extracted with chloroform. The residue obtained by distilling the extract is recrystallized from methanol-ethyl ether to obtain 2.0 g of the desired compound having a melting point of 87 ° C to 90 ° C.
The IR is shown in FIG.
【００３９】 元素分析 Ｃ20Ｈ24Ｎ2 Ｏ3 ・１．０Ｈ2 Ｏとして 理論値（％）：Ｃ，６７．０２； Ｈ，７．３１； Ｎ，７．８２ 実測値（％）：Ｃ，６７．１９； Ｈ，７．４６； Ｎ，７．７０Elemental analysis As C 20 H 24 N 2 O 3 .1.0H 2 O Theoretical value (%): C, 67.02; H, 7.31; N, 7.82 Measured value (%): C , 67.19; H, 7.46; N, 7.70.
【００４０】［実施例３］４−［［４−（２−カルボキ
シフェニル）−１−ピペラジニル］メチル］フェニル酢
酸 ４−ブロモメチルフェニル酢酸メチルエステル２．４
ｇ、２−ピペラジニル安息香酸エチルエステル酢酸塩
２．９ｇ、トリエチルアミン３mlおよびジオキサン８０
mlを用いて、実施例２と同様に反応処理して、エタノー
ル−水から再結晶して、融点１７９℃〜１８１℃の目的
化合物２．０ｇを得る。[Example 3] 4-[[4- (2-carboxyphenyl) -1-piperazinyl] methyl] phenylacetic acid 4-bromomethylphenylacetic acid methyl ester 2.4
g, 2-piperazinyl benzoic acid ethyl ester acetate 2.9 g, triethylamine 3 ml and dioxane 80
The reaction is carried out in the same manner as in Example 2 using ml and recrystallized from ethanol-water to obtain 2.0 g of the desired compound having a melting point of 179 ° C to 181 ° C.
【００４１】 元素分析 Ｃ20Ｈ22Ｎ2 Ｏ4 ・０．５Ｈ2 Ｏとして 理論値（％）：Ｃ，６６．１０； Ｈ，６．３８； Ｎ，７．７１ 実測値（％）：Ｃ，６６．２５； Ｈ，６．６４； Ｎ，７．６４Elemental analysis As C 20 H 22 N 2 O 4 .0.5H 2 O theoretical value (%): C, 66.10; H, 6.38; N, 7.71 actual measurement value (%): C , 66.25; H, 6.64; N, 7.64
【００４２】［実施例４］４−［［４−（２−ピリジ
ル）−１−ピペラジニル］メチル］フェニル酢酸塩酸塩 ４−ブロモメチルフェニル酢酸メチルエステル２．２
ｇ、１−（２−ピペラジニル）ピペラジン１．５ｇ、ト
リエチルアミン１．９mlおよびジオキサン７０mlを用い
て、実施例２と同様に反応処理して、２Ｎ塩酸水溶液に
て塩酸塩とした後、エタノール−エーテルから再結晶し
て、融点２１４℃〜２１６℃の目的化合物１．１ｇを得
る。[Example 4] 4-[[4- (2-pyridyl) -1-piperazinyl] methyl] phenylacetic acid hydrochloride 4-bromomethylphenylacetic acid methyl ester 2.2
g, 1- (2-piperazinyl) piperazine (1.5 g), triethylamine (1.9 ml) and dioxane (70 ml) were used to carry out a reaction treatment in the same manner as in Example 2 to give a hydrochloride salt with a 2N aqueous hydrochloric acid solution, and then ethanol-ether. Recrystallize from to give 1.1 g of the desired compound having a melting point of 214 ° C to 216 ° C.
【００４３】 元素分析 Ｃ18Ｈ21Ｎ3 Ｏ2 ・ＨＣｌ・１．２５Ｈ2 Ｏとして 理論値（％）：Ｃ，５８．３７； Ｈ，６．３３； Ｎ，１１．３５ 実測値（％）：Ｃ，５８．３９； Ｈ，６．２７； Ｎ，１１．２９Elemental analysis C 18 H 21 N 3 O 2 · HCl · 1.25H 2 O theoretical value (%): C, 58.37; H, 6.33; N, 11.35 actual value (%) : C, 58.39; H, 6.27; N, 11.29.
【００４４】［実施例５］４−［［４−（２−トリル）
−１−ピペラジニル］メチル］フェニル酢酸塩酸塩 ４−ブロモメチルフェニル酢酸メチルエステル２．２
ｇ、１−（２−トリル）ピペラジン塩酸塩１．９ｇ、ト
リエチルアミン２．５mlおよびジオキサン８０mlを用い
て、実施例２と同様に反応処理して、２Ｎ塩酸水溶液に
て塩酸塩とした後、エタノール−エーテルから再結晶し
て、融点２４９℃〜２５２℃の目的化合物１．７ｇを得
る。Example 5 4-[[4- (2-tolyl)
-1-Piperazinyl] methyl] phenylacetic acid hydrochloride 4-bromomethylphenylacetic acid methyl ester 2.2
g, 1- (2-tolyl) piperazine hydrochloride (1.9 g), triethylamine (2.5 ml) and dioxane (80 ml) were used to carry out a reaction treatment in the same manner as in Example 2 to give a hydrochloride with a 2N aqueous hydrochloric acid solution, and then ethanol. -Recrystallized from ether to give 1.7 g of the desired compound with a melting point of 249 ° C-252 ° C.
【００４５】 元素分析 Ｃ20Ｈ24Ｎ2 Ｏ2 ・ＨＣｌ・１．７５Ｈ2 Ｏとして 理論値（％）：Ｃ，６１．２２； Ｈ，７．３２； Ｎ，７．１４ 実測値（％）：Ｃ，６１．１９； Ｈ，６．９０； Ｎ，７．１１Elemental analysis Theoretical value (%) as C 20 H 24 N 2 O 2 .HCl.1.75H 2 O: C, 61.22; H, 7.32; N, 7.14 Measured value (%) : C, 61.19; H, 6.90; N, 7.11
【００４６】［実施例６］４−［（４−フェニル−１−
ピペラジニル）メチル］フェニル酢酸塩酸塩 ４−ブロモメチルフェニル酢酸メチルエステル２．３
ｇ、１−フェニルピペラジン２．０ｇ、トリエチルアミ
ン２mlおよびジオキサン８０mlを用いて、実施例２と同
様に反応処理して、２Ｎ塩酸水溶液にて塩酸塩とした
後、メタノール−エーテルから再結晶して、融点２３１
℃〜２３４℃の目的化合物２．０ｇを得る。Example 6 4-[(4-phenyl-1-
Piperazinyl) methyl] phenylacetic acid hydrochloride 4-bromomethylphenylacetic acid methyl ester 2.3
g, 1-phenylpiperazine 2.0 g, triethylamine 2 ml and dioxane 80 ml were treated in the same manner as in Example 2 to give a hydrochloride salt with a 2N aqueous hydrochloric acid solution, and then recrystallized from methanol-ether. Melting point 231
2.0 g of the target compound having a temperature of ℃ to 234 ℃ is obtained.
【００４７】 元素分析 Ｃ19Ｈ22Ｎ2 Ｏ2 ・ＨＣｌ・１．５Ｈ2 Ｏとして 理論値（％）：Ｃ，６１．０４； Ｈ，７．０１； Ｎ，７．４９ 実測値（％）：Ｃ，６１．０４； Ｈ，６．７２； Ｎ，７．４７Elemental analysis C 19 H 22 N 2 O 2 · HCl · 1.5H 2 O theoretical value (%): C, 61.04; H, 7.01; N, 7.49 actual measurement value (%) : C, 61.04; H, 6.72; N, 7.47
【００４８】［実施例７］４−［［４−（２−フルオロ
フェニル）−１−ピペラジニル］メチル］フェニル酢酸
塩酸塩 ４−ブロモメチルフェニル酢酸３．４ｇをメタノール５
０mlに懸濁させトリエチルアミン２．１mlを滴下し均一
溶液とする。次に、これに１−（２−フルオロフェニ
ル）ピペラジン２．７ｇをメタノール５０mlに溶解した
溶液を滴下終了後さらにトリエチルアミン２mlを滴下
し、室温で３０分間攪拌した後、さらに２時間加熱還流
した。次に溶媒を留去し残渣を水に溶解させ、不純物を
濾別した後、濾液を酢酸にて中和しクロロホルムにより
抽出を行った。抽出液を留去し残渣に２Ｎ塩酸水溶液を
加え塩酸塩とした後アセトンから再結晶し、融点２５３
℃〜２５５℃の目的化合物３．０ｇを得る。Example 7 4-[[4- (2-Fluorophenyl) -1-piperazinyl] methyl] phenylacetic acid hydrochloride 4-Bromomethylphenylacetic acid (3.4 g) in methanol (5)
It is suspended in 0 ml and 2.1 ml of triethylamine is added dropwise to make a uniform solution. Then, a solution prepared by dissolving 2.7 g of 1- (2-fluorophenyl) piperazine in 50 ml of methanol was added dropwise thereto, 2 ml of triethylamine was further added thereto, the mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 2 hours. Next, the solvent was distilled off, the residue was dissolved in water, impurities were filtered off, the filtrate was neutralized with acetic acid and extracted with chloroform. The extract was distilled off, and a 2N aqueous hydrochloric acid solution was added to the residue to give a hydrochloride, which was then recrystallized from acetone to give a melting point of 253
3.0 g of the target compound having a temperature of ℃ to 255 ℃ is obtained.
【００４９】 元素分析 Ｃ19Ｈ21Ｎ2 Ｏ2 Ｆ・ＨＣｌ・０．２５Ｈ2 Ｏとして 理論値（％）：Ｃ，６１．７９； Ｈ，６．１４； Ｎ，７．５８ 実測値（％）：Ｃ，６１．８５； Ｈ，５．９３； Ｎ，７．４７Elemental analysis C 19 H 21 N 2 O 2 F · HCl · 0.25H 2 O theoretical value (%): C, 61.79; H, 6.14; N, 7.58 actual value (%) ): C, 61.85; H, 5.93; N, 7.47.
【００５０】［実施例８］４−［［４−（２，５−ジメ
チルフェニル）−１−ピペラジニル］メチル］フェニル
酢酸塩酸塩 ４−ブロモメチルフェニル酢酸３．４ｇ、２，５−ジメ
チルフェニルピペラジン２．９ｇ、トリエチルアミン５
mlおよびメタノール１００mlを用いて、実施例７と同様
に反応処理して、エタノール−水から再結晶し、融点２
６０℃〜２６１℃の目的化合物２．３ｇを得る。Example 8 4-[[4- (2,5-Dimethylphenyl) -1-piperazinyl] methyl] phenylacetic acid hydrochloride 4-Bromomethylphenylacetic acid 3.4 g, 2,5-dimethylphenylpiperazine 2.9 g, triethylamine 5
ml and 100 ml of methanol, the reaction was carried out in the same manner as in Example 7, and recrystallized from ethanol-water to give a melting point of 2
2.3 g of the target compound having a temperature of 60 ° C to 261 ° C is obtained.
【００５１】 元素分析 Ｃ21Ｈ26Ｎ2 Ｏ2 ・ＨＣｌ・０．２５Ｈ2 Ｏとして 理論値（％）：Ｃ，６６．４８； Ｈ，７．３１； Ｎ，７．３８ 実測値（％）：Ｃ，６６．７１； Ｈ，７．２６； Ｎ，７．３６Elemental analysis C 21 H 26 N 2 O 2 · HCl · 0.25H 2 O theoretical value (%): C, 66.48; H, 7.31; N, 7.38 measured value (%) : C, 66.71; H, 7.26; N, 7.36
【００５２】［実施例９］４−［［４−（４−メトキシ
フェニル）−１−ピペラジニル］メチル］フェニル酢酸
２塩酸塩 ４−ブロモメチルフェニル酢酸３．４ｇ、１−（４−メ
トキシフェニル）ピペラジン２．９ｇ、トリエチルアミ
ン５mlおよびメタノール１００mlを用いて、実施例７と
同様に反応処理して、エタノール−エーテルから再結晶
し、融点２２５℃〜２３０℃の目的化合物２．４ｇを得
る。Example 9 4-[[4- (4-methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid dihydrochloride 3.4 g of 4-bromomethylphenylacetic acid, 1- (4-methoxyphenyl) Using 2.9 g of piperazine, 5 ml of triethylamine and 100 ml of methanol, the reaction treatment was carried out in the same manner as in Example 7 and recrystallization from ethanol-ether to obtain 2.4 g of the desired compound having a melting point of 225 ° C to 230 ° C.
【００５３】 元素分析 Ｃ20Ｈ24Ｎ2 Ｏ3 ・２ＨＣｌとして 理論値（％）：Ｃ，５８．１２； Ｈ，６．３４； Ｎ，６．７８ 実測値（％）：Ｃ，５８．０６； Ｈ，６．３８； Ｎ，６．７３Elemental analysis As C 20 H 24 N 2 O 3 .2HCl Theoretical value (%): C, 58.12; H, 6.34; N, 6.78 Measured value (%): C, 58.06 H, 6.38; N, 6.73
【００５４】［実施例１０］４−［［４−（３−メトキ
シフェニル）−１−ピペラジニル］メチル］フェニル酢
酸２塩酸塩 ４−ブロモメチルフェニル酢酸２．３ｇ、１−（３−メ
トキシフェニル）ピペラジン１．９ｇ、トリエチルアミ
ン３mlおよびメタノール１００mlを用いて、実施例７と
同様に反応処理して、エタノール−エーテルから再結晶
し、融点１７６℃〜１７９℃の目的化合物１．６ｇを得
る。Example 10 4-[[4- (3-Methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid dihydrochloride 2.3 g of 4-bromomethylphenylacetic acid, 1- (3-methoxyphenyl) Using 1.9 g of piperazine, 3 ml of triethylamine and 100 ml of methanol, the reaction was carried out in the same manner as in Example 7 and recrystallization from ethanol-ether gave 1.6 g of the desired compound having a melting point of 176 ° C to 179 ° C.
【００５５】 元素分析 Ｃ20Ｈ24Ｎ2 Ｏ3 ・２ＨＣｌ・０．２５Ｈ2 Ｏとして 理論値（％）：Ｃ，５７．４９； Ｈ，６．３９； Ｎ，６．７０ 実測値（％）：Ｃ，５７．７６； Ｈ，６．３５； Ｎ，６．８０Elemental analysis Theoretical value (%) as C 20 H 24 N 2 O 3 .2HCl.0.25H 2 O: C, 57.49; H, 6.39; N, 6.70 Measured value (%) : C, 57.76; H, 6.35; N, 6.80
【００５６】［実施例１１］４−［［４−（３−トリフ
ルオロメチル）−１−ピペラジニル］メチル］フェニル
酢酸塩酸塩 ４−ブロモメチルフェニル酢酸２．４ｇ、１−（３−ト
リフルオロメチル）フェニルピペラジン２．３ｇ、トリ
エチルアミン１．７mlおよびジオキサン１００mlを用い
て、実施例２と同様に反応処理して、２Ｎ塩酸水溶液に
て塩酸塩とした後、メタノール−アセトンから再結晶
し、融点１７３℃〜１７５℃の目的化合物２．３ｇを得
る。Example 11 4-[[4- (3-Trifluoromethyl) -1-piperazinyl] methyl] phenylacetic acid hydrochloride 4-bromomethylphenylacetic acid 2.4 g, 1- (3-trifluoromethyl) ) Phenylpiperazine (2.3 g), triethylamine (1.7 ml) and dioxane (100 ml) were used to carry out a reaction treatment in the same manner as in Example 2 to give a hydrochloride salt with a 2N hydrochloric acid aqueous solution, followed by recrystallization from methanol-acetone to give a melting point of 173. 2.3 g of the target compound having a temperature of from ℃ to 175 ℃ are obtained.
【００５７】 元素分析 Ｃ20Ｈ21Ｎ2 Ｏ2 Ｆ3 ・ＨＣｌ・１．２５Ｈ2 Ｏとして 理論値（％）：Ｃ，５４．９２； Ｈ，５．６５； Ｎ，６．４０ 実測値（％）：Ｃ，５４．７２； Ｈ，５．３８； Ｎ，６．１５Elemental analysis Theoretical value (%) as C 20 H 21 N 2 O 2 F 3 .HCl.1.25H 2 O: C, 54.92; H, 5.65; N, 6.40 measured value ( %): C, 54.72; H, 5.38; N, 6.15
【００５８】［実施例１２］４−［［４−［フェニル−
（２−ピリジル）メチル］−１−ピペラジニル］メチ
ル］フェニル酢酸３塩酸塩 ４−ブロモメチルフェニル酢酸メチルエステル２．８
ｇ、１−［フェニル−（２−ピリジル）メチル］ピペラ
ジン２．９ｇ、トリエチルアミン２mlおよびジオキサン
１００mlを用いて、実施例１と同様に反応処理して、ベ
ンゼン−ヘキサンから再結晶し、融点１２２℃〜１２３
℃の４−［［４−［フェニル−（２−ピリジル）メチ
ル］−１−ピペラジニル］メチル］フェニル酢酸メチル
エステル２．４７ｇを得る。[Example 12] 4-[[4- [phenyl-
(2-Pyridyl) methyl] -1-piperazinyl] methyl] phenylacetic acid trihydrochloride 4-bromomethylphenylacetic acid methyl ester 2.8
g, 1- [phenyl- (2-pyridyl) methyl] piperazine (2.9 g), triethylamine (2 ml) and dioxane (100 ml) were used to carry out a reaction treatment in the same manner as in Example 1 to recrystallize from benzene-hexane to give a melting point of 122 ° C. ~ 123
2.47 g of methyl 4-[[4- [phenyl- (2-pyridyl) methyl] -1-piperazinyl] methyl] phenylacetic acid at 0 ° C. are obtained.
【００５９】 元素分析 Ｃ26Ｈ29Ｎ3 Ｏ2 として 理論値（％）：Ｃ ７５．１５； Ｈ，７．０３； Ｎ，１０．１１ 実測値（％）：Ｃ，７４．８７； Ｈ，７．０５； Ｎ，１０．０７ このようにして得られた化合物１．０ｇを実施例１と同
様に加水分解を行い、２Ｎ塩酸水溶液にて塩酸塩とした
後、アセトンから再結晶して、融点１９３℃〜１９５℃
の目的化合物０．８ｇを得る。Elemental analysis As C 26 H 29 N 3 O 2 theoretical value (%): C 75.15; H, 7.03; N, 10.11 actual value (%): C, 74.87; H, 7.05; N, 10.07 1.0 g of the compound thus obtained was hydrolyzed in the same manner as in Example 1 to give a hydrochloride with a 2N hydrochloric acid aqueous solution, and then recrystallized from acetone. Melting point 193 ° C to 195 ° C
0.8 g of the target compound of
【００６０】 元素分析 Ｃ25Ｈ27Ｎ3 Ｏ2 ・３ＨＣｌ・Ｈ2 Ｏとして 理論値（％）：Ｃ，５６．７７； Ｈ，６．１０； Ｎ，７．９４ 実測値（％）：Ｃ，５６．６９； Ｈ，６．１５； Ｎ，７．６２Elemental analysis As C 25 H 27 N 3 O 2 .3HCl.H 2 O Theoretical value (%): C, 56.77; H, 6.10; N, 7.94 Measured value (%): C , 56.69; H, 6.15; N, 7.62.
【００６１】［実施例１３］４−［［４−［（４−クロ
ロフェニル）フェニルメチル］−１−ピペラジニル］メ
チル］フェニル酢酸 ４−ブロモメチルフェニル酢酸２．４ｇ、１−［（４−
クロロフェニル）フェニルメチル］ピペラジン２．９
ｇ、トリエチルアミン２．８mlおよびジオキサン１００
mlを用いて、実施例１と同様に反応処理して、ベンゼン
−ヘキサンから再結晶し、融点１１３℃〜１１５℃の４
−［［４−［（４−クロロフェニル）フェニルメチル］
−１−ピペラジニル］メチル］フェニル酢酸メチルエス
テル１．８ｇを得る。Example 13 4-[[4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] methyl] phenylacetic acid 2.4 g of 4-bromomethylphenylacetic acid, 1-[(4-
Chlorophenyl) phenylmethyl] piperazine 2.9
g, triethylamine 2.8 ml and dioxane 100
The reaction was carried out in the same manner as in Example 1 using ml, and recrystallized from benzene-hexane.
-[[4-[(4-chlorophenyl) phenylmethyl]]
1.8 g of -1-piperazinyl] methyl] phenylacetic acid methyl ester are obtained.
【００６２】 元素分析 Ｃ27Ｈ29Ｎ2 Ｏ2 Ｃｌとして 理論値（％）：Ｃ ７２．２３； Ｈ，６．５１； Ｎ，６．２４ 実測値（％）：Ｃ，７２．２８； Ｈ，６．３３； Ｎ，６．１２ このようにして得られた化合物１．８ｇを実施例１と同
様に加水分解を行い、イソプロピルアルコールから再結
晶して、無定形結晶の目的化合物１．５ｇを得る。Elemental analysis As C 27 H 29 N 2 O 2 Cl Theoretical value (%): C 72.23; H, 6.51; N, 6.24 Measured value (%): C, 72.28; H , 6.33; N, 6.12 1.8 g of the compound thus obtained was hydrolyzed in the same manner as in Example 1 and recrystallized from isopropyl alcohol to give 1.5 g of the target compound as an amorphous crystal. To get
【００６３】 元素分析 Ｃ26Ｈ27Ｎ2 Ｏ2 Ｃｌ・１．５Ｈ2 Ｏとして 理論値（％）：Ｃ，６７．６０； Ｈ，６．５５； Ｎ，６．０６ 実測値（％）：Ｃ，６７．５２； Ｈ，６．５２； Ｎ，５．７２Elemental analysis As C 26 H 27 N 2 O 2 Cl · 1.5H 2 O Theoretical value (%): C, 67.60; H, 6.55; N, 6.06 Actual value (%): C, 67.52; H, 6.52; N, 5.72.
【００６４】［実施例１４］ラット背部受動的皮膚アナ
フィラキシー反応（ＰＣＡ反応）に対する本化合物の経
口投与による効果 ラット背部ＰＣＡ反応に対する本化合物の経口投与によ
る効果について試験した。[Example 14] Effect of oral administration of the present compound on rat dorsal passive skin anaphylactic reaction (PCA reaction) The effect of oral administration of the present compound on rat dorsal PCA reaction was tested.
【００６５】（方法）ＳＬＣより購入したウィスター系
雄性ラット（体重約１００ｇ）を６０匹用いた。ラット
にペントバルビタール麻酔下、抗血清（１６倍希釈）１
００μl を背部に皮内注射し、その４８時間後に卵白ア
ルブミン（２５mg/kg ）とエバンスブルー（１２．５mg
/kg ）の混合液５ml/kg を静注し、ＰＣＡ反応を惹起さ
せた。ラットをＰＣＡ反応惹起３０分後に屠殺し、背部
の色素漏出部位を切取りホルムアミド６mlにて色素を抽
出し、吸光度（６２５nm）を測定した。試験物質は、Ｐ
ＣＡ反応惹起６０分前に経口投与した。(Method) Sixty male Wistar rats (body weight: about 100 g) purchased from SLC were used. Antisera (16-fold dilution) under anesthesia with pentobarbital in rats 1
After intradermal injection of 00 μl into the back, 48 hours later, ovalbumin (25 mg / kg) and Evans blue (12.5 mg
5 ml / kg of a mixed solution of (/ kg) was intravenously injected to induce a PCA reaction. Rats were sacrificed 30 minutes after the PCA reaction was induced, the dye leakage site on the back was cut off, the dye was extracted with 6 ml of formamide, and the absorbance (625 nm) was measured. The test substance is P
It was orally administered 60 minutes before the induction of the CA reaction.
【００６６】（結果）その結果を表１および表２に示
す。(Results) The results are shown in Tables 1 and 2.
【００６７】[0067]
【表１】 ラット背部ＰＣＡ反応に対する本化合物の経口投与による効果 試験物質 投与量 吸光度 抑制率 （mg/kg ） （Ａｂｓ．） （％） ０．５％ＣＭＣ − ０．４３８±０．０４８ − 実施例１の化合物 ３０ ０．１２８±０．０４１* ７０．８ 各値は平均±標準偏差（ｎ＝５）を示す。 対照群（ＣＭＣ）に対する有意差： *；ｐ＜０．０１． ＣＭＣ：カルボキシメチルセルロース[Table 1] Effect of oral administration of this compound on rat dorsal PCA reaction Test substance Dose Absorbance inhibition rate (mg / kg) (Abs.) (%) 0.5% CMC-0.438 ± 0.048- Implementation Compound of Example 1 30 0.128 ± 0.041 * 70.8 Each value represents mean ± standard deviation (n = 5). Significantly different from control group (CMC): * ; p <0.01. CMC: Carboxymethyl cellulose
【００６８】[0068]
【表２】 ラット背部ＰＣＡ反応に対する本化合物の経口投与による効果 試験物質 投与量 抑制率 （mg/kg ） （％） 実施例２の化合物 ３０ ６０．５** 実施例５の化合物 ３０ ５７．３** 実施例６の化合物 ３０ １９．５* 実施例７の化合物 ３０ ２３．８** 実施例９の化合物 ３０ ２２．５** 実施例１２のエステル体 ３０ ４９．０** 実施例１２のフリー体 ３０ ３８．２** 各値は平均±標準偏差（ｎ＝６〜７）を示す。 対照群（ＣＭＣ）に対する有意差： *；ｐ＜０．０５，**；ｐ＜０．０１．[Table 2] Effect of oral administration of this compound on rat dorsal PCA reaction Test substance Dose inhibition rate (mg / kg) (%) Compound of Example 2 30 60.5 ** Compound of Example 5 30 57.3 ** Compound of Example 6 30 19.5 * Compound of Example 7 30 23.8 ** Compound of Example 9 30 22.5 ** Ester of Example 12 30 49.0 ** of Example 12 Free form 30 38.2 ** Each value represents mean ± standard deviation (n = 6 to 7). Significantly different from control group (CMC): * ; p <0.05, ** ; p <0.01.
【００６９】表１から明らかなように、実施例１の化合
物の３０mg/kg の経口投与により、ＰＣＡ反応を７０．
８％と有意に抑制した。また、表２から明らかなよう
に、実施例２、５、６、７、９の化合物においても有意
な抗アレルギー作用が認められた。この結果から、本化
合物は抗アレルギー剤として有用であることが判った。As is apparent from Table 1, the PCA reaction was 70.degree. C. by oral administration of the compound of Example 1 at 30 mg / kg.
It was significantly suppressed to 8%. As is clear from Table 2, the compounds of Examples 2, 5, 6, 7, and 9 also showed significant antiallergic effects. From this result, it was found that the present compound is useful as an antiallergic agent.
【００７０】［実施例１５］ラット結膜受動的皮膚アナ
フィラキシー反応（ＰＣＡ反応）に対する本化合物の経
口投与による効果 ラット結膜ＰＣＡ反応に対する本化合物の経口投与によ
る効果について試験した。[Example 15] Effect of oral administration of the present compound on rat conjunctival passive cutaneous anaphylactic reaction (PCA reaction) The effect of oral administration of the present compound on rat conjunctival PCA reaction was tested.
【００７１】（方法）ＳＬＣより購入したウィスター系
雄性ラット（体重約１００ｇ）を１９匹用いた。ラット
にペントバルビタール麻酔下、抗血清（８倍希釈）５０
μl を眼瞼結膜下に注射し、その４８時間後に卵白アル
ブミン（２５mg/kg ）とエバンスブルー（１２．５mg/k
g ）の混合液５ml/kg を静注し、結膜ＰＣＡ反応を惹起
させた。ラットをＰＣＡ反応惹起３０分後に屠殺し、眼
瞼結膜の色素漏出部位を切取りホルムアミド３mlにて色
素を抽出し、吸光度（６２５nm）を測定した。試験物質
は、ＰＣＡ反応惹起６０分前に経口投与した。(Method) 19 male Wistar rats (body weight: about 100 g) purchased from SLC were used. Rats under pentobarbital anesthesia, antiserum (8-fold dilution) 50
After injection of μl subconjunctivally, 48 hours later, ovalbumin (25 mg / kg) and Evans blue (12.5 mg / k)
5 ml / kg of the mixed solution of g) was intravenously injected to induce the conjunctival PCA reaction. The rat was sacrificed 30 minutes after the PCA reaction was induced, the dye leakage site of the eyelid conjunctiva was cut out, and the dye was extracted with 3 ml of formamide, and the absorbance (625 nm) was measured. The test substance was orally administered 60 minutes before the induction of the PCA reaction.
【００７２】（結果）その結果を表３に示す。(Results) The results are shown in Table 3.
【００７３】[0073]
【表３】 ラット結膜ＰＣＡ反応に対する本化合物の経口投与による効果 試験物質 投与量 吸光度 抑制率 （mg/kg ） （Ａｂｓ．） （％） ０．５％ＣＭＣ − ０．６１１±０．２７６ − 実施例１の化合物 １０ ０．２１２±０．０３２* ６５．３ ３０ ０．１２８±０．０４６* ７９．１ １００ ０．１０４±０．０５２* ８３．０ 各値は平均±標準偏差（ｎ＝４〜５）を示す。 対照群（ＣＭＣ）に対する有意差: *；ｐ＜０．０１．[Table 3] Effect of oral administration of this compound on rat conjunctival PCA reaction Test substance Dose Absorbance inhibition rate (mg / kg) (Abs.) (%) 0.5% CMC-0.611 ± 0.276-Implementation Compound of Example 1 10 0.212 ± 0.032 * 65.3 30 0.128 ± 0.046 * 79.1 100 0.104 ± 0.052 * 83.0 Each value is mean ± standard deviation (n = 4-5) is shown. Significantly different from control group (CMC): * ; p <0.01.
【００７４】表３から明らかなように、本化合物の１
０、３０、１００mg/kg の経口投与により、用量依存的
に結膜ＰＣＡ反応を各々６５．３％、７９．１％、８
３．０％と有意に抑制した。この結果から、本化合物は
抗アレルギー剤として有用であることが判った。As is clear from Table 3, 1 of the present compound
Oral administration of 0, 30, and 100 mg / kg produced a dose-dependent conjunctival PCA response of 65.3%, 79.1%, and 8 respectively.
It was significantly suppressed to 3.0%. From this result, it was found that the present compound is useful as an antiallergic agent.
【００７５】［実施例１６］ラット結膜ＰＣＡ反応に対
する本化合物の点眼による効果 ラット結膜ＰＣＡ反応に対する本化合物の点眼による効
果について試験した。[Example 16] Effect of the present compound on the rat conjunctival PCA reaction by instillation The effect of the present compound on the rat conjunctival PCA reaction by instillation was tested.
【００７６】（方法）ＳＬＣより購入したウィスター系
雄性ラット（体重約１００ｇ）を２３匹用いた。ラット
にペントバルビタール麻酔下、抗血清（８倍希釈）５０
μl を眼瞼結膜下に注射し、その４８時間後に卵白アル
ブミン（２５mg/kg ）とエバンスブルー（１２．５mg/k
g ）の混合液５ml/kg を静注し、結膜ＰＣＡ反応を惹起
させた。ラットをＰＣＡ反応惹起後３０分後に屠殺し、
眼瞼結膜の色素漏出部位を切取りホルムアミド３mlにて
色素を抽出し、吸光度（６２５nm）を測定した。試験物
質は、ＰＣＡ反応惹起３０、６０分前に１０μl 点眼し
た。(Method) Twenty-three male Wistar rats (body weight: about 100 g) purchased from SLC were used. Rats under pentobarbital anesthesia, antiserum (8-fold dilution) 50
After injection of μl subconjunctivally, 48 hours later, ovalbumin (25 mg / kg) and Evans blue (12.5 mg / k)
5 ml / kg of the mixed solution of g) was intravenously injected to induce the conjunctival PCA reaction. Rats were sacrificed 30 minutes after the induction of PCA reaction,
The dye leakage site of the eyelid conjunctiva was cut off, the dye was extracted with 3 ml of formamide, and the absorbance (625 nm) was measured. The test substance was instilled in an amount of 10 μl 30 and 60 minutes before the induction of the PCA reaction.
【００７７】（結果）その結果を表４に示す。(Results) The results are shown in Table 4.
【００７８】[0078]
【表４】 ラット結膜ＰＣＡ反応に対する本化合物の点眼による効果 試験物質 濃度 吸光度 抑制率 （％） （Ａｂｓ．） （％） 生理食塩液 − ０．５０９±０．０７３ − 実施例１の化合物 ０．１２５ ０．４０９±０．１２８ １９．６ ０．２５ ０．３５０±０．１３２* ３１．２ ０．５ ０．２９３±０．０３０** ４２．４ 各値は平均±標準偏差（ｎ＝５〜６）を示す。 対照群（生理食塩液）に対する有意差：* ；ｐ＜０．０５，**；ｐ＜０．０１．[Table 4] Effect of the present compound on rat conjunctival PCA reaction by instillation Test substance Concentration Absorbance inhibition rate (%) (Abs.) (%) Physiological saline solution-0.509 ± 0.073-Compound of Example 1 125 0.409 ± 0.128 19.6 0.25 0.350 ± 0.132 * 31.2 0.5 0.293 ± 0.030 ** 42.4 Each value is mean ± standard deviation (n = 5-6) is shown. Significant difference from control group (physiological saline): * ; p <0.05, ** ; p <0.01.
【００７９】表４から明らかなように、本化合物は０．
１２５％、０．２５％、０．５％濃度溶液の点眼によ
り、結膜ＰＣＡ反応を各々１９．６％、３１．２％、４
２．４％と濃度依存的に抑制した。この結果から、本化
合物は抗アレルギー用点眼剤としても有用であることが
判った。As is clear from Table 4, the compound of the present invention has a pH of 0.
Conjunctival PCA reaction was measured by instillation of 125%, 0.25% and 0.5% concentration solutions, respectively, 19.6%, 31.2%, 4
It was suppressed to 2.4% in a concentration-dependent manner. From this result, it was found that the present compound is also useful as an antiallergic eye drop.
【００８０】［実施例１７］ラットヒスタミン炎症に対
する本化合物の経口投与による効果 本化合物のラットヒスタミン炎症に対する経口投与によ
る効果について試験した。Example 17 Effect of Oral Administration of this Compound on Rat Histamine Inflammation The effect of this compound by oral administration on rat histamine inflammation was tested.
【００８１】（方法）ＳＬＣより購入したウィスター系
雄性ラット（体重約１００ｇ）を５７匹用いた。ラット
にエバンスブルー５０mg/5ml/kg を静注し、直後に０．
１％二リン酸ヒスタミン溶液５０μl を背部に皮内注射
し、ヒスタミン炎症を惹起させた。ヒスタミン炎症惹起
３０分後にラットを屠殺し、背部の色素漏出部位を切取
り、ホルムアミド５mlにて色素を抽出し、吸光度（６２
５nm) を測定した。試験物質は、ヒスタミン炎症惹起６
０分前に経口投与した。(Method) Fifty-seven male Wistar rats (body weight: about 100 g) purchased from SLC were used. Evans blue 50 mg / 5 ml / kg was intravenously injected to the rat, and immediately after that, the dose of 0.
50 μl of a 1% histamine diphosphate solution was intradermally injected into the back to induce histamine inflammation. 30 minutes after the induction of histamine inflammation, the rat was sacrificed, the dye leakage site on the back was cut off, the dye was extracted with 5 ml of formamide, and the absorbance (62
5 nm) was measured. The test substance induces histamine inflammation 6
Oral administration was performed 0 minutes before.
【００８２】（結果）その結果を表５に示す。(Results) The results are shown in Table 5.
【００８３】[0083]
【表５】 ラットヒスタミン炎症に対する本化合物の経口投与による効果 試験物質 投与量 吸光度 抑制率 (mg/kg) (Abs.) （％） ０．５％ＣＭＣ − １．６２９±０．３５３ − 実施例１の化合物 ０．３ ０．４７９±０．０７６* ７０．６ １ ０．２５５±０．０６６* ８４．３ ３ ０．２００±０．１２２* ８７．７ ０．５％ＣＭＣ − ０．９１４±０．２９３ − 実施例２の化合物 ３ ０．７３４±０．２０１ １９．７ １０ ０．５８６±０．１７７* ３５．９ ３０ ０．３４７±０．０７１* ６２．０ １００ ０．３１６±０．１０４* ６５．４ 各値は平均±標準偏差（ｎ＝５〜７）を示す。 対照群（ＣＭＣ）に対する有意差： *；ｐ＜０．０１．[Table 5] Effect of oral administration of this compound on rat histamine inflammation Test substance Dose Absorbance inhibition rate (mg / kg) (Abs.) (%) 0.5% CMC-1.629 ± 0.353-Example Compound of 1 0.3 0.479 ± 0.076 * 70.6 1 0.255 ± 0.066 * 84.3 3 0.200 ± 0.122 * 87.7 0.5% CMC-0.914 ± 0.293-Compound of Example 3 3 0.734 ± 0.201 19.7 10 0.586 ± 0.177 * 35.9 30 0.347 ± 0.071 * 62.0 100 0.316 ± 0.104 * 65.4 Each value represents mean ± standard deviation (n = 5 to 7). Significantly different from control group (CMC): * ; p <0.01.
【００８４】表５から明らかなように、実施例１の化合
物は０．３、１、３mg/kg の経口投与により、用量依存
的にヒスタミン炎症を各々７０．６％、８４．３％、８
７．７％抑制した。また、実施例２の化合物は３、１
０、３０、１００mg/kg の経口投与により用量依存的に
ヒスタミン炎症を各々１９．７％、３５．９％、６２．
０％、６５．４％抑制した。この結果から、本化合物は
抗アレルギー剤として有用であることが判った。As is clear from Table 5, the compound of Example 1 was orally administered at doses of 0.3, 1 and 3 mg / kg to cause histamine inflammation in a dose-dependent manner at 70.6%, 84.3% and 8%, respectively.
It was suppressed by 7.7%. Further, the compound of Example 2 was 3, 1
Oral administration of 0, 30, and 100 mg / kg caused histamine inflammation in a dose-dependent manner at 19.7%, 35.9%, and 62.
It was suppressed by 0% and 65.4%. From this result, it was found that the present compound is useful as an antiallergic agent.
【００８５】［実施例１８］ラットヒスタミン眼瞼結膜
浮腫に対する本化合物の点眼による効果 本化合物のラットヒスタミン眼瞼結膜に対する点眼によ
る効果について試験した。[Example 18] Effect of the present compound by eye drops on rat histamine palpebral conjunctival edema The effect of the present compound by eye drops on rat histamine palpebral conjunctiva was tested.
【００８６】（方法）ＳＬＣより購入したウィスター系
雄性ラット（体重約１００ｇ）を１９匹用いた。ラット
にペントバルビタール麻酔下、０．１％二リン酸ヒスタ
ミン溶液５０μl を眼瞼結膜下に注射し、眼瞼結膜浮腫
を惹起させた。ヒスタミン眼瞼注射１時間後にラットを
屠殺し、結膜浮腫を切取り、重量（mg）を測定した。試
験物質は、ヒスタミン眼瞼注射の３０、６０分前に１０
μl ずつ点眼した。(Method) 19 male Wistar rats (body weight: about 100 g) purchased from SLC were used. Under anesthesia with pentobarbital, 50 μl of a 0.1% histamine diphosphate solution was injected subconjunctivally into the rat to induce palpebral conjunctival edema. One hour after the histamine eyelid injection, the rat was sacrificed, the conjunctival edema was excised, and the weight (mg) was measured. The test substance is 10 at 30 and 60 minutes before histamine eyelid injection.
Each μl was instilled.
【００８７】（結果）その結果を表６に示す。(Results) The results are shown in Table 6.
【００８８】[0088]
【表６】 ラットヒスタミン眼瞼結膜浮腫に対する本化合物の点眼による効果 試験物質 濃度 浮腫重量 抑制率 （％） （mg） （％） 生理食塩液 − ４７．８±１１．４ − 実施例１の化合物 ０．１２５ ２９．６± ８．４* ３８．１ ０．２５ ２４．４± ６．１* ４９．０ ０．５ １５．８± ４．５* ６６．９ 各値は平均±標準偏差（ｎ＝４〜５）を示す。 対照群（生理食塩液）に対する有意差： *；ｐ＜０．０１．[Table 6] Effect of the present compound on rat histamine palpebral conjunctival edema by instillation Test substance concentration Edema weight inhibition rate (%) (mg) (%) Physiological saline solution-47.8 ± 11.4-Compound of Example 1 0 .125 29.6 ± 8.4 * 38.1 0.25 24.4 ± 6.1 * 49.0 0.5 15.8 ± 4.5 * 66.9 Each value is mean ± standard deviation (n = 4 to 5). Significantly different from control group (physiological saline): * ; p <0.01.
【００８９】表６から明らかなように、本化合物は０．
１２５％、０．２５％、０．５％濃度溶液の点眼で各々
３８．１％、４９．０％、６６．９％と有意に浮腫重量
を抑制した。この結果から、本化合物は抗アレルギー点
眼剤として有用であることが判った。As is clear from Table 6, the present compound is 0.
The edema weight was significantly suppressed to 38.1%, 49.0%, and 66.9% by instillation of 125%, 0.25%, and 0.5% concentration solutions, respectively. From this result, it was found that the present compound is useful as an antiallergic eye drop.
【００９０】［実施例１９］ＤＮＦＢ（ジニトロフルオ
ロベンゼン）誘発接触性皮膚炎に対する本化合物の効果 ＤＮＦＢ誘発接触性皮膚炎に対する本化合物の効果につ
いて試験した。[Example 19] Effect of the present compound on DNFB (dinitrofluorobenzene) -induced contact dermatitis The effect of the present compound on DNFB-induced contact dermatitis was tested.
【００９１】（方法）日本クレアより購入した８週齢の
Ｃ５７ＢＬ／６Ｊ系雌性マウス３１匹を使用した。０．
５％ＤＮＦＢアセトン溶液３０μl を除毛したマウスの
腹部に塗布し、感作を行った。感作５日後にマウス右側
耳介内外面に０．１％ＤＮＦＢアセトン溶液５０μl を
塗布し惹起を行い、その２４時間後にマウス右側耳介の
厚みをダイヤルシックネスゲージを用いて測定し、惹起
前の厚みより浮腫率（％）を測定した。試験物質は、惹
起６０分前にマウス右側耳介内外面に５０μl を塗布し
た。(Method) 31 8-week-old C57BL / 6J strain female mice purchased from CLEA Japan, Inc. were used. 0.
Sensitization was performed by applying 30 μl of a 5% DNFB acetone solution to the abdomen of the hair-removed mouse. Five days after the sensitization, 50 μl of 0.1% DNFB acetone solution was applied to the inner and outer surfaces of the right auricle of the mouse to induce it, and 24 hours after that, the thickness of the right auricle of the mouse was measured using a dial thickness gauge, and before the induction. The edema rate (%) was measured from the thickness. 50 μl of the test substance was applied to the inner and outer surfaces of the right auricle of the mouse 60 minutes before induction.
【００９２】（結果）その結果を表７に示す。(Results) The results are shown in Table 7.
【００９３】[0093]
【表７】 ＤＮＦＢ誘発接触性皮膚炎に対する本化合物の効果 試験物質 濃度 浮腫率 抑制率 （％） （％） （％） メタノール − ８６．８±１８．６ − 実施例１の化合物 ０．１２５ ４２．３± ７．０* ５１．２ ０．２５ ３８．２±１２．２* ５６．０ ０．５ ３５．５± ７．９* ５９．１ インドメタシン １．０ ２１．９± ６．９* ７４．８ 各値は平均±標準偏差（ｎ＝６〜７）を示す。 対照群（メタノール）に対する有意差： * ；ｐ＜０．０１．[Table 7] Effect of this compound on DNFB-induced contact dermatitis Test substance concentration Edema rate Inhibition rate (%) (%) (%) Methanol-86.8 ± 18.6-Compound of Example 1 0.125 42 .3 ± 7.0 * 51.2 0.25 38.2 ± 12.2 * 56.0 0.5 35.5 ± 7.9 * 59.1 indomethacin 1.0 21.9 ± 6.9 * 74.8 Each value shows an average +/- standard deviation (n = 6-7). Significantly different from control group (methanol): * ; p <0.01.
【００９４】表７から明らかなように、本化合物は０．
１２５％、０．２５％、０．５％でＤＮＦＢ誘発耳介浮
腫をそれぞれ５１．２％、５６．０％、５９．１％と有
意に抑制した。また、インドメタシン１．０％は同浮腫
を７４．８％と有意に抑制した。この結果から、本化合
物は接触性皮膚炎に対し有用であることが判った。As is clear from Table 7, the compound of the present invention has a .0.
125%, 0.25%, and 0.5% significantly suppressed DNFB-induced ear edema with 51.2%, 56.0%, and 59.1%, respectively. Indomethacin 1.0% significantly suppressed the same edema with 74.8%. From this result, it was found that the present compound is useful for contact dermatitis.
【００９５】［実施例２０］アラキドン酸誘発耳介浮腫
に対する本化合物の効果 本化合物のアラキドン酸誘発耳介浮腫に対する効果につ
いて試験した。[Example 20] Effect of this compound on arachidonic acid-induced ear edema The effect of this compound on arachidonic acid-induced ear edema was tested.
【００９６】（方法）ＳＬＣより購入した５週齢のＩＣ
Ｒ系雄性マウス２５匹を用いた。マウスの右側耳介内外
面にアラキドン酸アセトン溶液（１２．５mg/ml ）を１
０μl ずつ耳介全体に拡がるように塗布し、耳介浮腫を
惹起させた。惹起１時間後にマウス右側耳介の厚みをダ
イヤルシックネスゲージを用いて測定し、惹起前の厚み
より浮腫率を算出した。試験物質は、惹起３０分前にマ
ウス右側耳介内外面に２０μl を塗布した。(Method) 5-week-old IC purchased from SLC
Twenty-five male R-type mice were used. Acetone arachidonic acid acetone solution (12.5 mg / ml) was applied to the inside and outside of the right auricle of mice
It was applied so as to spread over the entire auricle by 0 μl to induce auricular edema. One hour after induction, the thickness of the right auricle of the mouse was measured using a dial thickness gauge, and the edema rate was calculated from the thickness before induction. 20 μl of the test substance was applied to the inner and outer surfaces of the right auricle of the mouse 30 minutes before induction.
【００９７】（結果）その結果を表８に示す。(Results) The results are shown in Table 8.
【００９８】[0098]
【表８】 アラキドン酸誘発耳介浮腫に対する本化合物の効果 試験物質 濃度 浮腫率 抑制率 （％） （％） （％） メタノール − ６０．７±１４．０ − 実施例１の化合物 ０．２５ ４９．０± ９．４ １９．３ ０．５ ２４．５±１３．５* ５９．６ インドメタシン １．０ １７．２±１４．８* ７１．７ 各値は平均±標準偏差（ｎ＝６〜７）を示す。 対照群（メタノール）に対する有意差： *；ｐ＜０．０１．[Table 8] Effect of this compound on arachidonic acid-induced ear edema Test substance concentration Edema rate Inhibition rate (%) (%) (%) Methanol-60.7 ± 14.0-Compound of Example 0.25 49 0.0 ± 9.4 19.3 0.5 24.5 ± 13.5 * 59.6 Indomethacin 1.0 17.2 ± 14.8 * 71.7 Each value is mean ± standard deviation (n = 6 to 7) is shown. Significantly different from control group (methanol): * ; p <0.01.
【００９９】表８から明らかなように、０．５％の本化
合物（メタノールに溶解）はアラキドン酸誘発耳介浮腫
を有意に５９．６％抑制した。一方、１．０％インドメ
タシン（メタノールに溶解）は同浮腫を有意に７１．７
％抑制した。これらの結果から、本化合物は抗炎症剤と
して有用であることが判った。As is clear from Table 8, 0.5% of the present compound (dissolved in methanol) significantly suppressed arachidonic acid-induced ear edema by 59.6%. On the other hand, 1.0% indomethacin (dissolved in methanol) significantly caused the same edema to 71.7.
% Suppressed. From these results, it was found that the present compound is useful as an anti-inflammatory agent.
【０１００】［実施例２１］ラットカラゲニン足蹠浮腫
に対する本化合物の経口投与による効果 ラットカラゲニン足蹠浮腫に対する本化合物の経口投与
による効果について試験した。[Example 21] Effect of oral administration of the present compound on rat carrageenin footpad edema The effect of oral administration of the present compound on rat carrageenin footpad edema was tested.
【０１０１】（方法）ＳＬＣより購入した４週齢のＳ．
Ｄ．系雄性ラットを３７匹用いた。１％λ−カラゲニン
溶液０．１mlをラットの右側後肢足蹠皮下に注入して足
蹠浮腫を惹起させた。カラゲニン注射の２時間後に足容
積を測定し、浮腫率（％）を算出した。試験物質は、カ
ラゲニン注射の１時間前に経口投与した。(Method) 4-week-old S. cerevisiae purchased from SLC.
D. 37 male rats were used. 0.1 ml of a 1% λ-carrageenan solution was subcutaneously injected into the right hind footpad of the rat to induce footpad edema. The paw volume was measured 2 hours after the carrageenin injection, and the edema rate (%) was calculated. The test substances were administered orally 1 hour before the carrageenin injection.
【０１０２】（結果）その結果を表９および表１０に示
す。(Results) The results are shown in Tables 9 and 10.
【０１０３】[0103]
【表９】 ラットカラゲニン足蹠浮腫に対する本化合物の経口投与による効果 試験物質 投与量 浮腫率 抑制率 (mg/kg) （％） （％） ０．５％ＣＭＣ − ５８．２±１６．５ − 実施例２の化合物 １００ ２７．３± ７．２* ５３．０ インドメタシン ３０ ３７．９±１１．０* ３４．８ 各値は平均±標準偏差（ｎ＝６〜７）を示す。 対照群（ＣＭＣ）に対する有意差： *；ｐ＜０．０１．[Table 9] Effect of oral administration of this compound on rat carrageenin footpad edema Test substance Dose Edema rate Inhibition rate (mg / kg) (%) (%) 0.5% CMC-58.2 ± 16.5- Compound of Example 2 100 27.3 ± 7.2 * 53.0 Indomethacin 30 37.9 ± 11.0 * 34.8 Each value represents mean ± standard deviation (n = 6 to 7). Significantly different from control group (CMC): * ; p <0.01.
【０１０４】[0104]
【表１０】 ラットカラゲニン足蹠浮腫に対する本化合物の経口投与による効果 試験物質 投与量 抑制率 (mg/kg) （％） 実施例５の化合物 １００ ３９．３** 実施例６の化合物 １００ １６．６* 実施例７の化合物 １００ ４２．７** 各値は平均±標準偏差（ｎ＝６）を示す。 対照群（ＣＭＣ）に対する有意差： *；ｐ＜０．０５，**；ｐ＜０．０１．[Table 10] Effect of oral administration of this compound on rat carrageenin footpad edema Test substance Dose inhibition rate (mg / kg) (%) Compound of Example 5 100 39.3 ** Compound of Example 6 100 16. 6 * Compound of Example 7 100 42.7 ** Each value represents mean ± standard deviation (n = 6). Significantly different from control group (CMC): * ; p <0.05, ** ; p <0.01.
【０１０５】表９から明らかなように、実施例２の化合
物は１００mg/kg の経口投与により、ラットカラゲニン
足蹠浮腫を有意に５３．０％抑制した。また、表１０か
ら明らかなように、実施例５、６、７の化合物について
も有意な足蹠浮腫な抑制作用が認められた。一方、イン
ドメタシンは３０mg/kg の経口投与により、有意に３
４．８％抑制した。これらの結果から、本化合物は抗炎
症剤として有用であることが判った。As is clear from Table 9, the compound of Example 2 was orally administered at 100 mg / kg and significantly suppressed rat carrageenin footpad edema by 53.0%. Further, as is clear from Table 10, the compounds of Examples 5, 6 and 7 also had a significant inhibitory effect on footpad edema. On the other hand, indomethacin was significantly administered by oral administration of 30 mg / kg.
It was suppressed by 4.8%. From these results, it was found that the present compound is useful as an anti-inflammatory agent.
【０１０６】［製剤実施例１］内服錠 ４−［（４−ジフェニルメチル−１−ピペラジニル）メ
チル］フェニル酢酸３０mg 乳糖 ８０mg デンプン １７mg ステアリン酸マグネシウム ３mg 以上の成分を１錠分の材料として、常法により錠剤を成
型する。必要に応じて糖衣を付してもよい。[Formulation Example 1] Oral tablet 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid 30 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg Using the above ingredients as ingredients for one tablet, the usual method was used. To mold tablets. A sugar coating may be added if necessary.
【０１０７】［製剤実施例２］点眼剤 ４−［（４−ジフェニルメチル−１−ピペラジニル）メ
チル］フェニル酢酸１００mg ホウ酸 ７００mg ホウ砂 ４００mg 塩化ナトリウム ５００mg ｐ−オキシ安息香酸メチル ２６mg ｐ−オキシ安息香酸プロピル １４mg 滅菌精製水 全量１００ml 以上の成分を常法により混和して点眼剤とする。[Formulation Example 2] Eye drops 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid 100 mg Boric acid 700 mg Borax 400 mg Sodium chloride 500 mg Methyl p-oxybenzoate 26 mg p-Oxybenzoic acid Propyl 14 mg Sterile purified water Total 100 ml The above ingredients are mixed by a conventional method to give an eye drop.
【０１０８】［製剤実施例３］軟膏剤 ４−［（４−ジフェニルメチル−１−ピペラジニル）メ
チル］フェニル酢酸５００ｍｇ 親水軟膏 全量１００ｇ 以上の成分を常法により混和して軟膏剤とする。[Formulation Example 3] Ointment 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid 500 mg Hydrophilic ointment Total amount 100 g The above components are mixed by a conventional method to give an ointment.
【０１０９】 ［製剤実施例４］点眼剤 ４−［［４−（２−メトキシフェニル）−１−ピペラジニル］メチル］フェ ニル酢酸 ５００ｍｇ ホウ酸 ８００ｍｇ ホウ砂 ２００ｍｇ 塩化ナトリウム ５００ｍｇ クロロブタノール ３００ｍｇ 滅菌精製水 全量１００ｍｌ 以上の成分を常法により混和して点眼剤とする。[Formulation Example 4] Eye drops 4-[[4- (2-methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid 500 mg Boric acid 800 mg Borax 200 mg Sodium chloride 500 mg Chlorobutanol 300 mg Sterilized purified water Total amount 100 ml or more of the ingredients are mixed by a conventional method to prepare an eye drop.
【０１１０】[0110]
【発明の効果】本化合物のベンジルピペラジン誘導体お
よびその薬理学的に許容できる塩は、優れた抗アレルギ
ー作用および抗炎症作用を有しているので、各種アレル
ギー性疾患および炎症性疾患の治療のため有利に用いる
ことができる。EFFECTS OF THE INVENTION The benzylpiperazine derivative of the present compound and its pharmacologically acceptable salt have excellent antiallergic and antiinflammatory effects, and therefore are useful for the treatment of various allergic and inflammatory diseases. It can be used advantageously.
【図１】実施例１において合成した４−［（４−ジフェ
ニルメチル−１−ピペラジニル）メチル］フェニル酢酸
の赤外線吸収スペクトル（ＩＲ）を示す。FIG. 1 shows an infrared absorption spectrum (IR) of 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid synthesized in Example 1.
【図２】実施例２において合成した４−［［４−（２−
メトキシフェニル）−１−ピペラジニル］メチル］フェ
ニル酢酸の赤外線吸収スペクトル（ＩＲ）を示す。FIG. 2 shows 4-[[4- (2-
1 shows an infrared absorption spectrum (IR) of methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid.
Claims (20)
Ｖ）または式（Ｖ）で表される基を示し、Ｒ2 は水素原
子または低級アルキル基を示す。 【化２】 式（ＩＶ）中、Ｒ3 は水素原子、低級アルキル基、ピリ
ジン環またはハロゲン原子で置換されていてもよいベン
ゼン環を示し、Ｘはハロゲン原子を示す。式（Ｖ）中、
Ｒ4 およびＲ5 は、同一または異なって、水素原子、低
級アルキル基、低級アルコキシ基、ハロゲン原子または
カルボキシル基を示す。］で表されるベンジルピペラジ
ン誘導体またはその薬理学的に許容できる塩。1. The following formula (I): [In the formula (I), R 1 is a pyridine ring or the following formula (I
V) or a group represented by the formula (V), and R 2 represents a hydrogen atom or a lower alkyl group. Embedded image In formula (IV), R 3 represents a hydrogen atom, a lower alkyl group, a pyridine ring or a benzene ring which may be substituted with a halogen atom, and X represents a halogen atom. In formula (V),
R 4 and R 5 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a carboxyl group. ] The benzyl piperazine derivative represented by these, or its pharmacologically acceptable salt.
ペラジニル）メチル］フェニル酢酸メチルエステルであ
る請求項１記載のベンジルピペラジン誘導体またはその
薬理学的に許容できる塩。2. A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid methyl ester.
ペラジニル）メチル］フェニル酢酸である請求項１記載
のベンジルピペラジン誘導体またはその薬理学的に許容
できる塩。3. A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[(4-diphenylmethyl-1-piperazinyl) methyl] phenylacetic acid.
−１−ピペラジニル］メチル］フェニル酢酸である請求
項１記載のベンジルピペラジン誘導体またはその薬理学
的に許容できる塩。4. 4-[[4- (2-methoxyphenyl)
A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is -1-piperazinyl] methyl] phenylacetic acid.
ル）−１−ピペラジニル］メチル］フェニル酢酸である
請求項１記載のベンジルピペラジン誘導体またはその薬
理学的に許容できる塩。5. A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (2-carboxyphenyl) -1-piperazinyl] methyl] phenylacetic acid.
ペラジニル］メチル］フェニル酢酸である請求項１記載
のベンジルピペラジン誘導体またはその薬理学的に許容
できる塩。6. The benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (2-pyridyl) -1-piperazinyl] methyl] phenylacetic acid.
ラジニル］メチル］フェニル酢酸である請求項１記載の
ベンジルピペラジン誘導体またはその薬理学的に許容で
きる塩。7. The benzylpiperazine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (2-tolyl) -1-piperazinyl] methyl] phenylacetic acid.
ル）メチル］フェニル酢酸である請求項１記載のベンジ
ルピペラジン誘導体またはその薬理学的に許容できる
塩。8. A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[(4-phenyl-1-piperazinyl) methyl] phenylacetic acid.
−１−ピペラジニル］メチル］フェニル酢酸である請求
項１記載のベンジルピペラジン誘導体またはその薬理学
的に許容できる塩。9. 4-[[4- (2-fluorophenyl)
A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is -1-piperazinyl] methyl] phenylacetic acid.
ニル）−１−ピペラジニル］メチル］フェニル酢酸であ
る請求項１記載のベンジルピペラジン誘導体またはその
薬理学的に許容できる塩。10. The benzylpiperazine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (2,5-dimethylphenyl) -1-piperazinyl] methyl] phenylacetic acid.
ル）−１−ピペラジニル］メチル］フェニル酢酸である
請求項１記載のベンジルピペラジン誘導体またはその薬
理学的に許容できる塩。11. The benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (4-methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid.
ル）−１−ピペラジニル］メチル］フェニル酢酸である
請求項１記載のベンジルピペラジン誘導体またはその薬
理学的に許容できる塩。12. The benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (3-methoxyphenyl) -1-piperazinyl] methyl] phenylacetic acid.
ルフェニル）−１−ピペラジニル］メチル］フェニル酢
酸である請求項１記載のベンジルピペラジン誘導体また
はその薬理学的に許容できる塩。13. A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- (3-trifluoromethylphenyl) -1-piperazinyl] methyl] phenylacetic acid.
ジル）メチル］−１−ピペラジニル］メチル］フェニル
酢酸メチルエステルである請求項１記載のベンジルピペ
ラジン誘導体またはその薬理学的に許容できる塩。14. The benzylpiperazine derivative according to claim 1, which is 4-[[4- [phenyl- (2-pyridyl) methyl] -1-piperazinyl] methyl] phenylacetic acid methyl ester, or a pharmaceutically acceptable derivative thereof. salt.
ジル）メチル］−１−ピペラジニル］メチル］フェニル
酢酸である請求項１記載のベンジルピペラジン誘導体ま
たはその薬理学的に許容できる塩。15. The benzylpiperazine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4- [phenyl- (2-pyridyl) methyl] -1-piperazinyl] methyl] phenylacetic acid.
ル）フェニルメチル］−１−ピペラジニル］メチル］フ
ェニル酢酸メチルエステルである請求項１記載のベンジ
ルピペラジン誘導体またはその薬理学的に許容できる
塩。16. A benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is methyl 4-[[4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] methyl] phenylacetic acid. .
ル）フェニルメチル］−１−ピペラジニル］メチル］フ
ェニル酢酸である請求項１記載のベンジルピペラジン誘
導体またはその薬理学的に許容できる塩。17. The benzylpiperazine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is 4-[[4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] methyl] phenylacetic acid.
同義である。］で表されるピペラジン誘導体および次の
式（ＩＩＩ）［式中、Ｒ2 は前記と同義であり、Ｘはハ
ロゲン原子を示す。］で表される４−ハロゲン化メチル
フェニル酢酸エステルを反応させ、あるいは、これら化
合物をさらに加水分解させることを特徴とする請求項１
乃至１７記載のベンジルピペラジン誘導体またはその薬
理学的に許容できる塩の製造法。 【化３】 18. The following formula (II) [wherein, R 1 has the same meaning as defined above. ] The piperazine derivative represented by these, and the following formula (III) [In formula, R < 2 > is synonymous with the above and X shows a halogen atom. ] The 4-halogenated methyl phenylacetic acid ester represented by these is made to react, or these compounds are further hydrolyzed.
18. A method for producing a benzylpiperazine derivative or a pharmaceutically acceptable salt thereof according to any one of 1 to 17. Embedded image
ラジン誘導体またはその薬理学的に許容できる塩を有効
成分として含有してなる抗アレルギー剤。19. An anti-allergic agent comprising the benzylpiperazine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
ラジン誘導体またはその薬理学的に許容できる塩を有効
成分として含有してなる抗炎症剤。20. An anti-inflammatory agent comprising the benzylpiperazine derivative according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8171924A JPH09208570A (en) | 1995-07-10 | 1996-07-02 | Benzylpiperazine derivative |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17308595 | 1995-07-10 | ||
| JP7-173085 | 1995-07-10 | ||
| JP7-311772 | 1995-11-30 | ||
| JP31177295 | 1995-11-30 | ||
| JP8171924A JPH09208570A (en) | 1995-07-10 | 1996-07-02 | Benzylpiperazine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH09208570A true JPH09208570A (en) | 1997-08-12 |
Family
ID=27323553
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8171924A Withdrawn JPH09208570A (en) | 1995-07-10 | 1996-07-02 | Benzylpiperazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH09208570A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007023882A1 (en) * | 2005-08-26 | 2007-03-01 | Shionogi & Co., Ltd. | Derivative having ppar agonistic activity |
| JP2024528127A (en) * | 2021-07-30 | 2024-07-26 | コンフォ セラピューティクス エヌ．ベー． | Compounds for the treatment of pain, particularly neuropathic pain, and/or other diseases or disorders associated with AT2R and/or AT2R-mediated signaling |
-
1996
- 1996-07-02 JP JP8171924A patent/JPH09208570A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007023882A1 (en) * | 2005-08-26 | 2007-03-01 | Shionogi & Co., Ltd. | Derivative having ppar agonistic activity |
| US8097610B2 (en) | 2005-08-26 | 2012-01-17 | Shionogi & Co., Ltd. | Derivative having PPAR agonistic activity |
| JP2024528127A (en) * | 2021-07-30 | 2024-07-26 | コンフォ セラピューティクス エヌ．ベー． | Compounds for the treatment of pain, particularly neuropathic pain, and/or other diseases or disorders associated with AT2R and/or AT2R-mediated signaling |
| JP2025084799A (en) * | 2021-07-30 | 2025-06-03 | コンフォ セラピューティクス エヌ．ベー． | Compounds for the treatment of pain, in particular neuropathic pain, and/or other diseases or disorders associated with AT2R and/or AT2R-mediated signaling |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A300 | Withdrawal of application because of no request for examination |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 20030902 |