JPS635063A - Indane compound - Google Patents
Indane compoundInfo
- Publication number
- JPS635063A JPS635063A JP14828986A JP14828986A JPS635063A JP S635063 A JPS635063 A JP S635063A JP 14828986 A JP14828986 A JP 14828986A JP 14828986 A JP14828986 A JP 14828986A JP S635063 A JPS635063 A JP S635063A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- butyl
- piperazinyl
- lower alkyl
- formula
- 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.)
- Pending
Links
- -1 Indane compound Chemical class 0.000 title claims abstract description 29
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 6
- 238000003756 stirring Methods 0.000 abstract description 6
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 208000006673 asthma Diseases 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 13
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 11
- AGYZONZEHVHXEX-UHFFFAOYSA-N 2-[4-[2-(methylamino)ethyl]piperazin-1-yl]-1-(4-propan-2-ylsulfanylphenyl)ethanol Chemical compound C1CN(CCNC)CCN1CC(O)C1=CC=C(SC(C)C)C=C1 AGYZONZEHVHXEX-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 206010006482 Bronchospasm Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 230000007885 bronchoconstriction Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 210000003437 trachea Anatomy 0.000 description 4
- DSKYFUXPJXIWCL-UHFFFAOYSA-N 7-bromo-6-butyl-5h-cyclopenta[f][1,3]benzodioxole Chemical compound C1=C2CC(CCCC)=C(Br)C2=CC2=C1OCO2 DSKYFUXPJXIWCL-UHFFFAOYSA-N 0.000 description 3
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 3
- 229960004484 carbachol Drugs 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 150000002468 indanes Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UDGVKXHVBXZSJD-UHFFFAOYSA-N 6-butyl-7-methoxy-5h-cyclopenta[f][1,3]benzodioxole Chemical compound C1=C2CC(CCCC)=C(OC)C2=CC2=C1OCO2 UDGVKXHVBXZSJD-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- YKSVXVKIYYQWBB-UHFFFAOYSA-N 1-butylpiperazine Chemical compound CCCCN1CCNCC1 YKSVXVKIYYQWBB-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- QLEIDMAURCRVCX-UHFFFAOYSA-N 1-propylpiperazine Chemical compound CCCN1CCNCC1 QLEIDMAURCRVCX-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- HZUFMSJUNLSDSZ-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)prop-2-enal Chemical compound O=CC=CC1=CC=C2OCOC2=C1 HZUFMSJUNLSDSZ-UHFFFAOYSA-N 0.000 description 1
- CIHFEQYRFCLSLI-UHFFFAOYSA-N 8bh-indeno[1,2-d][1,3]dioxole Chemical compound C1=CC=C2C3OCOC3=CC2=C1 CIHFEQYRFCLSLI-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- SBUXRMKDJWEXRL-ROUUACIJSA-N cis-body Chemical compound O=C([C@H]1N(C2=O)[C@H](C3=C(C4=CC=CC=C4N3)C1)CC)N2C1=CC=C(F)C=C1 SBUXRMKDJWEXRL-ROUUACIJSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000000956 methoxy group Chemical class [H]C([H])([H])O* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- SMDQFHZIWNYSMR-UHFFFAOYSA-N sulfanylidenemagnesium Chemical compound S=[Mg] SMDQFHZIWNYSMR-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- CURCMGVZNYCRNY-UHFFFAOYSA-N trimethylazanium;iodide Chemical compound I.CN(C)C CURCMGVZNYCRNY-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明はインダン類化合物、更に詳細には、次の一般式
（Ｉ）
（式中、Ｒ１は低級アルキル基を示し、Ｒ２及びＲ３は
それぞれ低級アルキル基を示すか、または−緒になって
アルキレンジオキシ基を示し、Ｒ４及びＲ５はそれぞれ
置換基を有することのある低級アルキル基またはアリー
ル基を示すか、あるいは隣接する窒素原子と共に置換基
を有することのあるピペリジノ、ピペラジニル又はホモ
ピペラジノ基を示す。但し、Ｒ４及びＲ５が共にメチル
基の場合を除く）
で表わされるインダン類化合物に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to indane compounds, and more particularly, to compounds of the following general formula (I) (wherein R1 represents a lower alkyl group, and R2 and R3 each represent represents a lower alkyl group, or together represents an alkylenedioxy group, R4 and R5 each represent a lower alkyl group or an aryl group that may have a substituent, or together with the adjacent nitrogen atom, a substituent (However, cases in which both R4 and R5 are methyl groups are excluded.)
［従来の技術及びその問題点］
従来、インダン類化合物としては、２，３−置換−５，
６−メチレンジオキシインダン類が米国特許第４３９３
２２６号公報に開示されている。このものは冠面流量増
加作用を有することが知られているが気管支収縮抑制作
用については何ら示唆さえされていないのである。[Prior art and its problems] Conventionally, as indan compounds, 2,3-substituted-5,
6-methylene dioxyindanes are disclosed in U.S. Patent No. 4393.
It is disclosed in Publication No. 226. Although this substance is known to have an effect of increasing coronal flow, there is no suggestion whatsoever that it has an effect of suppressing bronchoconstriction.
［問題点を解決するための手段］
本発明者らは、インダン類化合物について種々研究を行
った結果、前記式（Ｉ＞で表わされる新規化合物が気管
支収縮抑制作用に優れたものであることを見出し、本発
明を完成した。[Means for Solving the Problems] As a result of conducting various studies on indane compounds, the present inventors have found that the novel compound represented by the above formula (I>) has an excellent bronchoconstriction inhibitory effect. The present invention has been completed.
すなわち本発明は、喘息治療薬として有用な新規な化合
物（１）を提供するものでおる。That is, the present invention provides a novel compound (1) useful as a therapeutic agent for asthma.
本発明化合物（１）において、Ｒ４、Ｒ５で表わされる
低級アルキル基の置換基としては、例えば置換基を有す
ることのあるアリール基、ヒドロキシ基、ジ低級アルキ
ルアミノ基、置換基を有することのあるピペラジニル基
、ピペリジル基等が挙げられる。また、Ｒ４、Ｒ５で表
わされるピペリジノ基、ピペラジニル基、ホモピペラジ
ノ基の置換基としては、例えば置換基を有することのあ
るベンジル基、アリール基、低級アルキル基、ヒドロキ
シ低級アルキル基、置換基を有することのあるフェニル
カルボニル等が挙げられる。In the compound (1) of the present invention, substituents for the lower alkyl group represented by R4 and R5 include, for example, an aryl group that may have a substituent, a hydroxy group, a di-lower alkylamino group that may have a substituent. Examples include piperazinyl group and piperidyl group. Further, as substituents for the piperidino group, piperazinyl group, and homopiperazino group represented by R4 and R5, for example, a benzyl group that may have a substituent, an aryl group, a lower alkyl group, a hydroxy lower alkyl group, and a substituent. Examples include certain phenylcarbonyl.
尚、本発明は上記−般式（Ｉ＞で表わされる化合物の全
ての異性体を包含する。Incidentally, the present invention includes all isomers of the compound represented by the above general formula (I>).
本発明のインダン類化合物は、例えば次に示される反応
式に従って、インデン類化合物（ｎ）を還元することに
より製造される。The indene compound of the present invention is produced by reducing an indene compound (n), for example, according to the reaction formula shown below.
（ｎ）
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は前記と同じ
）本反応は、無水エタノール等の溶媒中で、水素気流下
、常圧室温にて６〜８時間攪拌することによって行われ
る。(n) (In the formula, R1, R2, R3, R4 and R5 are the same as above) This reaction is carried out by stirring in a solvent such as anhydrous ethanol at normal pressure and room temperature under a hydrogen stream for 6 to 8 hours. It will be done.
−般式（Ｉｔ＞で表わされる原料化合物は、本発明者ら
によって製造された１７ｉ規化合物で、例えば次の反応
式に従って製造される（特願昭６１−２１７３２号）。- The raw material compound represented by the general formula (It>) is a 17i-order compound produced by the present inventors, for example, according to the following reaction formula (Japanese Patent Application No. 21732/1982).
（式中、Ｒ４、Ｒ２、Ｒ３、Ｒ４及びＲｓは前記と同じ
）−般式（１）で表わされる化合物のメタノール溶液に
氷−温冷却下塩素ガスを吹き込みメトキシ体（ＩＶ）を
得た後、更にこのメトキシ体（ＩＶ）と三臭化リンをク
ロロホルム溶媒中で水冷上反応させて式（Ｖ）を得て、
このブロム体（Ｖ）と第２＠アミン（Ｖｌ）を反応させ
ることにより化合物（ｎ）が得られる。(In the formula, R4, R2, R3, R4 and Rs are the same as above) - After blowing chlorine gas into the methanol solution of the compound represented by the general formula (1) under ice-temperature cooling to obtain the methoxy compound (IV) , Further, this methoxy form (IV) and phosphorus tribromide were reacted in a chloroform solvent with water cooling to obtain formula (V),
Compound (n) is obtained by reacting this bromine compound (V) with a secondary @amine (Vl).
また本反応のインダン類化合物は、次に示される反応式
に従っても製造される。The indane compounds of this reaction can also be produced according to the reaction formula shown below.
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲｓは前記と同じ
）本反応は、ジメチルスルホキサイド（ＤＭＳＯ）等の
溶媒中、トリエチルアミン等の塩基の存在下、７〜１０
時間加熱攪拌することによって行なわれる。(In the formula, R1, R2, R3, R4 and Rs are the same as above) This reaction is carried out in a solvent such as dimethyl sulfoxide (DMSO) in the presence of a base such as triethylamine,
This is done by heating and stirring for a period of time.
−般式（ＶＩ）で表わされる原料化合物は、ジャーナル
・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ
ｏｆＭｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ） ２
５巻４＠、４５２頁（１９８２年）の記載方法またはそ
れに準じて製造される。- The raw material compound represented by the general formula (VI) is published in the Journal of Medicinal Chemistry (Journal
of Medicinal Chemistry) 2
It is manufactured according to the method described in Vol. 5, 4@, p. 452 (1982), or according to the method described therein.
斯くして、得られた本発明のインダン類化合物（Ｉ＞は
、更に必要に応じて常法により塩酸塩、臭化水素荘塩、
過塩素酸塩等の無典塩及びフマール酸塩、コハク酸塩、
酒石酸塩、マレイン酸塩、シュウ酸塩等の有別黒塩とす
ることができる。The thus obtained indane compound (I>) of the present invention can be further treated with hydrochloride, hydrobromide salt,
Irregular salts such as perchlorates and fumarates, succinates,
It can be a special black salt such as tartrate, maleate, oxalate, etc.
［作用］
本発明化合物（１）の気管支収縮抑制作用を下記方法に
より試験した。結果は第１図及び第２図に示す。[Effect] The bronchoconstriction inhibitory effect of the compound (1) of the present invention was tested by the following method. The results are shown in Figures 1 and 2.
ダニ虫体（Ｄ、ｆａｒｉｎａｅ） ３００ｇをエーテル
を用いて脱脂し、０．０１モルのリン駿援耐液（ｆ）Ｈ
７，７） ３ｊ２で２回抽出後、１０００ｒ、 ｏ、
ｍで３０分間遠心分離して得られた上清をビスキング・
チューブ３８／３２ （Ｖｉｓｋｉｎｇｔｕｂｅ ３
Ｂ／３２） （牛丼化学製）に入れ精製水に対して４
°Ｃ１２４〜４８時間透析し、その内液をミクロ・ビュ
ーレット（ｍｉｃｒｏ−ｂｉｕｒｅｔ）法によって測定
し、蛋白質含四が３６．３％のものを濃縮し、凍結乾燥
しく以下ＡＧと称す）、これを−２０’Ｃで保存し、用
時精製水に溶解したものを使用した。300 g of mite body (D, farinae) was degreased with ether, and 0.01 mol of phosphorus support solution (f) H was degreased with ether.
7,7) After extraction twice with 3j2, 1000 r, o,
The supernatant obtained by centrifugation for 30 minutes at
Tube 38/32 (Viskingtube 3
B/32) (manufactured by Gyudon Kagaku) and add 4 to purified water.
Dialysis was carried out at 124 to 48 hours at 124 °C, and the internal solution was measured by the micro-biuret method.The protein content was concentrated to 36.3%, and this was freeze-dried (hereinafter referred to as AG). was stored at -20'C and dissolved in purified water before use.
飼育環境、温度２２±１°Ｃ１湿度４０％の恒温恒湿と
し、固形飼料及び水を以って飼育した体重３００〜３５
０３の雄性バー トＬ／ −（ｈａｒｔ＋ｅｙ）系モル
モットにＡＧ １００ｔＩ！Ｊをアラム（ａｌｕｍ）を
含む生理食塩水１１ｎｆ！に静かに溶解した液を４週間
間隔で４回、モルモットの腹腔内に注射して、能動感作
を行った。Breeding environment: Temperature: 22±1°C, humidity: 40%, and weight: 300 to 35 cm. Breeding with solid feed and water.
AG 100tI for 03 male Bart L/-(hart+ey) guinea pigs! J to physiological saline containing alum 11nf! active sensitization was performed by injecting the solution gently dissolved in the guinea pigs intraperitoneally four times at four-week intervals.
感作モルモットを撲殺し、充分放血した後、気管を摘出
した。摘出した気管はタイロード液で充分洗浄した後、
付着する組織片を注意深く取り除いた。気管像本は、気
管の軟骨部を縦に切開し、軟骨を１個含む小片に切断し
た。この小片の４個を軟骨部において１本の鎖につなぎ
合わせ気管筋標本とした。After the sensitized guinea pig was beaten to death and sufficient blood was exsanguinated, the trachea was removed. After thoroughly cleaning the removed trachea with Tyrode's solution,
Adhering tissue pieces were carefully removed. The trachea image was prepared by longitudinally incising the cartilage part of the trachea and cutting it into small pieces containing one piece of cartilage. Four of these small pieces were connected into one chain at the cartilage part to form a tracheal muscle specimen.
作製した気管筋標本は、タイロード液を満したマグヌス
槽（３７°Ｃ恒温）に懸垂し、２０分間放置後試験に供
した。The prepared tracheal muscle specimen was suspended in a Magnus bath (37°C constant temperature) filled with Tyrode's solution, left for 20 minutes, and then subjected to the test.
これらの標本はいずれも１０−７９ ／ｍｆ！のカルバ
コール（ｃａｒｂａｃｏｈｏ Ｉ ）を反復作用させて
収縮高が充分安定した後、もう１度１Ｏ−７ｙ／ｍのカ
ルバコールにて７分間収縮させた。この最終のカルバコ
ールによる収縮を基準収縮高として測定した。尚、これ
らの収縮はいずれも、アイソトニック・トランス・ジュ
ーサー（ｉｓｏｔｏｎｉｃ ｔｒａｎｓ ｄｕｃｅｒ）
ＩＥ−４０１３＞及びアンブリファイア−（ａｍｐｌ
１ｆｉｅｒ ＨＥ−４０１２＞にて測定した。Both of these specimens are 10-79/mf! After the contraction height was sufficiently stabilized by repeated application of carbachol (carbacoho I), contraction was performed once again for 7 minutes with 10-7 y/m of carbachol. This final carbachol-induced contraction was measured as the standard contraction height. Incidentally, both of these contractions are performed using an isotonic transducer.
IE-4013> and amblifier (ampl
1fier HE-4012>.
本発明化合物及びケトチフエン（対照薬）はＡＧ添添加
３カ
加した。コントロールは精製水を同伍加えて試験を行っ
た。シュルツデール（Ｓｃｈｕｌｔｚ−Ｄａｔｅ）反応
の惹起は、用時精製水に溶解したＡＧ（作用濃度 １０
−６！Ｊ／ｄ＞をマグヌス槽に添加して行った。添加後
、１，２，３， ５． １０及び１５分後の収縮高を経
時的に測定し、基準収縮高に対する収縮抑制率を算出し
た。The compound of the present invention and ketotiphen (control drug) were added at three times with AG addition. As a control, the test was conducted by adding the same amount of purified water. The Schultz-Date reaction can be induced by AG (working concentration 10
-6! J/d> was added to the Magnus bath. After addition, 1, 2, 3, 5. The shrinkage height after 10 and 15 minutes was measured over time, and the shrinkage inhibition rate with respect to the reference shrinkage height was calculated.
［発明の効果］
本発明のインダン類化合物（Ｉ＞は図１から明らかな如
＜ ５ｘ１０−５ｇ／威濃度で有意な気管支収縮抑制を
示しており、喘息治療薬として有用でおる。[Effects of the Invention] As is clear from FIG. 1, the indane compound (I) of the present invention exhibits significant inhibition of bronchoconstriction at a concentration of <5x10-5 g/kg, and is useful as a therapeutic agent for asthma.
［実施例］ 次に参考例及び実施例を挙げて説明する。[Example] Next, reference examples and examples will be given and explained.
参考例１
２−ｎ−ブチル−３−ブロモ−５，６−メチレンジオキ
シインデンの合成：
（１） ２−ｎ−ブチル−３−メトキシ−５，６−メチ
レンジオキシインデン
２−ｎ−ブチル−３−（３．４−メチレンジオキシフェ
ニル）アクリルアルデヒド１２ｇをメタノール８０ｄに
溶解し、氷−塩冷却下塩狼ガスを吹き込む。ｕＴＡクロ
マトグラフ（ｎ−ヘキサン：エーテル５／１）にて原料
消失したところで吹き込みを止めた。水を加え、エーテ
ル抽出し、水、飽和炭酸水素ナトリウム水溶液、水の順
に洗浄後、無水硫酸マグネシウムで乾燥し、減圧上濃縮
した。残漬はシリカゲルカラムクロマト（ｎ−ヘキサン
：エーテル１０／１）で°精製し、油状の２−ｎ−ブチ
ル−３−メトキシ−５、６−メチレンジオキシインデン
１１．４９（収率９０％）を得た。Reference Example 1 Synthesis of 2-n-butyl-3-bromo-5,6-methylenedioxyindene: (1) 2-n-butyl-3-methoxy-5,6-methylenedioxyindene 2-n-butyl -12 g of 3-(3.4-methylenedioxyphenyl)acrylaldehyde was dissolved in 80 d of methanol, and salt gas was blown into the solution under ice-salt cooling. Blowing was stopped when the raw material disappeared using a uTA chromatograph (n-hexane:ether 5/1). Water was added and extracted with ether. The mixture was washed with water, a saturated aqueous sodium bicarbonate solution, and water in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ether 10/1) to obtain oily 2-n-butyl-3-methoxy-5,6-methylenedioxyindene (11.49% yield) I got it.
■Ｒ ｖ ｎｅａｊｃｍ−＋ ：
ａＸ
１４６５、 １３３０， １０８５． １０３５（２）
２−ｎ−ブチル−３−ブロモ−５，６−メチレンジオ
キシインデン
２−ｎ−ブチル−３−メトキシ−５，６−メチレンジオ
キシインデン９．３３をクロロホルム１００ｄに溶解し
、水冷下三臭化リン１５．４ｇを１時間で滴下した。引
き続き４時間攪拌後室温に戻し、更に４時間攪拌した。■R v neajcm-+: aX 1465, 1330, 1085. 1035(2)
2-n-Butyl-3-bromo-5,6-methylenedioxyindene 9.33 g of 2-n-butyl-3-methoxy-5,6-methylenedioxyindene was dissolved in 100 d of chloroform, and cooled with water. 15.4 g of phosphorus chloride was added dropwise over 1 hour. After stirring for 4 hours, the mixture was returned to room temperature and further stirred for 4 hours.
水、５％水酸化ナトリウム水溶液、水の順で洗浄し、無
水硫酸マグネシウムで乾燥後減圧上濃縮した。残渣は、
シリカゲルカラムクロマト（ｎ−ヘキサン：エーテル２
０／１）で精製し、融点６３． ０〜６４． ０’Ｃの
２−〇ーブチルー３ーブロモー５，６−メチレンジオキ
シインデンの精品７：ＪＪ（収率６８％）を得た。The mixture was washed with water, a 5% aqueous sodium hydroxide solution, and water in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is
Silica gel column chromatography (n-hexane:ether 2
0/1) with a melting point of 63. 0-64. 0'C 2-0-butyl-3-bromo-5,6-methylenedioxyindene purified product 7:JJ (yield 68%) was obtained.
Ｉ Ｒ ｖＫ８ｒｃｍ−１：
ａｘ
１４７０、 １３３０， １０３８． ６５０参考例２
Ｎ−メチル−Ｎ−［２−［４−［２−（４−イソプロピ
ルチオフェニル）−２−ヒドロキシエチル］−１−ピペ
ラジニル］エチル］アミンの合成：
（１）４−イソプロピルチオ−α−［４−（２−ヒドロ
キシエチル）−１−ピペラジニル］アセトフェノン
１−ピペラジンエタノール３．６ｇと炭酸ナトリウム３
．９ｇを含むＤ Ｍ Ｓ ０３０ｄ溶液に、水冷下４−
イソプロピルチオーα−ブロモアセトフェノン５．０９
のＤＭ３０２０ｄ溶液をゆっくり滴下した。滴下後、室
温で１時間攪拌し、飽和塩化ナトリウム水溶液を加え、
クロロホルム抽出し、飽和塩化ナトリウム水溶液で１回
洗浄した。無水硫酸マグネシウムで乾燥後、減圧上濃縮
し、残渣をシリカゲルカラムクロマト（クロロホルム：
メタノール１０／１）で精製し、結晶４．８Ｓ？（収率
８１％）を得た。IR vK8rcm-1: ax 1470, 1330, 1038. 650 Reference Example 2 Synthesis of N-methyl-N-[2-[4-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]-1-piperazinyl]ethyl]amine: (1) 4-isopropylthio -α-[4-(2-hydroxyethyl)-1-piperazinyl]acetophenone 1-piperazine ethanol 3.6 g and sodium carbonate 3
．． 9 g of D M S 030d solution under water cooling.
Isopropylthio α-bromoacetophenone 5.09
DM3020d solution was slowly added dropwise. After dropping, stir at room temperature for 1 hour, add saturated sodium chloride aqueous solution,
It was extracted with chloroform and washed once with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:
Purified with methanol 10/1) to give crystals of 4.8S? (yield 81%).
ＩＲνに８ｒｃｍ−１：
ａｘ
３４００、２９４０．２Ｂ２０．１６８０．１５９０．
１１６５．９７５（２）４−イソプロピルチオ−α−図
一（２−゛クロロエチル）−１−ピペラジニル］アセト
フェノン
水冷下４−イソプロピルチオ−α−［４−（２−ヒドロ
キシエチル）−１−ピペラジニル］アセトフェノン４．
８ｇの塩化チオニル４０ｄ溶液を４時間攪拌したのち、
減圧上濃縮した。残渣に氷水を加え、炭酸ナトリウムで
アルカリ性とし、酢酸エチルで抽出、水洗の後、無水硫
酸マグネシウムで乾燥し減圧上濃縮した。残渣は、シリ
カゲルカラムクロマト（クロロホルム：アセトン１５／
１）で精製し、結晶２．３９（収率４５％）を得た。水
晶は不安定な為、直ちに次の工程に供した。8rcm-1 to IRν: ax 3400, 2940.2B20.1680.1590.
1165.975(2) 4-isopropylthio-α-[4-(2-hydroxyethyl)-1-piperazinyl] under water cooling with 4-isopropylthio-α-[4-(2-hydroxyethyl)-1-piperazinyl]acetophenone Acetophenone 4.
After stirring 8 g of thionyl chloride 40d solution for 4 hours,
Concentrate under reduced pressure. Ice water was added to the residue, made alkaline with sodium carbonate, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone 15/
1) to obtain crystal 2.39 (yield 45%). Since the crystal was unstable, it was immediately subjected to the next step.
Ｉ Ｒ１，ＩＫＢｒｃｍ−’ ：
ａｘ
２９３０、２８００．１６７０．１５８０．１２１５．
１０９０．９７０．８１５（３）４−イソプロピルチオ
−α−［４−［２−（Ｎ−メチルアミノ）エチル］−１
−ピペラジニル］アセトフェノン４−イソプロピルチオ
−α−［４−（２−クロロエチル）−１−ピペラジニル
］アセトフェノン３．４５９とヨウ化ナトリウム０．５
９の２０％メチルアミン含有メタノール５０ｄ溶液を、
封管中６０°Ｃで１０時間反応した。放冷後、減圧上濃
縮し、残渣をシリカゲルカラムクロマト（クロロホルム
：メタノール：４０％メチルアミン含有メタノール５：
１：０．１）で精製し、油状物２．５り（収率７４％）
を得た。I R1, IKBrcm-': ax 2930, 2800.1670.1580.1215.
1090.970.815(3) 4-isopropylthio-α-[4-[2-(N-methylamino)ethyl]-1
-piperazinyl]acetophenone 4-isopropylthio-α-[4-(2-chloroethyl)-1-piperazinyl]acetophenone 3.459 and sodium iodide 0.5
9 in methanol 50d solution containing 20% methylamine,
The reaction was carried out in a sealed tube at 60°C for 10 hours. After cooling, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol: 40% methylamine-containing methanol 5:
1:0.1) to produce 2.5 ml of oil (yield 74%)
I got it.
Ｉ Ｒｖ ＊ｅａ ｔｃｍ ’１；
ａｘ
３３００、２９２５．２８００．１６６５．１５８５．
１４４０．１１５０．７５０（４）Ｎ−メチル−Ｎ−［
２−［４−［２−（４−イソプロピルチオフェニル）−
２−ヒドロキシエチル］−１−ピペラジニル］エチル］
アミン
４−イソプロピルチオ−α−［４−［２−（Ｎ−メチル
アミノ）エチル］−１−ピペラジニル］アセトフェノン
１１．ｏｇのメタノール５０７！溶液に、水冷下水素化
ホウ素ナトリウム０．５９をゆっくり添加したのち、１
．５時間攪拌した。I Rv *ea tcm '1; ax 3300, 2925.2800.1665.1585.
1440.1150.750(4) N-methyl-N-[
2-[4-[2-(4-isopropylthiophenyl)-
2-hydroxyethyl]-1-piperazinyl]ethyl]
Amine 4-isopropylthio-α-[4-[2-(N-methylamino)ethyl]-1-piperazinyl]acetophenone 11. og methanol 507! After slowly adding 0.59 sodium borohydride to the solution under water cooling, 1
．． Stirred for 5 hours.
減圧上濃縮し、残渣をシリカゲルカラムクロマト（クロ
ロホルム：メタノール：４０％メチルアミン含有メタノ
ール５：１：０．１）で精製し、油状物３．１ｇ（収率
７７％）を得た。It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol:methanol containing 40% methylamine 5:1:0.1) to obtain 3.1 g of an oil (yield: 77%).
Ｉ Ｒｖ ｎｅａｊｃｍ −１”。I Rv neajcm -1”.
ａＸ
３１００、２９２０．２８００．１４４０．１１５０．
８２０尚、後記参考例で用いた他の第２級アミンは、市
販品あるいは既知の方法で合成したものを用いた。aX 3100, 2920.2800.1440.1150.
820 Note that other secondary amines used in the reference examples described later were commercially available products or those synthesized by known methods.
参考例３
２−ｎ−ブチル−１−［Ｎ−メチル−Ｎ−［２−（Ｎ’
、Ｎ−ジメチルアミノ）エチル］アミノ］−５，６−メ
チレンジオキシインデン
Ｎ、Ｎ、Ｎ’−トリメチルエチレンジアミン３５０ｍｙ
と炭酸ナトリウム３６０ｍｙを含むジメチルスルホキサ
イド溶液５ｍｌに、室温下２−ｎ−ブチル−３−ブロモ
−５，６−メチレンジオキシインデン５００ｍ３を加え
、１時間攪拌した。反応終了後、飽和炭酸水素ナトリウ
ム水溶液を加え、酢酸エチルで抽出し、水洗後無水硫駿
マグネシウムで乾燥し、減圧上濃縮した。残渣は、シリ
カゲルカラムクロマト（クロロホルム：メタノール ２
０／１）で精製し、油状物３６５ｍｆｆ（収率６８％）
を得た。Reference example 3 2-n-butyl-1-[N-methyl-N-[2-(N'
, N-dimethylamino)ethyl]amino]-5,6-methylenedioxyindene N,N,N'-trimethylethylenediamine 350my
500 ml of 2-n-butyl-3-bromo-5,6-methylenedioxyindene was added to 5 ml of a dimethyl sulfoxide solution containing 360 ml of sodium carbonate and 360 ml of sodium carbonate at room temperature, and the mixture was stirred for 1 hour. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol 2
0/1) to produce 365 mff of oil (yield 68%)
I got it.
ＮＭＲ（ＣＤＣｌ２）δ；
０．８８〜１．０２ （３Ｈ，ｍ、 〜ＣＨ３） 、
１．２４〜１．７６（４Ｈ，ｍ。NMR (CDCl2) δ; 0.88-1.02 (3H, m, ~CH3),
1.24-1.76 (4H, m.
〜ＣＨ２ＣＨ２〜）、２．２６（６Ｈ，Ｓ、Ｎ（ＣＨ３
） ３ ） 、２．３０（３Ｈ，ｓ。~CH2CH2~), 2.26(6H,S,N(CH3
) 3) , 2.30 (3H, s.
）−Ｎ−ＣＨ３） ２．３０〜２．８２（６Ｈ，ｍ、Ｎ
／′ｖＮ、 ’（ＣＨ２−）、４．１６（ＩＨ，Ｓ、Ｃ
Ｈ−Ｎ）、６．００ （２Ｈ，Ｓ、０ＣＨ２）、６．３
８（ＩＨ，ｓ、ＣＨ＝Ｃ）。)-N-CH3) 2.30 to 2.82 (6H, m, N
/'vN, '(CH2-), 4.16(IH,S,C
H-N), 6.00 (2H, S, 0CH2), 6.3
8 (IH, s, CH=C).
６．１８（１）１． ｓ、 ａｒｏｍ、 ）、７．１２
（ｔｔ−１，ｓ、 ａｒｏｍ、 ）ＩＲｖ用ｊｃｍ−１
；
２９２５、１４６０．１３１０．１０３５．７５０該化
合物をエーテルに溶解し塩酸ガスを吹き込み対応する塩
酸塩とした。6.18(1)1. s, arom, ), 7.12
(tt-1,s, arom, )jcm-1 for IRv
2925, 1460.1310.1035.750 The compound was dissolved in ether and hydrochloric acid gas was blown into the solution to obtain the corresponding hydrochloride.
融点１５９〜１６３°Ｃ（分解）
Ｉ Ｒ２）”” ｃｍ−１：
ａＸ
２９２０、２７００〜２１００．１４７０．１３２０．
１０３０゜参考例４
公知第２仮アミンを用いて、参考例３と同様にして以下
の化合物を得た。Melting point 159-163°C (decomposition) I R2)"" cm-1: aX 2920, 2700-2100.1470.1320.
1030° Reference Example 4 The following compound was obtained in the same manner as in Reference Example 3 using a known secondary temporary amine.
（１） ２−ｎ−ブチル−１−（４−エチル−１−ピペ
ラジニル）−５，６−メチレンジオキシインデン塩酸塩
融点１５５．０〜１５８、Ｏ’Ｃ
Ｉ ＲνにＢｒｃｍ−１：
ａＸ
２９２０、２７００〜２１００．１４７５．１３３０．
１０３０（２） ２−ｎ−ブチル−１−（４−ｎ−プロ
ピル−１−ピペラジニル）−５゜６−メチレンジオキシ
インデン塩酸塩
融点１４９．０〜１５２．０℃
Ｉ ＲＱ”” ｃｍ−１：
ａｘ
２９２５、２７００〜２１００．１４７５．１３３０．
１０３０．９３０（３） ２−ｎ−ブチル−１−（４−
ｎ−ブチル−１−ピペラジニル）−５，６−メチレンジ
オキシインデンＩＨ
融点１７７〜１８０°Ｃ（分解）
ＩＲνにＢｒ 、−１；
ａＸ
２９２０、２７００〜２１００．１．’１７０．１３２
０．１０２５．９２０実施例１
２−ｎ−ブチル−１−［Ｎ−メチル−Ｎ−［２−（Ｎ’
、Ｎ’−ジメチルアミノ）エチルコアミノ］−５，６−
メチレンジオキシインダン ［ユ］
２−ｎ−ブチル−３−［Ｎ−メチル−Ｎ−［２−（Ｎ’
、Ｎ’−ジメチルアミノ）エチル］アミノ］−５．６−
メチレンジオキシインデン塩酸塩３．８ｇと酸化白金１
５０ｍｇを含む無水エタノール１５（７の溶液を水素気
流化、常圧空温にて８時間攪拌した二酸化白金を濾別し
、濾液を濃縮後、残漬を水に溶解した。エーテルで洗浄
後、水層を１０％水酸化ナトリウムでアルカリ性とし、
酢酸エチルで抽出した。(1) 2-n-Butyl-1-(4-ethyl-1-piperazinyl)-5,6-methylenedioxyindene hydrochloride, melting point 155.0-158, O'C I Rv to Brcm-1: aX 2920 , 2700-2100.1475.1330.
1030(2) 2-n-Butyl-1-(4-n-propyl-1-piperazinyl)-5゜6-methylenedioxyindene hydrochloride Melting point 149.0-152.0℃ I RQ"" cm-1 : ax 2925, 2700-2100.1475.1330.
1030.930(3) 2-n-butyl-1-(4-
(n-butyl-1-piperazinyl)-5,6-methylenedioxyindene IH Melting point 177-180°C (decomposition) IRν to Br, -1; aX 2920, 2700-2100.1. '170.132
0.1025.920 Example 1 2-n-butyl-1-[N-methyl-N-[2-(N'
, N'-dimethylamino)ethylcoamino]-5,6-
Methylenedioxyindan [U] 2-n-Butyl-3-[N-methyl-N-[2-(N'
, N'-dimethylamino)ethyl]amino]-5.6-
3.8 g of methylene dioxyindene hydrochloride and 1 platinum oxide
A solution of anhydrous ethanol 15 (7) containing 50 mg was converted into a hydrogen gas stream and stirred at normal pressure and air temperature for 8 hours. Platinum dioxide was filtered off, the filtrate was concentrated, and the residue was dissolved in water. After washing with ether, water The layer was made alkaline with 10% sodium hydroxide,
Extracted with ethyl acetate.
飽和食塩水で洗浄後、無水硫駿マグネシウムで乾燥し、
減圧上濃縮した。残漬は、シリカゲルカラムクロマト（
酢酸エチル：メタノール１０／１ ）で精製し各々油状
物としてシス体［ユ］ １．４ｇ、トランス体［ユ］
６２ｍｙを１ｑだ。After washing with saturated saline, drying with anhydrous magnesium sulfur,
Concentrate under reduced pressure. The remaining residue was chromatographed using silica gel column chromatography (
Purified with ethyl acetate:methanol 10/1) to obtain 1.4 g of cis form [U] and 1.4 g of trans form [Y] as oils.
62my is 1q.
シス体［ユ］
ＮＭＲ（ＣＤＣｌ２ ）δ；
０、８０〜１．００（３Ｈ，ｍ、 〜ＣＨ３） 、 １
．１６〜３．１２ ［２２Ｈ，２，２０（６１１゜Ｓ、
Ｎ（ＣＨ３） ２ ）、２．２６（３Ｈ，Ｓ、ＣＨ３Ｎ
〜）１，３．８５ （ＩＨ，ｄ。Cis form [U] NMR (CDCl2) δ; 0, 80-1.00 (3H, m, ~CH3), 1
．． 16~3.12 [22H, 2, 20 (611°S,
N(CH3) 2 ), 2.26(3H,S,CH3N
~) 1,3.85 (IH, d.
Ｊ−３Ｈ２，ＣＨ−Ｎ ）、 ５．９０（２Ｈ，Ｓ、
−０ＣＨ２０−）、 ６．６０（ＩＨ，Ｓ、 ａｒｏｍ
＞、６．７８（ＩＨ，ｓ、ａｒｏｍ）
Ｉ Ｒν”””ｃｍ−’ ：
ａｘ
２９２０、１４６０，１２８０，１２，１０，１０３０
．８４０トランス体「ユ１
ＮＭＲ（ＣＤＣｌ２ ）δ：
０、８０〜１．０４（３Ｈ，ｍ、 〜ＣＩ＋３ ） 、
１ 、１０〜２．９０［２２Ｈ，２，１０（３Ｈ。J-3H2,CH-N), 5.90(2H,S,
-0CH20-), 6.60 (IH, S, aroma
>, 6.78 (IH, s, arom) I Rν"""cm-': ax 2920, 1460, 1280, 12, 10, 1030
．． 840 trans isomer “U1 NMR (CDCl2) δ: 0, 80-1.04 (3H, m, ~CI+3),
1, 10-2.90 [22H, 2, 10 (3H.
Ｓ、〜Ｎ−ＣＨ３）、２．２４（６Ｈ，Ｓ、Ｎ（ＣＨ３
） ２ ］、４．００（ＩＨ，ｄ。S, ~N-CH3), 2.24(6H,S,N(CH3
) 2 ], 4.00 (IH, d.
Ｊ＝７Ｈｚ、 ＣＨ−Ｎ）、 ５．９２ （２Ｈ，ｓ、
−０ＣＨ２０−）、 ６．６６（ｉｆｆ、 ｓ、 ａ
ｒｏｍ ）、 ６．７６（１）１． ｓ、 ａｒｏｍ、
）Ｉ Ｒｖ””ｃｍ−’ ：
ａＸ
２９２０、１４６０．１２８０．１２３０．１０３０．
８４０上記のシス体［ユ１とトランス体［ユ］の各々を
エーテルに溶解し、塩酸ガスを吹き込み、生成する沈１
澱を濾取し乾燥して対応する塩酸塩とした。J=7Hz, CH-N), 5.92 (2H,s,
-0CH20-), 6.66(if, s, a
rom), 6.76(1)1. s, arom,
)I Rv""cm-': aX 2920, 1460.1280.1230.1030.
840 Dissolve each of the above cis-isomer [U1] and trans-isomer [U] in ether, blow in hydrochloric acid gas, and generate precipitate 1.
The lees were filtered and dried to give the corresponding hydrochloride.
シス体［ユ］塩酸塩；
融点 ８７〜９１°Ｃ
Ｉ Ｒｖ”” ｃｍ−１：
ｍａｘ
２９２０、２７５０−２２００．１４７０．１２４０．
１０３０トランス体［ユコ塩酸塩
融点 ９８〜１０５°Ｃ
ＩＲｖにＢｒ Ｃｌｎ−＋ 。Cis [U]hydrochloride; Melting point 87-91°C I Rv"" cm-1: max 2920, 2750-2200.1470.1240.
1030 trans isomer [Yukohydrochloride melting point 98-105°C Br Cln-+ in IRv.
ｍａｘ
２９２０、２７５０−２２００．１４７０．１２４０．
１０３０実施例２
２−ｎ−ブチル−１−（４−エチル−１−ピペラジニル
）−５，６−メチレンジオキシインダン ［２］
実施例１と同様の方法で２−ｎ−ブチル−３−（４−エ
チル−１−ピペラジニル）−５，６−メチレンジオキシ
インデン塩酸塩２．５ｇとヱ化白金１０ｈ＋ｇの無水エ
タノール１０（７溶液を７時間反応後、シリカゲルカラ
ムクロマト（酢酸エチル：メタノール ２０／１ ）で
精製し、結晶としてシス体［２］ １．２５ ｇ、油
状物としてトランス体［２］７０ｍｇを得た。max 2920, 2750-2200.1470.1240.
1030 Example 2 2-n-butyl-1-(4-ethyl-1-piperazinyl)-5,6-methylenedioxyindan [2] 2-n-Butyl-3-( After reacting a solution of 2.5 g of 4-ethyl-1-piperazinyl)-5,6-methylenedioxyindene hydrochloride and 10 g of platinum chloride in anhydrous ethanol (10 (7)) for 7 hours, silica gel column chromatography (ethyl acetate: methanol 20/ 1) to obtain 1.25 g of the cis form [2] as crystals and 70 mg of the trans form [2] as an oil.
又、対応する塩酸塩も実施例１と同様の方法で得た。In addition, the corresponding hydrochloride was also obtained in the same manner as in Example 1.
シス体［２］
融点 ６０〜６２°Ｃ
ＮＭＲ（ＣＤＣｌ２）δ；
０．８０〜１．００（３Ｈ，ｍ、 ＮＣＨ３）、１．０
８（３Ｈ，ｔ、Ｊ＝８Ｈｚ。Cis form [2] Melting point 60-62°C NMR (CDCl2) δ; 0.80-1.00 (3H, m, NCH3), 1.0
8 (3H, t, J=8Hz.
Ｎ−ＣＨ２−ＣＨ３）、１．２０〜３．２０（１９旧、
３．８２ （ＩＨ，ｄ、 Ｊ＝４Ｈｚ。N-CH2-CH3), 1.20-3.20 (19 old,
3.82 (IH, d, J=4Hz.
Ｎ−ＣＨ）、 ５．９０（２Ｈ，ｓ、 −０ＣＨ２０−
）、 ６．６０（１Ｈ，ｓ、 ａｒｏｍ、 １１３、７
８（ＩＨ，Ｓ、 ａｒｏｍ、 ）ＩＲνＫＢｒｃｍ−１
：
ｍａｘ
２９２０、１４７０．１３００．１２４０．１０４０．
７５０シス体［２］塩駿塩
融点 １７６〜１７７°Ｃ
ＩＲν出ｃｍ−・；
２９２０、２７５０−２０００．１４７０．１３０５．
１２４０．１０３０トランス体［２］
ＮＭＲ（ＣＤＣｌ２ ）δ；
０．８Ｃ）〜１．１４（６Ｈ，ｍ、 ＮＣＨ３、ＮＣＨ
２ＣＨ３）、 １．２０〜３．０４（１９Ｈ） ３．８
８（ＩＨ，ｄ、 Ｊ＝７Ｈ２，Ｎ−ＣＨ）、 ５．８２
〜５．９６（２Ｈ，ｍ、 −０ＣＨ２０−） 、６．
６３（ＩＨ，ｓ、ａｒｏｍ、）、 ６゜７４（ＩＨ，ｓ
、 ａｒｏｍ、 ）Ｉ Ｒｌ）ｎｅａｔｃｍ−’ ：
ｍａｘ
２９２０、１４６０．１２８０．１２２５．１０３０．
７５０トランス体［２１塩酸塩
融点 １０１〜１０５°Ｃ
Ｉ ＲｖＫ８ｒｃｍ” ：
ｍａｘ
２９２０、２７５０−２０００．１４７０．１２９０．
１２４０．１０２５実施例３
２−ｎ−ブチル−１−（４−ｎ−プロピル−１−ピペラ
ジニル）−５，６−メチレンジオキシインデン ［旦］
実施例１と同様の方法で、２−ｎ−ブチル−３−（４−
ｎ−プロピル−１−ピペラジニル）−５，６−メチレン
ジオキシインデン塩鼠塩３．Ｏｇ、酸化白金１２（Ｍ＋
９の無水エタノール１５０ｍ！溶液を６時間反応後、シ
リカゲルカラムクロマト（酢酸エチル：メタノール２０
：１）で精製し、結晶としてシス体［３］ １’、２
ｇ、油状物としてトランス体［旦］ ６０ｆｎ３を得た
。N-CH), 5.90(2H,s, -0CH20-
), 6.60 (1H,s, arom, 113,7
8 (IH, S, arom, )IRνKBrcm-1
: max 2920, 1470.1300.1240.1040.
750 cis form [2] Salt melting point 176-177°C IRv output cm-; 2920, 2750-2000.1470.1305.
1240.1030 trans isomer [2] NMR (CDCl2) δ; 0.8C) ~ 1.14 (6H, m, NCH3, NCH
2CH3), 1.20-3.04 (19H) 3.8
8 (IH, d, J=7H2,N-CH), 5.82
~5.96 (2H, m, -0CH20-), 6.
63(IH,s,arom,), 6゜74(IH,s
, arom, ) I Rl) neatcm-': max 2920, 1460.1280.1225.1030.
750 trans isomer [21 hydrochloride melting point 101-105°C I RvK8rcm”: max 2920, 2750-2000.1470.1290.
1240.1025 Example 3 2-n-butyl-1-(4-n-propyl-1-piperazinyl)-5,6-methylenedioxyindene [Dan] In the same manner as in Example 1, 2-n- Butyl-3-(4-
n-propyl-1-piperazinyl)-5,6-methylenedioxyindene salt rat salt3. Og, platinum oxide 12 (M+
9 absolute ethanol 150m! After reacting the solution for 6 hours, silica gel column chromatography (ethyl acetate: methanol 20
:1) and purified as crystals in the cis form [3] 1', 2
g, trans isomer [dan] 60fn3 was obtained as an oily substance.
又、対応する塩酸塩も実施例１と同様の方法で得た。In addition, the corresponding hydrochloride was also obtained in the same manner as in Example 1.
シス体［旦］
融点 ７０〜７１℃
ＮＭＲ（ＣＤＣｌ２）δ：
０．８ｐ〜１．００（６Ｈ，ｎ、〜ＣＨ３，〜Ｃ１ｈ
）、 １．１０〜３．１４（２１Ｍ）３、８１ （ＩＨ
，ｄ、 Ｊ＝４Ｈｚ、 Ｎ−ＣＨ）、 ５．８８（２Ｈ
，Ｓ、 −０ＣＨ２０−）、 ６．５９（ＩＨ，Ｓ、
ａｒｏｍ、 ）、 ６．７８（ＩＨ，Ｓ、 ａｒｏｍ、
）ＩＲν出ｃｍ”：
２９２０、１４６０．１２７５．１２４０．１１４０．
１０３０．９２５シス体［旦］塩酸塩
融点 ２２５°Ｃ（分解）
ＩＲνにＢｒｃｍ−１；
ｍａｘ
２９２０、２７５０−２０００．１４７０．１３００．
１０２５．９２５トランス体［旦コ
ＮＭＲ（ＣＤＣｌ２）δ；
０．７６〜１．０６（６Ｈ，ｍ、 〜Ｃｔ１３ 、 Ｎ
ＣＨ３）、１．２０〜２．９２（２ｔＨ）３、８６（Ｉ
Ｈ，ｄ、 Ｊ＝７Ｈｚ、 Ｎ−ＣＱ）、 ５．８／１〜
５．９６ （２Ｈ，ｍ、 −０ＣＨ２０−＞６、６２（
ＩＨ，ｓ、 ａｒｏｍ、 ）、 ６．７４（ＩＨ，’
ｓ、 ａｒｏｍ、 ）Ｉ Ｒｖ ｎｅａ ｔｃｍ−１：
ｆｆ１ａＸ
２９２０．１４６０，１２８０，１２３０，１１４０，
１０３０．９４０，７５０トランス体［旦］塩駿塩
融点 １１２−１１５°Ｃ
Ｉ ＲシＫＢｒｃｍ−１：
ａＸ
２９２０、．２７５０−２０００．１４７０．１２８５
□１２４０．１１５０．１０３０．９２０実施例４
２−ｎ−ブチル−１−（４−ｎ−ブチル−１−ピペラジ
ニル）−５，６−メチレンジオキシインダン ［４］
実施例１と同様の方法で、２−ｎ−ブチル−３−（４−
ｎ−ブチル−１−ピペラジニル）−５，［３−メチレン
ジオキシインデン塩酸塩３．５９、酸化白金１４０ｍｙ
の無水エタノール１４０ｍ１溶液を６時間反応後シリカ
ゲルカラムクロマト（酢酸エチル：メタノール２０／１
）で精製し、結晶としてシス体［庄］１．４５ｇを得
た。対応する塩該塩も実施例１と同様の方法で得た。Cis body [dan] Melting point 70-71℃ NMR (CDCl2) δ: 0.8p-1.00 (6H,n, ~CH3, ~C1h
), 1.10-3.14 (21M) 3, 81 (IH
, d, J=4Hz, N-CH), 5.88 (2H
,S, -0CH20-), 6.59(IH,S,
arom, ), 6.78 (IH, S, arom,
)IRν output cm”: 2920, 1460.1275.1240.1140.
1030.925 cis form [dan] hydrochloride Melting point 225°C (decomposed) IRν to Brcm-1; max 2920, 2750-2000.1470.1300.
1025.925 trans isomer [Danco NMR (CDCl2) δ; 0.76-1.06 (6H, m, ~Ct13, N
CH3), 1.20-2.92 (2tH)3, 86 (I
H, d, J=7Hz, N-CQ), 5.8/1~
5.96 (2H,m, -0CH20->6,62(
IH,s, arom, ), 6.74(IH,'
s, arom, ) I Rv nea tcm-1: ff1aX 2920.1460, 1280, 1230, 1140,
1030.940,750 trans isomer [dan] salt melting point 112-115°C IRshiKBrcm-1: aX 2920,. 2750-2000.1470.1285
□1240.1150.1030.920 Example 4 2-n-butyl-1-(4-n-butyl-1-piperazinyl)-5,6-methylenedioxyindan [4] In the same manner as Example 1 , 2-n-butyl-3-(4-
n-butyl-1-piperazinyl)-5,[3-methylenedioxyindene hydrochloride 3.59, platinum oxide 140 my
After reacting for 6 hours with 140 ml of absolute ethanol solution, silica gel column chromatography (ethyl acetate:methanol 20/1
) to obtain 1.45 g of cis form [Sho] as crystals. The corresponding salt was also obtained in the same manner as in Example 1.
シス体［ユ］
融点 ６１〜６２°Ｃ
ＮＭＲ（ＣＤＣ１３）δ；
０１７６〜１．００（６Ｈ，ｍ、 〜Ｃｌ１３ 、〜Ｃ
Ｈ３）、１．１０〜３．１４（２３Ｈ）、３．７９（１
Ｈ，ｄ、Ｊ＝４Ｈ２，Ｎ−ＣＨ）、５．８８（ＩＨ，Ｓ
、−ＯＣＨ２０−） 。Cis form [U] Melting point 61-62°C NMR (CDC13) δ; 0176-1.00 (6H, m, ~Cl13, ~C
H3), 1.10-3.14 (23H), 3.79 (1
H, d, J = 4H2, N-CH), 5.88 (IH, S
, -OCH20-).
６、５８（１）１． ｓ、 ａｒｏｍ、 １６．７６４
１Ｈ，ｓ、 ａｒｏｍ、）ＩＲνにＢｒ ｃｍ、 ：
ａｘ
２９２５、１４７０．１２８０．１１４０．１０３０．
９３５シス体［４コ塩酸塩
融点 ２４Ｂ−２５１°Ｃ（分解）
ＩＲνにＢｒ ｏｍ−１゜
ａｘ
２９２０、２７５０−２０００．１４７０．１３００．
１２４０．１１５０．１０３０．９３０実施例５
２−ｎ−ブチル−１−［Ｎ−メチル−Ｎ−［２−［４−
［２−（４−イソプロピルチオフェニル）−２−ヒドロ
キシエチル１−１−ピペラジニル］エチル］アミノ］−
５，６−メチレンジオキシインダン ［互］
（シス−２−ｎ−ブチル−５，６−メチレンシオキシイ
ンダレンジオキシインダンー１−イル）トリメチルアン
モニウム アイオダイド［■″１ａ］ ７．（Ｉ７、
Ｎ−メチル−Ｎ−［２−［４−［２−（４−イソプロピ
ルチオフェニル）−２−ヒドロキシエチル］−１−ピペ
ラジニル］エチル］アミン４．５９及びトリエチルアミ
ン １．６９を含むＤＭＳ０５０ｍ溶液を８０°Ｃで１
０時間攪拌した。放冷後、飽和炭該水素ナトリウムを加
え、酢酸エチルで抽出した。飽和食塩水で洗浄後、無水
硫談マグネシウムで乾燥し、減圧上濃縮した。残渣はシ
リカゲルカラムクロマト（酢敢エチル：メタノール ２
０／１ ）で精製し、油状物としてシス体［５］ １．
５９、結晶としてトランス体［５］ ５５５０ｍを得
た。対応する塩酸塩も実施例１と同様の方法で得た。6, 58 (1) 1. s, arom, 16.764
1H, s, arom,) IRν to Br cm, : ax 2925, 1470.1280.1140.1030.
935 cis form [4 co-hydrochloride Melting point 24B-251°C (decomposed) IRν to Brom-1°ax 2920, 2750-2000.1470.1300.
1240.1150.1030.930 Example 5 2-n-butyl-1-[N-methyl-N-[2-[4-
[2-(4-isopropylthiophenyl)-2-hydroxyethyl 1-1-piperazinyl]ethyl]amino]-
5,6-methylenedioxyindan [mutual] (cis-2-n-butyl-5,6-methylenethioxyindandioxyindan-1-yl)trimethylammonium iodide [■″1a] 7. (I7,
A DMS050m solution containing 4.59% N-methyl-N-[2-[4-[2-(4-isopropylthiophenyl)-2-hydroxyethyl]-1-piperazinyl]ethyl]amine and 1.69% triethylamine was added to 80% 1 at °C
Stirred for 0 hours. After cooling, saturated sodium carbonate was added and extracted with ethyl acetate. After washing with saturated brine, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol 2
0/1) and purified as an oily substance [5] 1.
59, trans form [5] 5550m was obtained as a crystal. The corresponding hydrochloride was also obtained in the same manner as in Example 1.
シス体［互］
ＮＭＲ（ＣＤＣｌ２ ）δ；
０、８０〜１．００（３Ｈ，ｍ、 〜Ｃ１−１３） 、
１．１０〜１．９０［１３Ｈ，１，２４（６Ｈ。Cis form [mutual] NMR (CDCl2) δ; 0, 80-1.00 (3H, m, ~C1-13),
1.10-1.90 [13H, 1,24 (6H.
ｄ、Ｊ＝８Ｈｚ、−ＣＨ（ＣＨ３） ２）１，２．１０
〜３．８４［２１Ｈ，２，２７（３１−１゜Ｓ、Ｎ−Ｃ
Ｈ３）］、 ３．８８（ＩＨ，ｄ、Ｊ＝４Ｈ７，Ｎ−Ｃ
１）、４．６０〜４．８０（ＩＨ，ｍ、 ＣＨ−ＯＨ１
５，９２（２Ｈ，ｓ、 −ＯＣＨ２０−）、 ６．６０
（ＩＨ，ｓ。d, J=8Hz, -CH(CH3) 2) 1,2.10
~3.84[21H,2,27(31-1°S, N-C
H3)], 3.88 (IH, d, J=4H7, N-C
1), 4.60-4.80 (IH, m, CH-OH1
5,92 (2H,s, -OCH20-), 6.60
(IH, s.
ａｒｏｍ、 ）、 ６．８０（ＩＨ，Ｓ、 ａｒｏｍ、
）、 ７．２０〜７．４８（４Ｈ，ｍ、 ａｒｏｍ、
）Ｉ Ｒｖ ｎｅａｔｃｍ−１；
ａｘ
２９２０、１４Ｂ０．１３００．１２４０．１０３０．
７２５シス体［互］塩酸塩
融点 １５５−１６１°Ｃ
Ｉ Ｒｖ”” ｃｍ−’ ：
ａＸ
２９２０、２７５０−２０００．１４７０．１３Ｃ）０
．１２４０．１０３０．９３０トランス体［互］
融点 ８３〜８６°Ｃ
ＮＭＲ（ＣＤＣｌ２ ）δ；
０、８４〜１．０８（３Ｈ，ｍ、 〜ＣＨ３） 、 １
．２０〜１．８８［１３Ｈ，１，３０（６Ｎ。arom, ), 6.80 (IH, S, arom,
), 7.20-7.48 (4H, m, arom,
) I Rv neatcm-1; ax 2920, 14B0.1300.1240.1030.
725 cis [tau]hydrochloride Melting point 155-161°C I Rv""cm-': aX 2920, 2750-2000.1470.13C) 0
．． 1240.1030.930 trans isomer [mutual] Melting point 83-86°C NMR (CDCl2) δ; 0, 84-1.08 (3H, m, ~CH3), 1
．． 20-1.88 [13H, 1,30 (6N.
ｄ、Ｊ＝８Ｈ２，−ＣＨ（ＣＨ３） ２ ）］、２．１
４（３Ｈ，ｓ、Ｎ−ＣＨ３）、２．２０〜３．８４（１
８Ｈ）、 ４．０６（ＩＨ，ｄ、 Ｊ＝７１１ｚ、 Ｎ
−Ｃｌり、 ４．６６〜４．８８（Ｉｆ（、ｍ、Ｃｆ（
−０１−１）、 ５．９６（２ｔｌ、ｓ、’−０ＣＩ−
１２０−）、６．７２（１Ｎ、ｓ。d, J=8H2, -CH(CH3) 2 )], 2.1
4(3H,s,N-CH3), 2.20-3.84(1
8H), 4.06 (IH, d, J=711z, N
-Cl, 4.66-4.88 (If(, m, Cf(
-01-1), 5.96 (2tl,s,'-0CI-
120-), 6.72 (1N, s.
ａｒｏｍ、 ）、 ６．８０（１Ｈ，ｓ、 ａｒｏｍ
、 ）、 ７．２８ 〜７．５２ （４Ｈ，ｍ、 ａｒ
ｏｍ ）Ｉ Ｒν”” ｃｍ−’ ： ２９２０．１
４７０．１２９０．１２３０．１０３０．９４０ａＸ
トランス体［５］塩潴塩
融点 ２１５−２２１°Ｃ（分解）
にＢｒ
ＩＲシｌＩｌａｘｃｍ−１；
２９２０、２７５０−２０００．１４７０．１２８５．
１２３５．１０３０．９３０実施例６
実施例５と同様の方法で、化合物［ＶＨａｌ ４．０
ｇ、Ｎ、Ｎ、Ｎ’−トリメチルエチレンジアミン１．９
９及びトリエチルアミン１．３ｇを含むＤＭＳ０４０ｄ
溶液を７．５時間反応させ、シス体［ユ］ １．３１
３及びトランス体［ユ］３５０ｍｇを得た。これらは、
実施例１で得られたものと核磁気共鳴スペクトル、赤外
線吸収スペクトルが一致した。arom, ), 6.80 (1H,s, arom
, ), 7.28 ~ 7.52 (4H, m, ar
om) I Rν""cm-': 2920.1
470.1290.1230.1030.940aX Trans form [5] Shioba salt Melting point 215-221°C (decomposition) Br IR sil Ilaxcm-1; 2920, 2750-2000.1470.1285.
1235.1030.930 Example 6 In a similar manner to Example 5, the compound [VHal 4.0
g, N, N, N'-trimethylethylenediamine 1.9
DMS040d containing 9 and 1.3 g of triethylamine
The solution was reacted for 7.5 hours, and the cis form [U] 1.31
350 mg of trans isomer [Y] and trans isomer [U] were obtained. these are,
The nuclear magnetic resonance spectrum and infrared absorption spectrum matched those obtained in Example 1.
実施例７
実施例５と同様の方法で、化合物［ＶＩ［ａ］ ４．
０ｇ、Ｎ−エチルピペラジン１，７ｇ及びトリエチルア
ミン１．３９を含むＤＭＳＯ４０ｄ溶液を７．５時間反
応させ、シス体［２］ １．５９及びトランス体［２
］ ４４００ｍを得た。Example 7 Compound [VI[a] 4.
A DMSO40d solution containing 0 g, N-ethylpiperazine 1.7 g, and triethylamine 1.39 was reacted for 7.5 hours to obtain cis form [2] 1.59 and trans form [2].
] 4400m was obtained.
これらは、実施例２で得られたものと核磁気共鳴スペク
トル、赤外線吸収スペクトルが一致した。Their nuclear magnetic resonance spectra and infrared absorption spectra matched those obtained in Example 2.
実施例８
実施例５と同様の方法で、化合物［ＶｉＩａ］ ４．
０ｙ、Ｎ−ｎ−プロピルピペラジン１．７３及びトリエ
チルアミン１．２ｇを含むＤＭＳ０４０ｄ溶液を９時間
反応させ、シス体［３］１．０２９及びトランス体［３
］ ３３６０ｍを得た。Example 8 In the same manner as in Example 5, compound [ViIa] 4.
A DMS040d solution containing 1.73 g of N-propylpiperazine and 1.2 g of triethylamine was reacted for 9 hours to obtain 1.029 cis form [3] and 1.029 trans form [3].
] 3360m was obtained.
これらは、実施例３で得られたものと核磁気共鳴スペク
トル、赤外線吸収スペクトルが一致した。Their nuclear magnetic resonance spectra and infrared absorption spectra matched those obtained in Example 3.
実施例９
実施例５と同様の方法で、化合物［■ａ］ ４゜ｏｇ
、Ｎ−ｎ−ブチルピペラジン２．１９及びトリエチルア
ミン１．２ｇを含むＤＭＳＯ４０威溶液を７時間反応さ
せ、シス体［４］ １．１ＳＦ及び油状物としてトラ
ンス体［且］２３０ｍｇを得た。シス体［庄］は、実施
例４で得られたものと核磁気共鳴スペクトル、赤外線吸
収スペクトルが一致した。トランス体［４］の塩駿塩は
、実施例１と同様の方法で得た。・
トランス体［ユ］
ＮＭＲ（ＣＤＣｌ２）δ；
０．７４〜１．０６（６Ｈ，ｍ、〜ＣＭ３．〜ＣＨ３）
、 １．１０〜２．９６（２３Ｈ）３、８６（ＩＨ，ｄ
、 Ｊ＝７Ｈ２，Ｎ−ＣＩ）、 ５．８４〜５．９６（
２Ｈ，ｍ、 −０ＣＨ２０−＞６、６４（ＩＨ，ｓ、
ａｒｏｍ）、 ６．７６（ＩＨ，ｓ、 ａｒｏｍ、 ）
■ＲシｎｅａｔＩＪ−１；
ａｘ
２９２０、１４６５．１２８０．１１４０．１０３５．
７２５トランス体［ユ］塩薗塩
融点 １１５〜１１７°Ｃ
Ｉ Ｒν”” ｃｍ−’ ：
ａｘ
２９２０、２７５０−２０００．１４７０．１２８０．
１２４０．１１５０．１０３０．９２０Example 9 Compound [■a] 4゜og
A DMSO40 solution containing 2.19 g of N-n-butylpiperazine and 1.2 g of triethylamine was reacted for 7 hours to obtain 1.1 SF of the cis form [4] and 230 mg of the trans form [4] as an oil. The nuclear magnetic resonance spectrum and infrared absorption spectrum of the cis isomer [Sho] matched those obtained in Example 4. Shioshun salt of trans form [4] was obtained in the same manner as in Example 1.・Trans form [U] NMR (CDCl2) δ; 0.74-1.06 (6H, m, ~CM3.~CH3)
, 1.10-2.96 (23H) 3, 86 (IH, d
, J=7H2,N-CI), 5.84-5.96(
2H,m, -0CH20->6,64(IH,s,
arom), 6.76 (IH,s, arom, )
■RshineatIJ-1; ax 2920, 1465.1280.1140.1035.
725 Trans isomer [U]Shiozonoshio Melting point 115-117°C I Rν""cm-': ax 2920, 2750-2000.1470.1280.
1240.1150.1030.920
第１図は感作モルモット気管支筋の収縮抑制反応曲線を
示す。−〇−凹曲線コントロール、−・−曲線は実施例
１のトランス体［ユ］塩酸塩化合物、−６−曲線は実施
例３のトランス体［旦］塩薗塩化合物、−去一曲線は実
施例９のトランス体［４］塩酸塩化合物を表わし、干は
標準誤差を表わす。FIG. 1 shows the contraction inhibition response curve of sensitized guinea pig bronchial muscle. -〇-Concave curve control, -・- curve is trans form [U] hydrochloride compound of Example 1, -6- curve is trans form [Dan] Shiozono salt compound of Example 3, -1 curve is experimental It represents the trans-isomer [4] hydrochloride compound of Example 9, and the value represents the standard error.
Claims (1)
＿３はそれぞれ低級アルキル基を示すか、または一緒に
なってアルキレンジオキシ基を示し、Ｒ＿４及びＲ＿５
はそれぞれ置換基を有することのある低級アルキル基ま
たはアリール基を示すか、あるいは隣接する窒素原子と
共に置換基を有することのあるピペリジノ、ピペラジニ
ル又はホモピペラジノ基を示す。但し、Ｒ＿４及びＲ＿
５が共にメチル基の場合を除く）で表わされるインダン
類化合物。[Claims] The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a lower alkyl group, R_2 and R
_3 each represents a lower alkyl group or together represent an alkylenedioxy group, R_4 and R_5
each represents a lower alkyl group or aryl group which may have a substituent, or a piperidino, piperazinyl or homopiperazino group which may have a substituent together with the adjacent nitrogen atom. However, R_4 and R_
(except when both 5 are methyl groups).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14828986A JPS635063A (en) | 1986-06-26 | 1986-06-26 | Indane compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14828986A JPS635063A (en) | 1986-06-26 | 1986-06-26 | Indane compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS635063A true JPS635063A (en) | 1988-01-11 |
Family
ID=15449440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14828986A Pending JPS635063A (en) | 1986-06-26 | 1986-06-26 | Indane compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS635063A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007523154A (en) * | 2004-02-19 | 2007-08-16 | ペーページェー−シプシー | Novel synthesis method of substituted α-aminoindane derivatives |
-
1986
- 1986-06-26 JP JP14828986A patent/JPS635063A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007523154A (en) * | 2004-02-19 | 2007-08-16 | ペーページェー−シプシー | Novel synthesis method of substituted α-aminoindane derivatives |
| JP4790636B2 (en) * | 2004-02-19 | 2011-10-12 | ペーページェー−シプシー | Novel synthesis method of substituted α-aminoindane derivatives |
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