JPS6237627B2 - - Google Patents
Info
- Publication number
- JPS6237627B2 JPS6237627B2 JP54080505A JP8050579A JPS6237627B2 JP S6237627 B2 JPS6237627 B2 JP S6237627B2 JP 54080505 A JP54080505 A JP 54080505A JP 8050579 A JP8050579 A JP 8050579A JP S6237627 B2 JPS6237627 B2 JP S6237627B2
- Authority
- JP
- Japan
- Prior art keywords
- piperazinyl
- indane
- propoxy
- group
- butoxy
- 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.)
- Expired
Links
- 239000002253 acid Substances 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- -1 methoxy, ethoxy, propoxy Chemical group 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000000949 anxiolytic effect Effects 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N benzocyclopentane Natural products C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229960004782 chlordiazepoxide Drugs 0.000 description 3
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 241000906446 Theraps Species 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SAANSRGTBPGUIC-UHFFFAOYSA-N 5-(3-bromopropoxy)-2,3-dihydro-1h-indene Chemical compound BrCCCOC1=CC=C2CCCC2=C1 SAANSRGTBPGUIC-UHFFFAOYSA-N 0.000 description 1
- 241001279695 Attini Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 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
- 241000196324 Embryophyta Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 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
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012345 traction test Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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The present invention relates to piperazinyl alkoxyindanes and acid addition salts thereof. More specifically, the present invention relates to piperazinyl alkoxyindanes which have anxiolytic effects and are effective as sedatives. The compound of the present invention has the following general formula () These are piperazinyl alkoxyindanes represented by In the general formula (), n represents an integer of 3 or 4,
R represents a phenyl group or a pyridyl group. In addition, the phenyl group and pyridyl group are one or more groups selected from a halogen atom, a trifluoromethyl group, an alkoxy group, an alkylcarbonyl group,
May be replaced. Examples of halogen atoms include fluorine atoms, chlorine atoms, sulfur atoms, etc.; examples of alkoxy groups include lower alkoxy groups having 1 to 5 carbon atoms such as methoxy, ethoxy, propoxy, and butoxy groups; and alkylcarbonyl groups. Examples include lower alkylcarbonyl groups having 1 to 5 carbon atoms such as an acetyl group, a propionyl group, a butyryl group, and an isobutyryl group. The position of the substituent on the phenyl group and the pyridyl group and the position of the pyridyl group bonded to the piperazinyl group are not particularly limited. The compound of the present invention is produced as follows.
i.e. expression () (In the above formula, n represents an integer of 3 or 4, and X represents a halogen atom.) and the halogenoalkoxyindanes represented by the formula () (In the above formula, R has the same meaning as R in the general formula ()). Halogenoalkoxyindanes and piperazines react in a ratio of 1:1, but the reaction usually proceeds more smoothly when piperazine is used in excess. Therefore, 1 to 10 moles of piperazine are used per mole of halogenoalkoxyindan. Although the reaction proceeds satisfactorily even without a solvent, an inert solvent may be used to facilitate the reaction. As the solvent, water, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, lower alcohol, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but is usually from room temperature.
The temperature is 150â. The reaction time varies depending on the reaction temperature and the type of reactive solvent used as the raw material, but is usually in the range of 10 minutes to 20 hours. Furthermore, bases may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. Examples of the bases include inorganic salts such as potassium hydroxide, potassium carbonate, sodium hydroxide, sodium bicarbonate, and sodium carbonate, and tertiary organic amines such as pyridine and triethylamine. The amount used is usually 1 to 5 mol per mol of piperazine. In order to obtain a desired acid addition salt, after the reaction is complete, excess amines and solvent are removed by distillation or washing with water, and a strong aqueous base solution such as sodium hydroxide or potassium hydroxide is added to form the free piperazinyl alkoxyindanes. , and then extract the compound with a solvent such as ether, chloroform, benzene, or toluene. Further, by neutralizing by adding a desired acid, the desired acid addition salt can be obtained. Specific examples of the compounds of the present invention are illustrated below. 5-[3-(4-phenyl-1-piperazinyl)
Propoxy]indane 5-[4-(4-phenyl-1-piperazinyl)
butoxy]indane 4-[3-(4-phenyl-1-piperazinyl)
propoxy]indane 4-[4-(4-phenyl-1-piperazinyl)
Butoxy]indane 5-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(3-fluorophenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(2-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{4-[4-(4-fluorophenyl)-1-
Piperazinyl]butoxy}indane 5-{4-[4-(3-fluorophenyl)-1-
Piperazinyl]butoxy}indane 5-{4-[4-(2-fluorophenyl)-1-
Piperazinyl]butoxy}indane 4-{4-[4-(4-fluorophenyl)-1-
Piperazinyl]butoxy}indane 5-{3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(3-chlorophenyl)-1-piperazinyl]propoxy}indane 5-{ 3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(4-chlorophenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(3- chlorophenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy}indane 5-{4-[4-(4-chlorophenyl)-1-piperazinyl]butoxy }Indane 5-{4-[4-(3-chlorophenyl)-1-piperazinyl]butoxy}Indane 5-{4-[4-(2-chlorophenyl)-1-piperazinyl]butoxy}Indane 4-{4-[ 4-(4-chlorophenyl)-1-piperazinyl]butoxy}indan 4-{4-[4-(3-chlorophenyl)-1-piperazinyl]butoxy}indan 5-{3-[4-(4-trifluoromethyl) phenyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(2-trifluoromethyl phenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(4-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(3-trifluoromethyl phenyl)-1-piperazinyl]propoxy}indane 4-{3-[4-(2-trifluoromethylphenyl)-1-piperazinyl]propoxy}indane 5-{4-[4-(4-trifluoromethyl phenyl)-1-piperazinyl]butoxy}indan 5-{4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]butoxy}indan 5-{4-[4-(2-trifluoromethyl phenyl)-1-piperazinyl]butoxy}indane 4-{4-[4-(4-trifluoromethylphenyl)-1-piperazinyl]butoxy}indane 4-{4-[4-(3-trifluoromethyl phenyl)-1-piperazinyl]butoxy}indane 4-{4-[4-(2-trifluoromethylphenyl)-1-piperazinyl]butoxy}indane 5-{3-[4-(4-methoxyphenyl) )-1-
Piperazinyl]propoxy}indane 5-{3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(4-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(3-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 4-{3-[4-(2-methoxyphenyl)-1-
Piperazinyl]propoxy}indane 5-{4-[4-(4-methoxyphenyl)-1-
Piperazinyl]butoxy}indane 4-{4-[4-(4-methoxyphenyl)-1-
piperazinyl]butoxy}indane 5-{3-[4-(4-ethoxyphenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(4-propoxyphenyl)-1
-piperazinyl]propoxy}indane 5-{3-[4-(4-acetoxyphenyl)-1
-piperazinyl]propoxy}indane 4-{3-[4-(4-acetoxyphenyl)-1
-piperazinyl]propoxy}indane 5-{4-[4-(4-acetoxyphenyl)-1
-piperazinyl]butoxy}indane 5-{3-[4-(2-pyridyl)-1-piperazinyl]propoxy}indane 5-{3-[4-(3-pyridyl)-1-piperazinyl]propoxy}indane 5- {3-[4-(4-pyridyl)-1-piperazinyl]propoxy}indane 5-{4-[4-(2-pyridyl)-1-piperazinyl]butoxy}indane 4-{3-[4-(2 -pyridyl)-1-piperazinyl]propoxy}indane 4-{4-[4-(2-pyridyl)-1-piperazinyl]butoxy}indane 5-{3-[4-(4-chloro-2-pyridyl)-
1-Piperazinyl]propoxy}indane Acid addition salts of the above compounds are also included within the scope of the present invention. Acids used as addition salts include:
Inorganic acids such as hydrochloric acid, hydrooxalic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfone Examples include organic acids such as acid and methanesulfonic acid. The anxiolytic effects of the compounds of the present invention will be explained below. The anxiolytic effects of the compounds of the present invention were examined using the following method. Chlorodiazepoxide, known compound 17, as an anxiolytic or minor tranquilizer was used as a control drug. The results are shown in the table as the 50% effective dose (ED 50 , mg/KgPO). The animals used were ddy male mice (20-22 g).
Anti-fighting and anti-morphine effects were investigated as indicators of anxiolytic effects. That is, the anti-fighting effect was investigated from the suppressive effect (taming effect) on fighting that occurs by applying an electric shock of 28 V DC, 4-5 mA, 3 minutes to the foot via the grid (RETedeschi, DHTedeschi, A.
Mucha, L.Cook, PAMattis, EJFellows., J.
Pharmacol.exp.Therap., 125 , 28 (1959)). The anti-morphine effect was determined according to the method of Takagi et al.
Measured by the inhibitory effect on the tail-raising reaction caused by administering morphine 20 mg/Kgi.p (Hiroshi Takagi, Toshiharu Kamioka, Shinsaku Kobayashi, Yoshio Suzuki, Furuji Tachikawa, Japanese Pharmacological Journal, 66 , 107 (1970)) Muscle relaxant effect was investigated using the traction test method of Courvoisier et al. (S. Courvoisier, R. Ducrot, L.
Julou.ïŒâPsychotropic drugeâEd.by S.Gar
attini, V. Ghetti, p313 (Elsevier) 1957). LD50 was calculated by the Litchfield-Wilcoxon method. (JTLitchfield and F.Wilcoxon, J.Phar
macol.exp.Therap., 96 , 99 (1949)) As shown in Table 1, compounds 1, 4, and 5 were found to have anxiolytic effects superior to the control drugs, chlorodiazepoxide or 17. Among them, Compound 4 has lower toxicity and weaker muscle relaxant effect than chlorodiazepoxide, and is presumed to be a highly safe drug.
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ååç©ãšäœµãè¡šâïŒã«ç€ºãã[Table] Particularly effective range as a compound having anxiolytic effect is a compound represented by the general formula () where n is 3.
or an integer of 4, R is a phenyl group or a pyridyl group, and when this phenyl group or pyridyl group has a substituent, the substituent is a halogen atom, especially a fluorine atom, a chlorine atom, a carbon number of 1 to
3 alkoxy group, an alkylcarbonyl group having 1 to 3 carbon atoms, and a trifluoromethyl group.
The substitution position of the piperazinyl alkoxy group on the indane ring is particularly preferably the 4th or 5th position. A compound with particularly effective anxiolytic effects is 5-[3-(4-phenyl-1-piperazinyl)
propoxy]indane 4-[3-(4-phenyl-1-piperazinyl)
Propoxy]indane 5-[4-(4-phenyl-1-piperazinyl)
Butoxy]indane 5-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{4-[4-(4-fluorophenyl)-1-
piperazinyl]butoxy}indane 4-{3-[4-(4-fluorophenyl)-1-
Piperazinyl]propoxy}indane 5-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propoxy}indan and the like. Although the compound of the present invention can be administered by any method, the following method is preferably carried out. That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection, as well as oral administration are possible. The dosage is determined depending on the patient's age, health condition, weight, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc. Generally, the daily dose of the active ingredient is 0.5-50mg/
Kg body weight, usually 1-30 mg/Kg body weight, administered in one or more doses. When the compound of the present invention is administered orally, it is in the form of tablets, capsules, powders, liquids, elixirs, etc.
In the case of parenteral administration, it is used in a sterilized liquid form such as a liquid or suspension. When used in such forms, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. As an example of a solid carrier, conventional gelatin type capsules are used. The active ingredient may also be packaged as a tablet or powder, with or without adjuvants. These capsules, tablets, and powders generally contain 5 to
Contains 95% by weight of active ingredient, preferably 25-90%. That is, these dosage forms should contain 5 to 500 mg, preferably 25 to 250 mg of active ingredient. As the liquid carrier, water or oils of animal or plant origin or synthetic oils such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. are used. In general, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers, and in particular, in the case of injections using physiological saline, usually 0.5
~20%, preferably 1-10% by weight of active ingredient. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the active ingredient are preferred. In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers. As explained above, the compounds of the present invention can be effectively used as sedatives having anxiolytic effects. Production example 5-(3-bromopropoxy)indane 25.5g
(0.1 mol) and N-phenylpiperazine 17.8 g
(0.11 mol) and 15 g of triethylamine are dissolved in 300 ml of dimethylformamide and heated at 80°C for 2 hours. The reaction solution was added to 500 ml of 1N NaOH aqueous solution and extracted twice with 400 ml of ethyl ether. After washing the ethyl ether with saturated brine and drying over anhydrous sodium sulfate, the ethyl ether is distilled off. When 50 ml of 20% HCl-ethyl alcohol solution is added to the residual oily substance, crystals will precipitate. 5-[3-(4-
35 g (85.6%) of phenyl-1-piperazinyl)propoxy]indane are obtained. Compounds were produced in the same manner below, and the results are shown in Table 2 together with the above compounds.
ãè¡šããtableã
Claims (1)
ããã²ã³ååãããªãã«ãªãã¡ãã«åºãã¢ã«ã³ã
ã·åºåã³ã¢ã«ãã«ã«ã«ããã«åºããéžæãããïŒ
皮以äžã®åºã§çœ®æãããŠããŠããããããšãã«åº
ãŸãã¯ããªãžã«åºã瀺ããïŒã§è¡šããããããã©
ãžãã«ã¢ã«ã³ãã·ã€ã³ãã³é¡åã³ãã®é žä»å å¡©ã[Claims] 1. The following general formula (In the above formula, n represents an integer of 3 or 4, and R is 1 selected from a halogen atom, a trifluoromethyl group, an alkoxy group, and an alkylcarbonyl group.
Indicates a phenyl group or a pyridyl group which may be substituted with more than one type of group. ) Piperazinyl alkoxyindanes and their acid addition salts.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8050579A JPS565462A (en) | 1979-06-26 | 1979-06-26 | Piperazinylalkoxyindanes and their acid addition salt |
| US06/157,341 US4339580A (en) | 1979-06-26 | 1980-06-09 | Piperazinylalkoxyindanes and acid addition salts thereof |
| DE8080103462T DE3060445D1 (en) | 1979-06-26 | 1980-06-20 | Piperazinylalkoxyindanes and acid addition salts thereof |
| EP80103462A EP0021368B1 (en) | 1979-06-26 | 1980-06-20 | Piperazinylalkoxyindanes and acid addition salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8050579A JPS565462A (en) | 1979-06-26 | 1979-06-26 | Piperazinylalkoxyindanes and their acid addition salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS565462A JPS565462A (en) | 1981-01-20 |
| JPS6237627B2 true JPS6237627B2 (en) | 1987-08-13 |
Family
ID=13720161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8050579A Granted JPS565462A (en) | 1979-06-26 | 1979-06-26 | Piperazinylalkoxyindanes and their acid addition salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS565462A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS582343A (en) * | 1981-06-30 | 1983-01-07 | Osaka Soda Co Ltd | Vulcanizable rubber composition having excellent resistance to nitrogen oxide |
| JPS582344A (en) * | 1981-06-30 | 1983-01-07 | Osaka Soda Co Ltd | Vulcanizable rubber composition having excellent resistance to nitrogen oxide |
| US5219855A (en) * | 1988-01-29 | 1993-06-15 | Mitsubishi Kasei Corporation | Anxiolytic drug |
| JP2712222B2 (en) * | 1988-01-29 | 1998-02-10 | äžè±ååŠæ ªåŒäŒç€Ÿ | Anxiolytics |
-
1979
- 1979-06-26 JP JP8050579A patent/JPS565462A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS565462A (en) | 1981-01-20 |
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