JPH0443914B2 - - Google Patents
Info
- Publication number
- JPH0443914B2 JPH0443914B2 JP25146384A JP25146384A JPH0443914B2 JP H0443914 B2 JPH0443914 B2 JP H0443914B2 JP 25146384 A JP25146384 A JP 25146384A JP 25146384 A JP25146384 A JP 25146384A JP H0443914 B2 JPH0443914 B2 JP H0443914B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- carbon atoms
- benzoxepine
- alkyl group
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- -1 4-substituted-1-benzoxepine Chemical class 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 210000004556 brain Anatomy 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000005121 1-benzoxepines Chemical class 0.000 description 4
- HXXJUMQRVNQWSF-UHFFFAOYSA-N 2,3-dihydro-1-benzoxepine Chemical class O1CCC=CC2=CC=CC=C21 HXXJUMQRVNQWSF-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 208000024891 symptom Diseases 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
- 206010021143 Hypoxia Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- KLBCQBRUFJODSQ-UHFFFAOYSA-N 1-benzoxepin-5-ol Chemical class OC1=CC=COC2=CC=CC=C12 KLBCQBRUFJODSQ-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-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
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 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 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 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 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 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
- 238000005303 weighing Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LWZYUACNWRVDDJ-UHFFFAOYSA-N 1-benzoxepine Chemical compound O1C=CC=CC2=CC=CC=C12 LWZYUACNWRVDDJ-UHFFFAOYSA-N 0.000 description 1
- QUMRLXXCRQWODL-UHFFFAOYSA-N 1-methylpiperazin-1-ium;chloride Chemical compound [Cl-].C[NH+]1CCNCC1 QUMRLXXCRQWODL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- YKYVPFIBWVQZCE-UHFFFAOYSA-N 4-phenoxybutanoic acid Chemical class OC(=O)CCCOC1=CC=CC=C1 YKYVPFIBWVQZCE-UHFFFAOYSA-N 0.000 description 1
- GBEJJWHKEWTRSO-UHFFFAOYSA-N 8-chloro-3,4-dihydro-2h-1-benzoxepin-5-one Chemical compound O1CCCC(=O)C=2C1=CC(Cl)=CC=2 GBEJJWHKEWTRSO-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 208000002381 Brain Hypoxia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008748 Chorea Diseases 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
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000891 anti-reserpine Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 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
- 210000004027 cell Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000001966 cerebroprotective effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Description
産業上の利用分野
本発明は一般式(1)
［式中、Ａが炭素数１−３のアルコキシ基の場
合、Ｒは水素原子、炭素数１−３のアルキル基又
はフエニル基を表し、Ｙはピペリジル基、基
Industrial Application Field The present invention is based on the general formula (1) [In the formula, when A is an alkoxy group having 1-3 carbon atoms, R represents a hydrogen atom, an alkyl group having 1-3 carbon atoms, or a phenyl group, and Y is a piperidyl group or a group
【式】
（ここでR1及びR2は同一又は異なつた炭素数１
−３のアルキル基を表す）又は基[Formula] (where R 1 and R 2 are the same or different carbon numbers 1
-3 represents an alkyl group) or a group
【式】
（ここでR3は炭素数１−３のアルキル基を表す）
を表し；Ａがハロゲン原子の場合、Ｒは水素原
子、炭素数１−３のアルキル基又はフエニル基を
表し、Ｙは基[Formula] (Here, R 3 represents an alkyl group having 1-3 carbon atoms)
represents; when A is a halogen atom, R represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a phenyl group, and Y represents a group
【式】
（ここでR1及びR2は同一又は異なつた炭素数１
−３のアルキル基を表す）又は基[Formula] (where R 1 and R 2 are the same or different carbon numbers 1
-3 represents an alkyl group) or a group
【式】
（ここでR3は炭素数１−３のアルキル基を表す）
を表す。］を有する２，３−ジヒドロ−１−ベン
ズオキセピン誘導体およびその薬理学的に許容さ
れる塩に関する。
さらに詳しく述べれば一般式(1)で表わされる
２，３−ジヒドロ−１−ベンズオキセピン誘導体
は脳内における品質性障害および精神機能障害に
もとずく症状の改善・治療に有効な化合物であ
る。
ここで脳内の品質性障害とは脳梗塞後遺症、脳
出血後遺症、脳動脈硬化後遺症などの脳虚血性障
害に由来する諸症状および老年痴呆、初老期痴
呆、健忘症、頭部外傷後遺症、脳手術後遺症など
に由来する各種器質的障害を意味する。
又精神機能障害とは躁病、うつ病、神経症、パ
ーキンソン病、分裂病および分裂病様障害、舞踏
病および薬物やアルコールに由来する精神性機能
疾患を意味する。
従来技術
脳細胞は、その周囲の環境（細胞外液）と全く
かけ離れた細胞内環境を保持し、その差を維持し
て生きている。このため絶えずエネルギーを産生
し供給し続けていなければならない。
これらエネルギーの大部分は酸素とブドウ糖に
より支えられており、脳内にはほとんど貯蔵され
ておらず、常時血液から供給されている。
ここで脳に障害が起こり、酸素とブドウ糖の供
給が杜絶したとすると、一般的にはエネルギー代
謝障害は段階的に進行し、時間の経過とともに細
胞は機能を失い、やがて器質的にも崩壊し、その
機能を正常に営むことができなくなる。
故に、脳組織のエネルギー源を安全供給し、脳
神経細胞の外部環境を一定に保つために、脳血管
自身の脳血流を調整する機構がよく発達してい
る。
脳内の器質性障害および精神機能障害を内科的
に治療するために数多くの薬物が開発されてき
た。
１−ベンズオキセピン誘導体の骨格は既によく
知られており、その薬理作用としても抗炎症作
用、血液降下作用、局所麻酔作用、鎮痛作用など
の他に抗レゼルピン、モノアミン酸化酵素阻害、
抗アドレナリン作用などが知られている。
このように種々の作用を有するため、適当な誘
導を行なうことにより神経系および循環器系用薬
としての開発が考えられている。
この２，３−ジヒドロ−１−ベンズオキセピン
誘導体は例えばM.ProtivaらCollection
Czechoslov.Chem.Commun.37巻、868〜886頁、
1972年にも記述されている。
発明が解決しようとする問題点
そこで本発明者は、前述した脳内の各種障害に
起因する症状の改善・治療に効果のある化合物を
見い出すべく研究を行なつてきた。その結果前記
一般式(1)で表わされる２，３−ジヒドロ−１−ベ
ンズオキセピン誘導体が前記の各種障害に起因す
る症状の改善・治療に対して密接に関与している
と考えられている抗過酸化脂質作用および各種脳
神経細胞の酸素欠乏状態（脳アノキシア）に対し
きわめて有効であることを見出した。
問題を解決するための手段
本発明は一般式(1)
［式中、Ａが炭素数１−３のアルコキシ基の場
合、Ｒは水素原子、炭素数１−３のアルキル基又
はフエニル基を表し、Ｙはピペリジル基、基[Formula] (Here, R 3 represents an alkyl group having 1-3 carbon atoms)
represents. ] and a pharmacologically acceptable salt thereof. More specifically, the 2,3-dihydro-1-benzoxepine derivative represented by the general formula (1) is a compound effective in improving and treating symptoms caused by quality disorders and mental dysfunction in the brain. Here, quality-related disorders in the brain are symptoms derived from cerebral ischemic disorders such as after-effects of cerebral infarction, after-effects of cerebral hemorrhage, after-effects of cerebral arteriosclerosis, senile dementia, presenile dementia, amnesia, after-effects of head trauma, and brain surgery. Refers to various organic disorders resulting from after-effects. In addition, mental dysfunction means mania, depression, neurosis, Parkinson's disease, schizophrenia and schizophrenia-like disorder, chorea, and psychotic dysfunction derived from drugs and alcohol. Prior Art Brain cells maintain an intracellular environment that is completely different from the surrounding environment (extracellular fluid), and live by maintaining this difference. For this reason, energy must be constantly produced and supplied. Most of this energy is supported by oxygen and glucose, which is not stored in the brain and is constantly supplied from the blood. If a brain disorder occurs and the supply of oxygen and glucose is cut off, the energy metabolism disorder generally progresses in stages, with cells losing function over time and eventually organically collapsing. and become unable to perform its functions normally. Therefore, in order to safely supply the brain tissue with an energy source and maintain a constant external environment for brain neurons, the cerebrovascular system has a well-developed mechanism for regulating cerebral blood flow. A number of drugs have been developed to medically treat organic disorders and mental dysfunctions in the brain. The skeleton of 1-benzoxepine derivatives is already well known, and its pharmacological effects include anti-inflammatory, blood-lowering, local anesthetic, and analgesic effects, as well as anti-reserpine, monoamine oxidase inhibition,
It is known to have anti-adrenergic effects. Because it has such various effects, it is being considered to develop it as a drug for the nervous system and circulatory system by appropriately inducing it. This 2,3-dihydro-1-benzoxepine derivative is available from, for example, M. Protiva et al.
Czechoslov.Chem.Commun.Volume 37, Pages 868-886,
It was also written in 1972. Problems to be Solved by the Invention Therefore, the present inventor has conducted research in order to find a compound that is effective in improving and treating the symptoms caused by the various disorders in the brain described above. As a result, the 2,3-dihydro-1-benzoxepine derivative represented by the general formula (1) is believed to be an anti-inflammatory drug that is thought to be closely involved in the improvement and treatment of symptoms caused by the various disorders mentioned above. It has been found that it is extremely effective against oxidized lipid effects and the oxygen-deficient state (cerebral anoxia) of various brain nerve cells. Means for solving the problem The present invention is based on the general formula (1) [In the formula, when A is an alkoxy group having 1-3 carbon atoms, R represents a hydrogen atom, an alkyl group having 1-3 carbon atoms, or a phenyl group, and Y is a piperidyl group or a group
【式】
（ここでR1及びR2は同一又は異なつた炭素数１
−３のアルキル基を表す）又は基[Formula] (where R 1 and R 2 are the same or different carbon numbers 1
-3 represents an alkyl group) or a group
【式】
（ここでR3は炭素数１−３のアルキル基を表す）
を表し；Ａがハロゲン原子の場合、Ｒは水素原
子、炭素数１−３のアルキル基又はフエニル基を
表し、Ｙは基[Formula] (Here, R 3 represents an alkyl group having 1-3 carbon atoms)
represents; when A is a halogen atom, R represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a phenyl group, and Y represents a group
【式】
（ここでR1及びR2は同一又は異なつた炭素数１
−３のアルキル基を表す）又は基[Formula] (where R 1 and R 2 are the same or different carbon numbers 1
-3 represents an alkyl group) or a group
【式】
（ここでR3は炭素数１−３のアルキル基を表す）
を表す。を有する１−ベンズオキセピン誘導体お
よびその薬理学的に許容される塩に関する。前記
一般式(1)で表わされる２，３−ジヒドロ−１−ベ
ンズオキセピン誘導体およびその塩は以下の方法
により合成できる。
即ち、一般式(2)
（式中Ａはハロゲン原子又は炭素数１〜３のアル
コキシ基を表わす）で表わされるフエノール誘導
体とγ−ブチロラクトンを塩基存在下反応させる
ことにより一般式(3)
（式中Ａは前記と同一意義を表わす）で表わされ
る４−フエノキシ酪酸誘導体が得られる。
この化合物(3)を次いで酸を用いる還元反応に付
すことにより一般式(4)
（式中Ａは前記と同一意義を表わす）で表わされ
る１−ベンズオキセピン誘導体が得られる。還元
反応に用いる酸はポリリン酸、オキシ塩化リン又
は五酸化リンが好ましい。
この１−ベンズオキセピン誘導体をホルマリン
又はパラホルムアルデヒドと一般式Ｙ−Ｈ〔式中
Ｙはピペリジル基、基[Formula] (Here, R 3 represents an alkyl group having 1-3 carbon atoms)
represents. The present invention relates to a 1-benzoxepine derivative and a pharmacologically acceptable salt thereof. The 2,3-dihydro-1-benzoxepine derivative represented by the general formula (1) and its salt can be synthesized by the following method. That is, general formula (2) (wherein A represents a halogen atom or an alkoxy group having 1 to 3 carbon atoms) and γ-butyrolactone are reacted in the presence of a base to form the general formula (3). A 4-phenoxybutyric acid derivative represented by the formula (wherein A has the same meaning as above) is obtained. By subjecting this compound (3) to a reduction reaction using an acid, the general formula (4) is obtained. A 1-benzoxepine derivative represented by the formula (wherein A has the same meaning as above) is obtained. The acid used in the reduction reaction is preferably polyphosphoric acid, phosphorus oxychloride or phosphorus pentoxide. This 1-benzoxepine derivative is mixed with formalin or paraformaldehyde and has the general formula Y-H [wherein Y is a piperidyl group, a group
【式】
（ここでR1およびR2は同一又は異なつた炭素数
１〜３のアルキル基を表わす）又は基[Formula] (where R 1 and R 2 represent the same or different alkyl groups having 1 to 3 carbon atoms) or a group
【式】
（ここでR3は炭素数１〜３のアルキル基を表わ
す）を表わす〕
で示されるアミン類又はこのアミン類の塩を酸存
在下又は酸の存在なしで一般にマンニツヒ反応と
呼ばれている脱水縮合反応に付すことにより一般
式(5)
（式中ＡおよびＹは前記と同一意義を表わす）で
表わされる４−置換−１−ベンズオキセピン誘導
体が得られる。
この化合物(5)を次いで一般式R′−Ｘ（式中R′は
炭素数１〜３のアルキル基又はフエニル基を表わ
し、Ｘはハロゲン原子を表わす）で表わされるハ
ロゲン化合物と金属マグネシウムを用い調製した
グリニヤ試薬（R′−MgX、R′およびＸは前述し
たとおり）を加えることにより一般式（6a）
（式中Ａ、ＹおよびR′は前記と同一意義を表わ
す）
で表わされる５−ヒドロキシ−１−ベンズオキセ
ピン誘導体が得られる。
一方、一般式(5)で表わされる４−置換ベンズオ
キセピン誘導体を水素化ホウ素ナトリウム、水素
化シアノホウ素ナトリウム又は水素化ホウ素亜鉛
などの還元剤を用いケトン基を還元すると一般式
（6b）
（式中ＡおよびＹは前記と同一意義を表わす）
で表わされる５−ヒドロキシ−１−ベンズオキセ
ピン誘導体が得られる。
化合物（6a）、（6b）は芳香族炭化水素を溶媒
として、酸存在下加熱することにより脱水さすか
又は塩化チオニルとピリジンで脱水反応を起させ
ることにより本発明化合物である２，３−ジヒド
ロ−１−ベンズオキセピン誘導体が得られる。
ここで酸は塩酸、硫酸などを意味する。
斯しくて得られる本発明化合物(1)を各種酸、例
えば塩酸、硫酸、リン酸、臭化水素酸、酢酸、ト
リフルオロ酢酸、コハク酸、シユウ酸、リンゴ
酸、酒石酸、フマル酸、マレイン酸およびプロピ
オン酸と処理することにより各種その塩とするこ
とができる。
作 用
本発明に係る化合物の薬物試験を次のように行
なつた。
１ 抗脳虚血作用（断頭虚血に対する脳保護作
用）
体重22〜30ｇのddY系雄性マウスを１群６匹
とした。被験薬を腹腔内に投与し、投与30分後
に断頭した。断頭後、出現するあえぎ呼吸が停
止するまでの時間（Gasping Time）を測定
し、液体媒質のみを与えた対照群と比較した。
その結果、被験化合物中、25mg／Kgで呼吸時
間を有意に延長した化合物は実施例番号５の化
合物であり、50mg／Kgで有意に延長した化合物
は実施例番号４の化合物であつた。
２ 抗ハイポキシア作用（減圧低酸素下に対する
脳保護作用）
体重22〜30ｇのddY系雄型マウスを１群７〜
10匹使用した。マウスをデシケータ（容積：約
１）内に入れ、真空ポンプにて吸引し、デシ
ケータ内を180mmHgに調節した。被験薬は腹腔
内に投与し投与30分後に減圧した。減圧開始よ
り呼吸停止までの時間を生存時間とし、ハイポ
キシア負荷15分後経過しても生存していた場合
は、15分として計算し溶媒投与群と比較した。
その結果、被験化合物中、25mg／Kgで生存時間
を有意に延長した化合物は実施例５の化合物であ
り、50mg／Kgで有意に延長した化合物は実施例４
の化合物であつた。
実施例
次に実施例でもつて本発明をさらに具体的に説
明するが、本発明がこれら実施例に限定されない
ことはいうまでもない。
実施例 １
８−クロル−４−ジメチルアミノメチル−２，
３−ジヒドロ−１−ベンズオキセピン
８−クロル−４−ジメチルアミノメチル−５−
ヒドロキシ−２，３，４，５−テトラヒドロ−１
−ベンズオキセピン（3.4ミリモリ）および濃塩
酸２mlを50mlのベンゼンにとかしデイーン・スタ
ーク（Dean−Stark）の装置で水を除きながら１
時間還流した。溶媒を留去し、得られた残留物に
水を加え、次いで水層をアンモニアにてアルカリ
性としたのちエーテルで抽出した。エーテル層を
10％塩酸で抽出したのち、水層をアンモニア水に
てアルカリ性としエーテルで抽出した。このエー
テル層を水洗、乾燥（無水硫酸ナトリウム）後、
溶媒を留去した。得られた標記化合物912mg（収
率97％）をエタノール・ペンタンから再結晶し無
色針状晶を得た。
融点：169〜170.5℃
NMRスペクトル（CDCl3、δppm）：6.19（1H、
brs、オレフイン水素）
実施例 ２
８−メトキシ−４−ピペリジルメチル−２，３
−ジヒドロ−１−ベンズオキセピン
８−メトキシ−４−ピペリジノメチル−５−ヒ
ドロキシ−２，３，４，５−テトラヒドロ−１−
ベンズオキセピンを用い実施例１と同様に標記化
合物を得た。この化合物をエーテルとかし塩化水
素ガス飽和エーテルを加え塩酸塩を収率71％で得
た。
性状：（塩酸塩）無色板状晶
融点：（塩酸塩）206〜209℃
NMRスペクトル（遊離塩基、CDCl3、δppm）：
6.18（1H、br.s、オレフイン水素）
実施例１および２と同様にして実施例３、４お
よび５の化合物を得た。
実施例 ３
８−メトキシ−４−ピペリジノメチル−５−メ
チル−２，３−ジヒドロ−１−ベンズオキセピ
ン
実施例 ４
４−ジメチルアミノメチル−８−メトキシ−５
−フエニル−２，３−ジヒドロ−１−ベンズオ
キセピン
実施例 ５
８−クロル−４−（Ｎ−メチルピペラジン−１
−イル）メチル−５−フエニル−２，３−ジヒ
ドロ−１−ベンズオキセピン
以下に各々の収率および塩酸塩の融点を示す。[Formula] (wherein R 3 represents an alkyl group having 1 to 3 carbon atoms)] The amines represented by the formula or the salts of these amines are reacted in the presence or absence of an acid in a process generally called the Mannitz reaction. By subjecting it to a dehydration condensation reaction, the general formula (5) is obtained. A 4-substituted-1-benzoxepine derivative represented by the formula (wherein A and Y have the same meanings as above) is obtained. This compound (5) was then prepared using a halogen compound represented by the general formula R'-X (wherein R' represents an alkyl group having 1 to 3 carbon atoms or a phenyl group, and X represents a halogen atom) and metallic magnesium. General formula (6a) is obtained by adding the prepared Grignard reagent (R'-MgX, R' and X are as described above). A 5-hydroxy-1-benzoxepine derivative represented by the formula (wherein A, Y and R' have the same meanings as above) is obtained. On the other hand, when the ketone group of the 4-substituted benzoxepine derivative represented by general formula (5) is reduced using a reducing agent such as sodium borohydride, sodium cyanoborohydride, or zinc borohydride, general formula (6b) is obtained. A 5-hydroxy-1-benzoxepine derivative represented by the formula (wherein A and Y have the same meanings as above) is obtained. Compounds (6a) and (6b) are dehydrated by heating in the presence of an acid using an aromatic hydrocarbon as a solvent, or 2,3-dihydro, which is a compound of the present invention, is dehydrated by heating in the presence of an acid, or by causing a dehydration reaction with thionyl chloride and pyridine. A -1-benzoxepine derivative is obtained. Acid here means hydrochloric acid, sulfuric acid, etc. The thus obtained compound (1) of the present invention is treated with various acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, succinic acid, oxalic acid, malic acid, tartaric acid, fumaric acid, and maleic acid. By treating with propionic acid and propionic acid, various salts thereof can be obtained. Effects A drug test of the compound according to the present invention was conducted as follows. 1. Anti-cerebral ischemic effect (cerebroprotective effect against decapitation ischemia) ddY male mice weighing 22 to 30 g were included in each group of 6 mice. The test drug was administered intraperitoneally, and the animals were decapitated 30 minutes after administration. After decapitation, the time until gasping stopped appearing (Gasping Time) was measured and compared with a control group given only liquid medium. As a result, among the test compounds, the compound that significantly prolonged the respiration time at 25 mg/Kg was the compound of Example No. 5, and the compound that significantly prolonged the respiration time at 50 mg/Kg was the compound of Example No. 4. 2 Anti-hypoxia effect (brain protective effect against decompression hypoxia) ddY male mice weighing 22 to 30 g per group
10 were used. The mouse was placed in a desiccator (volume: approximately 1), suction was applied using a vacuum pump, and the inside of the desiccator was adjusted to 180 mmHg. The test drug was administered intraperitoneally, and the pressure was reduced 30 minutes after administration. The survival time was defined as the time from the start of decompression to the end of breathing, and if the animal remained alive even after 15 minutes of hypoxia challenge, it was calculated as 15 minutes and compared with the vehicle-administered group. As a result, among the test compounds, the compound of Example 5 significantly prolonged survival time at 25 mg/Kg, and the compound of Example 4 significantly prolonged survival time at 50 mg/Kg.
It was a compound of EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples. Example 1 8-chloro-4-dimethylaminomethyl-2,
3-dihydro-1-benzoxepine 8-chloro-4-dimethylaminomethyl-5-
Hydroxy-2,3,4,5-tetrahydro-1
- Benzoxepine (3.4 mmol) and 2 ml of concentrated hydrochloric acid were dissolved in 50 ml of benzene, and the water was removed using a Dean-Stark apparatus.
Refluxed for an hour. The solvent was distilled off, water was added to the resulting residue, and the aqueous layer was then made alkaline with ammonia and extracted with ether. the ether layer
After extraction with 10% hydrochloric acid, the aqueous layer was made alkaline with aqueous ammonia and extracted with ether. After washing this ether layer with water and drying (anhydrous sodium sulfate),
The solvent was distilled off. 912 mg (yield 97%) of the obtained title compound was recrystallized from ethanol/pentane to obtain colorless needle crystals. Melting point: 169-170.5℃ NMR spectrum ( CDCl3 , δppm): 6.19 (1H,
brs, olefin hydrogen) Example 2 8-methoxy-4-piperidylmethyl-2,3
-dihydro-1-benzoxepine 8-methoxy-4-piperidinomethyl-5-hydroxy-2,3,4,5-tetrahydro-1-
The title compound was obtained in the same manner as in Example 1 using benzoxepine. This compound was dissolved in ether and ether saturated with hydrogen chloride gas was added to obtain the hydrochloride in a yield of 71%. Properties: (Hydrochloride) colorless plate-like crystal Melting point: (Hydrochloride) 206-209°C NMR spectrum (free base, CDCl 3 , δppm):
6.18 (1H, br.s, olefin hydrogen) Compounds of Examples 3, 4 and 5 were obtained in the same manner as in Examples 1 and 2. Example 3 8-methoxy-4-piperidinomethyl-5-methyl-2,3-dihydro-1-benzoxepine Example 4 4-dimethylaminomethyl-8-methoxy-5
-Phenyl-2,3-dihydro-1-benzoxepine Example 5 8-chloro-4-(N-methylpiperazine-1
-yl) methyl-5-phenyl-2,3-dihydro-1-benzoxepine The yield and melting point of the hydrochloride are shown below.
【表】
参考例 １
４−（Ｎ−メチルピペラジン−１−イル）メチ
ル−８−クロル−２，３，４，５−テトラヒド
ロ−１−ベンズオキセピン−５−オン
８−クロル−２，３，４，５−テトラヒドロ−
１−ベンズオキセピン−５−オン（60ミリモル）、
Ｎ−メチルピペラジン塩酸塩180ミリモル、パラ
ホルムアルデヒド180ミリモルおよび濃塩酸0.5ml
を95％エタノール200mlにとかし５ないし６時間
加熱還流した。溶媒を留去し、得られた残留物に
希塩酸（150ml）加え、次いでエーテルを加えた。
エーテル層を分離し、水層を濃アンモニア水で塩
基性としクロロホルムで抽出した。
クロロホルム層を水で洗い、無水硫酸ナトリウ
ムで乾燥後濃縮した。得られた油状物をエーテル
にとかし塩化水素ガス飽和エーテルを加え、得ら
れた結晶をエタノール・エーテル混合溶媒より再
結晶した（収率36％）。
融点：168〜171℃（塩酸塩）
NMRスペクトル（遊離化合物、CDCl3、
δppm）：7.63（1H、ｄ、Ｊ＝11.6Hz）、7.04（1H、
dd、Ｊ＝11.6、2.6Hz）、7.07（1H、ｄ、Ｊ＝2.6
Hz）
参考例１と同様にして一般式(5)で表わされる化
合物を合成した。
参考例 ２
８−クロル−４−ジメチルアミノメチル−５−
ヒドロキシ−２，３，４，５−テトラヒドロ−
１−ベンズオキセピン
８−クロル−４−ジメチルアミノメチル−２，
３，４，５−テトラヒドロ−１−ベンズオキセピ
ン−５−オン（15ミリモル）を含水メタノール
100〜200ml（１％水・メタノール）にとかし、氷
冷撹拌下に水素化ホウ素ナトリウム（過剰）を
徐々に加え、薄層クロマトグラフイー上で原料が
消失するまで反応を続けた。
さらに室温で30分撹拌し、溶媒留去後得られた
残留物に水を加えクロロホルムで抽出した。クロ
ロホルム層を水洗、乾燥したのち溶媒を留去し、
得られた固型物をエーテル・ペンタンより再結晶
し標記化合物を収率74％で得た。
得られた標記化合物の４位ジメチルアミノメチ
ル基と５位のヒドロキシ基はトランスの配置を有
していた。
性状：無色プリズム晶
融点：99〜100℃
NMRスペクトル（CDCl3、δppm）：7.68（1H、
ｄ、Ｊ＝8.6Hz）、7.06（1H、dd、Ｊ＝8.6、2.2
Hz）、6.94（1H、ｄ、Ｊ＝2.2Hz）、4.84（1H、
ｄ、Ｊ＝8.2Hz）
参考例２と同様の方法で還元し、一般式（6b）
で表わされる化合物を合成した。。
参考例 ３
８−クロル−４（Ｎ−メチルピペラジン−１−
イル）メチル−５−フエニル−５−ヒドロキシ
−２，３，４，５−テトラヒドロ−１−ベンズ
オキセピン
フエニルマグネシウムプロミド（13〜15ミリモ
ル）のエーテル溶液に氷冷下８−クロル−４（Ｎ
−メチルピペラジン−１−イル）メチル−２，
３，４，５−テトラヒドロ−１−ベンズオキセピ
ン−５−オン（10ミリモル）のエーテル溶液を滴
下した。滴下後１時間加熱還流したのち、水を加
え過剰の試薬を分解しエーテル層を分離した。常
法どおり処理をし、得られた固型物をシリカゲル
カラムクロマトグラフイー（重量で30倍、溶出溶
媒：クロロホルム）に付し標記化合物を得た（収
率65％）。
融点：69〜71°
ここで得られた標記化合物４位（Ｎ−メチルピ
ペラジン−１−イル）メチル基と５位フエニル基
はトランスの立体配置を有していた。
この参考例３と同様にしてグリニヤ反応を用い
一般式（6a）で表わされる化合物を合成した。[Table] Reference example 1 4-(N-methylpiperazin-1-yl)methyl-8-chloro-2,3,4,5-tetrahydro-1-benzoxepin-5-one 8-chloro-2,3,4 ,5-tetrahydro-
1-benzoxepin-5-one (60 mmol),
180 mmol of N-methylpiperazine hydrochloride, 180 mmol of paraformaldehyde and 0.5 ml of concentrated hydrochloric acid.
was dissolved in 200 ml of 95% ethanol and heated under reflux for 5 to 6 hours. The solvent was distilled off, and dilute hydrochloric acid (150 ml) was added to the resulting residue, followed by ether.
The ether layer was separated, and the aqueous layer was made basic with concentrated aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained oil was dissolved in ether, ether saturated with hydrogen chloride gas was added, and the obtained crystals were recrystallized from a mixed solvent of ethanol and ether (yield 36%). Melting point: 168-171℃ (hydrochloride) NMR spectrum (free compound, CDCl3 ,
δppm): 7.63 (1H, d, J = 11.6Hz), 7.04 (1H,
dd, J = 11.6, 2.6Hz), 7.07 (1H, d, J = 2.6
Hz) A compound represented by general formula (5) was synthesized in the same manner as in Reference Example 1. Reference example 2 8-chloro-4-dimethylaminomethyl-5-
Hydroxy-2,3,4,5-tetrahydro-
1-benzoxepine 8-chloro-4-dimethylaminomethyl-2,
3,4,5-tetrahydro-1-benzoxepin-5-one (15 mmol) in aqueous methanol
The mixture was dissolved in 100 to 200 ml (1% water/methanol), and sodium borohydride (excess) was gradually added while stirring under ice cooling, and the reaction was continued until the raw material disappeared on thin layer chromatography. After further stirring at room temperature for 30 minutes, water was added to the residue obtained after distilling off the solvent, and the mixture was extracted with chloroform. After washing the chloroform layer with water and drying, the solvent was distilled off.
The obtained solid was recrystallized from ether/pentane to obtain the title compound in a yield of 74%. The dimethylaminomethyl group at the 4-position and the hydroxyl group at the 5-position of the obtained title compound had a trans configuration. Properties: Colorless prism crystal Melting point: 99-100℃ NMR spectrum (CDCl 3 , δppm): 7.68 (1H,
d, J=8.6Hz), 7.06 (1H, dd, J=8.6, 2.2
Hz), 6.94 (1H, d, J = 2.2Hz), 4.84 (1H,
d, J = 8.2Hz) Reduced in the same manner as in Reference Example 2 to form the general formula (6b)
A compound represented by was synthesized. . Reference example 3 8-chloro-4(N-methylpiperazine-1-
yl) Methyl-5-phenyl-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepine 8-Chlor-4(N
-methylpiperazin-1-yl)methyl-2,
An ether solution of 3,4,5-tetrahydro-1-benzoxepin-5-one (10 mmol) was added dropwise. After the dropwise addition, the mixture was heated under reflux for 1 hour, and then water was added to decompose the excess reagent and the ether layer was separated. The treatment was carried out in the usual manner, and the obtained solid substance was subjected to silica gel column chromatography (30 times by weight, elution solvent: chloroform) to obtain the title compound (yield 65%). Melting point: 69-71° The title compound obtained here had a (N-methylpiperazin-1-yl)methyl group at the 4-position and a phenyl group at the 5-position having a trans configuration. A compound represented by the general formula (6a) was synthesized using the Grignard reaction in the same manner as in Reference Example 3.
Claims (1)
合、Ｒは水素原子、炭素数１−３のアルキル基又
はフエニル基を表し、Ｙはピペリジル基、基 【式】 （ここでR1及びR2は同一又は異なつた炭素数１
−３のアルキル基を表す）又は基 【式】 （ここでR3は炭素数１−３のアルキル基を表す）
を表し；Ａがハロゲン原子の場合、Ｒは水素原
子、炭素数１−３のアルキル基又はフエニル基を
表し、Ｙは基 【式】 （ここでR1及びR2は同一又は異なつた炭素数１
−３のアルキル基を表す）又は基 【式】 （ここでR3は炭素数１−３のアルキル基を表す）
を表す。］を有する２，３−ジヒドロ−１−ベン
ズオキセピン誘導体及びその薬理学的に許容され
る塩。[Claims] 1. General formula [Wherein, when A is an alkoxy group having 1 to 3 carbon atoms, R represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a phenyl group, and Y is a piperidyl group, a group [formula] (where R 1 and R 2 are the same or different carbon numbers 1
-3 alkyl group) or group [Formula] (where R 3 represents an alkyl group having 1 to 3 carbon atoms)
When A is a halogen atom, R is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a phenyl group, and Y is a group [Formula] (where R 1 and R 2 are the same or different numbers of carbon atoms) 1
-3 alkyl group) or group [Formula] (where R 3 represents an alkyl group having 1 to 3 carbon atoms)
represents. ] and a pharmacologically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25146384A JPS61130286A (en) | 1984-11-28 | 1984-11-28 | 2,3-dihydro-1-benzoxepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25146384A JPS61130286A (en) | 1984-11-28 | 1984-11-28 | 2,3-dihydro-1-benzoxepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61130286A JPS61130286A (en) | 1986-06-18 |
| JPH0443914B2 true JPH0443914B2 (en) | 1992-07-20 |
Family
ID=17223194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25146384A Granted JPS61130286A (en) | 1984-11-28 | 1984-11-28 | 2,3-dihydro-1-benzoxepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61130286A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4571697A (en) * | 1996-10-16 | 1998-05-11 | Dainippon Pharmaceutical Co. Ltd. | {omega-(2,3-dihydro-1-benzoxepin-4-yl)alkyl}amine derivatives, process for the preparation thereof, and medicinal compositions containing the same |
| DE19755480A1 (en) * | 1997-12-13 | 1999-06-24 | Gruenenthal Gmbh | Substituted heterocyclic benzocycloalkenes and their use as analgesic substances |
| CN104844471B (en) * | 2015-04-21 | 2017-05-03 | 苏州远智医药科技有限公司 | Compound used as DOR receptor antagonist |
| CN109896991B (en) * | 2017-12-08 | 2020-11-20 | 苏州远智医药科技有限公司 | A kind of delta opioid receptor antagonist and its use and pharmaceutical composition |
-
1984
- 1984-11-28 JP JP25146384A patent/JPS61130286A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61130286A (en) | 1986-06-18 |
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