JPH0443915B2 - - Google Patents
Info
- Publication number
- JPH0443915B2 JPH0443915B2 JP25342584A JP25342584A JPH0443915B2 JP H0443915 B2 JPH0443915 B2 JP H0443915B2 JP 25342584 A JP25342584 A JP 25342584A JP 25342584 A JP25342584 A JP 25342584A JP H0443915 B2 JPH0443915 B2 JP H0443915B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- carbon atoms
- benzoxepine
- tetrahydro
- 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
- 150000001875 compounds Chemical class 0.000 claims description 35
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- -1 diisopropylamino group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 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
- LWZYUACNWRVDDJ-UHFFFAOYSA-N 1-benzoxepine Chemical compound O1C=CC=CC2=CC=CC=C12 LWZYUACNWRVDDJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 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 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 210000004556 brain Anatomy 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 150000005121 1-benzoxepines Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
- 239000012452 mother liquor Substances 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RTJFIGSGLFRXIX-UHFFFAOYSA-N 2h-1-benzoxepin-5-one Chemical class O=C1C=CCOC2=CC=CC=C12 RTJFIGSGLFRXIX-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
- 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
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 210000004027 cell Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000002035 prolonged effect Effects 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
- 238000010992 reflux Methods 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001424 substituent group Chemical group 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
- 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
- QUMRLXXCRQWODL-UHFFFAOYSA-N 1-methylpiperazin-1-ium;chloride Chemical compound [Cl-].C[NH+]1CCNCC1 QUMRLXXCRQWODL-UHFFFAOYSA-N 0.000 description 1
- JIWUESGGKYLPPG-UHFFFAOYSA-N 2-[4-[4-(2-hydroxy-4,4-dimethyl-2-morpholin-4-iumyl)phenyl]phenyl]-4,4-dimethyl-2-morpholin-4-iumol Chemical compound C1[N+](C)(C)CCOC1(O)C1=CC=C(C=2C=CC(=CC=2)C2(O)OCC[N+](C)(C)C2)C=C1 JIWUESGGKYLPPG-UHFFFAOYSA-N 0.000 description 1
- VPHKEZPJWHJLMH-UHFFFAOYSA-N 2-methyl-2,3,4,5-tetrahydro-1-benzoxepine Chemical compound O1C(C)CCCC2=CC=CC=C21 VPHKEZPJWHJLMH-UHFFFAOYSA-N 0.000 description 1
- KNTMEDNZPJADJU-UHFFFAOYSA-N 3,4-dihydro-2h-1-benzoxepin-5-one Chemical class O=C1CCCOC2=CC=CC=C12 KNTMEDNZPJADJU-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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 206010002660 Anoxia 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
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 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
- 241001465754 Metazoa 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
- 206010038669 Respiratory arrest Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 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
- 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
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 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
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003035 anti-peroxidant effect Effects 0.000 description 1
- 230000000891 anti-reserpine Effects 0.000 description 1
- 150000005119 benzoxepines Chemical class 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
- 210000004204 blood vessel 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
- 230000003727 cerebral blood flow 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 210000003792 cranial nerve Anatomy 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
- 230000004064 dysfunction Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect 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
- 231100000636 lethal dose Toxicity 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
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 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
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 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
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method 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
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic 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、R1は水素原子、炭素数１−４のアルキル基、
フエニル基又はアラルキル基を表し、R2は水素
原子又は炭素数２−３のアシル基を表し、Ｙはピ
ペリジル基、モルホリニル基、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 1 is a hydrogen atom, an alkyl group having 1-4 carbon atoms,
Represents a phenyl group or an aralkyl group, R 2 represents a hydrogen atom or an acyl group having 2-3 carbon atoms, and Y represents a piperidyl group, a morpholinyl group, or a group
【式】
（ここでR3及びR4は同一又は異なつた炭素数１
−４のアルキル基を表す）又は基[Formula] (Here, R 3 and R 4 are the same or different carbon numbers 1
-4 alkyl group) or group
【式】
（ここでR5は炭素数１−２のアルキル基を表す）
を表し；Ａがハロゲン原子の場合、R1は水素原
子、炭素数１−４のアルキル基、フエニル基又は
アラルキル基を表し、R2は水素原子又は炭素数
２−３のアシル基を表し、Ｙはモルホリニル基、
基[Formula] (Here, R 5 represents an alkyl group having 1-2 carbon atoms)
represents; when A is a halogen atom, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group; R 2 represents a hydrogen atom or an acyl group having 2 to 3 carbon atoms; Y is a morpholinyl group,
base
【式】
（ここでR3及びR4は同一又は異なつた炭素数１
−４のアルキル基を表す）又は基[Formula] (Here, R 3 and R 4 are the same or different carbon numbers 1
-4 alkyl group) or group
【式】
（ここでR5は炭素数１−２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１
−ベンズオキセピン誘導体の脳内における器質性
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に関する。
ここで脳内の器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定供給し、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は既によく知られ
た骨格であり、その薬理作用としても抗炎症作用
血圧降下作用、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１−ベンズ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、R1は水素原子、炭素数１−４のアルキル基、
フエニル基又はアラルキル基を表し、R2は水素
原子又は炭素数２−３のアシル基を表し、Ｙはピ
ペリジル基、モルホニル基、基[Formula] (Here, R 5 represents an alkyl group having 1-2 carbon atoms)
represents. ] and its pharmacologically acceptable salts. To explain in more detail, 1 expressed by the general formula (1)
-Improvement of symptoms caused by organic disorders and mental dysfunction in the brain caused by benzoxepine derivatives
Concerning therapeutically effective compounds. Organic 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, as well as 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 stably supply the brain tissue with an energy source and maintain a constant external environment for brain neurons, the cerebral blood vessels themselves have 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. 1-Benzoxepine derivatives are already well-known skeletons, and their pharmacological effects include anti-inflammatory, hypotensive, local anesthetic, and analgesic effects, as well as anti-reserpine, monoamine oxidase inhibition, and anti-adrenergic effects. It is being 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 1-benzuxepin derivative is, for example, M.
Protiva et al. Collection Czechoslov.Chem.
Commun, Vol. 37, pp. 868-886, 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 1-benzoxepine derivative represented by the general formula (1) has antiperoxidant lipid effects and various cranial nerve effects that are 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 oxygen-deprived cells (cerebral anoxia). 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 1 is a hydrogen atom, an alkyl group having 1-4 carbon atoms,
Represents a phenyl group or an aralkyl group, R2 represents a hydrogen atom or an acyl group having 2-3 carbon atoms, and Y represents a piperidyl group, a morphonyl group, or a group
【式】
（ここでR3及びR4は同一又は異なつた炭素数１
−４のアルキル基を表す）又は基[Formula] (Here, R 3 and R 4 are the same or different carbon numbers 1
-4 alkyl group) or group
【式】
（ここでR5は炭素数１−２のアルキル基を表す）
を表し；Ａがハロゲン原子の場合、R1は水素原
子、炭素数１−４のアルキル基、フエニル基又は
アラルキル基を表し、R2は水素原子又は炭素数
２−３のアシル基を表し、Ｙはモルホリニル基、[Formula] (Here, R 5 represents an alkyl group having 1-2 carbon atoms)
represents; when A is a halogen atom, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group; R 2 represents a hydrogen atom or an acyl group having 2 to 3 carbon atoms; Y is a morpholinyl group,
【式】
（ここでR3及びR4は同一又は異なつた炭素数１
−４のアルキル基を表す）又は基[Formula] (Here, R 3 and R 4 are the same or different carbon numbers 1
-4 alkyl group) or group
【式】
（ここでR5は炭素数１−２のアルキル基を表す）
を表す。
を有する１−ベンズオキセピンおよびその薬理学
的に許容される塩。前記一般式(1)で表わされる１
−ベンズオキセピン誘導体およびその塩は以下の
方法により合成することができる。
即ち、一般式(2)
（式中Ａはハロゲン原子又は低級アルコキシ基を
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環化反応に付
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−５−オン誘導体が得ら
れる。環化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−５−オン誘導体を
ホルマリン又はパラホルムアルデヒドと一般式Ｙ
−Ｈ
（ここでＹはモルホリニル基、ピペリジル基、基[Formula] (where R 5 represents an alkyl group having 1-2 carbon atoms). 1-benzoxepine and its pharmacologically acceptable salts. 1 represented by the above general formula (1)
-Benzoxepine derivatives and salts thereof can be synthesized by the following method. That is, general formula (2) (wherein A represents a halogen atom or a lower alkoxy group) 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 cyclization reaction using an acid, the general formula (4) is obtained. A 1-benzoxepin-5-one derivative represented by the formula (wherein A has the same meaning as above) is obtained. The acid used in the cyclization reaction is preferably polyphosphoric acid, phosphorus oxychloride or phosphorus pentoxide. This 1-benzoxepin-5-one derivative is combined with formalin or paraformaldehyde and the general formula Y
-H (where Y is a morpholinyl group, a piperidyl group, a group
【式】
（ここでR3およびR4は同一又は異なつて水素原
子又は炭素数１〜４のアルキル基を表す）、又は
基[Formula] (where R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), or a group
【式】（ここでR5は炭素数１又は
２のアルキル基を表わす）で表わされるアミン類
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R6−Ｘ
（式中R6は炭素数１〜４のアルキル基、フエニ
ル基又はアラルキル基を表わし、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
を用い調整したグリニヤ試薬（R6−MgX、R6お
よびＸは前記と同一意義を表わす）を加えること
により一般式（1a）
（式中Ａ、ＹおよびR6は前記と同一意義を表わ
す）
で表わされる本発明化合物は得られる。
この一般式（1a）で表わされる１−ベンズオ
キセピン誘導体に塩基存在下又は塩基なしでアシ
ル化剤、例えば無水酢酸、アセチルクロリド、無
水プロピオン酸又はプロピオニルクロリドと処理
することにより一般式（1b）
（式中R7は炭素数２又は３のアシル基を表わし、
Ａ、R6およびＹは前記と同一意義を表わす）
で表わされる本発明化合物（1b）は得られる。
一方、一般式(5)で表わされる４−置換１−ベン
ズオキセピン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
（1c）
（式中ＡおよびＹは前記と同一意義を表わす）
で表わされる本発明化合物は得られる。
この化合物（1c）を前述したアシル化反応を行
なうことにより一般式（1d）
（式中Ａ、ＹおよびR7は前記と同一意義を表わ
す）
で表わされる本発明化合物は得られる。
斯くし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理試験は次のように行
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、液体媒質のみを投与した対照群と比較し
た。
その結果、被験化合物中、50mg／Kgの投与量
で呼吸時間を有意に延長した化合物は実施例番
号21の化合物であつた。
２ 抗アノキシア作用（ヘミコリニウム−No.３投
与後の生存時間に対する作用）
体重23〜28ｇのddY系雄性マウスを１群９〜
10匹使用した。被験薬を腹腔内に投与し、投与
30分後にヘミコリニウム−No.３
（hemicholinium No.３）を５mg／Kg（100％致
死量）を静脈内に投与した。ヘミコリニウム−
No.３投与後、呼吸停止までの時間を測定し、対
照群（溶媒投与群）と比較した。
結果：被験化合物中、25mg／Kgの投与量で呼
吸時間を有意に延長した化合物は実施例番号21
の化合物であつた。
実施例
以下に実施例を示し、本発明を具体的に説明す
るが、本発明はこれら実施例に限定されないこと
は言うまでもない。
実施例 １
８−クロル−４−ジメチルアミノメチル−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
融点：99〜100℃
NMRスペクトル（CDCl3、δppm）：7.68（1H、
ｄ、Ｊ＝8.6Hz）、7.06（1H、ｄ、Ｊ＝8.6、2.2
Hz）、6.94（1H、ｄ、Ｊ＝2.2Hz）、4.84（1H、
ｄ、Ｊ＝8.2Hz）
以下に実施例１と同様にして行なつた実施例２
〜７の一般合成法を述べた：
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン−５−オン誘導体（15ミリモル）を１％
含水メタノール（100〜200ml）にとかし氷冷撹拌
下に水素化ホウ素ナトリウムを加え、実施例１と
同様に反応した。
得られた残留物を分別再結晶により４位と５位
がシス配置およびトランス配置の化合物を得た。
実施例 ２
７−メトキシ−４−モルホリノメチル−５−ヒ
ドロキシ−４，５−トランス−２，３，４，５
−テトラヒドロ−１−ベンズオキセピン
得られた油状物をベンゼン・ヘキサンより結晶
化させ収率46％で得られた。
性状：無色針状晶
融点：120〜121℃
NMRスペクトル（CDCl3、δppm）：7.29（1H、
ｄ、Ｊ＝３Hz）、6.87（1H、ｄ、Ｊ＝８Hz）、
6.63（1H、dd、Ｊ＝８、３Hz）、4.89（1H、ｄ、
Ｊ＝８Hz）、3.80（1H、ｓ）
実施例 ３
４，５−シス−５−ヒドロキシ−７−メトキシ
−４−モルホリノメチル−２，３，４，５−テ
トラヒドロ−１−ベンズオキセピン
実施例２の再結晶母液をエーテルにとかし、塩
酸飽和エーテルを加えた。析出した結晶をエタノ
ール・エーテルより再結晶し収率28％で標記化合
物を得た。
性状：無色針状晶（塩酸塩）
融点：184〜185℃（分解）〔塩酸塩〕
NMRスペクトル（δppm）：7.08（1H、ｄ、Ｊ＝
３Hz）、6.92（1H、ｄ、Ｊ＝８Hz）、6.65（1H、
dd、Ｊ＝8.3Hz）、5.11（1H、brs）、3.78（1H、
ｓ）
実施例 ４
４，５−トランス−５−ヒドロキシ−８−メト
キシ−４−ピペリジノメチル−２，３，４，５
−テトラヒドロ−１−ベンズオキセピン
得られた油状物をヘキサンから再結晶し収率67
％で標記化合物を得た。
性状：無色針状晶
融点：85〜86℃
NMRスペクトル（CDCl3、δppm）：7.63（1H、
ｄ、Ｊ＝９Hz）、6.62（1H、dd、Ｊ＝９、３
Hz）、6.49（1H、ｄ、Ｊ＝３Hz）、4.80（1H、ｄ、
Ｊ＝８Hz）、3.75（1H、ｓ）
実施例 ５
４，５−シス−５−ヒドロキシ−８−メトキシ
−４−ピペリジノメチル−２，３，４，５−テ
トラヒドロ−１−ベンズオキセピン
実施例４の油状結晶母液をヘキサンで再結晶し
標記化合物を収率11％で得た。
性状：無色針状晶
融点：91〜92℃
NMRスペクトル（CDCl3、δppm）：7.44（1H、
ｄ、Ｊ＝９Hz）、6.65（1H、dd、Ｊ＝９、３
Hz）、6.51（1H、ｄ、Ｊ＝３Hz）、5.18（1H、
brs）、3.76（1H、ｓ）
実施例 ６
４，５−シス−５−ヒドロキシ−７−メトキシ
−４−イソプロピルアミノメチル−２，３，
４，５−テトラヒドロ−１−ベンズオキセピン
得られた油状物をエーテル・ヘキサン混合溶媒
より再結晶し、標記化合物を収率17％で得た。
性状：無色針状晶
融点：125.5〜127℃
NMRスペクトル（CDCl3、δppm）：7.09（1H、
ｄ、Ｊ＝２、４Hz）、6.86（1H、ｄ、Ｊ＝6.0
Hz）、6.61（1H、dd、Ｊ＝6.0、2.4Hz）、5.10
（1H、brs）、3.76（1H、ｓ）
実施例 ７
４，５−トランス−５−ヒドロキシ−７−メト
キシ−４−イソプロピルアミノメチル−２，
３，４，５−テトラヒドロ−１−ベンズオキセ
ピン
実施例６の再結晶母液をエーテルにとかし、塩
酸飽和エーテルを加えた。溶媒を留去し、エタノ
ール・エーテルより再結晶し収率59％で標記化合
物を得た。
性状：無色針状晶
融点：146〜148℃
NMRスペクトル（遊離化合物、CDCl3、
δppm）：7.09（1H、ｄ、Ｊ＝2.4Hz）、6.86（1H、
ｄ、Ｊ＝6.0Hz）、6.61（1H、dd、Ｊ＝6.0、2.4
Hz）、5.10（1H、br.s）、3.76（1H、ｓ）
実施例 ８
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ブロミド（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の４位の（Ｎ−メチ
ルピペラジン−１−イル）メチル基と５位のフエ
ニル基はトランスの立体配置を有していた。
この実施例８と同様にして各種グリニヤ試薬を
用い実施例９〜20の化合物を合成した。実施例９
以下、４，５−トランスの表示は４位置換基と５
位アルキル基、フエニル基又はベンジル基がトラ
ンスの配置を有していることを表わす。
実施例 ９
４，５−トランス−４−ジエチルアミノメチル
−５−エチル−５−ヒドロキシ−７−メトキシ
−２，３，４，５−テトラヒドロ−１−ベンズ
オキセピン
収率 30％
融点：198−200℃（塩酸塩）
実施例 10
４，５−トランス−５−エチル−５−ヒドロキ
シ−７−メトキシ−４−ピペリジノメチル−
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン
収率 65％
融点：238〜239℃（塩酸塩）
実施例 11
４，５−トランス−５−エチル−５−ヒドロキ
シ−７−メトキシ−４−モルホリノメチル−
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン
収率 60％
融点：222〜223℃（塩酸塩）
実施例 12
４，５−トランス−４−ジメチルアミノメチル
−５−エチル−５−ヒドロキシ−８−メトキシ
−２，３，４，５−テトラヒドロ−１−ベンズ
オキセピン
収率：63％
融点：213〜214℃（塩酸塩）
実施例 13
４，５−トランス−５−エチル−５−ヒドロキ
シ−８−メトキシ−４−ピペリジノメチル−
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン
収率：53％
融点：217〜218℃（塩酸塩）
実施例 14
４，５−トランス−５−エチル−５−ヒドロキ
シ−８−メトキシ−４−モルホリノメチル−
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン
収率：34％
融点：182〜183℃（塩酸塩）
実施例 15
４，５−トランス−５−エチル−４−ジメチル
アミノメチル−５−ヒドロキシ−８−クロル−
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン
収率：32％
融点：196〜197℃
実施例 16
４，５−トランス−８−クロル−５−エチル−
５−ヒドロキシ−４−ピペリジノメチル−２，
３，４，５−テトラヒドロ−１−ベンズオキセ
ピン
収率：68％
融点：250℃以上（塩酸塩）
実施例 17
４，５−トランス−８−クロル−５−エチル−
５−ヒドロキシ−４−モルホリノメチル−２，
３，４，５−テトラヒドロ−１−ベンズオキセ
ピン
収率：60％
融点：179〜180℃（塩酸塩）
実施例 18
４，５−トランス−５−ベンジル−５−ヒドロ
キシ−８−メトキシ−４−ピペリジノメチル−
２，３，４，５−テトラヒドロ−１−ベンズオ
キセピン
収率：62％
融点：85〜86℃
実施例 19
４，５−トランス−８−クロル−５−ヒドロキ
シ−５−フエニル−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
収率：65％
融点：69〜71℃（無色針状晶）
IRスペクトル（KBr、cm-1）：3400、1600
NMRスペクトル（CDCl3、δppm）：1.92〜2.10
（ｍ、1H）、2.20〜3.00（ｍ、12H）、3.63（ｍ、
1H）、4.00（ｍ、1H）、7.05〜7.38（ｍ、7H）、
7.84（ｄ、1H、Ｊ＝9.2Hz）、8.42（br.s、1H）
元素分析（C22H27ClN2O2として）
Ｃ(%) Ｈ(%) Ｎ(%) Cl(%)
計算値：68.29 7.03 7.24 9.16
実測値：68.50 7.04 7.18 9.15
実施例 20
４，５−トランス−８−クロル−５−ヒドロキ
シ−４−（Ｎ−メチルピペラジン−１−イル）
メチル−５−フエニル−２，３，４，５−テト
ラヒドロ−１−ベンズオキセピン
性状：無色針状晶
融点：69.0〜71.0℃
IRスペクトル（KBr、cm-1）：3400、1600
NMRスペクトル（CDCl3、δppm）：1.92〜2.10
（ｍ、1H）、2.20〜3.00（ｍ、12H）、3.63（ｍ、
1H）、4.00（ｍ、1H）、7.05〜7.38（ｍ、7H）、
7.84（ｄ、1H、Ｊ＝9.2Hz）、8.42（br.s、1H）
元素分析：C22H27ClN2O2として
Ｃ(%) Ｈ(%) Ｎ(%) Cl(%)
計算値：68.29 7.03 7.24 9.16
実測値：68.50 7.04 7.18 9.15
実施例 21
４，５−トランス−５−アセトキシ−７−メト
キシ−４−モルホリノメチル−２，３，４，５
−テトラヒドロ−１−ベンズオキセピン
実施例２の表題化合物1.0ｇ（3.42ミリモル）
と無水酢酸697mg（6.68ミリモル）を20mlのベン
ゼンにとかし室温で17時間撹拌した。反応液にベ
ンゼンを加え希釈し水洗し、さらに飽和重炭酸ナ
トリウム水、水で順次洗浄した。乾燥後ベンゼン
を留去し、1.165ｇ（収率99％）で標記化合物を
得た。
性状：無色油状物質
IRスペクトル（フイルム、cm-1）：1745
NMRスペクトル（CDCl3、δppm）：1.70〜2.70
（9H、ｍ）、2.10（3H、ｓ）、3.50〜4.40（6H、
ｍ）、3.78（3H、ｓ）、5.92（1H、ｄ、Ｊ＝６
Hz）、6.60〜7.01（3H、ｍ）
実施例 22
４，５−トランス−５−アセトキシ−８−メト
キシ−４−モルホリノメチル−２，３，４，５
−テトラヒドロ−１−ベンズオキセピン
８−メトキシ−４−モルホリノメチル−２，
３，４，５−テトラヒドロ−１−ベンズオキセピ
ン−５−オンを水素化ホウ素ナトリウムを用い還
元し４，５−トランス−５−ヒドロキシ−８−メ
トキシ−４−モルホリノメチル−２，３，４，５
−テトラヒドロ−１−ベンズオキセピンとしたの
ち、実施例21と同様に無水酢酸と処理し標記化合
物を得た。
性状：無色油状物質
IRスペクトル（フイルム、cm-1）：1745
NMRスペクトル（CDCl3、δppm）：1.70〜2.70
（9H、ｍ）、2.04（3H、ｓ）、3.50〜450（6H、
ｍ）、3.75（3H、ｓ）、5.92（1H、ｄ、Ｊ＝4.5
Hz）、6.40〜6.70（2H、ｍ）、7.00〜7.30（1H、
ｍ）
実施例 23
５−ヒドロキシ−８−メトキシ−４−モルホリ
ノメチル−２，３，４，５−テトラヒドロ−１
−ベンズオキセピン
実施例１と同様にして反応を行なつた。反応
後、得られた油状物は、５位水酸基と４位モルホ
リノメチル基がシスおよびトランス配置の混合物
であつた。主生成物のNMRスペクトルデータを
示す。
NMRスペクトル（CDCl3、δppm）：1.6〜2.9（ｍ、
9H）3.55〜4.4（ｍ、6H）、3.77（ｓ、3H）、4.85
（ｍ、1H）、6.5〜6.8（ｍ、2H）、7.33（ｄ、1H、
Ｊ＝８Hz）
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）を加え、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。[Formula] (where R 5 represents an alkyl group having 1 or 2 carbon atoms) The amines or the salts of these amines are dehydrated in the presence or absence of an acid, generally known as the Mannitz reaction. General formula (5) can be obtained by subjecting it to a condensation reaction. 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) is then converted to the general formula R 6 -X (wherein R 6 is the number of carbon atoms A Grignard reagent prepared using a halogen compound represented by 1 to 4 alkyl, phenyl, or aralkyl groups, and X represents a halogen atom) and metallic magnesium (R 6 -MgX, R 6 and X are the same as above) The general formula (1a) is obtained by adding The compound of the present invention represented by the formula (wherein A, Y and R 6 have the same meanings as above) can be obtained. By treating the 1-benzoxepine derivative represented by general formula (1a) with an acylating agent such as acetic anhydride, acetyl chloride, propionic anhydride or propionyl chloride in the presence or absence of a base, the general formula (1b) is obtained. (In the formula, R 7 represents an acyl group having 2 or 3 carbon atoms,
A, R 6 and Y have the same meanings as above) The compound (1b) of the present invention is obtained. On the other hand, when the ketone group of 4-substituted 1-benzoxepine represented by general formula (5) is reduced using a reducing agent such as sodium borohydride, sodium cyanoborohydride, or zinc borohydride, general formula (1c) is obtained. (In the formula, A and Y represent the same meanings as above.) The compound of the present invention represented by the following is obtained. By subjecting this compound (1c) to the above-mentioned acylation reaction, the general formula (1d) is obtained. (In the formula, A, Y and R 7 have the same meanings as above.) The compound of the present invention represented by the following is obtained. 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. Effect Pharmacological testing 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 (Gasping Time) that appeared was measured and compared with a control group to which only liquid medium was administered. As a result, among the test compounds, the compound of Example No. 21 significantly prolonged the respiration time at a dose of 50 mg/Kg. 2 Anti-anoxia effect (effect on survival time after administration of hemicorinium No. 3) Groups of ddY male mice weighing 23-28 g
10 were used. The test drug is administered intraperitoneally.
After 30 minutes, hemicolinium-No.3
(hemicholinium No. 3) was administered intravenously at 5 mg/Kg (100% lethal dose). Hemicolinium
After No. 3 administration, the time until respiratory arrest was measured and compared with the control group (vehicle administration group). Results: Among the test compounds, the compound that significantly prolonged the respiration time at a dose of 25 mg/Kg was Example No. 21.
It was a compound of EXAMPLES The present invention will be specifically explained below 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-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 Melting point: 99-100℃ NMR spectrum (CDCl 3 , δppm): 7.68 (1H,
d, J=8.6Hz), 7.06 (1H, d, J=8.6, 2.2
Hz), 6.94 (1H, d, J = 2.2Hz), 4.84 (1H,
d, J = 8.2Hz) Below, Example 2 was carried out in the same manner as Example 1.
A general synthesis method for ~7 is described: 2,3,4,5-tetrahydro-1-benzoxepin-5-one derivative (15 mmol) at 1%
The mixture was dissolved in water-containing methanol (100 to 200 ml), and sodium borohydride was added while stirring under ice cooling, and the reaction was carried out in the same manner as in Example 1. The obtained residue was subjected to fractional recrystallization to obtain compounds having cis and trans configurations at the 4th and 5th positions. Example 2 7-methoxy-4-morpholinomethyl-5-hydroxy-4,5-trans-2,3,4,5
-Tetrahydro-1-benzoxepine The obtained oil was crystallized from benzene/hexane in a yield of 46%. Properties: Colorless needle crystals Melting point: 120-121℃ NMR spectrum (CDCl 3 , δppm): 7.29 (1H,
d, J = 3Hz), 6.87 (1H, d, J = 8Hz),
6.63 (1H, dd, J=8, 3Hz), 4.89 (1H, d,
J=8Hz), 3.80 (1H, s) Example 3 4,5-cis-5-hydroxy-7-methoxy-4-morpholinomethyl-2,3,4,5-tetrahydro-1-benzoxepine Example 2 The recrystallized mother liquor was dissolved in ether and ether saturated with hydrochloric acid was added. The precipitated crystals were recrystallized from ethanol/ether to obtain the title compound in a yield of 28%. Properties: Colorless needle crystals (hydrochloride) Melting point: 184-185℃ (decomposed) [hydrochloride] NMR spectrum (δppm): 7.08 (1H, d, J=
3Hz), 6.92 (1H, d, J=8Hz), 6.65 (1H,
dd, J=8.3Hz), 5.11 (1H, brs), 3.78 (1H,
s) Example 4 4,5-trans-5-hydroxy-8-methoxy-4-piperidinomethyl-2,3,4,5
-Tetrahydro-1-benzoxepine The obtained oil was recrystallized from hexane with a yield of 67
% of the title compound was obtained. Properties: Colorless needle crystals Melting point: 85-86℃ NMR spectrum (CDCl 3 , δppm): 7.63 (1H,
d, J = 9Hz), 6.62 (1H, dd, J = 9, 3
Hz), 6.49 (1H, d, J=3Hz), 4.80 (1H, d,
J=8Hz), 3.75 (1H, s) Example 5 4,5-cis-5-hydroxy-8-methoxy-4-piperidinomethyl-2,3,4,5-tetrahydro-1-benzoxepine Oil of Example 4 The crystal mother liquor was recrystallized from hexane to obtain the title compound in a yield of 11%. Properties: Colorless needle crystals Melting point: 91-92℃ NMR spectrum (CDCl 3 , δppm): 7.44 (1H,
d, J=9Hz), 6.65(1H, dd, J=9,3
Hz), 6.51 (1H, d, J = 3Hz), 5.18 (1H,
brs), 3.76 (1H, s) Example 6 4,5-cis-5-hydroxy-7-methoxy-4-isopropylaminomethyl-2,3,
4,5-Tetrahydro-1-benzoxepine The obtained oil was recrystallized from a mixed solvent of ether and hexane to obtain the title compound in a yield of 17%. Properties: Colorless needle crystals Melting point: 125.5-127℃ NMR spectrum (CDCl 3 , δppm): 7.09 (1H,
d, J = 2, 4Hz), 6.86 (1H, d, J = 6.0
Hz), 6.61 (1H, dd, J=6.0, 2.4Hz), 5.10
(1H, brs), 3.76 (1H, s) Example 7 4,5-trans-5-hydroxy-7-methoxy-4-isopropylaminomethyl-2,
3,4,5-Tetrahydro-1-benzoxepine The recrystallization mother liquor of Example 6 was dissolved in ether and ether saturated with hydrochloric acid was added. The solvent was distilled off, and the residue was recrystallized from ethanol/ether to obtain the title compound in a yield of 59%. Properties: Colorless needle crystals Melting point: 146-148℃ NMR spectrum (free compound, CDCl 3 ,
δppm): 7.09 (1H, d, J = 2.4Hz), 6.86 (1H,
d, J=6.0Hz), 6.61 (1H, dd, J=6.0, 2.4
Hz), 5.10 (1H, br.s), 3.76 (1H, s) Example 8 8-Chlor-4(N-methylpiperazine-1-
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 (N-methylpiperazin-1-yl)methyl group at the 4-position and the phenyl group at the 5-position of the title compound obtained here had a trans configuration. Compounds of Examples 9 to 20 were synthesized in the same manner as in Example 8 using various Grignard reagents. Example 9
Hereinafter, 4,5-trans is indicated by the 4-position substituent and the 5-position substituent.
Indicates that the alkyl group, phenyl group or benzyl group has a trans configuration. Example 9 4,5-trans-4-diethylaminomethyl-5-ethyl-5-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1-benzoxepine Yield 30% Melting point: 198-200°C ( Hydrochloride) Example 10 4,5-trans-5-ethyl-5-hydroxy-7-methoxy-4-piperidinomethyl-
2,3,4,5-tetrahydro-1-benzoxepine Yield 65% Melting point: 238-239°C (hydrochloride) Example 11 4,5-trans-5-ethyl-5-hydroxy-7-methoxy-4- Morpholinomethyl
2,3,4,5-tetrahydro-1-benzoxepine Yield 60% Melting point: 222-223°C (hydrochloride) Example 12 4,5-trans-4-dimethylaminomethyl-5-ethyl-5-hydroxy- 8-methoxy-2,3,4,5-tetrahydro-1-benzoxepine Yield: 63% Melting point: 213-214°C (hydrochloride) Example 13 4,5-trans-5-ethyl-5-hydroxy-8 -methoxy-4-piperidinomethyl-
2,3,4,5-tetrahydro-1-benzoxepine Yield: 53% Melting point: 217-218°C (hydrochloride) Example 14 4,5-trans-5-ethyl-5-hydroxy-8-methoxy-4 -morpholinomethyl-
2,3,4,5-tetrahydro-1-benzoxepine Yield: 34% Melting point: 182-183°C (hydrochloride) Example 15 4,5-trans-5-ethyl-4-dimethylaminomethyl-5-hydroxy -8-chlor-
2,3,4,5-tetrahydro-1-benzoxepine Yield: 32% Melting point: 196-197°C Example 16 4,5-trans-8-chloro-5-ethyl-
5-hydroxy-4-piperidinomethyl-2,
3,4,5-tetrahydro-1-benzoxepine Yield: 68% Melting point: 250°C or higher (hydrochloride) Example 17 4,5-trans-8-chloro-5-ethyl-
5-hydroxy-4-morpholinomethyl-2,
3,4,5-tetrahydro-1-benzoxepine Yield: 60% Melting point: 179-180°C (hydrochloride) Example 18 4,5-trans-5-benzyl-5-hydroxy-8-methoxy-4-piperidinomethyl −
2,3,4,5-tetrahydro-1-benzoxepine Yield: 62% Melting point: 85-86°C Example 19 4,5-trans-8-chloro-5-hydroxy-5-phenyl-4-(N- Methylpiperazin-1-yl) Methyl-2,3,4,5-tetrahydro-1-benzoxepine Yield: 65% Melting point: 69-71°C (colorless needles) IR spectrum (KBr, cm -1 ): 3400 , 1600 NMR spectrum ( CDCl3 , δppm): 1.92-2.10
(m, 1H), 2.20-3.00 (m, 12H), 3.63 (m,
1H), 4.00 (m, 1H), 7.05-7.38 (m, 7H),
7.84 (d, 1H, J=9.2Hz), 8.42 (br.s, 1H) Elemental analysis (as C 22 H 27 ClN 2 O 2 ) C (%) H (%) N (%) Cl (%) Calculation Value: 68.29 7.03 7.24 9.16 Actual value: 68.50 7.04 7.18 9.15 Example 20 4,5-trans-8-chloro-5-hydroxy-4-(N-methylpiperazin-1-yl)
Methyl-5-phenyl-2,3,4,5-tetrahydro-1-benzoxepine Properties: Colorless needle crystals Melting point: 69.0-71.0°C IR spectrum (KBr, cm -1 ): 3400, 1600 NMR spectrum (CDCl 3 , δppm): 1.92~2.10
(m, 1H), 2.20-3.00 (m, 12H), 3.63 (m,
1H), 4.00 (m, 1H), 7.05-7.38 (m, 7H),
7.84 (d, 1H, J=9.2Hz), 8.42 (br.s, 1H) Elemental analysis: as C 22 H 27 ClN 2 O 2 C(%) H(%) N(%) Cl(%) Calculated value : 68.29 7.03 7.24 9.16 Actual value: 68.50 7.04 7.18 9.15 Example 21 4,5-trans-5-acetoxy-7-methoxy-4-morpholinomethyl-2,3,4,5
-Tetrahydro-1-benzoxepine 1.0 g (3.42 mmol) of the title compound of Example 2
and 697 mg (6.68 mmol) of acetic anhydride were dissolved in 20 ml of benzene and stirred at room temperature for 17 hours. Benzene was added to the reaction mixture to dilute it, and the mixture was washed with water, and further washed successively with saturated aqueous sodium bicarbonate and water. After drying, benzene was distilled off to obtain 1.165 g (yield 99%) of the title compound. Properties: Colorless oil IR spectrum (film, cm -1 ): 1745 NMR spectrum (CDCl 3 , δppm): 1.70-2.70
(9H, m), 2.10 (3H, s), 3.50~4.40 (6H,
m), 3.78 (3H, s), 5.92 (1H, d, J=6
Hz), 6.60-7.01 (3H, m) Example 22 4,5-trans-5-acetoxy-8-methoxy-4-morpholinomethyl-2,3,4,5
-tetrahydro-1-benzoxepine 8-methoxy-4-morpholinomethyl-2,
3,4,5-tetrahydro-1-benzoxepin-5-one was reduced using sodium borohydride to give 4,5-trans-5-hydroxy-8-methoxy-4-morpholinomethyl-2,3,4,5
-tetrahydro-1-benzoxepine, and then treated with acetic anhydride in the same manner as in Example 21 to obtain the title compound. Properties: Colorless oil IR spectrum (film, cm -1 ): 1745 NMR spectrum (CDCl 3 , δppm): 1.70-2.70
(9H, m), 2.04 (3H, s), 3.50~450 (6H,
m), 3.75 (3H, s), 5.92 (1H, d, J=4.5
Hz), 6.40-6.70 (2H, m), 7.00-7.30 (1H,
m) Example 23 5-hydroxy-8-methoxy-4-morpholinomethyl-2,3,4,5-tetrahydro-1
-Benzoxepine The reaction was carried out in the same manner as in Example 1. After the reaction, the obtained oil was a mixture of a 5-position hydroxyl group and a 4-position morpholinomethyl group in cis and trans configurations. The NMR spectrum data of the main product is shown. NMR spectrum ( CDCl3 , δppm): 1.6-2.9 (m,
9H) 3.55-4.4 (m, 6H), 3.77 (s, 3H), 4.85
(m, 1H), 6.5-6.8 (m, 2H), 7.33 (d, 1H,
J=8Hz) 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.
Claims (1)
合、R1は水素原子、炭素数１−４のアルキル基、
フエニル基又はアラルキル基を表し、R2は水素
原子又は炭素数２−３のアシル基を表し、Ｙはピ
ペリジル基、モルホリニル基、基 【式】 （ここでR3及びR4は同一又は異なつた炭素数１
−４のアルキル基を表す）又は基 【式】 （ここでR5は炭素数１−２のアルキル基を表す）
を表し；Ａがハロゲン原子の場合、R1は水素原
子、炭素数１−４のアルキル基、フエニル基又は
アラルキル基を表し、R2は水素原子又は炭素数
２−３のアシル基を表し、Ｙはモルホリニル基、
基 【式】 （ここでR3及びR4は同一又は異なつた炭素数１
−４のアルキル基を表す）又は基 【式】 （ここでR5は炭素数１−２のアルキル基を表す）
を表す。］を有する１−ベンズオキセピンおよび
その薬理学的に許容される塩。 ２ 基Ａが７位又は８位である特許請求の範囲第
１項記載の化合物。 ３ 基【式】がジメチルアミノ基、ジエチ ルアミノ基、ジイソプロピルアミノ基、sec−ブ
チルアミノ基、メチルアミノ基、エチルアミノ
基、イソプロピルアミノ基、メチルイソプロピル
アミノ基、メチルプロピルアミノ基又はジ−sec
−ブチルアミノ基である特許請求の範囲第１項記
載の化合物。[Claims] 1. General formula [In the formula, when A is an alkoxy group having 1-3 carbon atoms, R 1 is a hydrogen atom, an alkyl group having 1-4 carbon atoms,
represents a phenyl group or an aralkyl group, R 2 represents a hydrogen atom or an acyl group having 2-3 carbon atoms, Y represents a piperidyl group, a morpholinyl group, or a group [Formula] (where R 3 and R 4 are the same or different) Carbon number 1
-4 alkyl group) or group [Formula] (where R 5 represents an alkyl group having 1-2 carbon atoms)
represents; when A is a halogen atom, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group; R 2 represents a hydrogen atom or an acyl group having 2 to 3 carbon atoms; Y is a morpholinyl group,
Group [Formula] (where R 3 and R 4 are the same or different and have 1 carbon number)
-4 alkyl group) or group [Formula] (where R 5 represents an alkyl group having 1-2 carbon atoms)
represents. ] 1-benzoxepine and its pharmacologically acceptable salts. 2. The compound according to claim 1, wherein the group A is at the 7th or 8th position. 3 Group [Formula] is dimethylamino group, diethylamino group, diisopropylamino group, sec-butylamino group, methylamino group, ethylamino group, isopropylamino group, methylisopropylamino group, methylpropylamino group, or di-sec
The compound according to claim 1, which is a -butylamino group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25342584A JPS61130287A (en) | 1984-11-30 | 1984-11-30 | 1-benzoxepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25342584A JPS61130287A (en) | 1984-11-30 | 1984-11-30 | 1-benzoxepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61130287A JPS61130287A (en) | 1986-06-18 |
| JPH0443915B2 true JPH0443915B2 (en) | 1992-07-20 |
Family
ID=17251212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25342584A Granted JPS61130287A (en) | 1984-11-30 | 1984-11-30 | 1-benzoxepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61130287A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10033459A1 (en) * | 2000-07-10 | 2002-01-24 | Gruenenthal Gmbh | Cyclic substituted aminomethyl compounds and drugs containing them |
-
1984
- 1984-11-30 JP JP25342584A patent/JPS61130287A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61130287A (en) | 1986-06-18 |
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