JPH03170431A - Treating agent for heart disease - Google Patents
Treating agent for heart diseaseInfo
- Publication number
- JPH03170431A JPH03170431A JP1310346A JP31034689A JPH03170431A JP H03170431 A JPH03170431 A JP H03170431A JP 1310346 A JP1310346 A JP 1310346A JP 31034689 A JP31034689 A JP 31034689A JP H03170431 A JPH03170431 A JP H03170431A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- triazine
- compound
- reference example
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000019622 heart disease Diseases 0.000 title claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 150000003918 triazines Chemical class 0.000 claims abstract description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 abstract description 57
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 24
- 102000056834 5-HT2 Serotonin Receptors Human genes 0.000 abstract description 9
- 108091005479 5-HT2 receptors Proteins 0.000 abstract description 9
- 230000003042 antagnostic effect Effects 0.000 abstract description 7
- 230000002265 prevention Effects 0.000 abstract description 2
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 208000031225 myocardial ischemia Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 23
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 22
- 239000013078 crystal Substances 0.000 description 21
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 21
- 238000000862 absorption spectrum Methods 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 15
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- -1 methoxy, ethoxy, propoxy Chemical group 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 229940126062 Compound A Drugs 0.000 description 11
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 11
- 230000017531 blood circulation Effects 0.000 description 11
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 208000010125 myocardial infarction Diseases 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
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- 238000012360 testing method Methods 0.000 description 10
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 210000002216 heart Anatomy 0.000 description 8
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- 229940079593 drug Drugs 0.000 description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
- 206010002383 Angina Pectoris Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000036584 pressor response Effects 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- FSZKLYCUEQGCKW-UHFFFAOYSA-N phenyl n-(oxomethylidene)carbamate Chemical compound O=C=NC(=O)OC1=CC=CC=C1 FSZKLYCUEQGCKW-UHFFFAOYSA-N 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
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- 238000010494 dissociation reaction Methods 0.000 description 3
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
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- 239000011780 sodium chloride Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 230000002861 ventricular Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 2
- FPCCSQOGAWCVBH-PSQIVULCSA-N 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]-1,1,2,2-tetratritioethyl]-1h-quinazoline-2,4-dione Chemical compound O=C1NC2=CC=CC=C2C(=O)N1C([3H])([3H])C([3H])([3H])N(CC1)CCC1C(=O)C1=CC=C(F)C=C1 FPCCSQOGAWCVBH-PSQIVULCSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
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- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- FJAWLKCGHBWXQW-UHFFFAOYSA-N azepine-2,4-dione Chemical compound O=C1CC(=O)N=CC=C1 FJAWLKCGHBWXQW-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000352 effect on angina Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- UUBJKHVFGWGJKX-UHFFFAOYSA-N hydrate tetrahydrochloride Chemical compound O.Cl.Cl.Cl.Cl UUBJKHVFGWGJKX-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000002966 stenotic effect Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940100050 virazole Drugs 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
[産業上の利用分野]
本発明は、式(I)
[式中、R1は水素原子、アルキル基又はハロゲン原子
、アルコキシ基、アルキル基及びトリハロゲンメチル基
より選ばれる1もしくは複数個の置換基で置換されても
よいアリール基を、R2は水素原子、アルキル基又はハ
ロゲン原子、アルコキシ基、アルキル基及びトリハロゲ
ノメチル基より選ばれる1もしくは複数個の置換基で置
換されてもよいアリール基を、n及びmはそれぞれO〜
6の整数を、Aは5〜7員環を示し、該環は1個の窒素
原子を共有して全4トリアジン環と縮合し且つその縮合
部の窒素原子の他に窒素原子、酸素原子及び硫黄原子よ
り選ばれるヘテロ原子を1もしくは2個含んでもよく又
1もしくは複数個の二重結合を含んでもよく、Qは次の
一般式(!■)fl4
(式中、R3は水素原子、水酸基又はハロゲン原子、水
酸基、アルキル基、アルコキシ基及びトリハロゲノメチ
ル基より選ばれる1もしくは2個の置換基で置換されて
もよいアリール基を、R4R5及びR6はそれぞれ水素
原子、ハロゲン原子、アルキル基、アルコキシ基または
トリハロゲノメチル基を示す。)で表される基又は次の
一般式( III )
(式中、Ar’及びAr’はそれぞれハロゲン原子、水
酸基、アルコキシ基、アルキル基及びトリハロゲノメチ
ル基より選ばれる1〜3個の置換基で置換されてもよい
アリール基又は芳香族複素環残基を示す.)で表される
基を示す.]で表される縮合トリアジン誘導体又はその
塩を有効成分とする心臓疾患の予防及び治療剤社関する
。Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound of formula (I) [wherein R1 is selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenmethyl group] An aryl group that may be substituted with one or more substituents, R2 is substituted with one or more substituents selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenomethyl group. n and m each represent an optionally substituted aryl group,
6 is an integer, A represents a 5- to 7-membered ring, which ring shares one nitrogen atom and is fused with all 4 triazine rings, and in addition to the nitrogen atom at the fused portion, a nitrogen atom, an oxygen atom, and It may contain one or two heteroatoms selected from sulfur atoms, or it may contain one or more double bonds, and Q is represented by the following general formula (!■)fl4 (wherein, R3 is a hydrogen atom, a hydroxyl group or an aryl group which may be substituted with one or two substituents selected from a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group and a trihalogenomethyl group, R4R5 and R6 are each a hydrogen atom, a halogen atom, an alkyl group, represents an alkoxy group or a trihalogenomethyl group) or a group represented by the following general formula (III) (wherein Ar' and Ar' are a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, and a trihalogenomethyl group, respectively) represents an aryl group or an aromatic heterocyclic residue which may be substituted with 1 to 3 substituents selected from the following. The present invention relates to a preventive and therapeutic agent for heart diseases containing a condensed triazine derivative or a salt thereof as an active ingredient.
[従来の技術]
狭心症,心筋梗塞,心不全の如き心臓疾患の治療剤とし
ては、β−ブロッカー.カルシウムブロッカー.強心剤
等が知られている。[Prior Art] β-blockers are used as therapeutic agents for heart diseases such as angina pectoris, myocardial infarction, and heart failure. Calcium blocker. Cardiotropes are known.
該疾患の治療薬については近年セロトニン2受容体拮抗
作用を有する薬剤の研究もなされているが、未だ充分な
効果を有するものは見い出されていない。As for therapeutic agents for this disease, research has been carried out in recent years on drugs having serotonin 2 receptor antagonistic action, but no drug with sufficient efficacy has yet been found.
[発明が解決しようとする問題点]
本発明者等は、前述の如き心臓疾患に対し優れた効果を
有するセロトニン2受容体拮抗薬を見いだすべく鋭意検
討した結果、本発明を完成した。[Problems to be Solved by the Invention] The present inventors have completed the present invention as a result of intensive studies to find a serotonin 2 receptor antagonist that has an excellent effect on heart diseases as described above.
[発明の構成]
本発明は、式(I)の縮合トリアジン誘導体又はその塩
を有効戊分とする心臓疾患の予防及び治療剤に関する。[Structure of the Invention] The present invention relates to a prophylactic and therapeutic agent for heart diseases, which contains a condensed triazine derivative of formula (I) or a salt thereof as an effective ingredient.
本発明にかかわる心臓疾患としては狭心症.心筋梗塞,
心不全,不整脈等をあげることができる。The heart disease related to the present invention is angina pectoris. myocardial infarction,
Possible causes include heart failure and arrhythmia.
次に、式(!)における置換基について以下に説明する
。Next, the substituents in formula (!) will be explained below.
アルキル基としては、メチル、エチル、イソブロビル、
n−プロビル、第三級ブチル、n−ブチル等の炭素数1
〜6のものをあげることができる。ハロゲン原子として
はフッ素、塩素、臭素、ヨウ素をあげることができる。Alkyl groups include methyl, ethyl, isobrobyl,
1 carbon number such as n-propyl, tertiary butyl, n-butyl, etc.
I can list ~6 things. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.
アルコキシ基としては、メトキシ、エトキシ、プロボキ
シ、プトキシ等の炭素数1〜6のものをあげることがで
きる。トリアジン環に縮合するA環としては、ビリジン
、ピラジン、ビロール、ビペリジン、ホモピベリジン、
ビロリジン、ビペラジン、ホモビペラジン、ビリミジン
、チアゾール、ビラゾール、オキサゾール、イソチアゾ
ール、イソキサゾール、トリアゾール、トリアジン、1
.4−オキサジン、1.3−オキサジン、1.4−チア
ジン、1.3−チアジン等の5〜7員の芳香族又は脂肪
族の複素環をあげることができる。アリール基としては
、フェニル、ナフチル、ビフェニル等をあげることがで
きる。式( IIT )の置換基における芳香族複素環
残基としては、ビリジル、ビリくジニル、チェニル、フ
リル、ピラゾリル、イミダゾリル、チアゾリル、オキサ
ゾリル、イソチアゾリル、イソキサゾリル等をあげるこ
とができる。Examples of the alkoxy group include those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, and poxy. Examples of the A ring fused to the triazine ring include pyridine, pyrazine, virol, biperidine, homopiveridine,
Virolidine, viperazine, homoviperazine, birimidine, thiazole, virazole, oxazole, isothiazole, isoxazole, triazole, triazine, 1
.. Examples include 5- to 7-membered aromatic or aliphatic heterocycles such as 4-oxazine, 1.3-oxazine, 1.4-thiazine, and 1.3-thiazine. Examples of the aryl group include phenyl, naphthyl, biphenyl, and the like. Examples of the aromatic heterocyclic residue in the substituent of formula (IIT) include biridyl, pyridinyl, chenyl, furyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and the like.
式(I)の化合物においては、A環がビベリジン、ホモ
ピベリジン又はチアゾールで、m及びnの和が0〜6の
整数で、Qが式(11’)(式中、R31は水素又は水
酸基を、Xはハロゲン原子を意味する)又は式(m’)
(式中、XI及びX2はそれぞれハロゲン原子を意味す
る)で示される基t蓉唸た☆ で套bを迦4化合物を好
ましいものとしてあげることができる。In the compound of formula (I), ring A is biveridine, homopiveridine or thiazole, the sum of m and n is an integer of 0 to 6, and Q is of formula (11') (wherein R31 is hydrogen or a hydroxyl group, (X means a halogen atom) or a group represented by the formula (m') (in the formula, XI and X2 each mean a halogen atom) be able to.
式(1)の化合物の塩としては塩酸、硫酸、硝酸、りん
酸等の鉱酸の酸付加塩、あるいはメタンスルホン酸、ペ
ンセンスルホン酸、トルエンスルホン酸等の有機スルホ
ン酸及び酒石酸、マレイン酸、フマール酸、りんご酸、
しゆう酸、乳酸、クエン酸等の有機カルボン酸の酸付加
塩をあげることが出来る。Salts of the compound of formula (1) include acid addition salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or organic sulfonic acids such as methanesulfonic acid, pencenesulfonic acid, and toluenesulfonic acid, and tartaric acid and maleic acid. , fumaric acid, malic acid,
Examples include acid addition salts of organic carboxylic acids such as oxalic acid, lactic acid, and citric acid.
次に、式(I)で表される縮合トリアジン誘導体の製造
法を説明する。Next, a method for producing the condensed triazine derivative represented by formula (I) will be explained.
+IV) (式中R’ ,R2,A,n,m及びQは前記と同じ。+IV) (In the formula, R', R2, A, n, m and Q are the same as above.
)
即ち、式(IV)で表される化合物をジメチルホルムア
ミド、テトラヒドロフラン、ジオキサン等の熔媒中式(
V)で表される化合物と各種脱水試薬、例えばトリフェ
ニールフォスフィンとアゾジカルボン酸ジアルキルエス
テルの混合物の存在下にO℃から溶媒の沸点までの温度
で反応させることにより目的とする式(1)の化合物を
製造することが出来る。) That is, a compound represented by formula (IV) is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, etc. by formula (IV).
The desired formula (1) is obtained by reacting the compound represented by V) with various dehydrating reagents, such as a mixture of triphenylphosphine and azodicarboxylic acid dialkyl ester, at a temperature from 0°C to the boiling point of the solvent. Compounds of can be produced.
又、式(IV)の化合物を次の式(VT)R’
Xs− (C}12) 。−CH− (CH2) −−
Q ( ’/I )(式中、x3はハロゲン原子、
パラトルエンスルホニルオキシ基又はメタンスルホニル
オキシ基を示し、R’,n,m及びQは前記と同じ)で
表される化合物と、等モル又はそれ以上の炭酸カリウム
、炭酸ナトリウムの如き炭酸アルカリ、水素化ナトリウ
ム、水素化カリウムの如き水素化アルカリもしくはトリ
エチルアくン、l.8−ジアザビシクロ[5,4.0]
−7−ウンデセンの如き有機塩基の存在下にエタノール
、メタノール、ジメチルホルムアミド、テトラヒドロフ
ラン、ジオキサン、ベンゼン等の有機溶媒中室温から溶
媒の沸点までの温度で反応させることによっても式(I
)の化合物を製造することが出来る。該反応においては
ヨウ化ナトリウム、ヨウ化カリウムの様なヨウ化アルカ
リを触媒量加えることも可能である。Further, the compound of formula (IV) is represented by the following formula (VT)R'Xs- (C}12). -CH- (CH2) --
Q ('/I) (where x3 is a halogen atom,
paratoluenesulfonyloxy group or methanesulfonyloxy group, R', n, m and Q are the same as above), and an equimolar or more amount of an alkali carbonate such as potassium carbonate or sodium carbonate, hydrogen Alkali hydrides such as sodium chloride, potassium hydride or triethyl hydride, l. 8-diazabicyclo[5,4.0]
The formula (I
) can be produced. In this reaction, it is also possible to add a catalytic amount of alkali iodide such as sodium iodide or potassium iodide.
次に、式(TV)で示される中間体について説明する。Next, the intermediate represented by formula (TV) will be explained.
該化合物中2H−ビリド[1.2−8]−1.3.5−
トリアジン−2.4(3H)一ジオン(西独特許公開公
報1922837号)、2H−ビリよド[1.2−al
−1.3.5−}リアジン−2.4(3H)一ジオン(
シンセシス、892頁, 1985年)、5−メチル−
2H一才キサゾロ[3.2−a]−1.3.5−}−リ
アジン−2 . 4 (3H)一ジオン(英国特許第1
328205号)、8−メチルイミダゾ[1 .2−a
l −1 .3 .5− トリアジン−2.4 (3H
,8H)一ジオン(Journal of Organ
ic Che−mistry,43.4774.197
8年)等の一部の化合物は公知であり、上記式(IV)
の化合物はこれらの文献に開示された方法を参考にして
製造することができる。2H-Virido[1.2-8]-1.3.5- in the compound
triazine-2.4(3H) monodione (West German Patent Publication No. 1922837), 2H-bilyodo[1.2-al
-1.3.5-}Ryazine-2.4(3H) monodione (
Synthesis, p. 892, 1985), 5-methyl-
2H one year old xazolo[3.2-a]-1.3.5-}-riazine-2. 4 (3H)-dione (British Patent No. 1
328205), 8-methylimidazo [1. 2-a
l −1. 3. 5-triazine-2.4 (3H
,8H) monodione (Journal of Organ
ic Che-mistry, 43.4774.197
Some of the compounds are known, such as
The compound can be produced by referring to the methods disclosed in these documents.
一般には、式(rv)の化合物は、以下の方法により製
造することができる。Generally, the compound of formula (rv) can be produced by the following method.
(VIE) (ff)(
式中、R2及びAは前記と同じ。)
即ち、式(VII )の化合物をフェノキシカルボニル
イソシアナートとジメチルホルムアくド、テトラヒドロ
フラン、ジオキサン等の溶媒中O℃から溶媒の沸点まで
の温度で反応させることにより式( IV)の化合物を
製造することができる。(VIE) (ff)(
In the formula, R2 and A are the same as above. ) That is, the compound of formula (IV) is produced by reacting the compound of formula (VII) with phenoxycarbonyl isocyanate in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, etc. at a temperature from 0°C to the boiling point of the solvent. be able to.
式(1)の化合物をラットに10日間連繞経口投与して
、その毒性を検討した結果aoomg/kgの経口投与
でも死亡例は見られず、式(1)の化合物およびその塩
は安全性が高いことが確認された。The compound of formula (1) was orally administered to rats for 10 consecutive days, and its toxicity was examined. No deaths were observed even after oral administration of aoomg/kg, indicating that the compound of formula (1) and its salts are safe. was confirmed to be high.
式(I)の化合物またはその塩は、錠剤、散剤、カプセ
ル剤、または注射剤などの剤型に製剤化可能であり、通
常経口、皮下、筋肉内、あるいは静脈内に投与される。The compound of formula (I) or a salt thereof can be formulated into a dosage form such as a tablet, powder, capsule, or injection, and is usually administered orally, subcutaneously, intramuscularly, or intravenously.
式(I)の化合物またはその塩の投与量は経口投与にお
いて戒大1人あたり通常30〜2000mg /日の範
囲はある。The dosage of the compound of formula (I) or a salt thereof is usually in the range of 30 to 2000 mg/day per person for oral administration.
〈発明の効果〉
式(1)の化合物及びその塩は強力且つ持続性に優れた
セロトニン2受容体拮抗作用を有し、更に虚血性の変化
を伴う心疾患の実験モデル、例えば、心筋梗塞モデル、
狭心症モデル等において優れた心機能改善作用、心筋壊
死改善作用、冠動脈内血栓形戒予防作用、心臓の微小循
環改善作用等を示した.
従って式(1)の化合物またはその塩は心疾患、中でも
虚血性の変化を伴う心疾患の予防または治療剤として優
れたものである。<Effects of the Invention> The compound of formula (1) and its salt have a strong and long-lasting serotonin 2 receptor antagonistic effect, and are also useful in experimental models of heart diseases accompanied by ischemic changes, such as myocardial infarction models. ,
It has shown excellent effects in improving cardiac function, myocardial necrosis, preventing thrombosis in coronary arteries, and improving cardiac microcirculation in angina models. Therefore, the compound of formula (1) or a salt thereof is excellent as a preventive or therapeutic agent for heart diseases, especially heart diseases accompanied by ischemic changes.
以下、本発明を参考例及び実施例により説明するが、本
発明はこれにより限定されるものではない。Hereinafter, the present invention will be explained by reference examples and examples, but the present invention is not limited thereto.
参考例1
3− [2− (4− (4−フルオロベンゾイル)レ
+A華 11 呂 )ノ ー イ ー ノ +1.1
−f:t+ 雪tオ1 ctoo − エトラ
ヒドロ−2H−ビリド[1.2−a ] −1.3.5
−トリアジン−2,4(3}1) 一ジオン(1)
6,7,8.9−テトラヒドロー2H−ピリド[1.2
−a ] −1.3.5 − トリアジン−2.4(3
H) 一ジオン
金属ナトリウム0.83gと無水エタノール40mlか
ら調製したソディウム・エトキサイドのエタノール溶液
に、水冷下2−アミノー3.4.5.8−テトラヒドロ
ピリジン塩酸塩4.8gを加えて室温で30分攪拌した
。不溶物を濾去後、濾液を減圧乾固した。残渣にテトロ
ヒドロフラン30mlを加えて懸濁し、氷’hFjl押
下フェノキシカルボニルイソシアナート5.9gを10
分間で滴下した。一夜室温に放置して析出した結晶を濾
取後、1.4gを得た。更に、濾液を減圧乾固して残渣
をシリカゲル・カラム(100g)に付し、5%メタノ
ール含有クロロホルムで溶出後、結晶2.04gを得た
。先の結晶と合わせ、表題化合物の無色結晶3.44g
を得た。Reference example 1 3-[2-(4-(4-fluorobenzoyl)+A 11 ro)No-i-no+1.1
-f: t+ snow to1 ctoo - etrahydro-2H-pyrid [1.2-a] -1.3.5
-triazine-2,4(3}1) monodione (1)
6,7,8.9-tetrahydro2H-pyrido [1.2
-a] -1.3.5 -triazine-2.4(3
H) To an ethanol solution of sodium ethoxide prepared from 0.83 g of sodium monodione metal and 40 ml of absolute ethanol, 4.8 g of 2-amino-3.4.5.8-tetrahydropyridine hydrochloride was added under water cooling, and the mixture was heated to 30 mL at room temperature. The mixture was stirred for a minute. After removing insoluble matter by filtration, the filtrate was dried under reduced pressure. Add 30 ml of tetrahydrofuran to the residue, suspend it, and add 5.9 g of phenoxycarbonyl isocyanate to 10
It was dripped in minutes. After leaving it at room temperature overnight, the precipitated crystals were collected by filtration, and 1.4 g was obtained. Further, the filtrate was dried under reduced pressure, and the residue was applied to a silica gel column (100 g), and after elution with chloroform containing 5% methanol, 2.04 g of crystals were obtained. Combined with the previous crystals, 3.44 g of colorless crystals of the title compound
I got it.
Nh A +oc−+oq ?1核
磁気共鳴スペクトル(ジメチルスルホキシドーd6)δ
: 1.6−1.9 (4H,m) ,2.65 (2
H,t)3.84 (2H,t) ,11.39 (1
1{,b) .赤外吸収スペクトルv (KBr)cm
一’:3450,3200,3070,1700,15
90,1490,1440,1390.
元素分析C7H9N302として
計算値(零): C,50.30; }1,5.43;
N,25.14.実測値 (%): C,5Q.37
. H,5.45; N,24.91.(2)37 [
2− [4− (4−フルオロベンゾイル)ビベリジン
−1−イル]エチルコー6.7,8.9−テトラヒドロ
−2H−ピリド[1.2−aコー1.3.5−トリアジ
ン−2.4(3H) 一ジオン上記参考例1(1)で
得た8,7,8.9−テトラヒド口−2H−ピリド[i
4−aコー1.3.5 − トリアジン−2.4(3H
) 一ジオン34.1g,4− (4−フル才ロベン
ゾイル)−1−(2−ヒドロキシエチル)ピベリジン5
1.2gとトリフェニルホスフィン56.1gをテトラ
ヒドロフラン900 mlに懸濁し水冷下にアゾジカル
ボン酸ジエチルエステル38gを15分を要して滴下し
た。室7品で20分間攪拌後、減圧下に溶媒を留去し、
残漬に酢酸エチル500 mlを加えてIN一塩酸で抽
出した。この1N一塩酸抽出液に炭酸カリウムを加えて
アルカリ性としクロロホルムで抽出した。無水硫酸ナト
リウムで乾燥し、溶媒を減圧留去した。得られた残渣を
エタノールより結晶化させ、続いてメタノールとエタノ
ールの混液より再結晶して目的化合物の無色結晶33.
7gを得た。Nh A +oc-+oq? 1 Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6) δ
: 1.6-1.9 (4H, m), 2.65 (2
H, t) 3.84 (2H, t) , 11.39 (1
1{,b). Infrared absorption spectrum v (KBr) cm
1': 3450, 3200, 3070, 1700, 15
90,1490,1440,1390. Calculated value (zero) as elemental analysis C7H9N302: C, 50.30; }1, 5.43;
N, 25.14. Actual value (%): C, 5Q. 37
.. H, 5.45; N, 24.91. (2) 37 [
2-[4-(4-fluorobenzoyl)biveridin-1-yl]ethyl-6.7,8.9-tetrahydro-2H-pyrido[1.2-a-1.3.5-triazine-2.4( 3H) monodione 8,7,8.9-tetrahydride-2H-pyrido[i
4-a-1.3.5-triazine-2.4 (3H
) monodione 34.1 g, 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piveridine 5
1.2 g and 56.1 g of triphenylphosphine were suspended in 900 ml of tetrahydrofuran, and 38 g of azodicarboxylic acid diethyl ester was added dropwise over 15 minutes while cooling with water. After stirring for 20 minutes in chamber 7, the solvent was distilled off under reduced pressure.
500 ml of ethyl acetate was added to the residue and extracted with IN monohydrochloric acid. This 1N monohydrochloric acid extract was made alkaline by adding potassium carbonate and extracted with chloroform. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol, and then recrystallized from a mixture of methanol and ethanol to obtain colorless crystals of the target compound.
7g was obtained.
融 点 170−172 ℃
核磁気共鳴スペクトル(重クロロホルム)δ: 1.8
−2.2 (IOH,m) ,2.26 (2H,t)
,2.81 (2}1,t) ,3.0−3.3 (
3H,m) ,3.84 (2}1,t) ,4.06
(2H,t) ,7.13 (2H,t) .7.9
5 (2H,dd) .
赤外吸収スペクトルν(KBr) cm−’ :173
0,1670,1600,1490,1450,141
0.元素分折CztH2sFN4Chとして計算値(零
): (:,62.99; H,6.29. N,13
.99.実測値代): C,Ii2.68. H,6.
2B. N,13.83.参考例2
3− [2−[4− (4−フルオロベンゾイル)ビベ
リジン−1−イルコエチルコー6.7,8.9−テトラ
ヒドロ−2H−ピリド[1.2−aコトリアジン−2.
4(3H) 一ジオン塩酸塩
上記参考例1で得た3 − [2 − [4 − (4
−フルオロベンゾイル)ビベリジン−1−イル]エチル
コー6.7,8.9−テトラヒドロ−2H−ビリド[1
.2−a ] −1.3.5 − トリアジン−2.4
(3H)一ジオン33.Ogを熱エタノール150m
lに溶解し濃塩酸5mlを加えた。冷却後、析出した結
晶を濾取し、エタノールより再結晶して表題化合物の無
色結晶27.4gを得た。Melting point 170-172°C Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.2 (IOH, m), 2.26 (2H, t)
,2.81 (2}1,t) ,3.0-3.3 (
3H,m) ,3.84 (2}1,t) ,4.06
(2H, t) ,7.13 (2H, t) . 7.9
5 (2H, dd). Infrared absorption spectrum ν (KBr) cm-': 173
0,1670,1600,1490,1450,141
0. Calculated value (zero) as elemental analysis CztH2sFN4Ch: (:, 62.99; H, 6.29. N, 13
.. 99. Actual value): C, Ii2.68. H, 6.
2B. N, 13.83. Reference Example 2 3-[2-[4-(4-fluorobenzoyl)viveridin-1-ylcoethylco6.7,8.9-tetrahydro-2H-pyrido[1.2-acotriazine-2.
4(3H) monodione hydrochloride 3-[2-[4-(4
-fluorobenzoyl)biveridin-1-yl]ethylco6.7,8.9-tetrahydro-2H-pyrido[1
.. 2-a]-1.3.5-triazine-2.4
(3H)-dione 33. Og in hot ethanol 150m
1 and added 5 ml of concentrated hydrochloric acid. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 27.4 g of colorless crystals of the title compound.
融 点 251i−259℃(分解)核6R気共鳴ス
ペクトル(重水)
δ: 1.4−2.4 (8H,m) ,2.86(2
H,t),3.1−4.0(9H,m) ,4.37(
2.t) .7.30 (2}1,t) ,8.07
(2H,dd) .赤外吸収スペクトルν(KBr)
cm−’ :3450.2940.2510,1730
,1670, 1500,1480,1420.
元素分析Cz+lhsFN403・HCIとして計算値
(堀): C,57.73. H,6.00. N,1
2.82.実測値 (%): C,57.50. L5
.82. N,12.59参考例3
3− [2− [4− (4−フルオロベンゾイル)ビ
ベリジン−1−イル]エチル]−1i,7,8.9−テ
トラヒドロ−2H−ビリド[1.2−a ] トリアジ
ン− 2,4 (3}1)一ジオン マレイン酸塩上記
参考例1で得た3−[2 − [4 − (4−フルオ
ロベンゾイル)ビベリジン−1−イル]エチル]−6.
7,8.9−テトラヒドロ−2H−ビリド[1.2−a
] トリアジン−2.4 (3}1)一ジオン2.0
gをメタノール50mlに溶解しマレイン酸0.58
gを加えた。溶媒を減圧濃縮し析出した結晶を濾取し、
90%含水エタノールから再結晶して表題化合物の無色
結晶1..27gを得た。Melting point 251i-259℃ (decomposition) Nuclear 6R gas resonance spectrum (heavy water) δ: 1.4-2.4 (8H, m), 2.86 (2
H, t), 3.1-4.0 (9H, m), 4.37 (
2. t). 7.30 (2}1,t) ,8.07
(2H, dd). Infrared absorption spectrum ν (KBr)
cm-' :3450.2940.2510,1730
, 1670, 1500, 1480, 1420. Calculated value as elemental analysis Cz+lhsFN403/HCI (Hori): C, 57.73. H, 6.00. N,1
2.82. Actual value (%): C, 57.50. L5
.. 82. N, 12.59 Reference Example 3 3-[2-[4-(4-fluorobenzoyl)biveridin-1-yl]ethyl]-1i,7,8.9-tetrahydro-2H-pyrido[1.2-a ] Triazine-2,4 (3}1) monodione maleate 3-[2-[4-(4-fluorobenzoyl)biveridin-1-yl]ethyl]-6 obtained in Reference Example 1 above.
7,8.9-tetrahydro-2H-pyride [1.2-a
] Triazine-2.4 (3}1)-dione 2.0
Dissolve g in 50 ml of methanol to obtain 0.58 maleic acid.
g was added. The solvent was concentrated under reduced pressure and the precipitated crystals were collected by filtration.
Recrystallization from 90% aqueous ethanol gave colorless crystals of the title compound.1. .. 27g was obtained.
融 点 180−183℃(分解)
核6n気共鳴スペクトル(ジメチルスルホキシドーda
) δ: 1.6−2.1 (8H,m) ,2.
71 (2}1,t) ,2.9−3.4?.5−3.
8(5}1m).4.12(2H,m).6.06(2
H,s),7.39(2H.t),a.to(zH,d
d)
赤外吸収スペクトルν(κBr) cm−’ :344
8.1734,1677,1596,1494.145
5元素分析C2■H2SFN403・C4H.04とし
て計算値(幻: C,58.13; }!.5.66.
N,10.85.実測値昧): C,58.28.
}1,5.64; N,10.87。Melting point 180-183℃ (decomposition) Nuclear 6n gas resonance spectrum (dimethyl sulfoxide da
) δ: 1.6-2.1 (8H, m), 2.
71 (2}1,t) ,2.9-3.4? .. 5-3.
8(5}1m). 4.12 (2H, m). 6.06 (2
H,s), 7.39 (2H.t), a. to(zH,d
d) Infrared absorption spectrum ν(κBr) cm-': 344
8.1734, 1677, 1596, 1494.145
Five element analysis C2■H2SFN403・C4H. Calculated value as 04 (phantom: C, 58.13; }!.5.66.
N, 10.85. Actual measurement value: C, 58.28.
}1,5.64; N,10.87.
参考例4
3− [2− [4− (4−フルオロベンゾイル)ピ
ベリジン−1−イル]エチル]−7.8−ジヒドロ−2
8,6H−ピロロ[1.2−a ]−1.3.5−トリ
アジン−2.4(3H) 一ジオン
(1) 7.8−ジヒドロー2}1.6H−ピロロ[1
.2−a ] −1.3.5 −トリアジン−2.4(
3H) 一ジオン参考例1(l)と同様にして2−イミ
ノピロリジン塩酸塩とフェノキシカルボニルイソシアネ
ートから表題化合物の無色結晶を得た.
融点 201−202℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 2.87 (2n,t) .2.07 (zo.
t) ,3.82 (2H.t) .11.25 (1
}1,bs) .
赤外吸収スペクトルυ(KBr) crn−’ :34
30.3210,3080.1?40,1710.18
90,1630,1440,1410.
元素分析(:6}1?N302として
計算値(!k): C,47.06. H,4.61.
N,27.44.実測値C’4”): C,47.1
5; H,4.40; N,27.33.(2)3−
[2− (4−(4−フルオロベンゾイル)ピベリジン
−1−イル]エチル]−7.8−ジヒドロ−2H,BH
−ピロロ[1.2−al−1.3.5 − }−リアジ
ン−2.4(3H)一ジオン
参考例4(l)で得た7.8−ジヒドロー28,6}1
−ビロロ(1.2−al −1.3.5−トリアジン
−2.4(3H)シオンと4−(4−フルオロベンゾイ
ル)−1一(2−ヒドロキシエチル)ピベリジンを参考
例1(2)に記載した方法と同様にしてN,N−ジメチ
ルホルムアミド中、トリフェニルホスインとアゾジカル
ボン酸ジエチルエステルを用いて縮合し、カラメル状の
表題化合物を得た。Reference Example 4 3-[2-[4-(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7.8-dihydro-2
8,6H-pyrrolo[1.2-a]-1.3.5-triazine-2.4(3H) monodione (1) 7.8-dihydro2}1.6H-pyrrolo[1
.. 2-a]-1.3.5-triazine-2.4(
3H) Monodione Colorless crystals of the title compound were obtained from 2-iminopyrrolidine hydrochloride and phenoxycarbonyl isocyanate in the same manner as in Reference Example 1(l). Melting point 201-202℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 2.87 (2n, t). 2.07 (zo.
t), 3.82 (2H.t). 11.25 (1
}1, bs). Infrared absorption spectrum υ (KBr) crn-': 34
30.3210,3080.1?40,1710.18
90, 1630, 1440, 1410. Elemental analysis (:6}1? Calculated value (!k) as N302: C, 47.06. H, 4.61.
N, 27.44. Actual measurement value C'4"): C, 47.1
5; H, 4.40; N, 27.33. (2) 3-
[2-(4-(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7.8-dihydro-2H,BH
-pyrrolo[1.2-al-1.3.5-}-riazine-2.4(3H) monodione 7.8-dihydro28,6}1 obtained in Reference Example 4(l)
-Virolo(1.2-al-1.3.5-triazine-2.4(3H)ion and 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piveridine in Reference Example 1(2) Condensation was carried out using triphenylphosine and azodicarboxylic acid diethyl ester in N,N-dimethylformamide in the same manner as described in , to obtain the caramel-like title compound.
核磁気共鳴スペクトル(重クロロホルム)δ :
1.7−1.9(4H,m),2.1−2.5(4H,
m),2.68(2}1.t).2.9−3.4(5H
,m).4.05 (4H,t−1ike) ,7.1
2 (2}1,t) .7.95(2}1,dd).
参考例5
3− [2− [4− (4−フルオロベンゾイル)ピ
ベリジン−1−イル]エチル]−7.8−ジヒドロ−2
8.8H−ピロO [1.2−a]−1.3.5 −
}リアジン−2.4(3H)一ジオン 塩酸塩1/2水
和物上記参考例4(2)で製した3− [2− [4−
(4−フルオロベンゾイル)ピベリジン−1−イル]エ
チル]−7.8−ジヒドロー28,6H−ピロロ[1.
2−a]−1.3.5 − トリアジン−2.4(3H
)一ジオン2.95gをメタノール50mlに溶解して
濃塩酸2mlを加えた後、減圧乾固した.残渣をエタノ
ールから結晶化し、表題化合物の無色粉末2.30gを
得た。Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.7-1.9 (4H, m), 2.1-2.5 (4H,
m), 2.68(2}1.t). 2.9-3.4 (5H
, m). 4.05 (4H, t-1ike) ,7.1
2 (2}1,t). 7.95 (2}1, dd). Reference Example 5 3-[2-[4-(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7.8-dihydro-2
8.8H-PyroO [1.2-a]-1.3.5-
}Ryazine-2.4(3H) monodione hydrochloride hemihydrate 3-[2-[4-
(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7,8-dihydro28,6H-pyrrolo[1.
2-a]-1.3.5-triazine-2.4(3H
) 2.95 g of dione was dissolved in 50 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was dried under reduced pressure. The residue was crystallized from ethanol to obtain 2.30 g of the title compound as a colorless powder.
融点 253−255℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 1.8−2.3 (6H.m) .2.91 (
2H.t) .3.0−3.5(4H,m),3.5−
4.0(5H,m).4.16(2H,t),7.37
(2H,t),8.09(2H,dd),10.68
(1}1,b) .
赤外吸収スペクトルν(KBr) am−’ :35B
0,2940,2510, 1730.1680. 1
630,1480,1450,1420.
元素分析CzoH23FN401HCl4/2H20と
して計算値C9g): C,55.62. H,5.8
3; N,12.97.実測値(!k): C,55.
69. H,5−.80. N,12.83.参考例6
3− [2− [4− (4−フルオロベンゾイル〉ピ
ベリジン−1−イル]エチル] −7.8.9.10−
テトラヒドロ−28,6H −1.3.5 −}−リア
ジノ〔l,2−al アゼピン−2.4(3H)一シオ
ン(1) 7,I1,9.10−テトラヒドロー28,
6}! −1.3.5−トリアジノ[1 . 2−a]
アゼビン−2.4(3H) 一ジオン1水和物
参考例1(l)の方法と同様にして3,4,5.8−テ
トラヒドロー7−アミノー2H−アゼピン塩酸塩とフェ
ノキシカルボニルイソシアナートから表題化合物の無色
粉末を得た。Melting point 253-255℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1.8-2.3 (6H.m). 2.91 (
2H. t). 3.0-3.5 (4H, m), 3.5-
4.0 (5H, m). 4.16 (2H, t), 7.37
(2H, t), 8.09 (2H, dd), 10.68
(1}1,b). Infrared absorption spectrum ν (KBr) am-': 35B
0,2940,2510, 1730.1680. 1
630, 1480, 1450, 1420. Elemental analysis Calculated value as CzoH23FN401HCl4/2H20 C9g): C, 55.62. H, 5.8
3; N, 12.97. Actual value (!k): C, 55.
69. H, 5-. 80. N, 12.83. Reference Example 6 3- [2- [4- (4-fluorobenzoyl>piveridin-1-yl]ethyl] -7.8.9.10-
Tetrahydro-28,6H -1.3.5-}-riadino[l,2-al azepine-2.4(3H)monosion (1) 7,I1,9.10-tetrahydro28,
6}! -1.3.5-triazino[1. 2-a]
Azevin-2.4 (3H) monodione monohydrate The title was obtained from 3,4,5.8-tetrahydro-7-amino-2H-azepine hydrochloride and phenoxycarbonyl isocyanate in the same manner as in Reference Example 1 (l). A colorless powder of the compound was obtained.
融 点 157−158 ℃
核磁気共鳴スペクトル(重クロロホルム)δ: 1.7
(6H,m) ,2.8 (21{,m)4.0(2
}1,m),11.0(LH,bS) .赤外吸収スペ
クトルν(KBr) cm−’ :3520.3200
−2800.1730,1670, 1600 ,14
80,1420.
元素分析CaH+ lFN302・H20として計算値
(%;): C,4B.24. H,6.58; N,
21.09.実測値<94): C,48.33. H
,6.42; N,21.02.(2)3− [2−
[4− (4−フルオロベンゾイル)ビベリジン−1−
イルコエチル] −7.8,9.10−テトラヒドロ−
2}1,6H −1.3.5 − トリアジノ[1 ,
2−al アゼビン−2,4(3}1) 一ジオン上
記参考例6(1)で製した7,8,9.10−テトラヒ
ドロー2}!,8H − トリアジノ[1 . 2−a
] アゼビン−2,4(3H) 一ジオンと4−(4
−フルオロベンゾイル)−1−(2−ヒドロキシエチル
)ビペリジンを参考例1(2)と同様にしてN,N−ジ
メチルホルムアよド中、トリフェニルホスフィンとアゾ
ジカルボン酸ジエチルエステルを用いて縮合し表題化合
物の無色結晶を得た。Melting point 157-158 ℃ Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.7
(6H,m) ,2.8 (21{,m)4.0(2
}1, m), 11.0 (LH, bS). Infrared absorption spectrum ν (KBr) cm-': 3520.3200
-2800.1730,1670, 1600,14
80,1420. Elemental analysis CaH+ IFN302・H20 Calculated value (%;): C, 4B. 24. H, 6.58; N,
21.09. Actual value <94): C, 48.33. H
, 6.42; N, 21.02. (2) 3- [2-
[4-(4-fluorobenzoyl)viveridin-1-
ylcoethyl] -7.8,9.10-tetrahydro-
2}1,6H-1.3.5-triazino[1,
2-al Azevin-2,4(3}1) One dione 7,8,9.10-tetrahydro2} produced in Reference Example 6(1) above! , 8H-triazino[1. 2-a
] Azevin-2,4(3H) monodione and 4-(4
-fluorobenzoyl)-1-(2-hydroxyethyl)biperidine was condensed using triphenylphosphine and azodicarboxylic acid diethyl ester in N,N-dimethylformade in the same manner as in Reference Example 1(2). Colorless crystals of the compound were obtained.
融 点 130−132 ℃
核磁気共鳴スペクトル(重クロロホルム)δ: 1.8
−2.0 (10}1,m) ,2.0−2.4 (2
H.m) ,2.69 (2H,t) ,3.0−3.
3 (38,m) ,4.0−4.2(4H,m),7
.13(2H,t).7.95 (2H,dd) .
赤外吸収スペクトルν(κBr) cm−’ :344
0,2950,1725,1670.1800,147
0,1440.
参考例7
3− [2− [4− (4−フルオロベンゾイル)ビ
ベリジン−1−イルコエチルコー7.8,9.10−テ
トラヒドロ−28,6H −1.3.5 − トリアジ
ノ[1.2一a] アゼピン−2.4(3H) 一ジオ
ンニ塩酸塩上記参考例6で得た3− [2− [4−
(4−フルオロベンゾイル)ビペリジン−1−イル]エ
チル]−7.8,9.10−テトラヒドロ−28,8H
−1.3.5?トリアジノ[1 . 2−a] アゼ
ピン−2.4(3H) 一ジオン3.83gをメタノ
ール50mlに溶解し、濃塩酸1.6mlを加えた後、
減圧乾固した。エタノールを加えて数回減圧濃縮後、エ
タノールとイソブロビルエーテルの混液から結晶化し、
表題化合物の無色粉末3.70gを得た。Melting point: 130-132°C Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.0 (10}1,m) ,2.0-2.4 (2
H. m), 2.69 (2H, t), 3.0-3.
3 (38, m), 4.0-4.2 (4H, m), 7
.. 13 (2H, t). 7.95 (2H, dd). Infrared absorption spectrum ν(κBr) cm-': 344
0,2950,1725,1670.1800,147
0,1440. Reference Example 7 3-[2-[4-(4-fluorobenzoyl)viveridin-1-ylcoethylco7.8,9.10-tetrahydro-28,6H-1.3.5-triazino[1.21a] Azepine-2.4(3H) monodione dihydrochloride 3-[2-[4-
(4-fluorobenzoyl)biperidin-1-yl]ethyl]-7.8,9.10-tetrahydro-28,8H
-1.3.5? Triazino [1. 2-a] Dissolve 3.83 g of azepine-2.4 (3H) dione in 50 ml of methanol, add 1.6 ml of concentrated hydrochloric acid,
It was dried under reduced pressure. After adding ethanol and concentrating under reduced pressure several times, it was crystallized from a mixture of ethanol and isobrobyl ether.
3.70 g of the title compound was obtained as a colorless powder.
融 点 172−176 ℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd,)
δ: L.S−2.2 (10N,m) ,2.8 (
2H,m) ,3.0−3.5 (4H,m) ,3.
5−3.9 (3H,+n) ,4.0−4.2 (4
H,m) y7.37 (2H,t) ,8.12(2
H,dd) .11.0(1}1,b) .赤外吸収ス
ペクトルv (KBr) cm−’ :3450,29
40,2360,1770,1725.1680,16
10,1580,1450,1430.1230元素分
析C2■H27FN403・2HG:1として計算値(
96): C,54.21; H,8.00; N,1
1.50.実測値(!t;)+ C,54.12; H
,6.33; N 11.42.参考例8
3− [3−[4− (4−フルオロベンゾイル)ビベ
リジン−1−イル)プロビルコー6.7,8.9テトラ
ヒドロ−2H−ビリド[1.2−a]−1.3.5−ト
リアジン−2.4(3H) 一シオン
上記参考例1(l)で得た6.7,8.9−テトラヒド
ロー2H−ピリド[l,2−a] −1.3.5 −
トリアジン−2.4(3}1)一ジオンと4−(4−フ
ルオロベンゾイル)−1−(3−ヒドロキシプロビル)
ピベリジンを参考例1(2)と同様にしてN,N−ジメ
チルホルムアミド中、トリフェニルホスフィンとアゾジ
カルボン酸ジエチルエステルを用いて縮合し、表題化合
物を得た。Melting point 172-176 ℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d,)
δ: L. S-2.2 (10N, m) ,2.8 (
2H, m), 3.0-3.5 (4H, m), 3.
5-3.9 (3H, +n) ,4.0-4.2 (4
H, m) y7.37 (2H, t) ,8.12 (2
H, dd). 11.0(1}1,b). Infrared absorption spectrum v (KBr) cm-': 3450,29
40,2360,1770,1725.1680,16
10,1580,1450,1430.1230 Elemental analysis C2 H27FN403/2HG: Calculated value (
96): C, 54.21; H, 8.00; N, 1
1.50. Actual value (!t;) + C, 54.12; H
, 6.33; N 11.42. Reference Example 8 3-[3-[4-(4-fluorobenzoyl)biveridin-1-yl)probilco6.7,8.9tetrahydro-2H-pyrido[1.2-a]-1.3.5- Triazine-2.4(3H) monosion 6.7,8.9-tetrahydro 2H-pyrido [l,2-a] -1.3.5 - obtained in Reference Example 1(l) above
Triazine-2.4(3}1) monodione and 4-(4-fluorobenzoyl)-1-(3-hydroxyprobyl)
Piveridine was condensed with triphenylphosphine and azodicarboxylic acid diethyl ester in N,N-dimethylformamide in the same manner as in Reference Example 1(2) to obtain the title compound.
核磁気共喝スペクトル(重クロロホルム)δ: 1.5
−2.1 (12H,m) .2.50 (2H, t
) ,2.7−3.1 (4H,m) ,3.2 (I
H,m) ,3.85 (2H,t) ,4.02 (
2H,t) ,7.13 (2H,t)7.95 (2
}1,dd) .
参考例9
3− [3− [4− (4−フルオロベンゾイル)ビ
ベリジン−1−イル]ブロビル] −6.7,8.9
−テトラヒドロ−2H−ビリド[1.2−a] −1.
3.5 −トリアジン−2.4(3}1)一ジオン マ
レイン酸塩1/2水和物
上記参考例8で得た3− [2− [4− (4−フル
オロベンゾイル)ビベリジン−1−イル]プロピルコー
6.7,8.9−テトラヒドロ−2H−ビリド[1,2
−al −1.3.5 −トリアジン−2.4(3}1
) 一ジオン0.76gを熱エタノール100 mlに
溶解しマレイン酸0.21 gを加えた。冷却し析出し
た結晶を濾取し、エタノールより再結晶して表題化合物
の無色結晶0.42gを得た。Nuclear magnetic coexcitation spectrum (deuterochloroform) δ: 1.5
-2.1 (12H, m). 2.50 (2H, t
) ,2.7-3.1 (4H,m) ,3.2 (I
H, m) ,3.85 (2H,t) ,4.02 (
2H,t) ,7.13 (2H,t)7.95 (2
}1, dd). Reference Example 9 3- [3- [4- (4-fluorobenzoyl) biveridin-1-yl] brovyl] -6.7, 8.9
-Tetrahydro-2H-pyrid [1.2-a] -1.
3.5-triazine-2.4(3}1) monodione maleate hemihydrate 3-[2-[4-(4-fluorobenzoyl)viveridine-1-] obtained in Reference Example 8 above yl]propylco6.7,8.9-tetrahydro-2H-pyrido[1,2
-al -1.3.5 -triazine-2.4(3}1
) 0.76 g of dione was dissolved in 100 ml of hot ethanol, and 0.21 g of maleic acid was added. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 0.42 g of colorless crystals of the title compound.
融点 87−89℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: L.S−2.2 (10}1,m) ,2.70
(2H, t) ,2.9−3.3 (4H,m)
.3.4−4 .0 (7H,m) ,6.04 (2
H,s) .7.39 (2H,t) ,8.10(2
}1.dd) .
赤外吸収スペクトルν(κBr) cm−’ :345
0,2970,1730,.1880.1600,14
90.元素分析C22H27FN403・C4H40.
・1/2H20として計算値(U: C,57.88.
H,5.98; N,10.38.実測値情): C
,57.50. H,6.30. N,10.18.参
考例10
3− [2− [ 4− (4−フルオロベンゾイル)
一4−ヒドロキシピペリジン−1−イル]エチル]−6
.7,8.9−テトラヒドロ−2H−ピリド[1。2−
a] −1.3.5 − トリアジン−2.4(3}1
) 一ジオン上記参考例1(1)で得た8,7,8.9
−テトラヒドロー2H−ピリド[1.2−a] −1.
3.5 − トリアジン−2,4(3}1)一ジオンと
4−(4−フルオロベンゾイル)−4−ヒドロキシ−1
−(2−ヒドロキシエチル)ビベリジンを参考例1(2
)と同様にしてN.N−ジメチルホルムアミド中、トリ
フエニルホスフィンとアゾジカルボン酸ジエチルエステ
ルを用いて縮合し、表題化合物の無色結晶を得た。Melting point 87-89℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: L. S-2.2 (10}1,m) ,2.70
(2H, t) , 2.9-3.3 (4H, m)
.. 3.4-4. 0 (7H, m) ,6.04 (2
H,s). 7.39 (2H,t) ,8.10(2
}1. dd). Infrared absorption spectrum ν(κBr) cm-': 345
0,2970,1730,. 1880.1600,14
90. Elemental analysis C22H27FN403/C4H40.
・Calculated value as 1/2H20 (U: C, 57.88.
H, 5.98; N, 10.38. Actual measurement information): C
, 57.50. H, 6.30. N, 10.18. Reference example 10 3- [2- [ 4- (4-fluorobenzoyl)
-4-hydroxypiperidin-1-yl]ethyl]-6
.. 7,8.9-tetrahydro-2H-pyrido[1.2-
a] -1.3.5 - triazine-2.4(3}1
) Dione 8,7,8.9 obtained in Reference Example 1(1) above
-Tetrahydro2H-pyrido [1.2-a] -1.
3.5-triazine-2,4(3}1) monodione and 4-(4-fluorobenzoyl)-4-hydroxy-1
-(2-hydroxyethyl)viveridine in Reference Example 1 (2)
) in the same way as N. Condensation was carried out using triphenylphosphine and azodicarboxylic acid diethyl ester in N-dimethylformamide to obtain colorless crystals of the title compound.
融点 217−220℃
核磁気共鳴スペクトル(重クロロホルム)δ: 1.6
−2.0 (8M,m) .2.3−2.7 (81{
,m) .3.68 (2H,t) .3.87 (2
H, t) .5.68 (IH,s) ,7.28(
2H,t) ,8.24 (2H,dd) .赤外吸収
スペクトルν(κBr) cm−’ :3450,29
50,1730,1670.160Q,1490,14
50,1410.
参考例11
3− [2− [4− (4−フルオロベンゾイル)−
4−ヒドロキシビベリジン−1−イル]エチル]−6.
7,8.9−テトラヒドロ−2H−ピリド[1.2−a
]−1.3.5−トリアジン−2.4(3H) 一ジオ
ン二塩酸塩1/2水和物
上記参考例10で得た3− [2− (4− (4−フ
ルオロベンゾイル)−4−ヒドロキシピペリジン−1−
イルコエチルコー6.7,8.9−テトラヒドロ−2H
−ピリド(1.2−al −1.3.5 − トリアジ
.ンー2 .4 (311) 一ジオン0.80gをメ
タノール30mlに溶解して濃塩酸0.4 mlを加え
た後、減圧濃縮した。Melting point 217-220℃ Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.6
-2.0 (8M, m). 2.3-2.7 (81{
,m). 3.68 (2H, t). 3.87 (2
H, t). 5.68 (IH,s) ,7.28(
2H, t) , 8.24 (2H, dd) . Infrared absorption spectrum ν(κBr) cm-': 3450,29
50,1730,1670.160Q,1490,14
50,1410. Reference example 11 3- [2- [4- (4-fluorobenzoyl)-
4-hydroxybiveridin-1-yl]ethyl]-6.
7,8.9-tetrahydro-2H-pyrido [1.2-a
]-1.3.5-triazine-2.4(3H) monodione dihydrochloride hemihydrate 3-[2-(4-(4-fluorobenzoyl)-4 obtained in Reference Example 10 above) -Hydroxypiperidine-1-
Ilcoethylco6.7,8.9-tetrahydro-2H
-Pyrido(1.2-al-1.3.5-triazine-2.4 (311)) 0.80 g of dione was dissolved in 30 ml of methanol, 0.4 ml of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. .
残漬にエタノールを加えて減圧濃縮を繰り返して析出し
た結晶を濾取、アセトンで洗浄し表題化合物の無色結晶
0.68gを得た。Ethanol was added to the residue and concentration under reduced pressure was repeated, and the precipitated crystals were collected by filtration and washed with acetone to obtain 0.68 g of colorless crystals of the title compound.
融点 178−184℃
核磁気共鳴スペクトル(ジメチルスルホキシドー66)
δ: 1.6−2.4(B}I.m) ,2.7(2}
1,t) ,3.0−3.6(6H,m).3.73(
2}1,t),4.1 (2H,t) ,7.2−7.
5 (3H,m) ,8.77(2}1,dd),11
.0(IH.b).赤外吸収スペクトルν(KBr)
cm−’ :3410,3220,2550,1780
,1730,1680,1610,1580,1440
.
元素分析C2+HzsFN404・2Hcl4/2H2
0として計算値(”4): C,50.60; H,5
。aa; N,1.1.24.実測値(U: C,50
.88; H,5.81; N,10.87.参考例1
2
3− [2 − [4 − (4−フルオロベンゾイル
)一4−フェニルピベリジン−1−イル]エチル]一6
.7,8.9−テトラヒドロ−2H−ピリド[1.2−
al−1.3.5−トリアジン−2.4(38)一ジオ
ン参考例1(1)で得た6,7,8.9−テトラヒドロ
−2H−ピリド[1.2−a] −1.3.5 − ト
リアジン−2.4(3H)一ジオンと4−(4−フルオ
ロベンゾイル)−4−フェニルー1−(2−ヒドロキシ
エチル)ビベリジンを参考例1(2)と同様にしてN,
N−ジメチルホルムアミド中、トリフェニルホスフィン
とアゾジカルボン酸ジエチルエステルを用いて縮合し、
表題化合物の油状物を得た。Melting point 178-184℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide 66)
δ: 1.6-2.4(B}I.m), 2.7(2}
1,t), 3.0-3.6(6H,m). 3.73(
2}1, t), 4.1 (2H, t), 7.2-7.
5 (3H, m), 8.77 (2}1, dd), 11
.. 0 (IH.b). Infrared absorption spectrum ν (KBr)
cm-': 3410, 3220, 2550, 1780
, 1730, 1680, 1610, 1580, 1440
.. Elemental analysis C2+HzsFN404・2Hcl4/2H2
Calculated value as 0 (“4): C, 50.60; H, 5
. aa; N, 1.1.24. Actual value (U: C, 50
.. 88; H, 5.81; N, 10.87. Reference example 1
2 3- [2-[4-(4-fluorobenzoyl)-4-phenylpiveridin-1-yl]ethyl]-6
.. 7,8.9-tetrahydro-2H-pyrido[1.2-
al-1.3.5-triazine-2.4(38) monodione 6,7,8.9-tetrahydro-2H-pyrido[1.2-a]-1 obtained in Reference Example 1(1). 3.5-triazine-2.4(3H) monodione and 4-(4-fluorobenzoyl)-4-phenyl-1-(2-hydroxyethyl)viveridine were treated with N,
condensation using triphenylphosphine and azodicarboxylic acid diethyl ester in N-dimethylformamide,
The title compound was obtained as an oil.
核磁気共鳴スペクトル(重クロロホルム)δ: 1.8
−2.9 (161{,m) ,3.8 (2H,t−
1ike) ,4.03 (2}1,t) ,6.89
(2H,t) ,7.26−7.48 (7H,m)
.参考例13
3− [2− [4− (4−フル才ロベンゾイル)−
4−フェニルビベリジン−1−イル]エチル]−6.7
,8.9−テトラヒドロ−2H−ピリド[1 . 2−
a]−1.3.5 − トリアジン−2 .4 (3H
) 一ジオンニ塩酸塩172永和物
上記参考例12で得た3− (2− [4− (4−フ
ルオロベンゾイル)−4−フェニルビベリジン−1−イ
ル]エチル]−6.7,8.9−テトラヒドロ−2H−
ビリド[1.2−a] −1.3.5 − トリアジン
−2.4 (3H)一ジオン0.75gをメタノール3
0mlに溶解して濃塩酸0.3 mlを加えた後、減圧
濃縮した。Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.9 (161{,m) ,3.8 (2H,t-
1ike) ,4.03 (2}1,t) ,6.89
(2H, t) , 7.26-7.48 (7H, m)
.. Reference Example 13 3- [2- [4- (4-fluorobenzoyl)-
4-phenylbiveridin-1-yl]ethyl]-6.7
, 8.9-tetrahydro-2H-pyrido [1. 2-
a]-1.3.5-triazine-2. 4 (3H
) Monodione dihydrochloride 172 elongated product 3-(2-[4-(4-fluorobenzoyl)-4-phenylbiveridin-1-yl]ethyl]-6.7,8. 9-tetrahydro-2H-
Virid[1.2-a]-1.3.5-triazine-2.4 (3H) monodione 0.75g methanol 3
After dissolving the solution in 0.0 ml and adding 0.3 ml of concentrated hydrochloric acid, the mixture was concentrated under reduced pressure.
残漬にエタノールを加えて減圧濃縮を繰り返した。残漬
をメタノールとエタノールの混液より再結晶して表題化
合物の無色粉末0.52gを得た。Ethanol was added to the residue and vacuum concentration was repeated. The residue was recrystallized from a mixture of methanol and ethanol to obtain 0.52 g of the title compound as a colorless powder.
融点 203−210℃
核磁気共鳴スペクトル(ジメチルスルホキシーd6)δ
: 1.6−2.0 (4H,m) ,2.4−3.1
(8}1,m) ,3.3 (2H,m) ,3.5
−3.7 (4H,m) ,4.1 (2H,t) .
7.1−7.7 (9H,m)11.2 (IH,b)
.
赤外吸収スペクトルν(KBr) c『’ :3410
,2960.2490.1770,1730,1680
,1[i20,1580,1500,1440.元素分
析C27H29FN40,・2}1et・1/2H20
として計算値(利: C,58.07; H,5.77
; N,10.03.実測値(*)+ C,58.28
. H,6.04. N. 9.70ド
参考例14
3− [2− (4− (4−フルオロベンゾイル)ビ
ペリジン−1−イル]エチル]−2H−ビリド[1.2
−a]−1.3.5−トリアジン−2.4(3H)
一ジオンニ塩酸塩
2H−ピリド[1.2−al−1.3.5−トリアジン
ー2.4(3H) 一ジオン0.42g,4−(4−
フルオロベンゾイル)−1−(2−ヒドロキシエチル)
ビベリジン0.67 gとトリフエニルホスフィン0.
82gをN,N−ジメチルホルムアミド10mlに懸濁
し、アゾジカルボン酸ジエチルエステル0.54gを滴
下した。室温で75分攪拌後、反応液を減圧乾固し、残
渣をエタノールから結晶化した。濾取後、表題化合物の
塩基0.7gを得た。得られた結晶をエタノール30m
lに溶解し、塩酸0.2 mlを加えて減圧濃縮後、析
出物を濾取し、表題化合物の無色粉末0.27gを得た
。Melting point 203-210℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxy d6) δ
: 1.6-2.0 (4H, m), 2.4-3.1
(8}1,m) ,3.3 (2H,m) ,3.5
-3.7 (4H, m), 4.1 (2H, t).
7.1-7.7 (9H, m) 11.2 (IH, b)
.. Infrared absorption spectrum ν(KBr) c′′ :3410
,2960.2490.1770,1730,1680
, 1 [i20, 1580, 1500, 1440. Elemental analysis C27H29FN40,・2}1et・1/2H20
Calculated value as (interest: C, 58.07; H, 5.77
; N, 10.03. Actual value (*) + C, 58.28
.. H, 6.04. N. 9.70 Reference Example 14 3-[2-(4-(4-fluorobenzoyl)biperidin-1-yl]ethyl]-2H-pyrido[1.2
-a]-1.3.5-triazine-2.4(3H)
monodione dihydrochloride 2H-pyrido[1.2-al-1.3.5-triazine-2.4(3H) monodione 0.42 g, 4-(4-
Fluorobenzoyl)-1-(2-hydroxyethyl)
0.67 g of viveridine and 0.67 g of triphenylphosphine.
82 g was suspended in 10 ml of N,N-dimethylformamide, and 0.54 g of azodicarboxylic acid diethyl ester was added dropwise. After stirring at room temperature for 75 minutes, the reaction solution was dried under reduced pressure, and the residue was crystallized from ethanol. After filtering, 0.7 g of the base of the title compound was obtained. The obtained crystals were mixed with 30 m of ethanol.
After adding 0.2 ml of hydrochloric acid and concentrating under reduced pressure, the precipitate was collected by filtration to obtain 0.27 g of the title compound as a colorless powder.
融 点 243−244℃(分解)
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 1.8−2.2 (4H,m) ,2.88−3
.97 (7H,m) ,4.38(2Lt),7.1
−7.5(4H,m)8.0−8.3(3H,m),8
.[i9(IH,d).11.02(IH,bS).赤
外吸収スペクトルν(KBr) cm−’ :3430
.2700−2200,・1730,1680,164
0,1590,1560,1440,1410.元素分
析C21H21FN40・2HC]として計算値(1;
): C,53.74; H,4.94. N,11.
94.実測値<96>: C,53.39. H,4.
83. N,11.83、参考例15
3− [2− [4− (4−フルオロベンゾイル)ー
ビベリジン−1−イル]エチル]−2}1−チアゾロ[
3.2−a] −1.3.5 − トリアジン−2.4
(31{)一ジオン
2H−チアゾロ[3.2−a] −1.3.5 − ト
リアジン−2.4(3H) 一ジオン1.69g,4−
(4−フルオロベンゾイル)−1−(2−ヒドロキシ
ェチル)ピベリジン2.51gとトリフェニルホスフィ
ン2.89gをN,N−ジメチルホルムアミド40ml
に懸濁し、水冷攪拌下アゾジカルボン酸ジエチルエステ
ル1.92gを滴下した。室温で30分攪拌後、反応液
を減圧乾固し、残漬に酢酸エチルを加えて濾取し、表題
化合物の無色結晶3.0gを得た。Melting point 243-244℃ (decomposed) Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1.8-2.2 (4H, m), 2.88-3
.. 97 (7H, m), 4.38 (2Lt), 7.1
-7.5 (4H, m) 8.0 - 8.3 (3H, m), 8
.. [i9(IH, d). 11.02 (IH, bS). Infrared absorption spectrum ν (KBr) cm-': 3430
.. 2700-2200, 1730, 1680, 164
0,1590,1560,1440,1410. Elemental analysis C21H21FN40・2HC] Calculated value (1;
): C, 53.74; H, 4.94. N, 11.
94. Actual value <96>: C, 53.39. H, 4.
83. N, 11.83, Reference Example 15 3-[2-[4-(4-fluorobenzoyl)-biveridin-1-yl]ethyl]-2}1-thiazolo[
3.2-a] -1.3.5 - triazine-2.4
(31{) monodione 2H-thiazolo[3.2-a] -1.3.5-triazine-2.4(3H) monodione 1.69 g, 4-
2.51 g of (4-fluorobenzoyl)-1-(2-hydroxyethyl)piveridine and 2.89 g of triphenylphosphine were added to 40 ml of N,N-dimethylformamide.
1.92 g of azodicarboxylic acid diethyl ester was added dropwise to the suspension under water-cooling and stirring. After stirring at room temperature for 30 minutes, the reaction solution was dried under reduced pressure, and ethyl acetate was added to the residue and collected by filtration to obtain 3.0 g of colorless crystals of the title compound.
融点 184−187℃
核磁気共鳴スペクトル(重クロロホルム)δ: 1.5
−1.9 (4H,m) ,2.2 (2H,m) ,
2.5 (28,m) .3.0 (2H,10) .
3.4 (IH,m) ,:l.!Is (2H,t)
,7.18<II{,d),7。34(2H,t)
,7.71(IH.d) ,8.05 (2o.da)
.
赤外吸収スペクトルv (KBr) cm−’ :34
50.307G,2940,2820,1750. 1
67G,1590.1550.
参考例16
3− [2− [4− (4−フルオロベンゾイル)ビ
ペリジン−1−イル]エチル]一2H−チアゾロ[3.
2−a] −1.3.5−トリアジン−2.4(3H)
一ジオン塩酸塩1/2水和物
上記参考例15で得た3− [2− [4− (4フル
オロベンゾイル)ピベリジン−1−イル]エチル]一2
H−チアゾロ[3.2−a]−1.3.5−トリアジン
−2.4(3}1) 一ジオン2.95gをメタノール
50[+11に懸濁し、濃塩酸2mlを加え、析出した
結晶を濾取し、少量のメタノールを含む熱水より再結晶
して表題化合物の無色粉末2.08gを得た。Melting point 184-187℃ Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.5
-1.9 (4H, m) , 2.2 (2H, m) ,
2.5 (28, m). 3.0 (2H, 10).
3.4 (IH, m) , :l. ! Is (2H, t)
,7.18<II{,d),7.34(2H,t)
,7.71 (IH.d) ,8.05 (2o.da)
.. Infrared absorption spectrum v (KBr) cm-': 34
50.307G, 2940, 2820, 1750. 1
67G, 1590.1550. Reference Example 16 3-[2-[4-(4-fluorobenzoyl)biperidin-1-yl]ethyl]-2H-thiazolo[3.
2-a]-1.3.5-triazine-2.4(3H)
Monodione hydrochloride hemihydrate 3-[2-[4-(4fluorobenzoyl)piveridin-1-yl]ethyl]-2 obtained in Reference Example 15 above
2.95 g of H-thiazolo[3.2-a]-1.3.5-triazine-2.4(3}1) monodione was suspended in methanol 50[+11], 2 ml of concentrated hydrochloric acid was added, and the crystals precipitated. was collected by filtration and recrystallized from hot water containing a small amount of methanol to obtain 2.08 g of the title compound as a colorless powder.
融 点 278−280℃(分解)
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 1 .Ii−2.2 (4}1,m) ,2.9
−3 .8 (7H,m) ,4.24 (2H,t)
,7.23 (IH,d) ,7.38 (2H,t
) .7.92 (IH,d) .8.11 (2H,
dd) .赤外吸収スペクトルν(KBr) cl”
:3/!70,1740,1670,1600,158
0,1550,1420.
元素分析 C+oH+aFN403S−}ICI・1
72H20として計算値(90 : C,50.95
. H,4.73 : N,12.51.実測値(96
) : C,51.29 . H,4.88 . N,
12.55.参考例17
3− [2− [4− [ビス(4−フルオロフェニル
)メチレン]ビベリジン−1−イル]エチル]−6.7
,8.9−テトラヒドロ−2}1− [1.2−8]
− 1.3.5−トリアジン−2.4(3H) 一ジオ
ン参考例1(l)で得た6,7,8.9−テトラヒドロ
ー2}1− [1.2−a] − 1.3.5−トリア
ジン−2.4(3}1)シオン1.87g, 4 −
[ビス(4−フルオロフエニル)メチレン]−1−(2
−ヒドロキシエチル)ビベリジン3.64gとトリフェ
ニルホスフィン3.15gをN,N−ジメチルホルムア
くド50mlに溶解して水冷攪拌下アゾジカルボン酸ジ
エチルエステル2.1gを滴下した。30分間攪拌後、
溶媒を減圧留去し、残渣をシリカゲル・カラム(180
g)に付し、3%メタノール含有クロロホルムで溶出し
て表題化合物の黄色油状物1.38gを得た。Melting point 278-280℃ (decomposed) Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1. Ii-2.2 (4}1,m) ,2.9
-3. 8 (7H, m), 4.24 (2H, t)
,7.23 (IH,d) ,7.38 (2H,t
). 7.92 (IH, d). 8.11 (2H,
dd). Infrared absorption spectrum ν(KBr) cl”
:3/! 70, 1740, 1670, 1600, 158
0,1550,1420. Elemental analysis C+oH+aFN403S-}ICI・1
Calculated value as 72H20 (90: C, 50.95
.. H, 4.73: N, 12.51. Actual value (96
): C, 51.29. H, 4.88. N,
12.55. Reference Example 17 3-[2-[4-[bis(4-fluorophenyl)methylene]biveridin-1-yl]ethyl]-6.7
,8.9-tetrahydro-2}1- [1.2-8]
- 1.3.5-triazine-2.4(3H) monodione 6,7,8.9-tetrahydro 2}1-[1.2-a] obtained in Reference Example 1(l) - 1.3 .5-triazine-2.4(3}1)ion 1.87g, 4-
[Bis(4-fluorophenyl)methylene]-1-(2
3.64 g of (hydroxyethyl)viveridine and 3.15 g of triphenylphosphine were dissolved in 50 ml of N,N-dimethylformamide, and 2.1 g of azodicarboxylic acid diethyl ester was added dropwise to the solution under stirring while cooling with water. After stirring for 30 minutes,
The solvent was distilled off under reduced pressure, and the residue was purified using a silica gel column (180
g) and eluted with chloroform containing 3% methanol to obtain 1.38 g of the title compound as a yellow oil.
核磁気共鳴スペクトル(重クロロホルム)δ: 1.8
−2.0 (4}1,m) .2.3 (4}1,m)
,2.5−2.8 (8}1,m) .3.8 (2
}1,t) ,4.07 (2H.t) ,6.96
(4H,d) .7.04 (4H,s) .
参考例18
3− [2− [4− [ビス(4−フルオロフェニル
)メチレン]ピペリジン−1−イル]エチル]−8.7
,8.9−テトラヒドロ−2H−ピリド[1 . 2−
a]−1.3.5−トリアジン−2.4(3H)一ジオ
ンニ塩酸上記参考例17で得た3−[2−[4− [ビ
ス(4−フルオロフェニル)メチレン]ビベリジン−1
−イル]エチル]−6.7,8.9−テトラヒドロ−2
8−ビリド[1.2−al −1.3.5 −トリアジ
ン−2.4(3H) 一ジオン1.38gをメタノー
ル50mlに溶解して濃塩酸0.8 mlを加えて減圧
乾固した。残渣をメタノールとイソプロバノールの混液
より結晶化、次じ再結晶して表題化合物の無色粉末1。Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.0 (4}1,m). 2.3 (4}1, m)
,2.5-2.8 (8}1,m). 3.8 (2
}1,t) ,4.07 (2H.t) ,6.96
(4H, d). 7.04 (4H, s). Reference Example 18 3-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]-8.7
, 8.9-tetrahydro-2H-pyrido [1. 2-
a]-1.3.5-triazine-2.4(3H) monodione dihydrochloric acid 3-[2-[4-[bis(4-fluorophenyl)methylene]viveridin-1 obtained in Reference Example 17 above
-yl]ethyl]-6.7,8.9-tetrahydro-2
1.38 g of 8-pyrido[1.2-al-1.3.5-triazine-2.4(3H) monodione was dissolved in 50 ml of methanol, 0.8 ml of concentrated hydrochloric acid was added, and the mixture was dried under reduced pressure. The residue was crystallized from a mixture of methanol and isoprobanol and then recrystallized to give the title compound as a colorless powder 1.
03gを得た。03g was obtained.
融点 192−195℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 1.7−2.0 (4H,m) ,2.5−2.
9 (6H,m) ,3.0−3.4 (4H,m)
,3.5−3.8 (4H,m) ,4.19 (2}
1,t) ,7.18 (8H,d) ,9.85 (
IH,s) ,11.41 (IH,bs) .
赤外吸収スペクトルν(KBr) cm” :3450
.255G,1760, 1730,1620.151
0,1450.
元素分析 CayH2aFJ402・2}ICIとし
て計算値(k) : C,58.81 ; }1,5.
48 ; N,10.16.実測値(X) : (:,
58.85 ; H,5.74 ; N,10.11.
参考例19
3− [2− [4−[ビス(4−フルオロフェニル)
メチレンコピベリジン−1−イル]エチルコー7,8−
ジヒドロ−2H,6H−ピロロ[1 , 2−a]1,
3.5 − トリアジン−2 .4 (3H) 一ジオ
ン参考例4(1)で製した7.8−ジヒドロー28.6
H一ピロロ[1,2−al −1.3.5 − トリア
ジン−2.4(3}1)一ジオンと1−(2−ヒドロキ
シエチル)−4−[ビス(4−フルオロフェニル)メチ
レン]ピペリジンを参考例17と同様にしてN,N−ジ
メチルホルムアミド中、トリフェニルホスフィンとアゾ
ジカルボン酸ジエチルエステルを用いて縮合し、表題化
合物の油状物を得た。Melting point 192-195℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1.7-2.0 (4H, m), 2.5-2.
9 (6H, m), 3.0-3.4 (4H, m)
,3.5-3.8 (4H,m) ,4.19 (2}
1,t) ,7.18 (8H,d) ,9.85 (
IH,s), 11.41 (IH,bs). Infrared absorption spectrum ν (KBr) cm”: 3450
.. 255G, 1760, 1730, 1620.151
0,1450. Elemental analysis CayH2aFJ402.2} Calculated value as ICI (k): C, 58.81; }1,5.
48; N, 10.16. Actual measurement value (X): (:,
58.85; H, 5.74; N, 10.11.
Reference Example 19 3-[2-[4-[bis(4-fluorophenyl)
Methylenecopiveridin-1-yl]ethylco7,8-
dihydro-2H,6H-pyrrolo[1,2-a]1,
3.5-Triazine-2. 4 (3H) Monodione 7.8-dihydro prepared in Reference Example 4(1) 28.6
H-pyrrolo[1,2-al-1.3.5-triazine-2.4(3}1)-dione and 1-(2-hydroxyethyl)-4-[bis(4-fluorophenyl)methylene] Piperidine was condensed with triphenylphosphine and azodicarboxylic acid diethyl ester in N,N-dimethylformamide in the same manner as in Reference Example 17 to obtain the title compound as an oil.
核磁気共鳴スペクトル(重クロロホルム)δ: 2,.
2−2.5 (8H,m) ,2.5−2.8 (6}
1,m) .3.02 (2H,t) ,4.1 (4
8,m) ,6.99 (8H,m) .参考例20
3− [2− [4− [ビス(4−フルオロフェニル
)メチレンコビベリジン−1−イル]エチル]一7.8
−ジヒドロ−2}1,6H−ビロロ[1 , 2−al
l,3.5 − トリアジン−2.4(3}1) 一ジ
オン ニ塩酸塩
上記参考例19で得た3− [2− [4− [ビス(
4−フルオロフェニル)メチレン]ピペリジン−1−イ
ルコエチル]−7.8−ジヒドロ−28,6H−ビロロ
[1.2−al −1.3.5 − トリアジン− 2
.4(3H)一ジオン2.44gをメタノール50ml
に溶解して濃塩酸1+nlを加えて減圧乾固した。残漬
をメタノールとイソプロバノールの混7夜より結晶化、
次いで再結晶して表題化合物の無色粉末1、Ogを得た
。Nuclear magnetic resonance spectrum (deuterochloroform) δ: 2,.
2-2.5 (8H, m) ,2.5-2.8 (6}
1, m). 3.02 (2H,t) ,4.1 (4
8, m), 6.99 (8H, m). Reference Example 20 3-[2-[4-[bis(4-fluorophenyl)methylenecobiveridin-1-yl]ethyl]-7.8
-dihydro-2}1,6H-virolo[1,2-al
l,3.5-triazine-2.4(3}1) monodione dihydrochloride 3-[2-[4-[bis(
4-fluorophenyl)methylene]piperidin-1-ylcoethyl]-7.8-dihydro-28,6H-virolo[1.2-al-1.3.5-triazine-2
.. 2.44 g of 4(3H)-dione in 50 ml of methanol
1+nl of concentrated hydrochloric acid was added and the mixture was dried under reduced pressure. The residue was mixed with methanol and isoprobanol for 7 nights to crystallize.
Then, it was recrystallized to obtain the title compound as a colorless powder 1, Og.
融点 173−180℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 2.10(2,m) ,2.3−2.7(4H,
m)2.90(2H,t) .2.9−3.4 (4H
,m) ,3.5−3.8(2H,m) ,3.88(
28,t) ,4.14 (2H,t) ,7.18
(8}1,d) .11.22 (IH,b) .赤外
吸収スペクトルν(KBr) cm−’ :3450,
1725 ,1550,1600,1580,1510
,1450,1420,1220.
元素分析 (;26H26F2N402・28Clと
して計算値情) : C,58.11 . H,5.2
5 . N,10.43.実測値侍) : C,58.
O[i . H,5.44 . N,10.63.参考
例21
3− [2− [4− [ビス(4−フルオロフェニル
)メチレン]ビペリジン−1−イルコエチル]−28−
チアゾロ[3.2−a] −1.3.5 − トリアジ
ンー2,4(3H) 一ジオン塩酸塩
2H−チアゾロ[3.2−a] −1.3.5 − ト
リアジンー2.4(3H) 一ジオン1.0 g,
1 − (2−ヒドロキシエチル)−4− [ビス(
4−フルオロフェニル)メチレンコピベリジン2.0g
とトリフェニルホスフィン1.86gをN,N−ジメチ
ルホルムアミド20mlに溶解して水冷攪拌下、アゾジ
カルボン酸ジエチルエステル1.25gを滴下した。3
0分間攪拌した後、溶媒を減圧留去し、残漬をシリカゲ
ル・カラム(120g)に付し、4%メタノール含有ク
ロロホルムで溶出した。溶媒を減圧留去後、表題化合?
の塩基である油状物買2.05gを得た。これをエタノ
ール50+nlに溶解して濃塩酸0.5 mlを加えた
後、溶媒を減圧留去した。エタノールを加えて減圧濃縮
を繰り返し、析出した結晶を濾取し、表題化合物の無色
結晶1.76gを得た。Melting point 173-180℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 2.10 (2, m), 2.3-2.7 (4H,
m) 2.90 (2H, t). 2.9-3.4 (4H
,m) ,3.5-3.8(2H,m) ,3.88(
28,t) ,4.14 (2H,t) ,7.18
(8}1,d). 11.22 (IH,b). Infrared absorption spectrum ν (KBr) cm-': 3450,
1725, 1550, 1600, 1580, 1510
, 1450, 1420, 1220. Elemental analysis (value information calculated as 26H26F2N402・28Cl): C, 58.11. H, 5.2
5. N, 10.43. Actual value Samurai): C, 58.
O[i. H, 5.44. N, 10.63. Reference Example 21 3-[2-[4-[bis(4-fluorophenyl)methylene]biperidin-1-ylcoethyl]-28-
Thiazolo[3.2-a] -1.3.5-triazine-2,4(3H) Monodione hydrochloride 2H-thiazolo[3.2-a] -1.3.5-triazine-2,4(3H) one dione 1.0 g,
1-(2-hydroxyethyl)-4-[bis(
4-fluorophenyl)methylenecopiveridine 2.0g
and triphenylphosphine (1.86 g) were dissolved in 20 ml of N,N-dimethylformamide, and 1.25 g of azodicarboxylic acid diethyl ester was added dropwise to the solution under water cooling and stirring. 3
After stirring for 0 minutes, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (120 g) and eluted with chloroform containing 4% methanol. After removing the solvent under reduced pressure, the title compound?
2.05 g of an oily base was obtained. After dissolving this in 50+nl of ethanol and adding 0.5 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. Ethanol was added and concentration under reduced pressure was repeated, and the precipitated crystals were collected by filtration to obtain 1.76 g of colorless crystals of the title compound.
融点 251−253℃
核磁気共鳴スペクトル(ジメチルスルホキシドーd6)
δ: 2.4−2.8 (4H,m) ,2.5−2.
9 (4}1,m) ,3.6−3.8 (2H,m)
,4.22 (2H,t) ,7.18 (9H,m
) ,7.73 (1}1,cl) ,11.2 (I
H,b) .赤外吸収スペクトルv (KBr) CO
I−’ :3450,2340,1740.1B50,
1580.15501500,1420.
元素分析 (:2SH2■F2N402S’HClと
して計算値(%) : C,58.08 . H.4.
48 ; N,10.84.実測値(66) : C,
57.94 . H,4.63 . N,10.84.
実施例1
1)セロトニン2受容体拮抗活性の測定SD−SLC雄
性ラットに被検化合物を精製氷に溶解して10mg/k
gの投与量で経口投与し、30分後にウレタン(Ig/
kg、腹腔内投与)とα−クロラロース( 8 0 m
g/ kg、腹腔内投与)で麻酔した。頚動脈にポリエ
チレンカニューレを挿入し、圧トランスデューサーを介
してポリグラフレコーダーに血圧を記録した。被検化合
物を投与した60分後にセロトニン(300μs/kg
)を静注して昇圧反応を観察した。精製氷を投与した対
照群の昇圧反応と被検化合物投与群の昇圧反応より昇圧
抑制率を算出してセロトニン2(以下, 5−HT2)
拮抗活性とした。試験結果を下記一表1に示した。Melting point 251-253℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 2.4-2.8 (4H, m), 2.5-2.
9 (4}1, m) , 3.6-3.8 (2H, m)
,4.22 (2H,t) ,7.18 (9H,m
) ,7.73 (1}1,cl) ,11.2 (I
H,b). Infrared absorption spectrum v (KBr) CO
I-': 3450, 2340, 1740.1B50,
1580.15501500,1420. Elemental analysis (calculated value (%) as: 2SH2■F2N402S'HCl: C, 58.08. H.4.
48; N, 10.84. Actual value (66): C,
57.94. H, 4.63. N, 10.84.
Example 1 1) Measurement of serotonin 2 receptor antagonistic activity Test compound was dissolved in purified ice and administered to SD-SLC male rats at 10 mg/k.
30 minutes later, urethane (Ig/
kg, intraperitoneal administration) and α-chloralose (80 m
g/kg, intraperitoneal administration). A polyethylene cannula was inserted into the carotid artery, and blood pressure was recorded on a polygraph recorder via a pressure transducer. 60 minutes after administering the test compound, serotonin (300μs/kg
) was injected intravenously and the pressor response was observed. The pressor suppression rate was calculated from the pressor response of the control group administered with purified ice and the pressor response of the test compound administration group, and was calculated as serotonin 2 (hereinafter referred to as 5-HT2).
It was defined as antagonistic activity. The test results are shown in Table 1 below.
2)交感神経アルファ1受容体拮抗活性の測定SD−S
LC雄性ラットに被検化合物を精製水に溶解して10m
g/kgの投与量で経口投与し、30分後にウレタン(
Ig/kg、腹腔内投与)とα−クロラロース( 8
0 mg/ kg、腹腔内投与)で麻酔した。頚動脈に
ポリエチレンカニューレを挿入し、圧トランスデューサ
ーを介してポリグラフレコーダーに血圧を記録した。被
検化合物を投与した60分後にフェニレフリン(100
μs/kg)を静注して昇圧反応を観察した。精製氷を
没与した対照群の昇圧反応と被検化合物投与群の昇圧反
応の値をもとに昇圧抑制率を算出して交感神経アルファ
1(以下α1)拮抗活性とした。試験結果を下記表1に
示した。2) Measurement of sympathetic alpha 1 receptor antagonist activity SD-S
Dissolve the test compound in purified water and inject 10 m
g/kg, and 30 minutes later, urethane (
Ig/kg, intraperitoneal administration) and α-chloralose (8
The mice were anesthetized with 0 mg/kg (intraperitoneal administration). A polyethylene cannula was inserted into the carotid artery, and blood pressure was recorded on a polygraph recorder via a pressure transducer. 60 minutes after administering the test compound, phenylephrine (100
μs/kg) was intravenously injected and the pressor response was observed. The pressor suppression rate was calculated based on the pressor response value of the control group given purified ice and the pressor response value of the test compound administration group, and was defined as the sympathetic alpha 1 (hereinafter α1) antagonistic activity. The test results are shown in Table 1 below.
3)マウス4日間毒性試験
雄性ddyマウスに被検化合物を1%メチルセルロース
液に溶解、または懸濁させ200 B/kHの用量で1
日1回4日間連続して経口投与した。一群の投与数を4
匹または5匹として最終投与の翌日までの死亡数を観察
した。対照群には1%メチルセルロース液を10ml/
kgの割合で経口投与した。試験結果を下記表1に示し
た。3) Mouse 4-day toxicity test The test compound was dissolved or suspended in 1% methylcellulose solution and administered to male ddy mice at a dose of 200 B/kH.
It was orally administered once a day for 4 consecutive days. The number of doses per group is 4.
The number of deaths was observed up to the next day after the final administration. The control group received 10ml/1% methylcellulose solution.
It was administered orally at a rate of 1.5 kg. The test results are shown in Table 1 below.
表1
参考例の
化合物
拮抗特性
5’H’b α1
毒 性
(死亡率)
2 93
3 93
l1 83
l8 93
20 83
21 93
9 l/5
3 9 0/5
0
6 0/5
l
3
上表から明らかなように、式(I)の化合物は強力なセ
ロトニン2受容体拮抗作用を示し且つセロトニン2受容
体拮抗作用の選択性及び安全性にも優れていた。Table 1 Compound antagonistic properties of reference example 5'H'b α1 Toxicity (mortality rate) 2 93 3 93 l1 83 l8 93 20 83 21 93 9 l/5 3 9 0/5 0 6 0/5 l 3 Above table As is clear from the above, the compound of formula (I) exhibited a strong serotonin 2 receptor antagonism, and was also excellent in the selectivity and safety of the serotonin 2 receptor antagonism.
実施例2 セロトニン2受容体結合活性雄性SOラット
を無麻酔下で断頭後,前頭皮質を分取し,粗膜標木を調
製した.標識リガンドとして3H−ケタンセリンを用い
.非特異的結合試薬にはメチセルガイドを使用した。こ
れらの試薬と式(I)の化合物またはその塩を5*メタ
ノールトリス緩衝液に溶解させてインキユベーションし
た後,GF/Bガエラスフィルター上で吸引濾過した。Example 2 Serotonin 2 Receptor Binding Activity Male SO rats were decapitated without anesthesia, the frontal cortex was isolated, and rough membrane markers were prepared. Using 3H-ketanserin as a labeled ligand. Methycel guide was used as a non-specific binding reagent. These reagents and the compound of formula (I) or its salt were dissolved in 5* methanol Tris buffer and incubated, followed by suction filtration on a GF/B Gaelas filter.
同フィルターに捕捉された3H−ケタンセリンの放射活
性を液体シンチレーションカウンターを用いて計測した
。この放射活性値からスキャチャードプロットを作成し
,粗膜標木のセロトニン2受容体の解離定数と受容体密
度を求めた。さらに式(I)の化合物またはその塩の受
容体結合阻害曲線から50*抑制濃度を求め,セロトニ
ン2受容体に対する結合の強さを示す解離定数を算出し
た。その結果, 3−[2−(4− (フルオロベンゾ
イル)ビペリジンー1−イル]エチル]−6.7,8.
9−テトラヒドロ−2H−ビリド[1.2−a ] −
1.3.5− トリアジン−2.4(3}1)−ジオン
(以下化合物Aと略す)の塩酸塩のセロトニン2受容体
に対する解離定数は15nMであった。The radioactivity of 3H-ketanserin captured on the same filter was measured using a liquid scintillation counter. A Scatchard plot was created from this radioactivity value, and the dissociation constant and receptor density of the serotonin 2 receptor of the crude membrane marker were determined. Further, the 50* inhibitory concentration was determined from the receptor binding inhibition curve of the compound of formula (I) or a salt thereof, and the dissociation constant indicating the strength of binding to the serotonin 2 receptor was calculated. As a result, 3-[2-(4-(fluorobenzoyl)biperidin-1-yl]ethyl]-6.7,8.
9-tetrahydro-2H-pyrido[1.2-a] -
The dissociation constant of the hydrochloride of 1.3.5-triazine-2.4(3}1)-dione (hereinafter abbreviated as compound A) to the serotonin 2 receptor was 15 nM.
実施例3 急性心筋梗塞モデルにおける効果実験材料お
よび方法
実験標木:雑種成犬(体重8〜20kg)をベントバル
ビタール( 30B/ kg,静脈内投与)麻酔下で人
工呼吸器を装着した後に開胸した。左冠状動脈前下行枝
を剥離した。左冠状動脈前下行技支配下の心筋に二一ド
ル型の白金電極を深さ約1cmに刺人し,水素ガスクリ
アランス法で心筋組織血流を測定した。大腿動脈にポリ
エチレンカニューレを入れ,血圧および心拍数を記録し
た。大腿動脈と頚静脈にカニューレを入れてそれぞれ.
薬剤投与用.採血用とした。実験標本の安定後に,左冠
状動脈前下行枝を動脈クランメで結紮した。結紮2時間
後に再潅流し.その後4時間観察して心臓を摘出した。Example 3 Effect on acute myocardial infarction model Experimental materials and methods Experimental marker: An adult mongrel dog (weight 8-20 kg) was placed on a ventilator under anesthesia with bentobarbital (30 B/kg, intravenous administration), and then the chest was opened. did. The left anterior descending coronary artery was removed. A twenty-one-dollar platinum electrode was inserted to a depth of about 1 cm into the myocardium under the control of the left anterior descending coronary artery, and myocardial tissue blood flow was measured using the hydrogen gas clearance method. A polyethylene cannula was inserted into the femoral artery, and blood pressure and heart rate were recorded. Cannulas were inserted into the femoral artery and jugular vein, respectively.
For drug administration. It was used for blood collection. After stabilization of the experimental specimen, the left anterior descending coronary artery was ligated with an arterial clamp. Reperfusion was performed 2 hours after ligation. Thereafter, the heart was removed after observation for 4 hours.
心臓の左冠状動脈前下行技から1%トリフェニルテトラ
ゾリウムクロライド溶液,大動脈から逆行性に0.5零
エバンスブルー溶液をそれぞれ約80mm}Igの圧で
流して心臓を15分間潅流し.二重染色した。その後心
臓を洗浄し.心尖部から,長軸に垂直にlcm幅で切断
した。左心室の心筋梗塞危険領域と正常領域を分離し,
それぞれの湿重量を測定した。各切片ごとの左心室重量
(心筋梗塞危険領域と正常領域の和)と危険領域重量を
それぞれ積算して,全体の左心室重量と危険領域重量を
算出した。さらに各断面のエバンスブルーで染色されな
かった部位(心荊梗塞危険領域)と心筋梗塞危険領域の
中でトリフェニルテトラゾリウムクロライドで赤く染色
されなかった白色残存部位(心筋梗塞領域)の面積を測
定して,左心室全体に対する心筋梗塞領域の割合(心筋
梗塞サイズ)を算出した。The heart was perfused for 15 minutes by flowing 1% triphenyltetrazolium chloride solution from the anterior descending left coronary artery of the heart and retrogradely flowing 0.50 Evans blue solution from the aorta at a pressure of approximately 80 mm}Ig. Double stained. Then wash the heart. A 1 cm wide section was cut perpendicular to the long axis from the apex of the heart. Separate the myocardial infarction risk area and normal area of the left ventricle,
The wet weight of each was measured. The left ventricular weight (sum of myocardial infarction risk area and normal area) and risk area weight for each section were integrated to calculate the overall left ventricular weight and risk area weight. Furthermore, the area of the area that was not stained with Evans blue (cardiac infarction risk area) and the white remaining area that was not stained red with triphenyltetrazolium chloride (myocardial infarction area) within the myocardial infarction risk area was measured in each cross section. The ratio of myocardial infarction area to the entire left ventricle (myocardial infarction size) was calculated.
薬剤の投与:薬剤または生理食塩水は左冠状動脈前下行
枝結紮の20分前から実験終了まで静脈内にlml/k
g/hrの割合で点滴注入した。薬剤の用量はlmg/
kg/hrとした。実験は次の2群より成る。Drug administration: Drugs or saline were administered intravenously at lml/k from 20 minutes before left anterior descending coronary artery ligation until the end of the experiment.
It was infused at a rate of g/hr. The dose of the drug is lmg/
kg/hr. The experiment consisted of the following two groups.
l.対照群(11例):生埋食塩水投与2.化合物Aの
塩酸塩投与群(12例)実験成績
表2
急性心筋梗塞モデルにおける効果
数値は平均値士標準誤差を示す。l. Control group (11 cases): administration of raw saline2. Compound A hydrochloride administration group (12 cases) Experimental Results Table 2 Effect values in the acute myocardial infarction model indicate the mean and standard error.
* P<0.05
上表から明らかなように,左冠状動脈前下行技を結紮再
潅流した後に対照群の心筋組織血流量は結紮前僅の約6
0*までの回復に留まったが,化合物A没与群では悪化
した心筋血流が対照群に対して有意に回復した。二群間
で左心室重量と危険域重量に差はなく.各心臓に加えら
れた傷害の程度は同等であったと考えられた。この条件
下で化合物Aは心筋梗塞サイズを有意に縮小させた。し
たがって化合物Aは虚血にともなって生じる微小循環障
害を改善し,心筋が懐死に陥ることを防ぐ作用のあるこ
とが明らかになり.さらに化合物Aの血圧への影響は比
較的ゆるやかであった。*P<0.05 As is clear from the above table, after ligation and reperfusion of the left anterior descending coronary artery, the myocardial tissue blood flow in the control group was only about 6.
Although the recovery remained to 0*, the worsened myocardial blood flow was significantly recovered in the compound A deprived group compared to the control group. There was no difference in left ventricular weight and risk area weight between the two groups. The degree of injury inflicted on each heart appeared to be comparable. Under these conditions Compound A significantly reduced myocardial infarct size. Therefore, it has been revealed that Compound A has the effect of improving the microcirculatory disorder caused by ischemia and preventing myocardial death. Furthermore, the effect of Compound A on blood pressure was relatively mild.
したがって.化合物Aは虚血を伴った心臓疾患の予防あ
るいは治療に有益な薬剤であることが示された。therefore. Compound A has been shown to be a useful drug for the prevention or treatment of heart diseases associated with ischemia.
実施例4 狭心症モデルにおける効果
実験材料および方法
実験標本:雑種成犬(体重8〜20kg)をベントバル
ビタール(30mg/kg,静脈内投与)麻酔下で人工
呼吸器を装着した後に開胸した。左冠状動脈前下行枝を
剥離した。左冠状動脈前下行枝に狭窄用のシリコンチュ
ーブをかけ.その近傍に血流速度測定用のブローブを装
着した。血流速度はパルスドップラー式血流計を用いて
測定した。左冠状動脈前下行枝の狭窄部位よりも末梢測
の分枝にカニューレを入れて冠動脈血圧を測定した。大
腿動脈にポリエチレンカニューレを入れ,血圧および心
拍数を記録した。大腿静脈にカニューレを入れて薬剤投
与に用いた。標本の安定後に左冠状動脈前下行技をその
血流速度が20*低下するように狭窄して,左冠状動脈
前下行技血流速度が周期的に低下する狭心症類似状態を
作成した。Example 4 Effect on angina model Experimental materials and methods Experimental specimen: An adult mongrel dog (weight 8-20 kg) was placed on a ventilator under anesthesia with bentobarbital (30 mg/kg, intravenous administration), and then the chest was opened. . The left anterior descending coronary artery was removed. A silicone tube for stenosis was placed on the left anterior descending coronary artery. A probe for measuring blood flow velocity was attached near it. Blood flow velocity was measured using a pulse Doppler blood flow meter. Coronary blood pressure was measured by inserting a cannula into a peripheral branch of the left anterior descending coronary artery beyond the stenotic site. A polyethylene cannula was inserted into the femoral artery, and blood pressure and heart rate were recorded. A cannula was inserted into the femoral vein and used for drug administration. After the specimen was stabilized, the left anterior descending coronary artery was narrowed so that its blood flow velocity decreased by 20* to create an angina-like condition in which the left anterior descending coronary artery blood velocity periodically decreased.
薬剤の投与:左冠状動脈前下行技血流速度が周期的に減
少する状態が生じた1時間後に,化合物Aのマレイン酸
塩を0.1B/kHの用量で,大腿静脈内に投与した。Administration of drug: One hour after the periodic decrease in the left anterior descending coronary artery blood flow velocity occurred, the maleate salt of Compound A was administered into the femoral vein at a dose of 0.1 B/kHz.
その後1時間の左冠状動脈前下行技血流速度が周期的に
減少する状態の変化を観察した。薬剤の効果は投与前後
の1時間あたりの血流速度の周期的減少が発生した回数
で表した。化合物Aのマレイン酸塩は生埋食塩水に溶解
させて用いた。After that, changes in the condition in which the left anterior descending coronary artery blood flow velocity periodically decreased were observed. The effect of the drug was expressed as the number of times that periodic decreases in blood flow velocity occurred per hour before and after administration. The maleate salt of Compound A was used after being dissolved in saline.
実験成績: 表3 狭心症モデルにおける効果 数値は平均値士標準誤差を示す。Experimental results: Table 3 Effect in angina model Values indicate standard error of the mean.
傘傘P<0.01 (投与前と比較)上表から明らか
なように.低用量の化合物Aの投与によって冠動脈血流
速度周期的減少回数は投与前に比べ有意に低下し,化合
物Aは狭心症の発作を抑える効果のあることが示された
。Umbrella Umbrella P<0.01 (compared to before administration) As is clear from the above table. Administration of a low dose of Compound A significantly reduced the number of periodic decreases in coronary blood flow velocity compared to before administration, indicating that Compound A is effective in suppressing angina attacks.
実施例5 ラット10日間経口投与による毒性値第l頁
の続き
[相]Int. CI.’
識別記号
庁内整理番−
513/04
341
7822−4(Example 5 Toxicity values by oral administration to rats for 10 days Continuation of page 1 [Phase] Int. C.I. ' Identification code: Office serial number - 513/04 341 7822-4 (
Claims (1)
子、アルコキシ基、アルキル基及びトリハロゲノメチル
基より選ばれる1もしくは複数個の置換基で置換されて
もよいアリール基を、R^2は水素原子、アルキル基又
はハロゲン原子、アルコキシ基、アルキル基及びトリハ
ロゲノメチル基より選ばれる1もしくは複数個の置換基
で置換されてもよいアリール基を、n及びmはそれぞれ
0〜6の整数を、Aは5〜7員環を示し、該環は1個の
窒素原子を共有してトリアジン環と縮合し且つその縮合
部の窒素原子の他に窒素原子、酸素原子及び硫黄原子よ
り選ばれるヘテロ原子を1もしくは2個含んでもよく又
1もしくは複数個の二重結合を含んでもよく、Qは次の
一般式 ▲数式、化学式、表等があります▼ (式中、R^3は水素原子、水酸基又はハロゲン原子、
水酸基、アルキル基、アルコキシ基及びトリハロゲノメ
チル基より選ばれる1もしくは2個の置換基で置換され
てもよいアリール基を、R^4、R^5及びR^6はそ
れぞれ水素原子、ハロゲン原子、アルキル基、アルコキ
シ基またはトリハロゲノメチル基を示す。)で表わされ
る基又は次の一般式 ▲数式、化学式、表等があります▼ (式中、Ar^1及びAr^2はそれぞれハロゲン原子
、水酸基、アルコキシ基、アルキル基及びトリハロゲノ
メチル基より選ばれる1〜3個の置換基で置換されても
よいアリール基又は芳香族複素環残基を示す。)で表さ
れる基を示す。]で表される縮合トリアジン誘導体又は
その塩を有効成分とする心臓疾患の予防及び治療剤。[Claims] The following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenomethyl group An aryl group that may be substituted with one or more substituents, and R^2 is one or more substituents selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenomethyl group. an aryl group which may be substituted with , n and m each represent an integer of 0 to 6, A represents a 5- to 7-membered ring, the ring shares one nitrogen atom and is fused with a triazine ring, and In addition to the nitrogen atom in the condensation part, it may contain one or two heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, and may also contain one or more double bonds, and Q is represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is a hydrogen atom, a hydroxyl group, or a halogen atom,
An aryl group that may be substituted with one or two substituents selected from a hydroxyl group, an alkyl group, an alkoxy group, and a trihalogenomethyl group, and R^4, R^5, and R^6 are a hydrogen atom and a halogen atom, respectively. , represents an alkyl group, an alkoxy group or a trihalogenomethyl group. ) or the following general formula ▲ Numerical formula, chemical formula, table, etc. represents an aryl group or an aromatic heterocyclic residue which may be substituted with 1 to 3 substituents. ] A prophylactic and therapeutic agent for heart diseases containing a condensed triazine derivative or a salt thereof as an active ingredient.
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1310346A JPH03170431A (en) | 1989-11-29 | 1989-11-29 | Treating agent for heart disease |
AT90110479T ATE111911T1 (en) | 1989-06-05 | 1990-06-01 | HETEROCYCLIC TRIAZINE OR TRIAZOLO COMPOUNDS WITH SEROTONIN 2 RECEPTOR ANTAGONIST ACTION. |
ES90110479T ES2064530T3 (en) | 1989-06-05 | 1990-06-01 | TRIAZINE OR HETERO-CYCLE TRIAZOLE COMPOUNDS WITH SEROTONIN 2-RECEPTOR ANTAGONIST ACTIVITY. |
DE69012653T DE69012653T2 (en) | 1989-06-05 | 1990-06-01 | Heterocyclic triazine or triazolo compounds with serotonin 2 receptor antagonist activity. |
EP90110479A EP0401707B1 (en) | 1989-06-05 | 1990-06-01 | Heterocyclic triazin or triazolo compounds having serotonin 2-receptor antagonistic activity |
DK90110479.4T DK0401707T3 (en) | 1989-06-05 | 1990-06-01 | Heterocyclic compound, a pharmaceutical drug and process for their preparation |
NO902439A NO174712C (en) | 1989-06-05 | 1990-06-01 | Analogous Process for Preparing Therapeutically Active Heterocyclic Compounds |
IL9459290A IL94592A (en) | 1989-06-05 | 1990-06-01 | Piperidinoalkyl-substituted fused, bicyclic 1,2,4-triazolone and 1.3.5-triazinedione derivatives, their preparation and pharmaceutical compositions containing them |
NZ233917A NZ233917A (en) | 1989-06-05 | 1990-06-01 | Heterocyclic fused triazinedione and triazolone derivatives for treating heart diseases |
FI902763A FI902763A0 (en) | 1989-06-05 | 1990-06-04 | HETEROCYCLIC FOERENING WITH ANTAGONISTIC ACTIVITY MOT SEROTONIN 2-RECEPTOR. |
CA002018220A CA2018220A1 (en) | 1989-06-05 | 1990-06-04 | Heterocyclic compound having serotonine 2-receptor antagonistic activity |
YU01087/90A YU108790A (en) | 1989-06-05 | 1990-06-04 | Heterocyclical compound with activity of serotonin-2-receptor antagonizing |
HU903489A HUT54365A (en) | 1989-06-05 | 1990-06-05 | Process for producing heterocyclic compounds of serotonin-2 receptor antagonistic activity and pharmaceutical compositions containing them |
CN90104557A CN1049161A (en) | 1989-06-05 | 1990-06-05 | Heterogeneous ring compound with serotonine 2-receptor antagonistic activity |
US07/533,644 US5232924A (en) | 1989-06-05 | 1990-06-05 | Heterocyclic compound having serotonine 2-receptor antagonistic activity |
KR1019900008264A KR910000755A (en) | 1989-06-05 | 1990-06-05 | Heterocyclic Compounds Having Serotonin 2-Receptor Antagonistic Activity |
AU56295/90A AU628579B2 (en) | 1989-06-05 | 1990-06-05 | Triazine or triazole condensed system having serotonin 2-receptor antagonistic activity |
PT94270A PT94270A (en) | 1989-06-05 | 1990-06-05 | PROCESS FOR THE PREPARATION OF HETEROCYCLIC COMPOUNDS WITH ANOTHER ACTIVITY OF SEROTONIN RECEPTOR 2 AND PHARMACEUTICAL COMPOSITIONS THAT CONTAINS THEM |
SU5001301 RU2057754C1 (en) | 1989-06-05 | 1991-08-27 | Heterocyclic compounds or their acid-additive salts |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1310346A JPH03170431A (en) | 1989-11-29 | 1989-11-29 | Treating agent for heart disease |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03170431A true JPH03170431A (en) | 1991-07-24 |
Family
ID=18004127
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1310346A Pending JPH03170431A (en) | 1989-06-05 | 1989-11-29 | Treating agent for heart disease |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03170431A (en) |
-
1989
- 1989-11-29 JP JP1310346A patent/JPH03170431A/en active Pending
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