JPH11503144A - 5H,10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−4−オン誘導体、それらの製造法、およびそれらを含む医療薬 - Google Patents
5H,10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−4−オン誘導体、それらの製造法、およびそれらを含む医療薬Info
- Publication number
- JPH11503144A JPH11503144A JP8530031A JP53003196A JPH11503144A JP H11503144 A JPH11503144 A JP H11503144A JP 8530031 A JP8530031 A JP 8530031A JP 53003196 A JP53003196 A JP 53003196A JP H11503144 A JPH11503144 A JP H11503144A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- imidazo
- indeno
- alk
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 79
- AQQPIVYLMVOXNA-UHFFFAOYSA-N 5h,10h-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one Chemical class C1=CC=C2C(NC(C3=NC=CN33)=O)=C3CC2=C1 AQQPIVYLMVOXNA-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims abstract description 7
- 239000004471 Glycine Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 159
- -1 N-ethylaminocarbonylmethyl Chemical group 0.000 claims description 107
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 239000002253 acid Substances 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 18
- 239000005695 Ammonium acetate Substances 0.000 claims description 18
- 235000019257 ammonium acetate Nutrition 0.000 claims description 18
- 229940043376 ammonium acetate Drugs 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- PUIKTBCBQYGZAS-UHFFFAOYSA-N 1h-indeno[1,2-b]pyrazine-2-carboxylic acid Chemical compound C1=CC=C2C3=NC=C(C(=O)O)NC3=CC2=C1 PUIKTBCBQYGZAS-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- CYZSSIWKIPDNSO-UHFFFAOYSA-N N-(5-methyl-7-oxo-2,5,8-triazatetracyclo[7.7.0.02,6.010,15]hexadeca-1(9),3,10(15),11,13-pentaen-13-yl)acetamide Chemical compound C1C2=CC(NC(C)=O)=CC=C2C2=C1N1C=CN(C)C1C(=O)N2 CYZSSIWKIPDNSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GGHJGIDXMGSZMF-UHFFFAOYSA-N 9-[(3-methylureido)methyl]-5h,10h-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one Chemical compound N1C(=O)C2=NC=CN2C(C2)=C1C1=C2C(CNC(=O)NC)=CC=C1 GGHJGIDXMGSZMF-UHFFFAOYSA-N 0.000 claims description 2
- KMLMGNPECMISSC-UHFFFAOYSA-N N-benzyl-7-oxo-2,5,8-triazatetracyclo[7.7.0.02,6.010,15]hexadeca-1(9),3,5,10(15),11,13-hexaene-13-carboxamide Chemical compound C=1C=C(C2=C(N3C=CN=C3C(=O)N2)C2)C2=CC=1C(=O)NCC1=CC=CC=C1 KMLMGNPECMISSC-UHFFFAOYSA-N 0.000 claims description 2
- HZSYGADTBLFLRD-UHFFFAOYSA-N N-benzyl-7-oxo-2,5,8-triazatetracyclo[7.7.0.02,6.010,15]hexadeca-1(9),3,5,10(15),11,13-hexaene-14-carboxamide Chemical compound C=1C=CC(C2=C(N3C=CN=C3C(=O)N2)C2)=C2C=1C(=O)NCC1=CC=CC=C1 HZSYGADTBLFLRD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- KGABLDAFOWCUMF-UHFFFAOYSA-N chembl24980 Chemical compound N1C(=O)C2=NC(C(O)=O)=CN2C(C2)=C1C1=C2C(CC(=O)O)=CC=C1 KGABLDAFOWCUMF-UHFFFAOYSA-N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000003367 polycyclic group Chemical group 0.000 claims description 2
- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- UUDAMDVQRQNNHZ-UHFFFAOYSA-N (S)-AMPA Chemical compound CC=1ONC(=O)C=1CC(N)C(O)=O UUDAMDVQRQNNHZ-UHFFFAOYSA-N 0.000 claims 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims 1
- 235000003704 aspartic acid Nutrition 0.000 claims 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims 1
- 238000000354 decomposition reaction Methods 0.000 claims 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims 1
- 239000002464 receptor antagonist Substances 0.000 claims 1
- 229940044551 receptor antagonist Drugs 0.000 claims 1
- 102000003678 AMPA Receptors Human genes 0.000 abstract description 5
- 108090000078 AMPA Receptors Proteins 0.000 abstract description 5
- 239000005557 antagonist Substances 0.000 abstract description 5
- 102000005962 receptors Human genes 0.000 abstract description 4
- 108020003175 receptors Proteins 0.000 abstract description 4
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 abstract description 3
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 2
- 230000036963 noncompetitive effect Effects 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 214
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 158
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 140
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 134
- 125000003118 aryl group Chemical group 0.000 description 124
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 123
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- 239000000203 mixture Substances 0.000 description 111
- 239000007787 solid Substances 0.000 description 111
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 109
- 239000011541 reaction mixture Substances 0.000 description 107
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 83
- 239000000243 solution Substances 0.000 description 81
- 230000002829 reductive effect Effects 0.000 description 67
- 239000012153 distilled water Substances 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- 229960000583 acetic acid Drugs 0.000 description 53
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 52
- 239000000047 product Substances 0.000 description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 44
- 238000002844 melting Methods 0.000 description 44
- 230000008018 melting Effects 0.000 description 44
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 41
- 239000012074 organic phase Substances 0.000 description 40
- 239000000725 suspension Substances 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 37
- 239000000377 silicon dioxide Substances 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 238000010992 reflux Methods 0.000 description 32
- 238000000921 elemental analysis Methods 0.000 description 30
- 239000000155 melt Substances 0.000 description 26
- 238000004587 chromatography analysis Methods 0.000 description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000003480 eluent Substances 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 239000002244 precipitate Substances 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- 238000001816 cooling Methods 0.000 description 19
- 238000001035 drying Methods 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- 239000002198 insoluble material Substances 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000001704 evaporation Methods 0.000 description 18
- 230000008020 evaporation Effects 0.000 description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 17
- 229910052794 bromium Inorganic materials 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- ZUUNZDIGHGJBAR-UHFFFAOYSA-N 1h-imidazole-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CNC(C(O)=O)=N1 ZUUNZDIGHGJBAR-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000012300 argon atmosphere Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 8
- 235000013985 cinnamic acid Nutrition 0.000 description 8
- 229930016911 cinnamic acid Natural products 0.000 description 8
- GATNVKATWLZAGO-UHFFFAOYSA-N diethyl 1h-imidazole-2,5-dicarboxylate Chemical compound CCOC(=O)C1=CNC(C(=O)OCC)=N1 GATNVKATWLZAGO-UHFFFAOYSA-N 0.000 description 8
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 7
- UHYNYIGCGVDBTC-UHFFFAOYSA-N ethyl 1h-imidazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=CN1 UHYNYIGCGVDBTC-UHFFFAOYSA-N 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 239000005973 Carvone Substances 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000052 vinegar Substances 0.000 description 6
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- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- BKHZQJRTFNFCTG-UHFFFAOYSA-N tris(2-methylphenyl) phosphite Chemical compound CC1=CC=CC=C1OP(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C BKHZQJRTFNFCTG-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 201000002498 viral encephalitis Diseases 0.000 description 1
- 201000010044 viral meningitis Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 式: [式中、 − Rは、水素原子、またはカルボキシ、アルコキシカルボニル、−CO−NR4 R5、−PO3H2、もしくは−CH2OH基を表し、 − R1は、−alk−NH2、−alk−NH−CO−R3、−alk−COO R4、alk−CO−NR5R6、もしくは−CO−NH−R7基を表し、 − R3は、アルキル、フェニル、フェニルアルキル、シクロアルキル、もしく は−NR6R8基を表し、 − R4は、水素原子もしくはアルキル基を表し、 − R5は、水素原子、またはアルキル、フェニル、シクロアルキル、もしくは フェニルアルキル基を表し、 − R6は、水素原子もしくはアルキル基を表すか、あるいはそうでなければ、 R5とR6とがそれらに結合する窒素原子と共に、1〜6の炭素原子および場合に よってはO、S、もしくはNから選択される一つもしくは複数の他の複素原子を 含む飽和もしくは不飽和の単環式もしくは多環式複素環を形成し、 − R7は、フェニル、フェニルアルキル、もしくは−alk−COOR4基を表 し、 − R8は、水素原子、またはアルキル、シクロアルキル、もしくはフェニルア ルキル基を表し、 − alkはアルキルもしくはアルキレン基を表し、 アルコキシ、アルキル、およびアルキレン基および部分は1〜6の炭素原子を含 み、かつ直鎖もしくは分岐鎖であり、そしてシクロアルキル基は3〜6の炭素原 子を含むことが理解される] の化合物、それらの塩、ならびにそれらの鏡像異性体およびジアステレオ異性体 。 2. R5とR6とがそれらに結合する窒素原子と共に複素環を形成する際には 、この複素環が、アゼチジン、ピロリジン、ピペリジン、ピペラジン、およびモ ルホリン環から選択される、請求の範囲1に記載の式(I)の化合物。 3. R1置換基が8−もしくは9−位に存在する、請求の範囲1もしくは2 に記載の式(I)の化合物。 4. 式中、Rが水素原子またはカルボキシ基を表し、R1が−alk−NH −CO−R3、−alk−COOR4、alk−CO−NR5R6、もしくは−CO −NH−R7基を表し、R3がアルキルもしくは−NR6R8基を表し、R4が水素 原子を表し、R5が水素原子を表し、R6がアルキル基を表し、そしてR7がフェ ニルアルキルもしくは−alk−COOR4基を表す、請求の範囲(I)に記載 の化合物、それらの塩、ならびにそれらの鏡像異性体およびジアステレオ異性体 。 5. 請求の範囲に記載の式(I)の以下の化合物: − (4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1,2−a]インデ ノ[1,2−e]ピラジン−9−イル)酢酸、 − N−メチル−2−(4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1 ,2−a]インデノ[1,2−e]ピラジン−9−イル)アセトアミド、 − N−[(4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1,2−a] インデノ[1,2−e]ピラジン−9−イル)メチル]アセトアミド、 − 9−[(3−メチルウレイド)メチル]−5H,10H−イミダゾ[1,2 −a]インデノ[1,2−e]ピラジン−4−オン、 − N−メチル−[4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1,2 −a]インデノ[1,2−e]ピラジン−8−イル]アセトアミド、 − 8−N−メチルカルボキシアミドメチル−4,5−ジヒドロ−4−オキソ− 10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カルボ ン酸、 − 8−カルボキシメチル−4,5−ジヒドロ−4−オキソ−10H−イミダゾ [1,2−a]インデノ[1,2−e]ピラジン−2−カルボン酸、 − 8−(3−メチルウレイド)メチル−5H,10H−イミダゾ[1,2−a ]インデノ[1,2−e]ピラジン−4−オン、 − 9−カルボキシメチル−4,5−ジヒドロ−4−オキソ−10H−イミダゾ [1,2−a]インデノ[1,2−e]ピラジン−2−カルボン酸、 − N−ベンジル−(4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1, 2−a]インデノ[1,2−e]ピラジン−9−イル)カルボキシアミド、 − N−[(4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1,2−a] インデノ[1,2−e]ピラジン−9−イル)カルボニル]グリシン、 − N−ベンジル−(4,5−ジヒドロ−4−オキソ−10H−イミダゾ[1, 2−a]インデノ[1,2−e]ピラジン−8−イル)カルボキシアミド、 − 8−(N−エチルアミノカルボニルメチル)−4,5−ジヒドロ−4−オキ ソ−10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カ ルボン酸、 − 8−(N−エチルアミノカルボニルメチル)−4,5−ジヒドロ−4−オキ ソ−10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カ ルボン酸エチル、 − 9−N−ベンジルカルバモイル−4,5−ジヒドロ−4−オキソ−10H− イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カルボン酸、 − 8−(2−カルボキシエチル)−4,5−ジヒドロ−4−オキソ−10H− イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カルボン酸、 − 9−[(3−メチルウレイド)メチル]−4,5−ジヒドロ−4−オキソ− 10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カルボ ン酸、 − 9−カルボキシメチル−4,5−ジヒドロ−4−オキソ−10H−イミダゾ [1,2−a]インデノ[1,2−e]ピラジン−2−リン酸、 − 9−N−メチルアミノカルボニルメチル−4,5−ジヒドロ−4−オキソ− 10H−イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カルボ ン酸、 − 9−(1−カルボキシエチル)−4,5−ジヒドロ−4−オキソ−10H− イミダゾ[1,2−a]インデノ[1,2−e]ピラジン−2−カルボン酸、 それらの塩、ならびにそれらの鏡像異性体およびジアステレオ異性体。 6. 式: [式中、RおよびR1は請求の範囲1におけるものと同一の意味を有し、そして alkはアルキル基を表す] の誘導体を酢酸アンモニウムの存在下で環化させ、その生成物を単離しかつ光学 的に塩に転化することを特徴とする、請求の範囲1に記載の化合物の製造のため の方法。 7. 請求の範囲1に記載の式(I)[式中、Rはカルボキシル基を表し、そ して/またはR1は−alk−COOR4基を表し、この式中R4は水素原子もし くは−CO−NH−R7基を表し、この式中R7は−a lk−COOR4基を表しかつR4は水素原子を表す]の化合物の製造のための、 式(I)[式中、Rはアルコキシカルボニル基を表し、そして/またはR1は− alk−COOR4基を表し、この式中R4はアルキル基または−CO−NH−R7 基を表し、この式中R7は−alk−COOR4基を表しかつR4基はアルキル基 を表す]の対応化合物を加水分解し、その生成物を単離しかつ光学的に塩に転化 することを特徴とする方法。 8. 式(I)[式中、Rは−PO3H2基を表す]の化合物の製造のための、 式: [式中、R1は請求の範囲1におけるものと同一の意味を有し、そしてRaはメチ ル、エチル、もしくはベンジル基を表す]の誘導体を加水分解し、その生成物を 単離しかつ光学的に塩に転化することを特徴とする方法。 9. 請求の範囲1に記載される式(I)[式中、Rは−CH2OH基を表す ]の化合物を製造するための、式(I)[式中、Rはアルコキシカルボニル基を 表す]の対応化合物を還元し、その生成物を単離しかつ光学的に塩に転化するこ とを特徴とする方法。 10.請求の範囲1に記載される式(I)[式中、Rは−CO−NR4R5基を 表す]の化合物の製造のための、トリアルキルアルミニウムと アミンHNR4R5の塩酸塩から形成されるアルミニウム複合体を、式(I)[式 中、Rはアルコキシカルボニル基を表す]の対応化合物と反応させ、その生成物 を単離しかつ光学的に塩に転化することを特徴とする方法。 11.請求の範囲1に記載される式(I)[式中、R1は−alk−NH−C O−R3基を表し、この式中R3は(1C)アルキル基を表す]の化合物を製造す るための、式(I)[式中、R1は−alk−NH2基を表す]の対応化合物を無 水酢酸と反応させ、その生成物を単離しかつ光学的に塩に転化することを特徴と する方法。 12.請求の範囲1に記載される式(I)[式中、R1は−alk−NH−C O−R3基を表し、この式中R3は−NH6R8基を表し、R6は水素原子を表し、 そしてR8は水素原子、またはアルキル、シクロアルキル、もしくはフェニルア ルキル基を表す]の化合物を製造するための、式(I)[式中、R1は−alk −NH2基を表す]の対応化合物を、イソシアナートRb−NCO[式中、Rbは トリメチルシリル、アルキル、シクロアルキル、もしくはフェニルアルキル基を 表す]と反応させ、そして場合によってはその後にシリル化された誘導体の加水 分解を実施し、その生成物を単離しかつ光学的に塩に転化することを特徴とする 方法。 13.請求の範囲1に記載される式(I)[式中、R1は−alk−NH−C O−R3基を表し、この式中R3は−NR6R8基を表し、R6は水素原子を表し、 そしてR8はアルキル、シクロアルキル、もしくはフェニルアルキル基を表す] の化合物を製造するための、式(I)[式中、R1は−alk−NH2基を表す] の対応化合物の、式: [式中、Rcはアルキル、シクロアルキル、もしくはフェニルアルキル基を表す ]の誘導体と反応させ、その生成物を単離しかつ光学的に塩に転化することを特 徴とする方法。 14.請求の範囲1に記載される式(I)[式中、R1は−alk−NH−C O−R3基を表し、この式中R3はアルキル、フェニル、フェニルアルキル、シク ロアルキル、もしくは−NR6R8基を表し、R6はアルキル基を表し、そしてR8 はアルキル,シクロアルキル、もしくはフェニルアルキル基を表す]の対応化合 物を製造するための、式(I)[式中、R1は−alk−NH2基を表す]の化合 物を、Hal−CO−R3誘導体[式中、Halはハロゲン原子を表し、そして R3は先のものと同一の意味を有する]と反応させ、その生成物を単離しかつ光 学的に塩に転化することを特徴とする方法。 15.請求の範囲1に記載の式(I)[式中、R1は−alk−CO−NR5R6 基を表す]を製造するための、式(I)[式中、R1は−alk−COOR4基 を表すか、もしくはR4が水素原子を表す場合にはその酸の反応性誘導体を表す ]をアミンHNR5R6と反応させ、その生成物を単離しかつ光学的に塩に転化す ることを特徴とする方法。 16.式(I)[式中、R1は−(1C)alk−NH2基を表す]の化合物を 製造するための、式: [式中、R1は式(I)におけるものと同一の意味を有する] の誘導体を水素化し、その生成物を単離しかつ光学的に塩に転化することを特徴 とする方法。 17.請求の範囲1もしくは5の内の一つに記載の式(I)の少なくとも一つ の化合物もしくはそのような化合物の塩を活性成分として含む医療薬。 18.請求の範囲1もしくは5の内の一つに記載の式(I)の少なくとも一つ の化合物もしくはそのような化合物の塩を活性成分として含む、α−アミノ−3 −ヒドロキシ−5−メチル−4−イソオキサゾールプロピオン酸(AMPA)の ためのレセプターのアンタゴニストである医療薬。 19.請求の範囲1もしくは5の内の一つに記載の式(I)の少なくとも一つ の化合物もしくはそのような化合物の塩を活性成分として含む、N−メチル−D −アスパラギン酸(NMDA)レセプターのグリシン部位の非競合性アンタゴニ ストである医療薬。 20.式: [式中、RおよびR1は請求の範囲1におけるものと同一の意味を有し、そして alkは直鎖もしくは分岐鎖の状態で1〜6の炭素原子を含むアルキル基を表す ]の生成物。
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FR9504013A FR2732681B1 (fr) | 1995-04-05 | 1995-04-05 | Derives de 10h-imidazo(1,2-a)indeno(1,2-e)pyrazin-4-one, leur preparation et les medicaments les contenant |
FR95/04013 | 1995-04-05 | ||
PCT/FR1996/000496 WO1996031511A1 (fr) | 1995-04-05 | 1996-04-02 | DERIVES DE 5H,10H-IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZIN-4-ONE, LEUR PREPARATION ET LES MEDICAMENTS LES CONTENANT |
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EP (1) | EP0820455B1 (ja) |
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AT (1) | ATE207923T1 (ja) |
AU (1) | AU705471B2 (ja) |
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CA (1) | CA2215469A1 (ja) |
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WO2008088820A2 (en) * | 2007-01-16 | 2008-07-24 | The Johns Hopkins University | Glutamate receptor antagonists and methods of use |
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1995
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1996
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