DE60217674T2 - Derivate heterocyclischer verbindungen und arzneimittel - Google Patents
Derivate heterocyclischer verbindungen und arzneimittel Download PDFInfo
- Publication number
- DE60217674T2 DE60217674T2 DE60217674T DE60217674T DE60217674T2 DE 60217674 T2 DE60217674 T2 DE 60217674T2 DE 60217674 T DE60217674 T DE 60217674T DE 60217674 T DE60217674 T DE 60217674T DE 60217674 T2 DE60217674 T2 DE 60217674T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- butyloxy
- isopropylamino
- optionally substituted
- acetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 229940126601 medicinal product Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 253
- -1 (C 1-6) -alkyl Chemical class 0.000 claims description 220
- 125000000217 alkyl group Chemical group 0.000 claims description 129
- 125000000623 heterocyclic group Chemical group 0.000 claims description 98
- 125000001424 substituent group Chemical group 0.000 claims description 65
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 61
- 150000002367 halogens Chemical class 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 125000004104 aryloxy group Chemical group 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 150000003254 radicals Chemical class 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 125000004414 alkyl thio group Chemical group 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000004434 sulfur atom Chemical group 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 12
- OJQMKCBWYCWFPU-UHFFFAOYSA-N ACT-333679 Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C(C)C)=CN=C1C1=CC=CC=C1 OJQMKCBWYCWFPU-UHFFFAOYSA-N 0.000 claims description 10
- 206010002383 Angina Pectoris Diseases 0.000 claims description 9
- 125000004450 alkenylene group Chemical group 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- KGBUCWKXCJJSRB-UHFFFAOYSA-N 2-[4-[(5,6-diphenyl-1,2,4-triazin-3-yl)-methylamino]butoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C)=NN=C1C1=CC=CC=C1 KGBUCWKXCJJSRB-UHFFFAOYSA-N 0.000 claims description 7
- WPZXTFRRQFGRER-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-methylamino]butoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C)=CN=C1C1=CC=CC=C1 WPZXTFRRQFGRER-UHFFFAOYSA-N 0.000 claims description 7
- LYTWBSZEUQJOJC-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butylsulfinyl]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCS(=O)CC(O)=O)C(C)C)=CN=C1C1=CC=CC=C1 LYTWBSZEUQJOJC-UHFFFAOYSA-N 0.000 claims description 7
- PHZQASXWAMHTJF-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyridin-2-yl)-methylamino]butoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C)=CC=C1C1=CC=CC=C1 PHZQASXWAMHTJF-UHFFFAOYSA-N 0.000 claims description 7
- GIAJAINERPSFTK-UHFFFAOYSA-N 2-[4-[[4,5-bis(4-methylphenyl)pyrimidin-2-yl]-methylamino]butoxy]acetic acid Chemical compound C=1C=C(C)C=CC=1C1=NC(N(CCCCOCC(O)=O)C)=NC=C1C1=CC=C(C)C=C1 GIAJAINERPSFTK-UHFFFAOYSA-N 0.000 claims description 7
- VDZCBRPBWPGWGD-UHFFFAOYSA-N 2-[4-[[5,6-bis(4-methylphenyl)-1,2,4-triazin-3-yl]-propan-2-ylamino]butoxy]acetic acid Chemical compound C=1C=C(C)C=CC=1C1=NC(N(CCCCOCC(O)=O)C(C)C)=NN=C1C1=CC=C(C)C=C1 VDZCBRPBWPGWGD-UHFFFAOYSA-N 0.000 claims description 7
- UMRLJXBGRGYTHA-UHFFFAOYSA-N 2-[4-[[5,6-bis(4-methylphenyl)pyrazin-2-yl]-propan-2-ylamino]butoxy]acetic acid Chemical compound C=1C=C(C)C=CC=1C1=NC(N(CCCCOCC(O)=O)C(C)C)=CN=C1C1=CC=C(C)C=C1 UMRLJXBGRGYTHA-UHFFFAOYSA-N 0.000 claims description 7
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- SYISIAMJPWFCME-HJWRWDBZSA-N 2-[(z)-4-[(5,6-diphenylpyrazin-2-yl)-methylamino]but-2-enoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(C\C=C/COCC(O)=O)C)=CN=C1C1=CC=CC=C1 SYISIAMJPWFCME-HJWRWDBZSA-N 0.000 claims description 6
- ZQAGCDSFTAEWIL-UHFFFAOYSA-N 2-[4-[(4,5-diphenylpyrimidin-2-yl)-methylamino]butoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C)=NC=C1C1=CC=CC=C1 ZQAGCDSFTAEWIL-UHFFFAOYSA-N 0.000 claims description 6
- YLSSLUSGTJRYKH-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-ethylamino]butoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)CC)=CN=C1C1=CC=CC=C1 YLSSLUSGTJRYKH-UHFFFAOYSA-N 0.000 claims description 6
- WAJSUUFYQYSGPC-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butylsulfanyl]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCSCC(O)=O)C(C)C)=CN=C1C1=CC=CC=C1 WAJSUUFYQYSGPC-UHFFFAOYSA-N 0.000 claims description 6
- JYOSRDIPTBENEZ-UHFFFAOYSA-N 7-[(5,6-diphenylpyrazin-2-yl)-methylamino]heptanoic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCCCC(O)=O)C)=CN=C1C1=CC=CC=C1 JYOSRDIPTBENEZ-UHFFFAOYSA-N 0.000 claims description 6
- 208000000575 Arteriosclerosis Obliterans Diseases 0.000 claims description 6
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 210000004351 coronary vessel Anatomy 0.000 claims description 6
- 239000001301 oxygen Chemical group 0.000 claims description 6
- 208000037803 restenosis Diseases 0.000 claims description 6
- PYKJCHOBFJYKNO-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]-n-morpholin-4-ylsulfonylacetamide Chemical compound C=1N=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=NC=1N(C(C)C)CCCCOCC(=O)NS(=O)(=O)N1CCOCC1 PYKJCHOBFJYKNO-UHFFFAOYSA-N 0.000 claims description 5
- SAMGSDXPOBGQGJ-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]-n-pyrrolidin-1-ylsulfonylacetamide Chemical compound C=1N=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=NC=1N(C(C)C)CCCCOCC(=O)NS(=O)(=O)N1CCCC1 SAMGSDXPOBGQGJ-UHFFFAOYSA-N 0.000 claims description 5
- BJNJPZZFWUALHB-UHFFFAOYSA-N 2-[4-[methyl-(4-oxido-5,6-diphenylpyrazin-4-ium-2-yl)amino]butoxy]acetic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C)=C[N+]([O-])=C1C1=CC=CC=C1 BJNJPZZFWUALHB-UHFFFAOYSA-N 0.000 claims description 5
- 206010014513 Embolism arterial Diseases 0.000 claims description 5
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 5
- ORRGBVOZGUBWAV-UHFFFAOYSA-N [2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]acetyl]sulfamic acid Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(O)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 ORRGBVOZGUBWAV-UHFFFAOYSA-N 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 230000002093 peripheral effect Effects 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 4
- 208000003782 Raynaud disease Diseases 0.000 claims description 4
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 4
- 206010038563 Reocclusion Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 4
- 238000002399 angioplasty Methods 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 4
- IDKVKYBHZLRXAD-UHFFFAOYSA-M sodium;n-[2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]acetyl]sulfamate Chemical compound [Na+].C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS([O-])(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 IDKVKYBHZLRXAD-UHFFFAOYSA-M 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 4
- NSKQNEDFPGXWDS-UHFFFAOYSA-N 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]-n-(2-methylphenyl)sulfonylacetamide Chemical compound C=1N=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=NC=1N(C(C)C)CCCCOCC(=O)NS(=O)(=O)C1=CC=CC=C1C NSKQNEDFPGXWDS-UHFFFAOYSA-N 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 206010012665 Diabetic gangrene Diseases 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 201000001429 Intracranial Thrombosis Diseases 0.000 claims description 3
- 208000025865 Ulcer Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 210000002798 bone marrow cell Anatomy 0.000 claims description 3
- 238000000502 dialysis Methods 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 230000002085 persistent effect Effects 0.000 claims description 3
- 238000002054 transplantation Methods 0.000 claims description 3
- 231100000397 ulcer Toxicity 0.000 claims description 3
- XOIYZMDJFLKIEI-UHFFFAOYSA-N (hydroxysulfonimidoyl)oxybenzene Chemical compound NS(=O)(=O)OC1=CC=CC=C1 XOIYZMDJFLKIEI-UHFFFAOYSA-N 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 11
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 10
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 8
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 5
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 4
- 125000004429 atom Chemical group 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 3
- 206010011985 Decubitus ulcer Diseases 0.000 claims 2
- 208000023589 ischemic disease Diseases 0.000 claims 2
- CNRAYJCLTOYDQK-UHFFFAOYSA-N 2,3-bis(4-methylphenyl)pyrazine Chemical compound C1=CC(C)=CC=C1C1=NC=CN=C1C1=CC=C(C)C=C1 CNRAYJCLTOYDQK-UHFFFAOYSA-N 0.000 claims 1
- 206010056489 Coronary artery restenosis Diseases 0.000 claims 1
- 206010017577 Gait disturbance Diseases 0.000 claims 1
- 206010061216 Infarction Diseases 0.000 claims 1
- 241001024304 Mino Species 0.000 claims 1
- 206010061340 Peripheral embolism Diseases 0.000 claims 1
- 150000005840 aryl radicals Chemical class 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 208000019622 heart disease Diseases 0.000 claims 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims 1
- 230000007574 infarction Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 169
- 239000000126 substance Substances 0.000 description 151
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 108
- 239000002904 solvent Substances 0.000 description 96
- 230000002829 reductive effect Effects 0.000 description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- 238000002844 melting Methods 0.000 description 68
- 230000008018 melting Effects 0.000 description 68
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 65
- 238000006243 chemical reaction Methods 0.000 description 65
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 238000003756 stirring Methods 0.000 description 61
- 238000000921 elemental analysis Methods 0.000 description 60
- 239000000203 mixture Substances 0.000 description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000010898 silica gel chromatography Methods 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 125000004663 dialkyl amino group Chemical group 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 238000000034 method Methods 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
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- 235000011121 sodium hydroxide Nutrition 0.000 description 24
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 21
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 21
- 125000003710 aryl alkyl group Chemical group 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 20
- 125000001188 haloalkyl group Chemical group 0.000 description 20
- VUGNCPVAXWZTOL-UHFFFAOYSA-N 5-chloro-2,3-diphenylpyrazine Chemical compound C=1C=CC=CC=1C1=NC(Cl)=CN=C1C1=CC=CC=C1 VUGNCPVAXWZTOL-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- SSDWYVZYRYDZGM-UHFFFAOYSA-N 5-chloro-2,3-bis(4-methylphenyl)pyrazine Chemical compound C1=CC(C)=CC=C1C1=NC=C(Cl)N=C1C1=CC=C(C)C=C1 SSDWYVZYRYDZGM-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000007858 starting material Substances 0.000 description 14
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 13
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- 239000012300 argon atmosphere Substances 0.000 description 11
- XBGLEYNNICHJND-UHFFFAOYSA-N methyl 2-(4-bromobutoxy)acetate Chemical compound COC(=O)COCCCCBr XBGLEYNNICHJND-UHFFFAOYSA-N 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 125000000547 substituted alkyl group Chemical group 0.000 description 11
- DBKSSENEKWOVKL-UHFFFAOYSA-N 4-(methylamino)butan-1-ol Chemical compound CNCCCCO DBKSSENEKWOVKL-UHFFFAOYSA-N 0.000 description 10
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- 239000002178 crystalline material Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
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- 239000003054 catalyst Substances 0.000 description 8
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- 239000000018 receptor agonist Substances 0.000 description 8
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- CMYMZVFFNGQVBM-UHFFFAOYSA-N tert-butyl 2-(4-bromobutoxy)acetate Chemical compound CC(C)(C)OC(=O)COCCCCBr CMYMZVFFNGQVBM-UHFFFAOYSA-N 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 7
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- MJGCPIJLBXBMDG-UHFFFAOYSA-N methyl 2-[4-[(5,6-diphenylpyrazin-2-yl)-methylamino]butoxy]acetate Chemical compound C=1C=CC=CC=1C1=NC(N(C)CCCCOCC(=O)OC)=CN=C1C1=CC=CC=C1 MJGCPIJLBXBMDG-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- ALXXRHXYGNYJKE-UHFFFAOYSA-N methyl 7-[(5,6-diphenylpyrazin-2-yl)-methylamino]heptanoate Chemical compound C=1C=CC=CC=1C1=NC(N(C)CCCCCCC(=O)OC)=CN=C1C1=CC=CC=C1 ALXXRHXYGNYJKE-UHFFFAOYSA-N 0.000 description 1
- JVOGCUWXDSZSTA-UHFFFAOYSA-N methyl 8-[(5,6-diphenylpyrazin-2-yl)-methylamino]octanoate Chemical compound C=1C=CC=CC=1C1=NC(N(C)CCCCCCCC(=O)OC)=CN=C1C1=CC=CC=C1 JVOGCUWXDSZSTA-UHFFFAOYSA-N 0.000 description 1
- IZIJRYNUYQXBPG-UHFFFAOYSA-N methyl 8-bromooctanoate Chemical compound COC(=O)CCCCCCCBr IZIJRYNUYQXBPG-UHFFFAOYSA-N 0.000 description 1
- UEWKXXYDRZHKCR-UHFFFAOYSA-N methyl 9-bromononanoate Chemical compound COC(=O)CCCCCCCCBr UEWKXXYDRZHKCR-UHFFFAOYSA-N 0.000 description 1
- CRVGTESFCCXCTH-UHFFFAOYSA-N methyl diethanolamine Chemical compound OCCN(C)CCO CRVGTESFCCXCTH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- ZYWUVGFIXPNBDL-UHFFFAOYSA-N n,n-diisopropylaminoethanol Chemical compound CC(C)N(C(C)C)CCO ZYWUVGFIXPNBDL-UHFFFAOYSA-N 0.000 description 1
- KNXKXSNTQFVSCS-UHFFFAOYSA-N n-(4-bromobutyl)-5,6-diphenyl-n-propan-2-ylpyrazin-2-amine Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCBr)C(C)C)=CN=C1C1=CC=CC=C1 KNXKXSNTQFVSCS-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([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
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000014040 negative regulation of leukocyte activation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
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- KHIWWQKSHDUIBK-UHFFFAOYSA-M periodate Chemical compound [O-]I(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-M 0.000 description 1
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- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- 150000003217 pyrazoles Chemical class 0.000 description 1
- 229940070891 pyridium Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- BHPMMMPLAOUHNL-UHFFFAOYSA-M sodium;2-[4-(5,6-diphenylpyrazin-2-yl)sulfinylbutoxy]acetate Chemical compound [Na+].C=1C=CC=CC=1C1=NC(S(=O)CCCCOCC(=O)[O-])=CN=C1C1=CC=CC=C1 BHPMMMPLAOUHNL-UHFFFAOYSA-M 0.000 description 1
- LCUOCNIYIZPWEH-UHFFFAOYSA-M sodium;2-[4-[(5,6-diphenylpyrazin-2-yl)-ethylamino]butoxy]acetate Chemical compound [Na+].C=1C=CC=CC=1C1=NC(N(CCCCOCC([O-])=O)CC)=CN=C1C1=CC=CC=C1 LCUOCNIYIZPWEH-UHFFFAOYSA-M 0.000 description 1
- DNCILXOCFMZALV-UHFFFAOYSA-M sodium;2-[4-[(5,6-diphenylpyridin-2-yl)-methylamino]butoxy]acetate Chemical compound [Na+].C=1C=CC=CC=1C1=NC(N(CCCCOCC([O-])=O)C)=CC=C1C1=CC=CC=C1 DNCILXOCFMZALV-UHFFFAOYSA-M 0.000 description 1
- ZTMFIBWCBWPQHM-UHFFFAOYSA-M sodium;2-[4-[methyl-(3-methyl-5,6-diphenylpyrazin-2-yl)amino]butoxy]acetate Chemical compound [Na+].C=1C=CC=CC=1C=1N=C(C)C(N(CCCCOCC([O-])=O)C)=NC=1C1=CC=CC=C1 ZTMFIBWCBWPQHM-UHFFFAOYSA-M 0.000 description 1
- BGPSMKBWDNGNLY-UHFFFAOYSA-M sodium;2-[5-(5,6-diphenylpyrazin-2-yl)pentoxy]acetate Chemical compound [Na+].C=1C=CC=CC=1C1=NC(CCCCCOCC(=O)[O-])=CN=C1C1=CC=CC=C1 BGPSMKBWDNGNLY-UHFFFAOYSA-M 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- TUUHUIWOSNBFMI-QXMHVHEDSA-N tert-butyl 2-[(z)-4-[(5,6-diphenylpyrazin-2-yl)-methylamino]but-2-enoxy]acetate Chemical compound C=1C=CC=CC=1C1=NC(N(C\C=C/COCC(=O)OC(C)(C)C)C)=CN=C1C1=CC=CC=C1 TUUHUIWOSNBFMI-QXMHVHEDSA-N 0.000 description 1
- FNEDUEKMQBQSDH-UHFFFAOYSA-N tert-butyl 2-[4-[(4,5-diphenylpyrimidin-2-yl)-methylamino]butoxy]acetate Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)OC(C)(C)C)C)=NC=C1C1=CC=CC=C1 FNEDUEKMQBQSDH-UHFFFAOYSA-N 0.000 description 1
- IMYUIRRKYZVGIV-UHFFFAOYSA-N tert-butyl 2-[4-[(5,6-diphenylpyrazin-2-yl)-ethylamino]butoxy]acetate Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)OC(C)(C)C)CC)=CN=C1C1=CC=CC=C1 IMYUIRRKYZVGIV-UHFFFAOYSA-N 0.000 description 1
- SOYVQPCDESZDGY-UHFFFAOYSA-N tert-butyl 2-[4-[[5,6-bis(4-fluorophenyl)pyrazin-2-yl]-methylamino]butoxy]acetate Chemical compound C=1C=C(F)C=CC=1C1=NC(N(CCCCOCC(=O)OC(C)(C)C)C)=CN=C1C1=CC=C(F)C=C1 SOYVQPCDESZDGY-UHFFFAOYSA-N 0.000 description 1
- FRRCEMKSCSFARM-UHFFFAOYSA-N tert-butyl 2-[4-[[5,6-bis(4-methoxyphenyl)pyrazin-2-yl]-methylamino]butoxy]acetate Chemical compound C1=CC(OC)=CC=C1C1=NC=C(N(C)CCCCOCC(=O)OC(C)(C)C)N=C1C1=CC=C(OC)C=C1 FRRCEMKSCSFARM-UHFFFAOYSA-N 0.000 description 1
- YDDSGJNQVZDXLI-UHFFFAOYSA-N tert-butyl 2-[4-[methyl-(3-methyl-5,6-diphenylpyrazin-2-yl)amino]butoxy]acetate Chemical compound C=1C=CC=CC=1C=1N=C(C)C(N(CCCCOCC(=O)OC(C)(C)C)C)=NC=1C1=CC=CC=C1 YDDSGJNQVZDXLI-UHFFFAOYSA-N 0.000 description 1
- XBHDWFMJLMOWCM-UHFFFAOYSA-N tert-butyl-dimethyl-(2-piperidin-3-ylethoxy)silane Chemical compound CC(C)(C)[Si](C)(C)OCCC1CCCNC1 XBHDWFMJLMOWCM-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP2001129765 | 2001-04-26 | ||
JP2001129765 | 2001-04-26 | ||
PCT/JP2002/004118 WO2002088084A1 (fr) | 2001-04-26 | 2002-04-25 | Derives de composes heterocycliques et medicaments |
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DE60217674D1 DE60217674D1 (de) | 2007-03-08 |
DE60217674T2 true DE60217674T2 (de) | 2007-10-11 |
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DE60217674T Expired - Lifetime DE60217674T2 (de) | 2001-04-26 | 2002-04-25 | Derivate heterocyclischer verbindungen und arzneimittel |
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US (1) | US7205302B2 (en:Method) |
EP (1) | EP1400518B1 (en:Method) |
JP (1) | JP4479152B2 (en:Method) |
KR (1) | KR100921760B1 (en:Method) |
CN (1) | CN1301973C (en:Method) |
BE (1) | BE2016C051I2 (en:Method) |
BR (1) | BRPI0209249B8 (en:Method) |
CA (1) | CA2445344C (en:Method) |
DE (1) | DE60217674T2 (en:Method) |
DK (1) | DK1400518T3 (en:Method) |
ES (1) | ES2276931T3 (en:Method) |
FR (1) | FR16C0042I2 (en:Method) |
LU (1) | LU93266I2 (en:Method) |
MX (1) | MXPA03009800A (en:Method) |
NL (1) | NL300836I2 (en:Method) |
PT (1) | PT1400518E (en:Method) |
RU (1) | RU2283835C3 (en:Method) |
TW (1) | TWI316055B (en:Method) |
WO (1) | WO2002088084A1 (en:Method) |
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WO2024133620A1 (en) | 2022-12-22 | 2024-06-27 | Actelion Pharmaceuticals Ltd | In vitro dissolution test |
CN116143704B (zh) * | 2023-02-27 | 2025-05-27 | 广州楷石生物科技有限公司 | 司来帕格体内代谢物的一氧化氮供体药物 |
TW202444370A (zh) | 2023-03-23 | 2024-11-16 | 瑞士商艾克泰聯製藥有限公司 | 包含二苯基吡衍生物之醫藥組成物 |
KR20250008015A (ko) | 2023-07-06 | 2025-01-14 | 재단법인대구경북과학기술원 | 셀렉시팍을 포함하는 퇴행성 뇌질환의 예방 또는 치료용 약학 조성물 |
CN117510465A (zh) * | 2023-11-03 | 2024-02-06 | 四川轻化工大学 | 一种5,6-二苯基吡嗪-2-哌啶类化合物及其制备方法和应用 |
CN118619893A (zh) * | 2023-12-27 | 2024-09-10 | 石家庄四药有限公司 | Pgi2受体激动剂化合物、药物组合物和应用 |
CN118598820B (zh) * | 2024-02-06 | 2025-07-08 | 石家庄四药有限公司 | 一种二苯基三嗪类化合物及其制备方法和应用 |
CN118750498B (zh) * | 2024-07-22 | 2025-07-08 | 石家庄四药有限公司 | 一种包括化合物syn045的药物组合物、制剂及制备方法 |
CN118903146A (zh) * | 2024-07-22 | 2024-11-08 | 石家庄四药有限公司 | 包括化合物syn045的药物组合物、制剂及其制备方法 |
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CA1128507A (en) * | 1977-05-17 | 1982-07-27 | James M. Gullo | Pharmacologically active substituted 1,2,4-triazines |
US4513135A (en) | 1982-03-05 | 1985-04-23 | Eli Lilly And Company | Diaryl-pyrazine derivatives affecting GABA binding |
FR2665159B1 (fr) | 1990-07-24 | 1992-11-13 | Rhone Poulenc Sante | Nouveaux derives de la pyridine et de la quinoleine, leur preparation et les compositions pharmaceutiques qui les contiennent. |
JPH06501926A (ja) | 1990-08-06 | 1994-03-03 | 藤沢薬品工業株式会社 | 複素環式化合物 |
US5219510A (en) * | 1990-09-26 | 1993-06-15 | Eastman Kodak Company | Method of manufacture of cellulose ester film |
JP3169413B2 (ja) * | 1992-01-31 | 2001-05-28 | エーザイ株式会社 | イミダゾール誘導体 |
JPH0733752A (ja) | 1993-07-16 | 1995-02-03 | Sankyo Co Ltd | ジフェニルピラジン誘導体及び除草剤 |
AUPP003297A0 (en) * | 1997-10-27 | 1997-11-20 | Fujisawa Pharmaceutical Co., Ltd. | 4,5-diaryloxazole compounds |
AUPQ253199A0 (en) * | 1999-08-30 | 1999-09-23 | Fujisawa Pharmaceutical Co., Ltd. | Non-prostanoid prostaglandin I2-agonist |
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2002
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- 2002-04-25 CA CA2445344A patent/CA2445344C/en not_active Expired - Lifetime
- 2002-04-25 KR KR1020037014044A patent/KR100921760B1/ko not_active Expired - Lifetime
- 2002-04-25 JP JP2002585386A patent/JP4479152B2/ja not_active Expired - Lifetime
- 2002-04-25 RU RU2003134190A patent/RU2283835C3/ru active Protection Beyond IP Right Term
- 2002-04-25 DK DK02722772T patent/DK1400518T3/da active
- 2002-04-25 PT PT02722772T patent/PT1400518E/pt unknown
- 2002-04-25 US US10/476,196 patent/US7205302B2/en active Active
- 2002-04-25 BR BRPI0209249A patent/BRPI0209249B8/pt active IP Right Grant
- 2002-04-25 ES ES02722772T patent/ES2276931T3/es not_active Expired - Lifetime
- 2002-04-25 MX MXPA03009800A patent/MXPA03009800A/es active IP Right Grant
- 2002-04-25 CN CNB028089774A patent/CN1301973C/zh not_active Expired - Lifetime
- 2002-04-25 WO PCT/JP2002/004118 patent/WO2002088084A1/ja active IP Right Grant
- 2002-04-25 EP EP02722772A patent/EP1400518B1/en not_active Expired - Lifetime
- 2002-04-25 DE DE60217674T patent/DE60217674T2/de not_active Expired - Lifetime
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- 2016-10-18 NL NL300836C patent/NL300836I2/nl unknown
- 2016-10-19 LU LU93266C patent/LU93266I2/fr unknown
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EP1400518B1 (en) | 2007-01-17 |
JPWO2002088084A1 (ja) | 2004-09-09 |
EP1400518A1 (en) | 2004-03-24 |
CA2445344A1 (en) | 2002-11-07 |
RU2003134190A (ru) | 2005-06-10 |
TWI316055B (en:Method) | 2009-10-21 |
BRPI0209249B8 (pt) | 2021-05-25 |
LU93266I2 (fr) | 2016-12-19 |
DE60217674D1 (de) | 2007-03-08 |
CA2445344C (en) | 2011-07-26 |
JP4479152B2 (ja) | 2010-06-09 |
EP1400518A4 (en) | 2005-04-20 |
ES2276931T3 (es) | 2007-07-01 |
MXPA03009800A (es) | 2004-01-29 |
FR16C0042I2 (fr) | 2017-03-17 |
KR20040015174A (ko) | 2004-02-18 |
FR16C0042I1 (fr) | 2016-12-09 |
US7205302B2 (en) | 2007-04-17 |
WO2002088084A1 (fr) | 2002-11-07 |
RU2283835C2 (ru) | 2006-09-20 |
US20040102436A1 (en) | 2004-05-27 |
BE2016C051I2 (en:Method) | 2021-07-19 |
BRPI0209249B1 (pt) | 2016-04-26 |
DK1400518T3 (da) | 2007-03-26 |
NL300836I2 (en:Method) | 2016-11-16 |
RU2283835C3 (ru) | 2021-02-15 |
CN1516690A (zh) | 2004-07-28 |
PT1400518E (pt) | 2007-03-30 |
KR100921760B1 (ko) | 2009-10-15 |
CN1301973C (zh) | 2007-02-28 |
BR0209249A (pt) | 2004-06-08 |
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