TWI768156B - 新穎緩激肽ｂ２受體拮抗劑及其用途 - Google Patents

Info

Publication number

TWI768156B

TWI768156B TW107141872A TW107141872A TWI768156B TW I768156 B TWI768156 B TW I768156B TW 107141872 A TW107141872 A TW 107141872A TW 107141872 A TW107141872 A TW 107141872A TW I768156 B TWI768156 B TW I768156B

Authority

TW

Taiwan

Prior art keywords

methyl

fluoro

chloro

compound

atoms

Prior art date

2017-11-24

Links

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• 229940123765 Bradykinin B2 receptor antagonist Drugs 0.000 title 1
• 239000003359 bradykinin B2 receptor antagonist Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 295
• 101800004538 Bradykinin Proteins 0.000 claims abstract description 50
• QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 claims abstract description 50
• QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 claims abstract description 50
• 238000002360 preparation method Methods 0.000 claims abstract description 24
• 239000003814 drug Substances 0.000 claims abstract description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
• 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 8
• 102100035792 Kininogen-1 Human genes 0.000 claims abstract 3
• -1 cyclopropyl pentyl Chemical group 0.000 claims description 102
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 66
• 150000003839 salts Chemical class 0.000 claims description 61
• 239000000243 solution Substances 0.000 claims description 57
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 48
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
• 125000005843 halogen group Chemical group 0.000 claims description 31
• 125000004432 carbon atom Chemical group C* 0.000 claims description 28
• 229910052760 oxygen Inorganic materials 0.000 claims description 28
• 201000010099 disease Diseases 0.000 claims description 27
• 125000000217 alkyl group Chemical group 0.000 claims description 24
• 229910052731 fluorine Inorganic materials 0.000 claims description 24
• 125000001153 fluoro group Chemical group F* 0.000 claims description 23
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 19
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 19
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• 229910052717 sulfur Inorganic materials 0.000 claims description 16
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 229940079593 drug Drugs 0.000 claims description 14
• 229920006395 saturated elastomer Polymers 0.000 claims description 14
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
• 238000006467 substitution reaction Methods 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 125000000623 heterocyclic group Chemical group 0.000 claims description 9
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 8
• 229910052805 deuterium Inorganic materials 0.000 claims description 8
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
• 125000002950 monocyclic group Chemical group 0.000 claims description 7
• 125000004434 sulfur atom Chemical group 0.000 claims description 7
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 5
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 239000000126 substance Substances 0.000 claims description 5
• 239000002671 adjuvant Substances 0.000 claims description 4
• YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 3
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
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• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 2
• 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
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• 150000003254 radicals Chemical class 0.000 claims description 2
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• 125000004431 deuterium atom Chemical group 0.000 claims 3
• 150000001983 dialkylethers Chemical class 0.000 claims 1
• 239000002464 receptor antagonist Substances 0.000 abstract description 13
• 229940044551 receptor antagonist Drugs 0.000 abstract description 13
• 238000003786 synthesis reaction Methods 0.000 description 119
• 230000015572 biosynthetic process Effects 0.000 description 117
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 73
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 67
• 239000000203 mixture Substances 0.000 description 59
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 50
• 102400000967 Bradykinin Human genes 0.000 description 47
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
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• 102000005962 receptors Human genes 0.000 description 38
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• 238000006243 chemical reaction Methods 0.000 description 35
• 238000003756 stirring Methods 0.000 description 35
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• 238000010828 elution Methods 0.000 description 32
• 239000000741 silica gel Substances 0.000 description 32
• 229910002027 silica gel Inorganic materials 0.000 description 32
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
• 229910001868 water Inorganic materials 0.000 description 26
• 239000007832 Na2SO4 Substances 0.000 description 23
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
• 238000003556 assay Methods 0.000 description 23
• 210000004027 cell Anatomy 0.000 description 23
• 239000012044 organic layer Substances 0.000 description 23
• 229910052938 sodium sulfate Inorganic materials 0.000 description 23
• 235000011152 sodium sulphate Nutrition 0.000 description 23
• XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 22
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• 125000001424 substituent group Chemical group 0.000 description 20
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 17
• 230000000694 effects Effects 0.000 description 17
• 238000000034 method Methods 0.000 description 17
• 208000002193 Pain Diseases 0.000 description 16
• 208000006673 asthma Diseases 0.000 description 16
• 230000036407 pain Effects 0.000 description 16
• 239000011734 sodium Substances 0.000 description 16
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
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