ES2987744T3 - Inhibidores de calicreína plasmática y usos de los mismos - Google Patents

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Publication number

ES2987744T3

ES2987744T3 ES20785878T ES20785878T ES2987744T3 ES 2987744 T3 ES2987744 T3 ES 2987744T3 ES 20785878 T ES20785878 T ES 20785878T ES 20785878 T ES20785878 T ES 20785878T ES 2987744 T3 ES2987744 T3 ES 2987744T3

Authority

ES

Spain

Prior art keywords

nitrogen

oxygen

sulfur

membered

methyl

Prior art date

2019-09-18

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.)

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• 102000003827 Plasma Kallikrein Human genes 0.000 title abstract description 7
• 108090000113 Plasma Kallikrein Proteins 0.000 title abstract description 7
• 229940127379 Kallikrein Inhibitors Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 156
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 483
• 229910052757 nitrogen Inorganic materials 0.000 claims description 258
• 125000005842 heteroatom Chemical group 0.000 claims description 236
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 233
• 229910052760 oxygen Inorganic materials 0.000 claims description 233
• 239000001301 oxygen Substances 0.000 claims description 233
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 219
• 229910052717 sulfur Chemical group 0.000 claims description 219
• 239000011593 sulfur Chemical group 0.000 claims description 219
• 125000001931 aliphatic group Chemical group 0.000 claims description 132
• 229920006395 saturated elastomer Polymers 0.000 claims description 132
• 229910052739 hydrogen Inorganic materials 0.000 claims description 91
• 239000001257 hydrogen Substances 0.000 claims description 91
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 68
• 229910052736 halogen Inorganic materials 0.000 claims description 54
• 150000002367 halogens Chemical class 0.000 claims description 40
• 125000002619 bicyclic group Chemical group 0.000 claims description 38
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 35
• 150000003839 salts Chemical class 0.000 claims description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 29
• 125000002950 monocyclic group Chemical group 0.000 claims description 28
• 229910052799 carbon Inorganic materials 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 125000005549 heteroarylene group Chemical group 0.000 claims description 17
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
• 125000004429 atom Chemical group 0.000 claims description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
• 150000002431 hydrogen Chemical group 0.000 claims 10
• 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 145
• 239000003112 inhibitor Substances 0.000 abstract description 5
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 331
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 279
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 214
• 230000015572 biosynthetic process Effects 0.000 description 195
• 238000003786 synthesis reaction Methods 0.000 description 194
• 239000007787 solid Substances 0.000 description 177
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 176
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 171
• 239000012043 crude product Substances 0.000 description 128
• 239000000243 solution Substances 0.000 description 107
• 238000000034 method Methods 0.000 description 103
• 238000005160 1H NMR spectroscopy Methods 0.000 description 96
• 238000010586 diagram Methods 0.000 description 95
• -1 which inhibits pKal Proteins 0.000 description 90
• 235000019439 ethyl acetate Nutrition 0.000 description 85
• 239000000047 product Substances 0.000 description 73
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
• 239000011541 reaction mixture Substances 0.000 description 72
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 68
• 239000012044 organic layer Substances 0.000 description 61
• 239000012267 brine Substances 0.000 description 60
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 60
• 239000011734 sodium Substances 0.000 description 53
• 238000006243 chemical reaction Methods 0.000 description 52
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
• 238000002953 preparative HPLC Methods 0.000 description 46
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 44
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 42
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
• 238000010898 silica gel chromatography Methods 0.000 description 39
• 239000002253 acid Substances 0.000 description 38
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
• VCKDWMFJGINCMK-UHFFFAOYSA-N 1-[(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl]triazole-4-carboxylic acid Chemical compound C1(CC1)C=1C=CC=2N(C=1)C=C(N=2)CN1N=NC(=C1)C(=O)O VCKDWMFJGINCMK-UHFFFAOYSA-N 0.000 description 28
• 206010019860 Hereditary angioedema Diseases 0.000 description 27
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 26
• 125000003118 aryl group Chemical group 0.000 description 26
• 125000001072 heteroaryl group Chemical group 0.000 description 23
• 125000001424 substituent group Chemical group 0.000 description 23
• YJDUDWFCXPKVMA-UHFFFAOYSA-N 1-[(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl]pyrazole-4-carboxylic acid Chemical compound C1(CC1)C=1C=CC=2N(C=1)C=C(N=2)CN1N=CC(=C1)C(=O)O YJDUDWFCXPKVMA-UHFFFAOYSA-N 0.000 description 22
• 201000010099 disease Diseases 0.000 description 20
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 18
• 238000000746 purification Methods 0.000 description 18
• 238000011282 treatment Methods 0.000 description 18
• 101100485158 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) wzzE gene Proteins 0.000 description 16
• 101150089110 metN gene Proteins 0.000 description 16
• 239000000523 sample Substances 0.000 description 16
• 241001465754 Metazoa Species 0.000 description 14
• 239000003795 chemical substances by application Substances 0.000 description 14
• 238000002360 preparation method Methods 0.000 description 14
• 206010012688 Diabetic retinal oedema Diseases 0.000 description 13
• 201000011190 diabetic macular edema Diseases 0.000 description 13
• 208000035475 disorder Diseases 0.000 description 13
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 239000008194 pharmaceutical composition Substances 0.000 description 12
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 11
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
• 239000003921 oil Substances 0.000 description 11
• 235000019198 oils Nutrition 0.000 description 11
• 235000010378 sodium ascorbate Nutrition 0.000 description 11
• PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 11
• 229960005055 sodium ascorbate Drugs 0.000 description 11
• PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 11
• SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 10
• UVLZSVAPDKZAPW-UHFFFAOYSA-N FC1=C(C(=CC=C1OC)N1N=NN=C1)CN Chemical compound FC1=C(C(=CC=C1OC)N1N=NN=C1)CN UVLZSVAPDKZAPW-UHFFFAOYSA-N 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
• 206010030113 Oedema Diseases 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• 239000008177 pharmaceutical agent Substances 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• 229940124597 therapeutic agent Drugs 0.000 description 10
• 239000012298 atmosphere Substances 0.000 description 9
• 102100035792 Kininogen-1 Human genes 0.000 description 8
• 238000005481 NMR spectroscopy Methods 0.000 description 8
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 8
• 125000000217 alkyl group Chemical group 0.000 description 8
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
• 239000000284 extract Substances 0.000 description 8
• 238000003818 flash chromatography Methods 0.000 description 8
• DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 8
• 235000019260 propionic acid Nutrition 0.000 description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• 101800004538 Bradykinin Proteins 0.000 description 7
• 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 description 7
• 239000007821 HATU Substances 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
• 125000002947 alkylene group Chemical group 0.000 description 7
• 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 description 7
• 239000003826 tablet Substances 0.000 description 7
• SBUXBHALPHVDFT-UHFFFAOYSA-N 1-methyltriazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)N=N1 SBUXBHALPHVDFT-UHFFFAOYSA-N 0.000 description 6
• AHVGRFIBDLMDOU-UHFFFAOYSA-N BrC1=CC=C(C(=C1CNC(=O)C=1N=NN(C=1)CC=1N=C2N(C=C(C=C2)C2CC2)C=1)F)OC Chemical compound BrC1=CC=C(C(=C1CNC(=O)C=1N=NN(C=1)CC=1N=C2N(C=C(C=C2)C2CC2)C=1)F)OC AHVGRFIBDLMDOU-UHFFFAOYSA-N 0.000 description 6
• SVBCYIOLAKYOHQ-UHFFFAOYSA-N C1(CC1)C=1C=CC=2N(C=1)C=C(N=2)CN1N=NC(=C1)C(=O)NCC1=C(C(=CC=C1N1N=NN=C1)OC)F Chemical compound C1(CC1)C=1C=CC=2N(C=1)C=C(N=2)CN1N=NC(=C1)C(=O)NCC1=C(C(=CC=C1N1N=NN=C1)OC)F SVBCYIOLAKYOHQ-UHFFFAOYSA-N 0.000 description 6
• 108700040183 Complement C1 Inhibitor Proteins 0.000 description 6
• CGDLTZQHSOPECY-UHFFFAOYSA-N NC=1SC(=CN=1)CNC(=O)C=1N=NN(C=1)CC=1N=C2N(C=C(C=C2)C2CC2)C=1 Chemical compound NC=1SC(=CN=1)CNC(=O)C=1N=NN(C=1)CC=1N=C2N(C=C(C=C2)C2CC2)C=1 CGDLTZQHSOPECY-UHFFFAOYSA-N 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• 150000001412 amines Chemical class 0.000 description 6
• 239000012472 biological sample Substances 0.000 description 6
• 210000004369 blood Anatomy 0.000 description 6
• 239000008280 blood Substances 0.000 description 6
• 210000004027 cell Anatomy 0.000 description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
• FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 6
• 238000001871 ion mobility spectroscopy Methods 0.000 description 6
• 230000001404 mediated effect Effects 0.000 description 6
• 229910052938 sodium sulfate Inorganic materials 0.000 description 6
• 235000011152 sodium sulphate Nutrition 0.000 description 6
• 208000024891 symptom Diseases 0.000 description 6
• 210000001519 tissue Anatomy 0.000 description 6
• JLGDFGQGYAZVLW-UHFFFAOYSA-N 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine Chemical compound ClCC=1N=C2N(C=C(C=C2)C2CC2)C=1 JLGDFGQGYAZVLW-UHFFFAOYSA-N 0.000 description 5
• BBYIRRCVJZYNIH-UHFFFAOYSA-N 5-cyclopropylpyridin-2-amine Chemical compound C1=NC(N)=CC=C1C1CC1 BBYIRRCVJZYNIH-UHFFFAOYSA-N 0.000 description 5
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