JP7269923B2 - 呼吸器疾患治療のためのＥＮａＣ阻害剤としてのビス（ペンタヒドロキシヘキシル）アミノ置換された２－｛［（３－アミノ－ピラジン－２－イル）ホルムアミド］メチル｝－１Ｈ－１，３－ベンゾジアゾール－３－イウム誘導体 - Google Patents

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Publication number

JP7269923B2

JP7269923B2 JP2020521539A JP2020521539A JP7269923B2 JP 7269923 B2 JP7269923 B2 JP 7269923B2 JP 2020521539 A JP2020521539 A JP 2020521539A JP 2020521539 A JP2020521539 A JP 2020521539A JP 7269923 B2 JP7269923 B2 JP 7269923B2

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JP

Japan

Prior art keywords

general formula

mmol

amino

methyl

compounds

Prior art date

2017-10-17

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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• -1 3-amino-pyrazin-2-yl Chemical group 0.000 title claims description 66
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 50
• 238000011282 treatment Methods 0.000 title claims description 36
• 208000023504 respiratory system disease Diseases 0.000 title claims description 19
• 239000002713 epithelial sodium channel blocking agent Substances 0.000 title description 11
• 125000003277 amino group Chemical group 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 230
• 238000000034 method Methods 0.000 claims description 41
• 150000001450 anions Chemical class 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 125000005843 halogen group Chemical group 0.000 claims description 21
• 229910052757 nitrogen Inorganic materials 0.000 claims description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 19
• 125000000623 heterocyclic group Chemical group 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 17
• 238000002360 preparation method Methods 0.000 claims description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
• 125000003118 aryl group Chemical group 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• 230000002265 prevention Effects 0.000 claims description 15
• 239000002253 acid Substances 0.000 claims description 14
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 13
• 235000019256 formaldehyde Nutrition 0.000 claims description 12
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 230000001404 mediated effect Effects 0.000 claims description 11
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 229940079593 drug Drugs 0.000 claims description 10
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 9
• 125000001424 substituent group Chemical group 0.000 claims description 9
• 201000009267 bronchiectasis Diseases 0.000 claims description 8
• JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 6
• NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 6
• LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 claims description 6
• 229960002657 orciprenaline Drugs 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 229960002052 salbutamol Drugs 0.000 claims description 6
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 5
• 206010006451 bronchitis Diseases 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 208000007451 chronic bronchitis Diseases 0.000 claims description 5
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
• 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 4
• 206010014561 Emphysema Diseases 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 201000008937 atopic dermatitis Diseases 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 206010021198 ichthyosis Diseases 0.000 claims description 4
• 230000000155 isotopic effect Effects 0.000 claims description 4
• XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 3
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 3
• ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 claims description 3
• NXXDCISNGBHPDQ-BDFRAOSTSA-O 3,5-diamino-N-[[5-[(3R)-3-[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]pyrrolidine-1-carbonyl]-1,3-diethylbenzimidazol-1-ium-2-yl]methyl]-6-chloropyrazine-2-carboxamide Chemical compound O[C@@H](CN([C@H]1CN(CC1)C(=O)C=1C=CC2=C(N(C(=[N+]2CC)CNC(=O)C2=NC(=C(N=C2N)N)Cl)CC)C=1)C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)[C@H]([C@@H]([C@@H](CO)O)O)O NXXDCISNGBHPDQ-BDFRAOSTSA-O 0.000 claims description 3
• IFVIWWYIXKAVKJ-RGGGPRGCSA-O 3,5-diamino-N-[[5-[4-[[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]piperidine-1-carbonyl]-1,3-diethylbenzimidazol-1-ium-2-yl]methyl]-6-chloropyrazine-2-carboxamide Chemical compound O[C@@H](CN(C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)CC1CCN(CC1)C(=O)C=1C=CC2=C(N(C(=[N+]2CC)CNC(=O)C2=NC(=C(N=C2N)N)Cl)CC)C=1)[C@H]([C@@H]([C@@H](CO)O)O)O IFVIWWYIXKAVKJ-RGGGPRGCSA-O 0.000 claims description 3
• JHZFPMALDVFNJI-GORFEGJJSA-O 3,5-diamino-N-[[5-[4-[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]piperidine-1-carbonyl]-1,3-diethylbenzimidazol-1-ium-2-yl]methyl]-6-chloropyrazine-2-carboxamide Chemical compound O[C@@H](CN(C1CCN(CC1)C(=O)C=1C=CC2=C(N(C(=[N+]2CC)CNC(=O)C2=NC(=C(N=C2N)N)Cl)CC)C=1)C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)[C@H]([C@@H]([C@@H](CO)O)O)O JHZFPMALDVFNJI-GORFEGJJSA-O 0.000 claims description 3
• UAUOPGOIPXZSOE-FXQFKFQWSA-O 3-amino-N-[[5-[4-[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]piperidine-1-carbonyl]-1,3-diethylbenzimidazol-1-ium-2-yl]methyl]-6-bromopyrazine-2-carboxamide Chemical compound NC=1C(=NC(=CN=1)Br)C(=O)NCC1=[N+](C2=C(N1CC)C=C(C=C2)C(=O)N1CCC(CC1)N(C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)CC UAUOPGOIPXZSOE-FXQFKFQWSA-O 0.000 claims description 3
• 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 3
• MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims description 3
• KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 3
• VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 3
• ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 3
• UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 3
• CQECBMYFFXSJRQ-JERILIGOSA-O N-[2-[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]ethyl]-2-[[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]methyl]-1,3-diethylbenzimidazol-1-ium-5-carboxamide Chemical compound O[C@@H](CN(CCNC(=O)C=1C=CC2=C(N(C(=[N+]2CC)CNC(=O)C2=NC(=C(N=C2N)N)Cl)CC)C=1)C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)[C@H]([C@@H]([C@@H](CO)O)O)O CQECBMYFFXSJRQ-JERILIGOSA-O 0.000 claims description 3
• JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims description 3
• VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 claims description 3
• GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 3
• YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 claims description 3
• 239000000048 adrenergic agonist Substances 0.000 claims description 3
• 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 3
• 239000003242 anti bacterial agent Substances 0.000 claims description 3
• 229940088710 antibiotic agent Drugs 0.000 claims description 3
• 239000000739 antihistaminic agent Substances 0.000 claims description 3
• 229940125715 antihistaminic agent Drugs 0.000 claims description 3
• GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 claims description 3
• 229960004574 azelastine Drugs 0.000 claims description 3
• 229950000210 beclometasone dipropionate Drugs 0.000 claims description 3
• 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 claims description 3
• 229960000585 bitolterol mesylate Drugs 0.000 claims description 3
• HODFCFXCOMKRCG-UHFFFAOYSA-N bitolterol mesylate Chemical compound CS([O-])(=O)=O.C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)C[NH2+]C(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 HODFCFXCOMKRCG-UHFFFAOYSA-N 0.000 claims description 3
• 229960004436 budesonide Drugs 0.000 claims description 3
• 229960001803 cetirizine Drugs 0.000 claims description 3
• 229960003291 chlorphenamine Drugs 0.000 claims description 3
• SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 claims description 3
• 239000003246 corticosteroid Substances 0.000 claims description 3
• 229960001334 corticosteroids Drugs 0.000 claims description 3
• 238000010511 deprotection reaction Methods 0.000 claims description 3
• 229960001271 desloratadine Drugs 0.000 claims description 3
• 229960000533 dornase alfa Drugs 0.000 claims description 3
• 108010067396 dornase alfa Proteins 0.000 claims description 3
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 3
• 229960003592 fexofenadine Drugs 0.000 claims description 3
• 229960000676 flunisolide Drugs 0.000 claims description 3
• 229960001469 fluticasone furoate Drugs 0.000 claims description 3
• XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 claims description 3
• 229960000289 fluticasone propionate Drugs 0.000 claims description 3
• WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims description 3
• 229960002848 formoterol Drugs 0.000 claims description 3
• BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 3
• 239000000938 histamine H1 antagonist Substances 0.000 claims description 3
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• QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 claims description 3
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• JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 3
• 229960002744 mometasone furoate Drugs 0.000 claims description 3
• WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 claims description 3
• 229960005127 montelukast Drugs 0.000 claims description 3
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• 229960005205 prednisolone Drugs 0.000 claims description 3
• OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
• 229960004618 prednisone Drugs 0.000 claims description 3
• XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
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• YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 3
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