NO322856B1 - Pyrazolo[4,3-d]pyrimidinderivater - Google Patents

Info

Publication number

NO322856B1

NO322856B1 NO20021694A NO20021694A NO322856B1 NO 322856 B1 NO322856 B1 NO 322856B1 NO 20021694 A NO20021694 A NO 20021694A NO 20021694 A NO20021694 A NO 20021694A NO 322856 B1 NO322856 B1 NO 322856B1

Authority

NO

Norway

Prior art keywords

ethyl

ylsulfonyl

pyrazolo

dihydro

pyridin

Prior art date

1999-10-11

Links

• Espacenet
• Global Dossier
• Discuss

• DSKLYHDHQJANOE-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidine Chemical compound C1=NC=N[C]2C=NN=C21 DSKLYHDHQJANOE-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 671
• 238000002360 preparation method Methods 0.000 claims description 271
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 201
• 239000000203 mixture Substances 0.000 claims description 180
• 238000000034 method Methods 0.000 claims description 125
• -1 piperazin-1-ylsulfonyl group Chemical group 0.000 claims description 107
• 238000006243 chemical reaction Methods 0.000 claims description 93
• 150000003839 salts Chemical class 0.000 claims description 87
• 239000002904 solvent Substances 0.000 claims description 84
• 239000002585 base Substances 0.000 claims description 59
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 55
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 54
• 125000000217 alkyl group Chemical group 0.000 claims description 49
• 125000001424 substituent group Chemical group 0.000 claims description 42
• 239000003795 chemical substances by application Substances 0.000 claims description 39
• 239000012453 solvate Substances 0.000 claims description 38
• 238000007363 ring formation reaction Methods 0.000 claims description 37
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
• 239000003814 drug Substances 0.000 claims description 31
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
• 150000001412 amines Chemical class 0.000 claims description 22
• 230000015572 biosynthetic process Effects 0.000 claims description 22
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
• 206010057671 Female sexual dysfunction Diseases 0.000 claims description 18
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 125000004432 carbon atom Chemical group C* 0.000 claims description 17
• 230000001568 sexual effect Effects 0.000 claims description 17
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
• 229940079593 drug Drugs 0.000 claims description 16
• 239000000651 prodrug Substances 0.000 claims description 16
• 229940002612 prodrug Drugs 0.000 claims description 16
• 125000006239 protecting group Chemical group 0.000 claims description 16
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
• 239000002253 acid Substances 0.000 claims description 15
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 230000004064 dysfunction Effects 0.000 claims description 14
• 201000001881 impotence Diseases 0.000 claims description 14
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 238000009472 formulation Methods 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 238000011282 treatment Methods 0.000 claims description 11
• 238000009109 curative therapy Methods 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
• 230000008569 process Effects 0.000 claims description 10
• 238000011321 prophylaxis Methods 0.000 claims description 10
• YPFZMBHKIVDSNR-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 YPFZMBHKIVDSNR-UHFFFAOYSA-N 0.000 claims description 9
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
• 208000035475 disorder Diseases 0.000 claims description 9
• 239000002243 precursor Substances 0.000 claims description 9
• 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 8
• 238000005859 coupling reaction Methods 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 238000002638 palliative care Methods 0.000 claims description 8
• 239000002590 phosphodiesterase V inhibitor Substances 0.000 claims description 8
• 125000004193 piperazinyl group Chemical group 0.000 claims description 8
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 7
• UEYQJQVBUVAELZ-UHFFFAOYSA-N 2-Hydroxynicotinic acid Chemical compound OC(=O)C1=CC=CN=C1O UEYQJQVBUVAELZ-UHFFFAOYSA-N 0.000 claims description 7
• 206010011953 Decreased activity Diseases 0.000 claims description 7
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 7
• 208000021663 Female sexual arousal disease Diseases 0.000 claims description 7
• 208000027520 Somatoform disease Diseases 0.000 claims description 7
• 239000012351 deprotecting agent Substances 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 208000027753 pain disease Diseases 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 241001465754 Metazoa Species 0.000 claims description 6
• 229910052783 alkali metal Inorganic materials 0.000 claims description 6
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
• 241000282412 Homo Species 0.000 claims description 5
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
• 230000003301 hydrolyzing effect Effects 0.000 claims description 5
• 239000007788 liquid Substances 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
• 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 4
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
• 125000000623 heterocyclic group Chemical group 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 229910052698 phosphorus Inorganic materials 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
• WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 3
• DYDBSYBLOUPXRA-UHFFFAOYSA-N 2-(1-acetylazetidin-3-yl)-5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CN(C(C)=O)C1 DYDBSYBLOUPXRA-UHFFFAOYSA-N 0.000 claims description 3
• JQXAVRJTJOJMSE-UHFFFAOYSA-N 2-(cyclobutylmethyl)-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(C)CC3)OCCOC)=O)C2=C(CC)N1CC1CCC1 JQXAVRJTJOJMSE-UHFFFAOYSA-N 0.000 claims description 3
• IIOTWDDVVSFHRF-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCN(C)C)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 IIOTWDDVVSFHRF-UHFFFAOYSA-N 0.000 claims description 3
• IRRFCGLDMVZFOU-UHFFFAOYSA-N 2-[5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]-n,n-dimethylacetamide Chemical compound C1=C(C=2NC(=O)C3=NN(CC(=O)N(C)C)C(CC)=C3N=2)C(OCCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 IRRFCGLDMVZFOU-UHFFFAOYSA-N 0.000 claims description 3
• YTHWHVYWWVOQGG-UHFFFAOYSA-N 2-butan-2-yl-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C(C)CC)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 YTHWHVYWWVOQGG-UHFFFAOYSA-N 0.000 claims description 3
• OBEWPUCJDXQPSA-UHFFFAOYSA-N 5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(OCCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 OBEWPUCJDXQPSA-UHFFFAOYSA-N 0.000 claims description 3
• KXXCQTLFOCTZGD-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CN(CC)C1 KXXCQTLFOCTZGD-UHFFFAOYSA-N 0.000 claims description 3
• CZNILTGORLWQMB-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CN(C)C1 CZNILTGORLWQMB-UHFFFAOYSA-N 0.000 claims description 3
• UXDCRIGPYLLISI-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(3-methoxypropyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCCOC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 UXDCRIGPYLLISI-UHFFFAOYSA-N 0.000 claims description 3
• CVJJVQHDUKHESY-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-[2-(methylamino)ethyl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCNC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 CVJJVQHDUKHESY-UHFFFAOYSA-N 0.000 claims description 3
• WHZLAQCYTKWPJL-UHFFFAOYSA-N 5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methylpropoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC=1N(CCOC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCC(C)C)=CC=1S(=O)(=O)N1CCN(CC)CC1 WHZLAQCYTKWPJL-UHFFFAOYSA-N 0.000 claims description 3
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
• 240000008042 Zea mays Species 0.000 claims description 3
• 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims description 3
• 235000002017 Zea mays subsp mays Nutrition 0.000 claims description 3
• 229910052799 carbon Inorganic materials 0.000 claims description 3
• 235000005822 corn Nutrition 0.000 claims description 3
• 239000012954 diazonium Substances 0.000 claims description 3
• IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical group [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 3
• 230000001404 mediated effect Effects 0.000 claims description 3
• 239000003960 organic solvent Substances 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
• FDNDOIVWZKHWRI-UHFFFAOYSA-N 2-(2-ethoxyethyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(CCOCC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCCOC)=CC=1S(=O)(=O)N1CCN(CC)CC1 FDNDOIVWZKHWRI-UHFFFAOYSA-N 0.000 claims description 2
• OZRATLVKWROBMN-UHFFFAOYSA-N 2-(cyclobutylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2CC1CCC1 OZRATLVKWROBMN-UHFFFAOYSA-N 0.000 claims description 2
• IDGMCMZGKXIFAF-UHFFFAOYSA-N 2-(cyclopropylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2CC1CC1 IDGMCMZGKXIFAF-UHFFFAOYSA-N 0.000 claims description 2
• VMKMXEFVKPDPDC-UHFFFAOYSA-N 2-butan-2-yl-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(C(C)CC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCCOC)=CC=1S(=O)(=O)N1CCN(CC)CC1 VMKMXEFVKPDPDC-UHFFFAOYSA-N 0.000 claims description 2
• IJUGCQRVRBBAFH-UHFFFAOYSA-N 2-butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(CCCC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCCOC)=CC=1S(=O)(=O)N1CCN(C)CC1 IJUGCQRVRBBAFH-UHFFFAOYSA-N 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• VYGYAGDQYNLXDJ-UHFFFAOYSA-N 3-ethyl-2-(1-ethylazetidin-3-yl)-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-phenylmethoxypyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1N(CC)CC1N1C(CC)=C(N=C(NC2=O)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(CC)CC3)OCC=3C=CC=CC=3)C2=N1 VYGYAGDQYNLXDJ-UHFFFAOYSA-N 0.000 claims description 2
• VYFHWUGIGFPUHL-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)=C1 VYFHWUGIGFPUHL-UHFFFAOYSA-N 0.000 claims description 2
• NLNFVNNWOWUWAC-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methylpropyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(CC(C)C)C(CC)=C3N=2)=C1 NLNFVNNWOWUWAC-UHFFFAOYSA-N 0.000 claims description 2
• IGCPMJCXVPUWSC-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(pyridin-2-ylmethyl)pyridin-3-yl]-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C(C=C1C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)=CN=C1CC1=CC=CC=N1 IGCPMJCXVPUWSC-UHFFFAOYSA-N 0.000 claims description 2
• AWXZPTUDNDPUMO-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-propan-2-yloxypyridin-3-yl]-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OC(C)C)C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)=C1 AWXZPTUDNDPUMO-UHFFFAOYSA-N 0.000 claims description 2
• RQYWQMXXGVLLGB-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-propoxypyridin-3-yl]-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(OCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 RQYWQMXXGVLLGB-UHFFFAOYSA-N 0.000 claims description 2
• COVMDAYFLBAMRZ-UHFFFAOYSA-N 5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CN(C)C1 COVMDAYFLBAMRZ-UHFFFAOYSA-N 0.000 claims description 2
• UZINTNOLWNTVTM-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C=3N(CCOC)N=C(CC)C=3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 UZINTNOLWNTVTM-UHFFFAOYSA-N 0.000 claims description 2
• JMIOIYJBQYLMRL-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-methoxypropan-2-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C(C)COC)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 JMIOIYJBQYLMRL-UHFFFAOYSA-N 0.000 claims description 2
• KUXHHRADFMWCSR-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methylpropyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CC(C)C)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 KUXHHRADFMWCSR-UHFFFAOYSA-N 0.000 claims description 2
• DQODXJXNANLCEB-UHFFFAOYSA-N 6-(2-cyclobutylpropyl)-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-2-methylpyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(C)N=C(C(N2CC(C)C3CCC3)=O)C=1N=C2C(C(=NC=1)OCCOC)=CC=1S(=O)(=O)N1CCN(C)CC1 DQODXJXNANLCEB-UHFFFAOYSA-N 0.000 claims description 2
• 239000000010 aprotic solvent Substances 0.000 claims description 2
• 125000004104 aryloxy group Chemical group 0.000 claims description 2
• 125000002393 azetidinyl group Chemical group 0.000 claims description 2
• 238000007796 conventional method Methods 0.000 claims description 2
• 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
• 239000011707 mineral Substances 0.000 claims description 2
• JISQHCORFFRLLW-UHFFFAOYSA-N n-[2-[3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-propoxypyridin-3-yl]-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl]-n-methylacetamide Chemical compound C1=C(C=2NC(=O)C3=NN(CCN(C)C(C)=O)C(CC)=C3N=2)C(OCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 JISQHCORFFRLLW-UHFFFAOYSA-N 0.000 claims description 2
• GKOWDLWWAZINFZ-UHFFFAOYSA-N n-[2-[5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl]-n-methylmethanesulfonamide Chemical compound C1=C(C=2NC(=O)C3=NN(CCN(C)S(C)(=O)=O)C(CC)=C3N=2)C(OCCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 GKOWDLWWAZINFZ-UHFFFAOYSA-N 0.000 claims description 2
• 229910017604 nitric acid Inorganic materials 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 229910052721 tungsten Inorganic materials 0.000 claims description 2
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 2
• WRAPEVAEFSIHPM-UHFFFAOYSA-N 5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CN(CC)C1 WRAPEVAEFSIHPM-UHFFFAOYSA-N 0.000 claims 1
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 402
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 363
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 240
• 239000000243 solution Substances 0.000 description 206
• 230000002829 reductive effect Effects 0.000 description 160
• 239000011541 reaction mixture Substances 0.000 description 120
• 239000007787 solid Substances 0.000 description 96
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
• 235000019441 ethanol Nutrition 0.000 description 89
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 88
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 87
• 229960001866 silicon dioxide Drugs 0.000 description 84
• 239000000741 silica gel Substances 0.000 description 83
• 229910002027 silica gel Inorganic materials 0.000 description 83
• 238000004440 column chromatography Methods 0.000 description 82
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 76
• UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 62
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 54
• 239000012043 crude product Substances 0.000 description 44
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 42
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
• 238000010828 elution Methods 0.000 description 40
• 238000010992 reflux Methods 0.000 description 38
• 101150041968 CDC13 gene Proteins 0.000 description 37
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 37
• 239000000284 extract Substances 0.000 description 32
• 239000010410 layer Substances 0.000 description 30
• 102100024085 Alpha-aminoadipic semialdehyde dehydrogenase Human genes 0.000 description 28
• 239000011734 sodium Substances 0.000 description 28
• 239000000543 intermediate Substances 0.000 description 27
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 27
• 235000017557 sodium bicarbonate Nutrition 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
• XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 25
• 101710135349 Venom phosphodiesterase Proteins 0.000 description 22
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
• 229910021529 ammonia Inorganic materials 0.000 description 21
• 239000000047 product Substances 0.000 description 20
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 20
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 235000019198 oils Nutrition 0.000 description 18
• 239000002516 radical scavenger Substances 0.000 description 18
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 17
• 229910000024 caesium carbonate Inorganic materials 0.000 description 17
• 239000000460 chlorine Substances 0.000 description 17
• 229910052751 metal Inorganic materials 0.000 description 17
• 239000002184 metal Substances 0.000 description 17
• XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 16
• 239000012267 brine Substances 0.000 description 16
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
• 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 15
• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 15
• 239000008346 aqueous phase Substances 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
• BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 14
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 14
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 14
• 239000012074 organic phase Substances 0.000 description 14
• 239000000843 powder Substances 0.000 description 14
• 239000002244 precipitate Substances 0.000 description 14
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 13
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 13
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
• 239000006260 foam Substances 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• 238000003786 synthesis reaction Methods 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
• 239000012442 inert solvent Substances 0.000 description 10
• 239000002480 mineral oil Substances 0.000 description 10
• 235000010446 mineral oil Nutrition 0.000 description 10
• VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 10
• 229920006395 saturated elastomer Polymers 0.000 description 10
• 239000002002 slurry Substances 0.000 description 10
• 239000012312 sodium hydride Substances 0.000 description 10
• 239000000758 substrate Substances 0.000 description 10
• 229910002651 NO3 Inorganic materials 0.000 description 9
• NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• 201000001880 Sexual dysfunction Diseases 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• 150000004703 alkoxides Chemical class 0.000 description 9
• 239000006185 dispersion Substances 0.000 description 9
• 239000002552 dosage form Substances 0.000 description 9
• 231100000872 sexual dysfunction Toxicity 0.000 description 9
• 239000007858 starting material Substances 0.000 description 9
• ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 8
• FRDAATYAJDYRNW-UHFFFAOYSA-N 3-methyl-3-pentanol Chemical compound CCC(C)(O)CC FRDAATYAJDYRNW-UHFFFAOYSA-N 0.000 description 8
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 8
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
• 208000004403 Prostatic Hyperplasia Diseases 0.000 description 8
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
• 239000003054 catalyst Substances 0.000 description 8
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
• 208000033808 peripheral neuropathy Diseases 0.000 description 8
• 239000012071 phase Substances 0.000 description 8
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 8
• 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 8
• 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 8
• 229910052708 sodium Inorganic materials 0.000 description 8
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 7
• XTPUQGFKKAURLH-UHFFFAOYSA-N 5-ethyl-4-nitro-1h-pyrazole-3-carboxamide Chemical compound CCC=1NN=C(C(N)=O)C=1[N+]([O-])=O XTPUQGFKKAURLH-UHFFFAOYSA-N 0.000 description 7
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
• 239000007864 aqueous solution Substances 0.000 description 7
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 7
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
• 239000001257 hydrogen Substances 0.000 description 7
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
• 239000000546 pharmaceutical excipient Substances 0.000 description 7
• 239000011591 potassium Substances 0.000 description 7
• RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
• GYWKKQHZMMSMKE-UHFFFAOYSA-N 5-ethyl-1-(2-methoxyethyl)-4-nitropyrazole-3-carboxamide Chemical compound CCC1=C([N+]([O-])=O)C(C(N)=O)=NN1CCOC GYWKKQHZMMSMKE-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• 229920000858 Cyclodextrin Polymers 0.000 description 6
• 208000032131 Diabetic Neuropathies Diseases 0.000 description 6
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 238000001816 cooling Methods 0.000 description 6
• 210000005226 corpus cavernosum Anatomy 0.000 description 6
• HHEIMYAXCOIQCJ-UHFFFAOYSA-N ethyl 2,2-dimethylpropanoate Chemical compound CCOC(=O)C(C)(C)C HHEIMYAXCOIQCJ-UHFFFAOYSA-N 0.000 description 6
• 150000002431 hydrogen Chemical class 0.000 description 6
• 229960004592 isopropanol Drugs 0.000 description 6
• 229910052700 potassium Inorganic materials 0.000 description 6
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
• 230000003389 potentiating effect Effects 0.000 description 6
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 6
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 5
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
• 238000004458 analytical method Methods 0.000 description 5
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 5
• 230000036772 blood pressure Effects 0.000 description 5
• 238000009835 boiling Methods 0.000 description 5
• 125000004122 cyclic group Chemical group 0.000 description 5
• 150000004820 halides Chemical class 0.000 description 5
• 239000003112 inhibitor Substances 0.000 description 5
• IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 5
• 239000002808 molecular sieve Substances 0.000 description 5
• 201000001119 neuropathy Diseases 0.000 description 5
• 230000007823 neuropathy Effects 0.000 description 5
• 239000012038 nucleophile Substances 0.000 description 5
• 238000005580 one pot reaction Methods 0.000 description 5
• 229920001223 polyethylene glycol Polymers 0.000 description 5
• 125000003226 pyrazolyl group Chemical group 0.000 description 5
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
• 229910000029 sodium carbonate Inorganic materials 0.000 description 5
• 238000003756 stirring Methods 0.000 description 5
• 238000006467 substitution reaction Methods 0.000 description 5
• 150000003512 tertiary amines Chemical class 0.000 description 5
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
• 239000008096 xylene Substances 0.000 description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• GHKYDKKHTDOYEI-UHFFFAOYSA-N 4-amino-5-ethyl-1-(2-methoxyethyl)pyrazole-3-carboxamide Chemical compound CCC1=C(N)C(C(N)=O)=NN1CCOC GHKYDKKHTDOYEI-UHFFFAOYSA-N 0.000 description 4
• 201000004384 Alopecia Diseases 0.000 description 4
• 208000024827 Alzheimer disease Diseases 0.000 description 4
• 206010002153 Anal fissure Diseases 0.000 description 4
• 206010002383 Angina Pectoris Diseases 0.000 description 4
• 208000016583 Anus disease Diseases 0.000 description 4
• 201000001320 Atherosclerosis Diseases 0.000 description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
• 208000007342 Diabetic Nephropathies Diseases 0.000 description 4
• 206010013935 Dysmenorrhoea Diseases 0.000 description 4
• 208000009531 Fissure in Ano Diseases 0.000 description 4
• 206010019280 Heart failures Diseases 0.000 description 4
• 206010020772 Hypertension Diseases 0.000 description 4
• 206010021639 Incontinence Diseases 0.000 description 4
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
• 206010027476 Metastases Diseases 0.000 description 4
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 4
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
• 206010028980 Neoplasm Diseases 0.000 description 4
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
• 208000018262 Peripheral vascular disease Diseases 0.000 description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
• 208000005107 Premature Birth Diseases 0.000 description 4
• 201000004681 Psoriasis Diseases 0.000 description 4
• 206010039085 Rhinitis allergic Diseases 0.000 description 4
• 206010040893 Skin necrosis Diseases 0.000 description 4
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
• 229920002472 Starch Polymers 0.000 description 4
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
• WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
• 239000012346 acetyl chloride Substances 0.000 description 4
• 206010001053 acute respiratory failure Diseases 0.000 description 4
• 239000000443 aerosol Substances 0.000 description 4
• 125000003342 alkenyl group Chemical group 0.000 description 4
• 239000002168 alkylating agent Substances 0.000 description 4
• 229940100198 alkylating agent Drugs 0.000 description 4
• 201000009961 allergic asthma Diseases 0.000 description 4
• 201000010105 allergic rhinitis Diseases 0.000 description 4
• 235000019270 ammonium chloride Nutrition 0.000 description 4
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
• 208000006673 asthma Diseases 0.000 description 4
• 230000002567 autonomic effect Effects 0.000 description 4
• 229940077388 benzenesulfonate Drugs 0.000 description 4
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
• 206010006451 bronchitis Diseases 0.000 description 4
• 239000011575 calcium Substances 0.000 description 4
• MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 4
• 201000011510 cancer Diseases 0.000 description 4
• 239000002775 capsule Substances 0.000 description 4
• 239000001569 carbon dioxide Substances 0.000 description 4
• 229910002092 carbon dioxide Inorganic materials 0.000 description 4
• 208000023819 chronic asthma Diseases 0.000 description 4
• ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
• 208000029078 coronary artery disease Diseases 0.000 description 4
• 238000002425 crystallisation Methods 0.000 description 4
• 230000008025 crystallization Effects 0.000 description 4
• DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 4
• 208000033679 diabetic kidney disease Diseases 0.000 description 4
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
• 150000002148 esters Chemical group 0.000 description 4
• 238000001631 haemodialysis Methods 0.000 description 4
• 230000003676 hair loss Effects 0.000 description 4
• 230000000322 hemodialysis Effects 0.000 description 4
• 208000014617 hemorrhoid Diseases 0.000 description 4
• FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
• 230000008706 hypoxic vasoconstriction Effects 0.000 description 4
• 230000008991 intestinal motility Effects 0.000 description 4
• 230000000155 isotopic effect Effects 0.000 description 4
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
• 235000019341 magnesium sulphate Nutrition 0.000 description 4
• 229910052987 metal hydride Inorganic materials 0.000 description 4
• 150000004681 metal hydrides Chemical class 0.000 description 4
• 230000009401 metastasis Effects 0.000 description 4
• UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
• 201000006417 multiple sclerosis Diseases 0.000 description 4
• FCVTUHVLKGWQKP-UHFFFAOYSA-N n-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)pyrazol-4-yl]-2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxamide Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(=O)NC1=C(CC)N(CCOC)N=C1C(N)=O FCVTUHVLKGWQKP-UHFFFAOYSA-N 0.000 description 4
• 239000006199 nebulizer Substances 0.000 description 4
• BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
• 230000000269 nucleophilic effect Effects 0.000 description 4
• 239000012044 organic layer Substances 0.000 description 4
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
• 235000019271 petrolatum Nutrition 0.000 description 4
• 201000011461 pre-eclampsia Diseases 0.000 description 4
• 208000002815 pulmonary hypertension Diseases 0.000 description 4
• WAJNANMQOPCIPO-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-7-one Chemical class O=C1N=CN=C2C=NN=C12 WAJNANMQOPCIPO-UHFFFAOYSA-N 0.000 description 4
• 230000009467 reduction Effects 0.000 description 4
• 238000006722 reduction reaction Methods 0.000 description 4
• 201000004193 respiratory failure Diseases 0.000 description 4
• 229940001593 sodium carbonate Drugs 0.000 description 4
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
• 208000020431 spinal cord injury Diseases 0.000 description 4
• 230000006641 stabilisation Effects 0.000 description 4
• 238000011105 stabilization Methods 0.000 description 4
• 229940032147 starch Drugs 0.000 description 4
• 239000008107 starch Substances 0.000 description 4
• 235000019698 starch Nutrition 0.000 description 4
• 239000000126 substance Substances 0.000 description 4
• 208000024891 symptom Diseases 0.000 description 4
• 208000011580 syndromic disease Diseases 0.000 description 4
• PCRIWLRXFJTJPJ-UHFFFAOYSA-N 2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylic acid Chemical compound C1=C(C(O)=O)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 PCRIWLRXFJTJPJ-UHFFFAOYSA-N 0.000 description 3
• 206010061666 Autonomic neuropathy Diseases 0.000 description 3
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• 241000283690 Bos taurus Species 0.000 description 3
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
• 206010007559 Cardiac failure congestive Diseases 0.000 description 3
• 208000005171 Dysmenorrhea Diseases 0.000 description 3
• 108010010803 Gelatin Proteins 0.000 description 3
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
• 206010021518 Impaired gastric emptying Diseases 0.000 description 3
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
• 241000557624 Nucifraga Species 0.000 description 3
• 235000019502 Orange oil Nutrition 0.000 description 3
• 241000283973 Oryctolagus cuniculus Species 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• 206010036590 Premature baby Diseases 0.000 description 3
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
• 239000003513 alkali Substances 0.000 description 3
• 238000005804 alkylation reaction Methods 0.000 description 3
• 125000003277 amino group Chemical group 0.000 description 3
• 125000004429 atom Chemical group 0.000 description 3
• 239000008280 blood Substances 0.000 description 3
• 210000004369 blood Anatomy 0.000 description 3
• 229910052791 calcium Inorganic materials 0.000 description 3
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
• 150000003857 carboxamides Chemical class 0.000 description 3
• 230000003197 catalytic effect Effects 0.000 description 3
• 239000007810 chemical reaction solvent Substances 0.000 description 3
• 229910000366 copper(II) sulfate Inorganic materials 0.000 description 3
• 239000006071 cream Substances 0.000 description 3
• 238000006880 cross-coupling reaction Methods 0.000 description 3
• 238000010511 deprotection reaction Methods 0.000 description 3
• 201000010099 disease Diseases 0.000 description 3
• 210000003238 esophagus Anatomy 0.000 description 3
• CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
• 150000002170 ethers Chemical class 0.000 description 3
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
• 239000012065 filter cake Substances 0.000 description 3
• 208000001288 gastroparesis Diseases 0.000 description 3
• 239000008273 gelatin Substances 0.000 description 3
• 229920000159 gelatin Polymers 0.000 description 3
• 235000019322 gelatine Nutrition 0.000 description 3
• 235000011852 gelatine desserts Nutrition 0.000 description 3
• 125000001188 haloalkyl group Chemical group 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• 238000000338 in vitro Methods 0.000 description 3
• 238000011065 in-situ storage Methods 0.000 description 3
• 230000002401 inhibitory effect Effects 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• 229910052744 lithium Inorganic materials 0.000 description 3
• 229910052749 magnesium Inorganic materials 0.000 description 3
• 239000011777 magnesium Substances 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• 238000002844 melting Methods 0.000 description 3
• 230000008018 melting Effects 0.000 description 3
• 239000002674 ointment Substances 0.000 description 3
• 239000010502 orange oil Substances 0.000 description 3
• 230000002093 peripheral effect Effects 0.000 description 3
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
• 235000013772 propylene glycol Nutrition 0.000 description 3
• 210000001525 retina Anatomy 0.000 description 3
• 239000011780 sodium chloride Substances 0.000 description 3
• 235000010288 sodium nitrite Nutrition 0.000 description 3
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
• 239000007921 spray Substances 0.000 description 3
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
• 230000009466 transformation Effects 0.000 description 3
• 238000000844 transformation Methods 0.000 description 3
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
• LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
• LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 2
• SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
• DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
• AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 2
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
• IQVOLDCMCJDUFR-UHFFFAOYSA-N 2-(2-ethoxyethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(CCOCC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 IQVOLDCMCJDUFR-UHFFFAOYSA-N 0.000 description 2
• RXWOHFUULDINMC-UHFFFAOYSA-N 2-(3-nitrothiophen-2-yl)acetic acid Chemical compound OC(=O)CC=1SC=CC=1[N+]([O-])=O RXWOHFUULDINMC-UHFFFAOYSA-N 0.000 description 2
• ZOSSPVVBOIYOBG-UHFFFAOYSA-N 2-(cyclobutylmethyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(CC4CCC4)C(CC)=C3N=2)=C1 ZOSSPVVBOIYOBG-UHFFFAOYSA-N 0.000 description 2
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
• UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 2
• XKRXMWPVDJKAJI-UHFFFAOYSA-N 2-cyclobutyl-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C2CCC2)=C1 XKRXMWPVDJKAJI-UHFFFAOYSA-N 0.000 description 2
• GMRKCXFZJBCTEM-UHFFFAOYSA-N 2-cyclobutyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CCC1 GMRKCXFZJBCTEM-UHFFFAOYSA-N 0.000 description 2
• ZUWITCSMJULFEU-UHFFFAOYSA-N 2-oxo-5-sulfo-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(S(O)(=O)=O)=CNC1=O ZUWITCSMJULFEU-UHFFFAOYSA-N 0.000 description 2
• JVXDFTZWKFHULK-UHFFFAOYSA-N 4-amino-1h-pyrazole-5-carboxamide Chemical class NC(=O)C=1NN=CC=1N JVXDFTZWKFHULK-UHFFFAOYSA-N 0.000 description 2
• OEOQYHINYSQQOO-UHFFFAOYSA-N 4-nitro-5-propyl-1h-pyrazole-3-carboxamide Chemical compound CCCC1=NNC(C(N)=O)=C1[N+]([O-])=O OEOQYHINYSQQOO-UHFFFAOYSA-N 0.000 description 2
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
• KYLOFMQLLNEPBT-UHFFFAOYSA-N 5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-2-[2-(dimethylamino)ethyl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCN(C)C)C(CC)=C3N=2)C(OCCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 KYLOFMQLLNEPBT-UHFFFAOYSA-N 0.000 description 2
• USCAQVLUGMUUDT-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-2-(2-methoxyethyl)-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC=1N(CCOC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 USCAQVLUGMUUDT-UHFFFAOYSA-N 0.000 description 2
• WDDGZVPNBSLANI-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-hydroxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCO)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 WDDGZVPNBSLANI-UHFFFAOYSA-N 0.000 description 2
• IPKJZIIPYPKKDR-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-2-(2-methoxyethyl)-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC=1N(CCOC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 IPKJZIIPYPKKDR-UHFFFAOYSA-N 0.000 description 2
• AJOWMAMISRGPEP-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(C)CC1 AJOWMAMISRGPEP-UHFFFAOYSA-N 0.000 description 2
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
• 206010027654 Allergic conditions Diseases 0.000 description 2
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
• ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
• 101000856746 Bos taurus Cytochrome c oxidase subunit 7A1, mitochondrial Proteins 0.000 description 2
• DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
• 239000004215 Carbon black (E152) Substances 0.000 description 2
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
• 229920002785 Croscarmellose sodium Polymers 0.000 description 2
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
• 102000004190 Enzymes Human genes 0.000 description 2
• 108090000790 Enzymes Proteins 0.000 description 2
• 239000001856 Ethyl cellulose Substances 0.000 description 2
• ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 2
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
• 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
• TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
• AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 2
• 238000005481 NMR spectroscopy Methods 0.000 description 2
• 239000007832 Na2SO4 Substances 0.000 description 2
• 239000004264 Petrolatum Substances 0.000 description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
• 229940124639 Selective inhibitor Drugs 0.000 description 2
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
• 239000004147 Sorbitan trioleate Substances 0.000 description 2
• PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
• 239000003929 acidic solution Substances 0.000 description 2
• 230000002378 acidificating effect Effects 0.000 description 2
• 230000009471 action Effects 0.000 description 2
• 230000003213 activating effect Effects 0.000 description 2
• 230000029936 alkylation Effects 0.000 description 2
• 208000026935 allergic disease Diseases 0.000 description 2
• 239000003125 aqueous solvent Substances 0.000 description 2
• 125000003118 aryl group Chemical group 0.000 description 2
• 150000001502 aryl halides Chemical class 0.000 description 2
• 238000003556 assay Methods 0.000 description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
• 239000011324 bead Substances 0.000 description 2
• 230000008901 benefit Effects 0.000 description 2
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
• 230000004071 biological effect Effects 0.000 description 2
• 239000012455 biphasic mixture Substances 0.000 description 2
• 239000006227 byproduct Substances 0.000 description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
• 150000001733 carboxylic acid esters Chemical class 0.000 description 2
• 150000001735 carboxylic acids Chemical class 0.000 description 2
• NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
• 235000015165 citric acid Nutrition 0.000 description 2
• 239000011248 coating agent Substances 0.000 description 2
• 238000000576 coating method Methods 0.000 description 2
• ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
• OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
• 230000008878 coupling Effects 0.000 description 2
• 238000010168 coupling process Methods 0.000 description 2
• 229960001681 croscarmellose sodium Drugs 0.000 description 2
• 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
• 238000000354 decomposition reaction Methods 0.000 description 2
• 230000001419 dependent effect Effects 0.000 description 2
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
• SPBWMYPZWNFWES-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N SPBWMYPZWNFWES-UHFFFAOYSA-N 0.000 description 2
• 238000001035 drying Methods 0.000 description 2
• 239000003995 emulsifying agent Substances 0.000 description 2
• WGZCSAGASVIPAI-UHFFFAOYSA-N ethyl 2-chloro-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound N1=C(Cl)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(CC)CC2)=C1 WGZCSAGASVIPAI-UHFFFAOYSA-N 0.000 description 2
• YOXICXXCICYQKS-UHFFFAOYSA-N ethyl 2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound N1=C(OCC)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(CC)CC2)=C1 YOXICXXCICYQKS-UHFFFAOYSA-N 0.000 description 2
• 235000019325 ethyl cellulose Nutrition 0.000 description 2
• 229920001249 ethyl cellulose Polymers 0.000 description 2
• 238000001704 evaporation Methods 0.000 description 2
• 230000008020 evaporation Effects 0.000 description 2
• 208000030533 eye disease Diseases 0.000 description 2
• 229910052731 fluorine Inorganic materials 0.000 description 2
• 238000001640 fractional crystallisation Methods 0.000 description 2
• 239000000446 fuel Substances 0.000 description 2
• 125000000524 functional group Chemical group 0.000 description 2
• 235000011187 glycerol Nutrition 0.000 description 2
• 210000001308 heart ventricle Anatomy 0.000 description 2
• FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
• 238000004128 high performance liquid chromatography Methods 0.000 description 2
• 229930195733 hydrocarbon Natural products 0.000 description 2
• 150000002430 hydrocarbons Chemical class 0.000 description 2
• 238000005984 hydrogenation reaction Methods 0.000 description 2
• 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
• 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
• 239000005457 ice water Substances 0.000 description 2
• 238000001727 in vivo Methods 0.000 description 2
• 239000004615 ingredient Substances 0.000 description 2
• 239000007926 intracavernous injection Substances 0.000 description 2
• 238000001990 intravenous administration Methods 0.000 description 2
• 229910052740 iodine Inorganic materials 0.000 description 2
• 208000002551 irritable bowel syndrome Diseases 0.000 description 2
• ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
• 239000006210 lotion Substances 0.000 description 2
• 239000000314 lubricant Substances 0.000 description 2
• 235000019359 magnesium stearate Nutrition 0.000 description 2
• 238000005259 measurement Methods 0.000 description 2
• 229910044991 metal oxide Inorganic materials 0.000 description 2
• 150000004706 metal oxides Chemical class 0.000 description 2
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
• GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
• 230000004048 modification Effects 0.000 description 2
• 238000012986 modification Methods 0.000 description 2
• 239000003607 modifier Substances 0.000 description 2
• 150000004712 monophosphates Chemical class 0.000 description 2
• 235000001968 nicotinic acid Nutrition 0.000 description 2
• 239000011664 nicotinic acid Substances 0.000 description 2
• 229960003512 nicotinic acid Drugs 0.000 description 2
• LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
• 231100000252 nontoxic Toxicity 0.000 description 2
• 230000003000 nontoxic effect Effects 0.000 description 2
• 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
• TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
• 239000001301 oxygen Substances 0.000 description 2
• 229910052760 oxygen Inorganic materials 0.000 description 2
• 229910052763 palladium Inorganic materials 0.000 description 2
• 238000007911 parenteral administration Methods 0.000 description 2
• 230000037361 pathway Effects 0.000 description 2
• 229940066842 petrolatum Drugs 0.000 description 2
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
• 238000001144 powder X-ray diffraction data Methods 0.000 description 2
• 238000000746 purification Methods 0.000 description 2
• 150000003217 pyrazoles Chemical class 0.000 description 2
• 125000001453 quaternary ammonium group Chemical group 0.000 description 2
• 238000004007 reversed phase HPLC Methods 0.000 description 2
• HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
• 238000002821 scintillation proximity assay Methods 0.000 description 2
• 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
• 210000002027 skeletal muscle Anatomy 0.000 description 2
• 235000009518 sodium iodide Nutrition 0.000 description 2
• 229940083618 sodium nitroprusside Drugs 0.000 description 2
• 239000008109 sodium starch glycolate Substances 0.000 description 2
• 229920003109 sodium starch glycolate Polymers 0.000 description 2
• 229940079832 sodium starch glycolate Drugs 0.000 description 2
• 229910052938 sodium sulfate Inorganic materials 0.000 description 2
• 235000011152 sodium sulphate Nutrition 0.000 description 2
• 235000019337 sorbitan trioleate Nutrition 0.000 description 2
• 229960000391 sorbitan trioleate Drugs 0.000 description 2
• 238000001228 spectrum Methods 0.000 description 2
• HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
• 239000000375 suspending agent Substances 0.000 description 2
• 238000013268 sustained release Methods 0.000 description 2
• 239000012730 sustained-release form Substances 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 2
• 210000001519 tissue Anatomy 0.000 description 2
• 125000003944 tolyl group Chemical group 0.000 description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
• 210000005166 vasculature Anatomy 0.000 description 2
• DPXABRZASYWNOE-RXMQYKEDSA-N (2R)-2-methylbutane-1-sulfonic acid Chemical compound CC[C@@H](C)CS(O)(=O)=O DPXABRZASYWNOE-RXMQYKEDSA-N 0.000 description 1
• BTANRVKWQNVYAZ-SCSAIBSYSA-N (2R)-butan-2-ol Chemical compound CC[C@@H](C)O BTANRVKWQNVYAZ-SCSAIBSYSA-N 0.000 description 1
• BTANRVKWQNVYAZ-BYPYZUCNSA-N (2S)-butan-2-ol Chemical compound CC[C@H](C)O BTANRVKWQNVYAZ-BYPYZUCNSA-N 0.000 description 1
• JYVLIDXNZAXMDK-RXMQYKEDSA-N (2r)-pentan-2-ol Chemical compound CCC[C@@H](C)O JYVLIDXNZAXMDK-RXMQYKEDSA-N 0.000 description 1
• LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
• CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 1
• WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
• MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
• YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
• NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
• DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
• JEHHBSFWXNNGBI-UHFFFAOYSA-N 1-(2-methoxyethyl)-4-nitro-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=C([N+]([O-])=O)C(C(N)=O)=NN1CCOC JEHHBSFWXNNGBI-UHFFFAOYSA-N 0.000 description 1
• XWPYRBXBZULFKE-UHFFFAOYSA-N 1-(5-bromo-6-chloropyridin-3-yl)sulfonyl-4-ethylpiperazine Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(Cl)C(Br)=C1 XWPYRBXBZULFKE-UHFFFAOYSA-N 0.000 description 1
• DMXGFDSGVSISBY-UHFFFAOYSA-N 1-(5-bromo-6-chloropyridin-3-yl)sulfonyl-4-methylpiperazine Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CN=C(Cl)C(Br)=C1 DMXGFDSGVSISBY-UHFFFAOYSA-N 0.000 description 1
• ZMCLXTAKNVTOJO-UHFFFAOYSA-N 1-(5-bromo-6-ethoxypyridin-3-yl)sulfonyl-4-ethylpiperazine Chemical compound C1=C(Br)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 ZMCLXTAKNVTOJO-UHFFFAOYSA-N 0.000 description 1
• RDXXMEQXCWOIFC-UHFFFAOYSA-N 1-(5-bromo-6-ethoxypyridin-3-yl)sulfonyl-4-methylpiperazine Chemical compound C1=C(Br)C(OCC)=NC=C1S(=O)(=O)N1CCN(C)CC1 RDXXMEQXCWOIFC-UHFFFAOYSA-N 0.000 description 1
• LKMWWOKLUDPKDP-UHFFFAOYSA-N 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethyl-4-nitropyrazole-3-carboxamide Chemical compound CCC1=C([N+]([O-])=O)C(C(N)=O)=NN1CCO[Si](C)(C)C(C)(C)C LKMWWOKLUDPKDP-UHFFFAOYSA-N 0.000 description 1
• OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
• FOZVXADQAHVUSV-UHFFFAOYSA-N 1-bromo-2-(2-bromoethoxy)ethane Chemical compound BrCCOCCBr FOZVXADQAHVUSV-UHFFFAOYSA-N 0.000 description 1
• HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 1
• CAFAOQIVXSSFSY-UHFFFAOYSA-N 1-ethoxyethanol Chemical group CCOC(C)O CAFAOQIVXSSFSY-UHFFFAOYSA-N 0.000 description 1
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
• WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
• WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-UHFFFAOYSA-N 0.000 description 1
• QLEIDMAURCRVCX-UHFFFAOYSA-N 1-propylpiperazine Chemical compound CCCN1CCNCC1 QLEIDMAURCRVCX-UHFFFAOYSA-N 0.000 description 1
• 238000005160 1H NMR spectroscopy Methods 0.000 description 1
• OXQHJIGWZNIQDS-UHFFFAOYSA-N 2,2-dimethoxybutane Chemical compound CCC(C)(OC)OC OXQHJIGWZNIQDS-UHFFFAOYSA-N 0.000 description 1
• RYNFWKBAUMOGOO-UHFFFAOYSA-N 2,5-diethylpyrazole-3-carboxylic acid Chemical compound CCC=1C=C(C(O)=O)N(CC)N=1 RYNFWKBAUMOGOO-UHFFFAOYSA-N 0.000 description 1
• MVINGZXKOVPFKX-UHFFFAOYSA-N 2-(1,3-benzoxazol-2-yl)-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C=2OC3=CC=CC=C3N=2)=C1 MVINGZXKOVPFKX-UHFFFAOYSA-N 0.000 description 1
• HOSHWJFJTDRLSY-UHFFFAOYSA-N 2-(1-acetylpiperidin-4-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CCN(C(C)=O)CC1 HOSHWJFJTDRLSY-UHFFFAOYSA-N 0.000 description 1
• SQEAOJIOKHEZSL-UHFFFAOYSA-N 2-(2-methoxyethyl)-4-nitro-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=NN(CCOC)C(C(N)=O)=C1[N+]([O-])=O SQEAOJIOKHEZSL-UHFFFAOYSA-N 0.000 description 1
• PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
• JFTKLBDUXIPJPG-UHFFFAOYSA-N 2-(4-aminophenyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=CC=C(N)C=C1 JFTKLBDUXIPJPG-UHFFFAOYSA-N 0.000 description 1
• XKUCRVCDTWWQTL-UHFFFAOYSA-N 2-(6-chloropyrimidin-4-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=CC(Cl)=NC=N1 XKUCRVCDTWWQTL-UHFFFAOYSA-N 0.000 description 1
• KYHGMLQWBPPPGF-UHFFFAOYSA-N 2-(azetidin-3-yl)-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-pentan-2-yloxypyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CCCC(C)OC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC1=C2CC)=NC(=O)C1=NN2C1CNC1 KYHGMLQWBPPPGF-UHFFFAOYSA-N 0.000 description 1
• AMDBFHJQMFFWBV-UHFFFAOYSA-N 2-(azetidin-3-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC1=C2CC)=NC(=O)C1=NN2C1CNC1 AMDBFHJQMFFWBV-UHFFFAOYSA-N 0.000 description 1
• MRVKISAJENLFTB-UHFFFAOYSA-N 2-(cyclobutylmethyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-pyrrolidin-1-ylpyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C(C=C1C=2NC(=O)C3=NN(CC4CCC4)C(CC)=C3N=2)=CN=C1N1CCCC1 MRVKISAJENLFTB-UHFFFAOYSA-N 0.000 description 1
• UNXPOOHHOFQHOO-UHFFFAOYSA-N 2-(cyclopentylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2CC1CCCC1 UNXPOOHHOFQHOO-UHFFFAOYSA-N 0.000 description 1
• YBWFBUINTRROIH-UHFFFAOYSA-N 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCO[Si](C)(C)C(C)(C)C)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 YBWFBUINTRROIH-UHFFFAOYSA-N 0.000 description 1
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
• FJHGMUDVUAXUEK-UHFFFAOYSA-N 2-amino-4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C(N)=C1 FJHGMUDVUAXUEK-UHFFFAOYSA-N 0.000 description 1
• RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
• JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 description 1
• CBEDHUWRUQKFEX-UHFFFAOYSA-N 2-bromooxolane Chemical compound BrC1CCCO1 CBEDHUWRUQKFEX-UHFFFAOYSA-N 0.000 description 1
• IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
• BBVQDWDBTWSGHQ-UHFFFAOYSA-N 2-chloro-1,3-benzoxazole Chemical compound C1=CC=C2OC(Cl)=NC2=C1 BBVQDWDBTWSGHQ-UHFFFAOYSA-N 0.000 description 1
• ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 1
• XBPPLECAZBTMMK-UHFFFAOYSA-N 2-chloro-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CCl XBPPLECAZBTMMK-UHFFFAOYSA-N 0.000 description 1
• GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 1
• XTUONRBNDFFKMH-UHFFFAOYSA-N 2-cyclohexyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CCCCC1 XTUONRBNDFFKMH-UHFFFAOYSA-N 0.000 description 1
• AWTKWYNUEPYTKP-UHFFFAOYSA-N 2-cyclopentyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CCCC1 AWTKWYNUEPYTKP-UHFFFAOYSA-N 0.000 description 1
• LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 1
• GLSREOLUIPGEMD-UHFFFAOYSA-N 2-ethoxy-5-nitropyridine-3-carboxylic acid Chemical compound CCOC1=NC=C([N+]([O-])=O)C=C1C(O)=O GLSREOLUIPGEMD-UHFFFAOYSA-N 0.000 description 1
• XCMJQQOMGWGGSI-UHFFFAOYSA-N 2-ethoxypyridine-3-carboxylic acid Chemical compound CCOC1=NC=CC=C1C(O)=O XCMJQQOMGWGGSI-UHFFFAOYSA-N 0.000 description 1
• MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
• LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
• LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
• ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
• STSWPBIENBHBND-UHFFFAOYSA-N 3,6-dichloro-5-ethoxycarbonylpyridine-2-sulfonic acid Chemical compound CCOC(=O)C1=CC(Cl)=C(S(O)(=O)=O)N=C1Cl STSWPBIENBHBND-UHFFFAOYSA-N 0.000 description 1
• PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 1
• UZTBWIADHKSPTG-UHFFFAOYSA-N 3-ethyl-2-(2-methoxyethyl)-5-[5-(4-methylpiperazin-1-yl)sulfonyl-2-(2-methylpropoxy)pyridin-3-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(CCOC)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCC(C)C)=CC=1S(=O)(=O)N1CCN(C)CC1 UZTBWIADHKSPTG-UHFFFAOYSA-N 0.000 description 1
• KPSBFMNMIOHYPY-UHFFFAOYSA-N 3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-2-(2-methylpropyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCC=1N(CC(C)C)N=C(C(N2)=O)C=1N=C2C(C(=NC=1)OCCOC)=CC=1S(=O)(=O)N1CCN(C)CC1 KPSBFMNMIOHYPY-UHFFFAOYSA-N 0.000 description 1
• UZXBVHSZAINNCM-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(1-methoxypropan-2-yloxy)pyridin-3-yl]-2-(2-hydroxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OC(C)COC)C(C=2NC(=O)C3=NN(CCO)C(CC)=C3N=2)=C1 UZXBVHSZAINNCM-UHFFFAOYSA-N 0.000 description 1
• QQXLMOBJFYPLBM-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-(1-methoxypropan-2-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C(C)COC)=C1 QQXLMOBJFYPLBM-UHFFFAOYSA-N 0.000 description 1
• FOOKSXFTEWJFEU-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-phenyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C=2C=CC=CC=2)=C1 FOOKSXFTEWJFEU-UHFFFAOYSA-N 0.000 description 1
• SISGKOAGBAJWPA-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methylpropoxy)pyridin-3-yl]-2-(1-methylpiperidin-4-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCC(C)C)C(C=2NC(=O)C3=NN(C(CC)=C3N=2)C2CCN(C)CC2)=C1 SISGKOAGBAJWPA-UHFFFAOYSA-N 0.000 description 1
• BBPNZVJTVWJYCT-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-propoxypyridin-3-yl]-2-[2-(methylamino)ethyl]-4h-pyrazolo[4,3-d]pyrimidin-7-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=C(C=2NC3=C(CC)N(CCNC)N=C3C(=O)N=2)C(OCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 BBPNZVJTVWJYCT-UHFFFAOYSA-N 0.000 description 1
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
• XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 1
• RMTOBEKVSJFANN-UHFFFAOYSA-N 4-[5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]benzonitrile Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=CC=C(C#N)C=C1 RMTOBEKVSJFANN-UHFFFAOYSA-N 0.000 description 1
• YZLURMSOHHDSEI-UHFFFAOYSA-N 4-amino-2-(2-methoxyethyl)-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=NN(CCOC)C(C(N)=O)=C1N YZLURMSOHHDSEI-UHFFFAOYSA-N 0.000 description 1
• YIAXJRMRAWYVOG-UHFFFAOYSA-N 4-amino-5-ethyl-1h-pyrazole-3-carboxamide Chemical compound CCC=1NN=C(C(N)=O)C=1N YIAXJRMRAWYVOG-UHFFFAOYSA-N 0.000 description 1
• QYDDQYQBBQASQB-UHFFFAOYSA-N 4-amino-5-ethyl-2-(2-methoxyethyl)pyrazole-3-carboxamide Chemical compound CCC1=NN(CCOC)C(C(N)=O)=C1N QYDDQYQBBQASQB-UHFFFAOYSA-N 0.000 description 1
• WTLTYNIWFANVBQ-UHFFFAOYSA-N 4-nitro-5-propyl-1h-pyrazole-3-carboxylic acid Chemical compound CCCC=1NN=C(C(O)=O)C=1[N+]([O-])=O WTLTYNIWFANVBQ-UHFFFAOYSA-N 0.000 description 1
• BATQJVQLMGRROE-UHFFFAOYSA-N 5-(2-ethoxypyridin-3-yl)pyrazolo[4,3-d]pyrimidin-3-one Chemical compound CCOC1=NC=CC=C1C1=NC=C(N=NC2=O)C2=N1 BATQJVQLMGRROE-UHFFFAOYSA-N 0.000 description 1
• GOGJDFLHQGFALX-KRWDZBQOSA-N 5-[2-[(2s)-butan-2-yl]oxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(O[C@@H](C)CC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 GOGJDFLHQGFALX-KRWDZBQOSA-N 0.000 description 1
• XHEWFWLSKNTLNI-UHFFFAOYSA-N 5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-methylsulfonylpiperidin-4-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CCN(S(C)(=O)=O)CC1 XHEWFWLSKNTLNI-UHFFFAOYSA-N 0.000 description 1
• IEKBOZAFRXXLHO-UHFFFAOYSA-N 5-[2-butoxy-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(OCCCC)=NC=C1S(=O)(=O)N1CCN(C)CC1 IEKBOZAFRXXLHO-UHFFFAOYSA-N 0.000 description 1
• ZOYZVDYPQZRIFO-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1,3-thiazol-2-yl)-4h-pyrazolo[4,3-d]pyrimidin-7-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=NC=CS1 ZOYZVDYPQZRIFO-UHFFFAOYSA-N 0.000 description 1
• XKMPNUJSWZDBSC-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one;ethyl acetate Chemical compound CCOC(C)=O.C1=C(C=2NC(=O)C3=NN(CCOC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 XKMPNUJSWZDBSC-UHFFFAOYSA-N 0.000 description 1
• WMEHLBHAZNTVML-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(4-nitrophenyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=CC=C([N+]([O-])=O)C=C1 WMEHLBHAZNTVML-UHFFFAOYSA-N 0.000 description 1
• JMIOIYJBQYLMRL-MRXNPFEDSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-[(2r)-1-methoxypropan-2-yl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(C(CC)=C3N=2)[C@H](C)COC)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 JMIOIYJBQYLMRL-MRXNPFEDSA-N 0.000 description 1
• AZGBDPULDMVEHU-MRXNPFEDSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-[(2r)-2-methoxypropyl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(C[C@@H](C)OC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 AZGBDPULDMVEHU-MRXNPFEDSA-N 0.000 description 1
• AZGBDPULDMVEHU-INIZCTEOSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-[(2s)-2-methoxypropyl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1=C(C=2NC(=O)C3=NN(C[C@H](C)OC)C(CC)=C3N=2)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 AZGBDPULDMVEHU-INIZCTEOSA-N 0.000 description 1
• NMEFXGPLRHHGTK-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-phenyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=CC=CC=C1 NMEFXGPLRHHGTK-UHFFFAOYSA-N 0.000 description 1
• LTMFISHMFXAIDU-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-pyrazin-2-yl-4h-pyrazolo[4,3-d]pyrimidin-7-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC1=C2CC)=NC(=O)C1=NN2C1=CN=CC=N1 LTMFISHMFXAIDU-UHFFFAOYSA-N 0.000 description 1
• RNLQPIKEGLINPA-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-pyridin-2-yl-4h-pyrazolo[4,3-d]pyrimidin-7-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC1=C2CC)=NC(=O)C1=NN2C1=CC=CC=N1 RNLQPIKEGLINPA-UHFFFAOYSA-N 0.000 description 1
• QJHYJZXHHUUKFL-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-pyrimidin-2-yl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1=NC=CC=N1 QJHYJZXHHUUKFL-UHFFFAOYSA-N 0.000 description 1
• HBKVBJQMILKDAL-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-6-methyl-2-(oxolan-2-yl)pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C(C)OC1=NC=C(C=C1C=1N(C(C=2C(N=1)=C(N(N=2)C1OCCC1)CC)=O)C)S(=O)(=O)N1CCN(CC1)CC HBKVBJQMILKDAL-UHFFFAOYSA-N 0.000 description 1
• UKUOUKZDQRZMPM-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-1-(2-methoxyethyl)-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(CCOC)C(C(N2)=O)=C1N=C2C(C(=NC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 UKUOUKZDQRZMPM-UHFFFAOYSA-N 0.000 description 1
• BXIIVRFUQABYFR-UHFFFAOYSA-N 5-ethoxycarbonyl-6-oxo-1h-pyridine-3-sulfonic acid Chemical compound CCOC(=O)C1=CC(S(O)(=O)=O)=CN=C1O BXIIVRFUQABYFR-UHFFFAOYSA-N 0.000 description 1
• ILMFQVLABCULLJ-UHFFFAOYSA-N 5-ethyl-1h-pyrazole-3-carboxamide Chemical compound CCC=1C=C(C(N)=O)NN=1 ILMFQVLABCULLJ-UHFFFAOYSA-N 0.000 description 1
• SNZWUHRXJROWQL-UHFFFAOYSA-N 5-ethyl-2-(2-methoxyethyl)-4-nitropyrazole-3-carboxamide Chemical compound CCC1=NN(CCOC)C(C(N)=O)=C1[N+]([O-])=O SNZWUHRXJROWQL-UHFFFAOYSA-N 0.000 description 1
• UDYWTLMYXXTHKR-UHFFFAOYSA-N 5-ethyl-4-nitro-1h-pyrazole-3-carboxylic acid Chemical compound CCC=1NN=C(C(O)=O)C=1[N+]([O-])=O UDYWTLMYXXTHKR-UHFFFAOYSA-N 0.000 description 1
• MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 description 1
• QYPSYPPSHXDFLV-UHFFFAOYSA-N 5-propyl-1h-pyrazole-3-carboxylic acid Chemical compound CCCC1=CC(C(O)=O)=NN1 QYPSYPPSHXDFLV-UHFFFAOYSA-N 0.000 description 1
• JWMATMHMCVQDDI-UHFFFAOYSA-N 6-ethoxy-5-[5-ethyl-1-(2-methoxyethyl)pyrazol-3-yl]pyridin-3-amine;1,2,4,7-tetrahydropyrazolo[4,3-d]pyrimidin-3-one Chemical compound C1NC=NC2=C1NNC2=O.CCOC1=NC=C(N)C=C1C1=NN(CCOC)C(CC)=C1 JWMATMHMCVQDDI-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
• WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
• NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
• 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
• 200000000007 Arterial disease Diseases 0.000 description 1
• 108010011485 Aspartame Proteins 0.000 description 1
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
• 102000000584 Calmodulin Human genes 0.000 description 1
• 108010041952 Calmodulin Proteins 0.000 description 1
• 241000282472 Canis lupus familiaris Species 0.000 description 1
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
• 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
• RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
• 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
• DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
• RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
• 208000019505 Deglutition disease Diseases 0.000 description 1
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
• 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
• 206010013924 Dyskinesia oesophageal Diseases 0.000 description 1
• 208000030644 Esophageal Motility disease Diseases 0.000 description 1
• JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
• PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
• 208000010412 Glaucoma Diseases 0.000 description 1
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
• 239000004471 Glycine Substances 0.000 description 1
• 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
• 240000007472 Leucaena leucocephala Species 0.000 description 1
• 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
• 240000003183 Manihot esculenta Species 0.000 description 1
• 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
• 229930195725 Mannitol Natural products 0.000 description 1
• NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
• UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
• VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
• WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
• 239000005642 Oleic acid Substances 0.000 description 1
• ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
• 206010061323 Optic neuropathy Diseases 0.000 description 1
• BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
• 229910019142 PO4 Inorganic materials 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
• 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
• 229920001214 Polysorbate 60 Polymers 0.000 description 1
• GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 1
• 239000007868 Raney catalyst Substances 0.000 description 1
• 229910000564 Raney nickel Inorganic materials 0.000 description 1
• GOOHAUXETOMSMM-VKHMYHEASA-N S-propylene oxide Chemical compound C[C@H]1CO1 GOOHAUXETOMSMM-VKHMYHEASA-N 0.000 description 1
• 229920002125 Sokalan® Polymers 0.000 description 1
• 244000061456 Solanum tuberosum Species 0.000 description 1
• 235000002595 Solanum tuberosum Nutrition 0.000 description 1
• HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• 239000005864 Sulphur Substances 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
• 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
• 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
• 239000009975 Urodyn Substances 0.000 description 1
• 238000002441 X-ray diffraction Methods 0.000 description 1
• TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• 235000010358 acesulfame potassium Nutrition 0.000 description 1
• 229960004998 acesulfame potassium Drugs 0.000 description 1
• 239000000619 acesulfame-K Substances 0.000 description 1
• 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 150000001263 acyl chlorides Chemical class 0.000 description 1
• 125000002252 acyl group Chemical group 0.000 description 1
• 150000001298 alcohols Chemical class 0.000 description 1
• 125000001931 aliphatic group Chemical group 0.000 description 1
• 150000001340 alkali metals Chemical class 0.000 description 1
• 150000001342 alkaline earth metals Chemical class 0.000 description 1
• 125000004450 alkenylene group Chemical group 0.000 description 1
• 150000001350 alkyl halides Chemical class 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
• 125000006242 amine protecting group Chemical group 0.000 description 1
• 150000001413 amino acids Chemical class 0.000 description 1
• 150000001450 anions Chemical class 0.000 description 1
• 239000007900 aqueous suspension Substances 0.000 description 1
• 125000005333 aroyloxy group Chemical group 0.000 description 1
• 208000021328 arterial occlusion Diseases 0.000 description 1
• IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
• 239000000605 aspartame Substances 0.000 description 1
• 235000010357 aspartame Nutrition 0.000 description 1
• 229960003438 aspartame Drugs 0.000 description 1
• 239000012131 assay buffer Substances 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• 238000010533 azeotropic distillation Methods 0.000 description 1
• 150000001539 azetidines Chemical class 0.000 description 1
• 229910052788 barium Inorganic materials 0.000 description 1
• DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
• ZIQCCIAIROIHHR-UHFFFAOYSA-N benzene;boric acid Chemical compound OB(O)O.C1=CC=CC=C1 ZIQCCIAIROIHHR-UHFFFAOYSA-N 0.000 description 1
• SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
• 229940092714 benzenesulfonic acid Drugs 0.000 description 1
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
• 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
• 235000019445 benzyl alcohol Nutrition 0.000 description 1
• KHRLPNHFWHYDSC-UHFFFAOYSA-N benzyl n-[2-(4-amino-3-carbamoyl-5-ethylpyrazol-1-yl)ethyl]-n-methylcarbamate Chemical compound CCC1=C(N)C(C(N)=O)=NN1CCN(C)C(=O)OCC1=CC=CC=C1 KHRLPNHFWHYDSC-UHFFFAOYSA-N 0.000 description 1
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
• 229910052790 beryllium Inorganic materials 0.000 description 1
• ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• 239000011230 binding agent Substances 0.000 description 1
• 230000017531 blood circulation Effects 0.000 description 1
• 150000001639 boron compounds Chemical class 0.000 description 1
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
• 229940098773 bovine serum albumin Drugs 0.000 description 1
• SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
• KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 1
• 244000309464 bull Species 0.000 description 1
• ARLICSNDRXJHSP-UHFFFAOYSA-N butyl 3-[5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]azetidine-1-carboxylate Chemical compound C1N(C(=O)OCCCC)CC1N1C(CC)=C(N=C(NC2=O)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(CC)CC3)OCC)C2=N1 ARLICSNDRXJHSP-UHFFFAOYSA-N 0.000 description 1
• GQNGVPGVCFTYBZ-UHFFFAOYSA-N butyl 4-[5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCCCC)CCC1N1C(CC)=C(N=C(NC2=O)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(CC)CC3)OCC)C2=N1 GQNGVPGVCFTYBZ-UHFFFAOYSA-N 0.000 description 1
• 229910052792 caesium Inorganic materials 0.000 description 1
• TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
• 229910000019 calcium carbonate Inorganic materials 0.000 description 1
• 229960003563 calcium carbonate Drugs 0.000 description 1
• XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
• BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
• 239000000292 calcium oxide Substances 0.000 description 1
• ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
• 150000001718 carbodiimides Chemical class 0.000 description 1
• 229960001631 carbomer Drugs 0.000 description 1
• 229910002091 carbon monoxide Inorganic materials 0.000 description 1
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
• 239000001768 carboxy methyl cellulose Substances 0.000 description 1
• 239000004203 carnauba wax Substances 0.000 description 1
• 235000013869 carnauba wax Nutrition 0.000 description 1
• 239000004359 castor oil Substances 0.000 description 1
• 235000019438 castor oil Nutrition 0.000 description 1
• 150000001768 cations Chemical class 0.000 description 1
• 235000010980 cellulose Nutrition 0.000 description 1
• 229920002678 cellulose Polymers 0.000 description 1
• 239000001913 cellulose Substances 0.000 description 1
• 229920002301 cellulose acetate Polymers 0.000 description 1
• 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
• 229940081733 cetearyl alcohol Drugs 0.000 description 1
• 239000007795 chemical reaction product Substances 0.000 description 1
• 238000005660 chlorination reaction Methods 0.000 description 1
• 125000001309 chloro group Chemical group Cl* 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 229940001468 citrate Drugs 0.000 description 1
• 229960004106 citric acid Drugs 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 238000004040 coloring Methods 0.000 description 1
• 230000009918 complex formation Effects 0.000 description 1
• 238000013270 controlled release Methods 0.000 description 1
• 229920001577 copolymer Polymers 0.000 description 1
• 229910052802 copper Inorganic materials 0.000 description 1
• 239000010949 copper Substances 0.000 description 1
• JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
• 238000007887 coronary angioplasty Methods 0.000 description 1
• 239000006184 cosolvent Substances 0.000 description 1
• 239000007822 coupling agent Substances 0.000 description 1
• 229960000913 crospovidone Drugs 0.000 description 1
• 239000013078 crystal Substances 0.000 description 1
• 229960003280 cupric chloride Drugs 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 229940097362 cyclodextrins Drugs 0.000 description 1
• KOGOBKOHQTZGIS-UHFFFAOYSA-N cyclohexyl methanesulfonate Chemical compound CS(=O)(=O)OC1CCCCC1 KOGOBKOHQTZGIS-UHFFFAOYSA-N 0.000 description 1
• ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical compound OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 description 1
• VROBVTOKXNHTBI-UHFFFAOYSA-N cyclopentylmethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1CCCC1 VROBVTOKXNHTBI-UHFFFAOYSA-N 0.000 description 1
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
• 230000003111 delayed effect Effects 0.000 description 1
• 239000007933 dermal patch Substances 0.000 description 1
• 239000002274 desiccant Substances 0.000 description 1
• 238000001514 detection method Methods 0.000 description 1
• 229910052805 deuterium Inorganic materials 0.000 description 1
• 235000019700 dicalcium phosphate Nutrition 0.000 description 1
• 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
• 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
• 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
• 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
• ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
• 238000007907 direct compression Methods 0.000 description 1
• 238000006073 displacement reaction Methods 0.000 description 1
• 238000004090 dissolution Methods 0.000 description 1
• 238000009826 distribution Methods 0.000 description 1
• 238000007908 dry granulation Methods 0.000 description 1
• 229940112141 dry powder inhaler Drugs 0.000 description 1
• 230000009977 dual effect Effects 0.000 description 1
• 238000010410 dusting Methods 0.000 description 1
• 239000000975 dye Substances 0.000 description 1
• 230000004406 elevated intraocular pressure Effects 0.000 description 1
• 230000001804 emulsifying effect Effects 0.000 description 1
• 239000008387 emulsifying waxe Substances 0.000 description 1
• 238000010931 ester hydrolysis Methods 0.000 description 1
• 230000032050 esterification Effects 0.000 description 1
• 238000005886 esterification reaction Methods 0.000 description 1
• CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
• MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
• YFONSBZEAHNVCW-UHFFFAOYSA-N ethyl 5-ethyl-1h-pyrazole-3-carboxylate Chemical compound CCOC(=O)C=1C=C(CC)NN=1 YFONSBZEAHNVCW-UHFFFAOYSA-N 0.000 description 1
• 125000004494 ethyl ester group Chemical group 0.000 description 1
• 239000004744 fabric Substances 0.000 description 1
• 239000000945 filler Substances 0.000 description 1
• 238000001914 filtration Methods 0.000 description 1
• 239000012467 final product Substances 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 239000011737 fluorine Substances 0.000 description 1
• 239000012458 free base Substances 0.000 description 1
• 229910021485 fumed silica Inorganic materials 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 230000005714 functional activity Effects 0.000 description 1
• 239000007789 gas Substances 0.000 description 1
• 239000000499 gel Substances 0.000 description 1
• 239000007903 gelatin capsule Substances 0.000 description 1
• 239000012362 glacial acetic acid Substances 0.000 description 1
• 229940050410 gluconate Drugs 0.000 description 1
• 239000008103 glucose Substances 0.000 description 1
• ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
• 229940049654 glyceryl behenate Drugs 0.000 description 1
• 229960002449 glycine Drugs 0.000 description 1
• QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 description 1
• 239000008187 granular material Substances 0.000 description 1
• 238000005469 granulation Methods 0.000 description 1
• 230000003179 granulation Effects 0.000 description 1
• 239000010439 graphite Substances 0.000 description 1
• 229910002804 graphite Inorganic materials 0.000 description 1
• 125000004438 haloalkoxy group Chemical group 0.000 description 1
• 125000005843 halogen group Chemical group 0.000 description 1
• 230000026030 halogenation Effects 0.000 description 1
• 238000005658 halogenation reaction Methods 0.000 description 1
• 150000004688 heptahydrates Chemical class 0.000 description 1
• UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
• 150000004677 hydrates Chemical class 0.000 description 1
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
• 150000005828 hydrofluoroalkanes Chemical class 0.000 description 1
• 239000000017 hydrogel Substances 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
• 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
• 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
• JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
• 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
• 230000001771 impaired effect Effects 0.000 description 1
• 238000010348 incorporation Methods 0.000 description 1
• 230000001939 inductive effect Effects 0.000 description 1
• 238000001802 infusion Methods 0.000 description 1
• 230000005764 inhibitory process Effects 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• 229940030980 inova Drugs 0.000 description 1
• 239000013067 intermediate product Substances 0.000 description 1
• 238000001361 intraarterial administration Methods 0.000 description 1
• 238000007917 intracranial administration Methods 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 238000007912 intraperitoneal administration Methods 0.000 description 1
• 238000007913 intrathecal administration Methods 0.000 description 1
• 238000007915 intraurethral administration Methods 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
• 239000003456 ion exchange resin Substances 0.000 description 1
• 229920003303 ion-exchange polymer Polymers 0.000 description 1
• 238000002955 isolation Methods 0.000 description 1
• QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
• 150000002576 ketones Chemical class 0.000 description 1
• 229940001447 lactate Drugs 0.000 description 1
• 229960001375 lactose Drugs 0.000 description 1
• JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 description 1
• 229940057995 liquid paraffin Drugs 0.000 description 1
• 229910000103 lithium hydride Inorganic materials 0.000 description 1
• 208000002780 macular degeneration Diseases 0.000 description 1
• 229910001629 magnesium chloride Inorganic materials 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• 239000000594 mannitol Substances 0.000 description 1
• 235000010355 mannitol Nutrition 0.000 description 1
• 238000001819 mass spectrum Methods 0.000 description 1
• 239000011159 matrix material Substances 0.000 description 1
• HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
• 230000002503 metabolic effect Effects 0.000 description 1
• 150000002736 metal compounds Chemical class 0.000 description 1
• 229910000000 metal hydroxide Inorganic materials 0.000 description 1
• 150000004692 metal hydroxides Chemical class 0.000 description 1
• 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
• 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
• 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
• 229920000609 methyl cellulose Polymers 0.000 description 1
• 229940050176 methyl chloride Drugs 0.000 description 1
• 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
• SURZCVYFPAXNGN-UHFFFAOYSA-N methyl-carbamic acid ethyl ester Chemical compound CCOC(=O)NC SURZCVYFPAXNGN-UHFFFAOYSA-N 0.000 description 1
• 235000010981 methylcellulose Nutrition 0.000 description 1
• 239000001923 methylcellulose Substances 0.000 description 1
• 239000008108 microcrystalline cellulose Substances 0.000 description 1
• 229940016286 microcrystalline cellulose Drugs 0.000 description 1
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
• 235000010755 mineral Nutrition 0.000 description 1
• 150000007522 mineralic acids Chemical class 0.000 description 1
• 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
• 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
• PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
• 238000006396 nitration reaction Methods 0.000 description 1
• 150000002828 nitro derivatives Chemical class 0.000 description 1
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
• 239000012299 nitrogen atmosphere Substances 0.000 description 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
• LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
• ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
• 238000010915 one-step procedure Methods 0.000 description 1
• 208000020911 optic nerve disease Diseases 0.000 description 1
• LMYJGUNNJIDROI-UHFFFAOYSA-N oxan-4-ol Chemical compound OC1CCOCC1 LMYJGUNNJIDROI-UHFFFAOYSA-N 0.000 description 1
• GSEZHCLWHDZJAB-UHFFFAOYSA-N oxan-4-yl methanesulfonate Chemical compound CS(=O)(=O)OC1CCOCC1 GSEZHCLWHDZJAB-UHFFFAOYSA-N 0.000 description 1
• 230000020477 pH reduction Effects 0.000 description 1
• 239000012188 paraffin wax Substances 0.000 description 1
• 235000019809 paraffin wax Nutrition 0.000 description 1
• 239000002245 particle Substances 0.000 description 1
• 210000003899 penis Anatomy 0.000 description 1
• PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
• 239000007967 peppermint flavor Substances 0.000 description 1
• 229940124531 pharmaceutical excipient Drugs 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• 238000003408 phase transfer catalysis Methods 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
• 239000010452 phosphate Substances 0.000 description 1
• 239000011574 phosphorus Substances 0.000 description 1
• UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
• 108091008695 photoreceptors Proteins 0.000 description 1
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
• 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
• 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
• 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
• 229940113124 polysorbate 60 Drugs 0.000 description 1
• 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
• 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
• 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
• 235000015497 potassium bicarbonate Nutrition 0.000 description 1
• 239000011736 potassium bicarbonate Substances 0.000 description 1
• 229910000027 potassium carbonate Inorganic materials 0.000 description 1
• NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
• 229910000105 potassium hydride Inorganic materials 0.000 description 1
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
• 239000003755 preservative agent Substances 0.000 description 1
• 230000002335 preservative effect Effects 0.000 description 1
• 239000003223 protective agent Substances 0.000 description 1
• 230000002685 pulmonary effect Effects 0.000 description 1
• 230000002285 radioactive effect Effects 0.000 description 1
• 239000012429 reaction media Substances 0.000 description 1
• 238000011084 recovery Methods 0.000 description 1
• 238000005932 reductive alkylation reaction Methods 0.000 description 1
• 230000004044 response Effects 0.000 description 1
• 230000002207 retinal effect Effects 0.000 description 1
• 238000012552 review Methods 0.000 description 1
• 229910052701 rubidium Inorganic materials 0.000 description 1
• IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
• 238000007127 saponification reaction Methods 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 208000012201 sexual and gender identity disease Diseases 0.000 description 1
• 208000015891 sexual disease Diseases 0.000 description 1
• 150000004760 silicates Chemical class 0.000 description 1
• 239000000377 silicon dioxide Substances 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
• 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
• 239000001509 sodium citrate Substances 0.000 description 1
• NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
• 229960001790 sodium citrate Drugs 0.000 description 1
• 159000000000 sodium salts Chemical class 0.000 description 1
• 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
• 239000008247 solid mixture Substances 0.000 description 1
• 235000011076 sorbitan monostearate Nutrition 0.000 description 1
• 239000001587 sorbitan monostearate Substances 0.000 description 1
• 229940035048 sorbitan monostearate Drugs 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 229960002920 sorbitol Drugs 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 229910052712 strontium Inorganic materials 0.000 description 1
• CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 229940124530 sulfonamide Drugs 0.000 description 1
• 150000003456 sulfonamides Chemical class 0.000 description 1
• 150000003460 sulfonic acids Chemical class 0.000 description 1
• HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 230000002194 synthesizing effect Effects 0.000 description 1
• 239000007916 tablet composition Substances 0.000 description 1
• 239000000454 talc Substances 0.000 description 1
• 229910052623 talc Inorganic materials 0.000 description 1
• 229940095064 tartrate Drugs 0.000 description 1
• XHLCOJUEKSXUTP-UHFFFAOYSA-N tert-butyl 3-[3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-pentan-2-yloxypyridin-3-yl]-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]azetidine-1-carboxylate Chemical compound CCCC(C)OC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC1=C2CC)=NC(=O)C1=NN2C1CN(C(=O)OC(C)(C)C)C1 XHLCOJUEKSXUTP-UHFFFAOYSA-N 0.000 description 1
• XPDIKRMPZNLBAC-UHFFFAOYSA-N tert-butyl 3-iodoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(I)C1 XPDIKRMPZNLBAC-UHFFFAOYSA-N 0.000 description 1
• XXBDTKYKFFIAEY-UHFFFAOYSA-N tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1 XXBDTKYKFFIAEY-UHFFFAOYSA-N 0.000 description 1
• HETKPZZEMFLZLD-UHFFFAOYSA-N tert-butyl 4-[5-[2-butoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-7-oxo-4h-pyrazolo[4,3-d]pyrimidin-2-yl]piperidine-1-carboxylate Chemical compound CCCCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C1CCN(C(=O)OC(C)(C)C)CC1 HETKPZZEMFLZLD-UHFFFAOYSA-N 0.000 description 1
• WOEQSXAIPTXOPY-UHFFFAOYSA-N tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1 WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 1
• RFDSJHHLGFFVHD-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)-n-methylcarbamate Chemical compound OCCN(C)C(=O)OC(C)(C)C RFDSJHHLGFFVHD-UHFFFAOYSA-N 0.000 description 1
• 238000010998 test method Methods 0.000 description 1
• 238000012360 testing method Methods 0.000 description 1
• BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
• 230000000699 topical effect Effects 0.000 description 1
• 238000005809 transesterification reaction Methods 0.000 description 1
• 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
• PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
• 229940029284 trichlorofluoromethane Drugs 0.000 description 1
• WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
• 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
• 229910052722 tritium Inorganic materials 0.000 description 1
• 238000001665 trituration Methods 0.000 description 1
• 206010046459 urethral obstruction Diseases 0.000 description 1
• 239000001993 wax Substances 0.000 description 1
• 238000005550 wet granulation Methods 0.000 description 1
• 239000003871 white petrolatum Substances 0.000 description 1
• 239000000230 xanthan gum Substances 0.000 description 1
• 229920001285 xanthan gum Polymers 0.000 description 1
• 229940082509 xanthan gum Drugs 0.000 description 1
• 235000010493 xanthan gum Nutrition 0.000 description 1
• 239000000811 xylitol Substances 0.000 description 1
• 235000010447 xylitol Nutrition 0.000 description 1
• HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
• 229960002675 xylitol Drugs 0.000 description 1
• 229910052727 yttrium Inorganic materials 0.000 description 1
• VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1