CZ287916B6 - Derivát sulfonamidu, způsob jeho přípravy a jeho použití - Google Patents
Derivát sulfonamidu, způsob jeho přípravy a jeho použití Download PDFInfo
- Publication number
- CZ287916B6 CZ287916B6 CZ19971874A CZ187497A CZ287916B6 CZ 287916 B6 CZ287916 B6 CZ 287916B6 CZ 19971874 A CZ19971874 A CZ 19971874A CZ 187497 A CZ187497 A CZ 187497A CZ 287916 B6 CZ287916 B6 CZ 287916B6
- Authority
- CZ
- Czechia
- Prior art keywords
- pyrimidin
- methoxyphenoxy
- hydroxyethoxy
- tetrazol
- tert
- Prior art date
Links
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title claims description 9
- -1 thiocarbamoyl Chemical group 0.000 claims abstract description 348
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 208000035475 disorder Diseases 0.000 claims abstract description 19
- 102000002045 Endothelin Human genes 0.000 claims abstract description 16
- 108050009340 Endothelin Proteins 0.000 claims abstract description 16
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims abstract description 16
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 16
- 230000000694 effects Effects 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 206010020772 Hypertension Diseases 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 9
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 8
- 206010047163 Vasospasm Diseases 0.000 claims abstract description 8
- 208000028867 ischemia Diseases 0.000 claims abstract description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 6
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 3
- 125000000815 N-oxide group Chemical group 0.000 claims abstract 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 61
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 30
- QRKMGCXMJZJTGC-UHFFFAOYSA-N ethyl n-pyridin-2-ylcarbamate Chemical compound CCOC(=O)NC1=CC=CC=N1 QRKMGCXMJZJTGC-UHFFFAOYSA-N 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 12
- HXAZFIXWZPERHB-UHFFFAOYSA-N 5-propan-2-ylpyridine-2-sulfonic acid Chemical compound CC(C)C1=CC=C(S(O)(=O)=O)N=C1 HXAZFIXWZPERHB-UHFFFAOYSA-N 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- WAZRBGCDCZBPNI-UHFFFAOYSA-N 4-tert-butyl-n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 WAZRBGCDCZBPNI-UHFFFAOYSA-N 0.000 claims description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 6
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical group 0.000 claims description 5
- KQEDHQBKCPFYND-UHFFFAOYSA-N ethyl n-(1,3-benzodioxol-5-yl)carbamate Chemical compound CCOC(=O)NC1=CC=C2OCOC2=C1 KQEDHQBKCPFYND-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- XYDHSCZUHCZWHJ-UHFFFAOYSA-N 5-methylpyridine-2-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)N=C1 XYDHSCZUHCZWHJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000001411 amidrazones Chemical class 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000012948 isocyanate Substances 0.000 claims description 4
- 150000002513 isocyanates Chemical class 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 3
- WEUUDVAKLXYINL-UHFFFAOYSA-N 4-tert-butyl-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxidopyridin-1-ium-4-yl)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C[N+]([O-])=CC=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 WEUUDVAKLXYINL-UHFFFAOYSA-N 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- UMIYJHCDVVUVTQ-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]-2,5-dimethoxybenzenesulfonamide Chemical compound COC1=CC=C(OC)C(S(=O)(=O)NC=2C(=C(OCCO)N=C(N=2)C=2C=C(N=CC=2)C#N)OC=2C(=CC=CC=2)OC)=C1 UMIYJHCDVVUVTQ-UHFFFAOYSA-N 0.000 claims description 3
- FNMAQJQQWOBFAW-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]-4-methylbenzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(C)C=C1 FNMAQJQQWOBFAW-UHFFFAOYSA-N 0.000 claims description 3
- DVECLMOWYVDJRM-UHFFFAOYSA-N pyridine-3-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CN=C1 DVECLMOWYVDJRM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- JIBMEFUIGPATLZ-UHFFFAOYSA-N 1,3-benzodioxole-4-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC2=C1OCO2 JIBMEFUIGPATLZ-UHFFFAOYSA-N 0.000 claims description 2
- OSZMFMOUPMOEQY-UHFFFAOYSA-N 4-[4-[(4-tert-butylphenyl)sulfonylamino]-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-2-yl]pyridine-2-carboxylic acid Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(O)=O)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 OSZMFMOUPMOEQY-UHFFFAOYSA-N 0.000 claims description 2
- DQWVRLQQDDEQAS-UHFFFAOYSA-N 4-tert-butyl-n-[2-(3-cyanophenyl)-5-(2-methoxyphenoxy)-6-(2-phenylmethoxyethoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(C=CC=2)C#N)OCCOCC=2C=CC=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 DQWVRLQQDDEQAS-UHFFFAOYSA-N 0.000 claims description 2
- RWIVKELYZQOGEK-UHFFFAOYSA-N 4-tert-butyl-n-[2-(3-cyanophenyl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(C=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 RWIVKELYZQOGEK-UHFFFAOYSA-N 0.000 claims description 2
- AZOLXEIREUVZOP-UHFFFAOYSA-N 4-tert-butyl-n-[5-(2-methoxyphenoxy)-6-(2-phenylmethoxyethoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C=2NN=NN=2)OCCOCC=2C=CC=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 AZOLXEIREUVZOP-UHFFFAOYSA-N 0.000 claims description 2
- QZHFMZFRGBARNQ-UHFFFAOYSA-N 4-tert-butyl-n-[5-(2-methoxyphenoxy)-6-(2-phenylmethoxyethoxy)-2-[3-(2h-tetrazol-5-yl)phenyl]pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(C=CC=2)C=2NN=NN=2)OCCOCC=2C=CC=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 QZHFMZFRGBARNQ-UHFFFAOYSA-N 0.000 claims description 2
- YTBGKHFJEQITFY-UHFFFAOYSA-N 4-tert-butyl-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxidopyridin-1-ium-2-yl)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2[N+](=CC=CC=2)[O-])OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 YTBGKHFJEQITFY-UHFFFAOYSA-N 0.000 claims description 2
- PYISJSMYIAQHKL-UHFFFAOYSA-N CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=NC=C(C=C4)C(C)C)C5=CC(=NC=C5)C6=NN=NN6 Chemical compound CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=NC=C(C=C4)C(C)C)C5=CC(=NC=C5)C6=NN=NN6 PYISJSMYIAQHKL-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- NLPBOPFGLGUZMN-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1=NC(C=2C=C(N=CC=2)C#N)=NC(OCCO)=C1OC1=CC=CC=C1OC NLPBOPFGLGUZMN-UHFFFAOYSA-N 0.000 claims description 2
- ZTWJEDKVMNINTP-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]-4-methylsulfanylbenzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(SC)C=C1 ZTWJEDKVMNINTP-UHFFFAOYSA-N 0.000 claims description 2
- ZBNTWRRRSSLODB-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-2,5-dimethoxybenzenesulfonamide Chemical compound COC1=CC=C(OC)C(S(=O)(=O)NC=2C(=C(OCCO)N=C(N=2)C=2C=C(N=CC=2)C=2NN=NN=2)OC=2C(=CC=CC=2)OC)=C1 ZBNTWRRRSSLODB-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- XHPDXTVFSCBPCB-UHFFFAOYSA-N 1,3-benzodioxol-5-yl-[2-[5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]-2-[2-(2H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]oxyethyl]carbamic acid Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCN(C(O)=O)C=2C=C3OCOC3=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 XHPDXTVFSCBPCB-UHFFFAOYSA-N 0.000 claims 1
- WOZCSRYOBKSMBL-UHFFFAOYSA-N 1,3-benzodioxole-5-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=C2OCOC2=C1 WOZCSRYOBKSMBL-UHFFFAOYSA-N 0.000 claims 1
- MEZNPUULYGXXFL-UHFFFAOYSA-N 3,4-dimethoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1OC MEZNPUULYGXXFL-UHFFFAOYSA-N 0.000 claims 1
- AKWQIIYQULODLI-UHFFFAOYSA-N 4-tert-butyl-n-[2-(4-cyanophenyl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=CC(=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 AKWQIIYQULODLI-UHFFFAOYSA-N 0.000 claims 1
- QDJAWRXIOAVQCD-UHFFFAOYSA-N CCN(C1=CC=CC=N1)C(=O)OOC2(NC(=C(C=N2)OC3=CC=CC=C3OC)NS(=O)(=O)C4=C(C=CC(=C4)OC)OC)C5=CC(=NC=C5)C6=NNN=N6 Chemical compound CCN(C1=CC=CC=N1)C(=O)OOC2(NC(=C(C=N2)OC3=CC=CC=C3OC)NS(=O)(=O)C4=C(C=CC(=C4)OC)OC)C5=CC(=NC=C5)C6=NNN=N6 QDJAWRXIOAVQCD-UHFFFAOYSA-N 0.000 claims 1
- LKYLWTQBQBSTDE-UHFFFAOYSA-N CCN(C1=CC=CC=N1)C(=O)OOC2=C(C(=NC(=N2)C3=CC(=CC=C3)C4=NNN=N4)S(=O)(=O)C5=CC=C(C=C5)C(C)(C)C)OC6=CC=CC=C6OC Chemical compound CCN(C1=CC=CC=N1)C(=O)OOC2=C(C(=NC(=N2)C3=CC(=CC=C3)C4=NNN=N4)S(=O)(=O)C5=CC=C(C=C5)C(C)(C)C)OC6=CC=CC=C6OC LKYLWTQBQBSTDE-UHFFFAOYSA-N 0.000 claims 1
- WQSFUQVRTRUVOJ-UHFFFAOYSA-N CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=CN=CC=C4)C5=CC(=NC=C5)C6=NN=NN6 Chemical compound CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=CN=CC=C4)C5=CC(=NC=C5)C6=NN=NN6 WQSFUQVRTRUVOJ-UHFFFAOYSA-N 0.000 claims 1
- IYQMGOHWEHIWPE-UHFFFAOYSA-N COC(C=CC=C1)=C1OC(C(N)=NC(C1=CC(C2=NN=NN2)=NC=C1)=N1)=C1OCCO.OS(C1=CC=CN=C1)(=O)=O Chemical compound COC(C=CC=C1)=C1OC(C(N)=NC(C1=CC(C2=NN=NN2)=NC=C1)=N1)=C1OCCO.OS(C1=CC=CN=C1)(=O)=O IYQMGOHWEHIWPE-UHFFFAOYSA-N 0.000 claims 1
- COSIPCASJIRDLQ-UHFFFAOYSA-N [6-(1,3-benzodioxol-5-ylsulfonylamino)-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl] N-ethyl-N-pyridin-2-ylcarbamoperoxoate Chemical compound C(C)N(C(OOC1=NC(=NC(=C1OC1=C(C=CC=C1)OC)NS(=O)(=O)C1=CC2=C(OCO2)C=C1)C1=CC(=NC=C1)C1=NN=NN1)=O)C1=NC=CC=C1 COSIPCASJIRDLQ-UHFFFAOYSA-N 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- UYBHREFITGVQLM-UHFFFAOYSA-N n-[5-(2-chloro-5-methoxyphenoxy)-2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=C(Cl)C(OC=2C(=NC(=NC=2NS(=O)(=O)C=2N=CC(=CC=2)C(C)C)C=2C=C(N=CC=2)C#N)OCCO)=C1 UYBHREFITGVQLM-UHFFFAOYSA-N 0.000 claims 1
- NZBHBMWOKBFMAW-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-3,4-dimethoxybenzenesulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1S(=O)(=O)NC1=NC(C=2C=C(N=CC=2)C=2NN=NN=2)=NC(OCCO)=C1OC1=CC=CC=C1OC NZBHBMWOKBFMAW-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 1
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 15
- RUEMLKUMKKDJTF-UHFFFAOYSA-N (2z)-n-diazoniopyridine-2-carboximidate Chemical compound [N-]=[N+]=NC(=O)C1=CC=CC=N1 RUEMLKUMKKDJTF-UHFFFAOYSA-N 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 235000019270 ammonium chloride Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- 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 8
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- FSISZPWQLFHTPZ-UHFFFAOYSA-N 1,3-benzodioxole-5-carbonyl azide Chemical compound [N-]=[N+]=NC(=O)C1=CC=C2OCOC2=C1 FSISZPWQLFHTPZ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 238000011065 in-situ storage Methods 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
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 4
- BJYATIGZOWMIHX-UHFFFAOYSA-N 4-tert-butylbenzenesulfonamide;potassium Chemical compound [K].CC(C)(C)C1=CC=C(S(N)(=O)=O)C=C1 BJYATIGZOWMIHX-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 102000010180 Endothelin receptor Human genes 0.000 description 3
- 108050001739 Endothelin receptor Proteins 0.000 description 3
- 102100033902 Endothelin-1 Human genes 0.000 description 3
- 101800004490 Endothelin-1 Proteins 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- 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 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- QPUXZGQASDDLMQ-UHFFFAOYSA-N diethyl 2-(2-methoxyphenoxy)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)OC1=CC=CC=C1OC QPUXZGQASDDLMQ-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JDRHDDKIYMTMHI-UHFFFAOYSA-N 1-phenylmethoxyethanol;sodium Chemical compound [Na].CC(O)OCC1=CC=CC=C1 JDRHDDKIYMTMHI-UHFFFAOYSA-N 0.000 description 2
- LQWXEEDCMLEVHU-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)pyridine Chemical compound N1=CC=CC=C1C1=NNN=N1 LQWXEEDCMLEVHU-UHFFFAOYSA-N 0.000 description 2
- MUUPAXHBJVYQGF-UHFFFAOYSA-N 2-[6-amino-5-(2-methoxyphenoxy)-2-[2-(2H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]oxyethanol Chemical compound COC1=CC=CC=C1OC1=C(N)N=C(C=2C=C(N=CC=2)C2=NNN=N2)N=C1OCCO MUUPAXHBJVYQGF-UHFFFAOYSA-N 0.000 description 2
- KMZDGFFJSARATI-UHFFFAOYSA-N 3-[5-(2-methoxyphenoxy)-4,6-dioxo-1h-pyrimidin-2-yl]benzonitrile Chemical compound COC1=CC=CC=C1OC1C(=O)N=C(C=2C=C(C=CC=2)C#N)NC1=O KMZDGFFJSARATI-UHFFFAOYSA-N 0.000 description 2
- SDFQMDWIFGNAGM-UHFFFAOYSA-N 4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidine Chemical compound COC1=CC=CC=C1OC1=C(Cl)N=C(C=2C=CN=CC=2)N=C1Cl SDFQMDWIFGNAGM-UHFFFAOYSA-N 0.000 description 2
- AFVWOEIXJJCKJT-UHFFFAOYSA-N 4-hydroxy-5-(2-methoxyphenoxy)-2-pyridin-4-yl-1h-pyrimidin-6-one Chemical compound COC1=CC=CC=C1OC1=C(O)N=C(C=2C=CN=CC=2)N=C1O AFVWOEIXJJCKJT-UHFFFAOYSA-N 0.000 description 2
- WSNKHKVQQXYVTI-UHFFFAOYSA-N 4-tert-butyl-n-[2-(2-cyanopyridin-4-yl)-5-(2-methoxyphenoxy)-6-(2-phenylmethoxyethoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCOCC=2C=CC=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 WSNKHKVQQXYVTI-UHFFFAOYSA-N 0.000 description 2
- OWRNHBUDZZRGAL-UHFFFAOYSA-N 4-tert-butyl-n-[2-(6-cyanopyridin-2-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=C(C=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 OWRNHBUDZZRGAL-UHFFFAOYSA-N 0.000 description 2
- OKJMXQQLHKEACI-UHFFFAOYSA-N 4-tert-butyl-n-[6-chloro-2-(3-cyanophenyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC1=C(Cl)N=C(C=2C=C(C=CC=2)C#N)N=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 OKJMXQQLHKEACI-UHFFFAOYSA-N 0.000 description 2
- LKIFUCLFSNQTRU-UHFFFAOYSA-N 4-tert-butyl-n-[6-chloro-2-(4-cyanophenyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC1=C(Cl)N=C(C=2C=CC(=CC=2)C#N)N=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 LKIFUCLFSNQTRU-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- HQMLTKZVBUVTKS-UHFFFAOYSA-N CC(C)C(C=C1)=CN=C1S(O)(=O)=O.COC(C=CC=C1)=C1OC(C(N)=NC(C1=CC(C2=NN=NN2)=NC=C1)=N1)=C1OCCO Chemical compound CC(C)C(C=C1)=CN=C1S(O)(=O)=O.COC(C=CC=C1)=C1OC(C(N)=NC(C1=CC(C2=NN=NN2)=NC=C1)=N1)=C1OCCO HQMLTKZVBUVTKS-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- GYZKCMRPFJRTKQ-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]-3,4-dimethoxybenzenesulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1S(=O)(=O)NC1=NC(C=2C=C(N=CC=2)C#N)=NC(OCCO)=C1OC1=CC=CC=C1OC GYZKCMRPFJRTKQ-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- JHTLPSNDZNHQDZ-UHFFFAOYSA-N 1,3-benzodioxole-5-sulfonamide Chemical compound NS(=O)(=O)C1=CC=C2OCOC2=C1 JHTLPSNDZNHQDZ-UHFFFAOYSA-N 0.000 description 1
- RECMXJOGNNTEBG-UHFFFAOYSA-N 1-phenylmethoxyethanol Chemical compound CC(O)OCC1=CC=CC=C1 RECMXJOGNNTEBG-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- HMLNNNPJTZXILV-UHFFFAOYSA-N 2-[6-amino-5-(2-chloro-5-methoxyphenoxy)-2-[2-(2H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]oxyethanol Chemical compound COC1=CC=C(Cl)C(OC=2C(=NC(=NC=2N)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1 HMLNNNPJTZXILV-UHFFFAOYSA-N 0.000 description 1
- WPQFHUORSWAEOP-UHFFFAOYSA-N 2-azido-3,4-diphenyl-1h-phosphole Chemical compound [N-]=[N+]=NC=1PC=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 WPQFHUORSWAEOP-UHFFFAOYSA-N 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- MKQNYQGIPARLKO-UHFFFAOYSA-N 2-methoxybenzenesulfonamide Chemical compound COC1=CC=CC=C1S(N)(=O)=O MKQNYQGIPARLKO-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UIISHESBWIBGED-UHFFFAOYSA-N 3-cyanobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=CC(C#N)=C1 UIISHESBWIBGED-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- IHAJHRVAYWPOPV-UHFFFAOYSA-N 4,6-dichloro-5-(2-methoxyphenoxy)-2-(1-oxidopyridin-1-ium-4-yl)pyrimidine Chemical compound COC1=CC=CC=C1OC1=C(Cl)N=C(C=2C=C[N+]([O-])=CC=2)N=C1Cl IHAJHRVAYWPOPV-UHFFFAOYSA-N 0.000 description 1
- UDJSKOBLGUNZNB-UHFFFAOYSA-N 4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine Chemical compound COC1=CC=CC=C1OC1=C(Cl)N=CN=C1Cl UDJSKOBLGUNZNB-UHFFFAOYSA-N 0.000 description 1
- HJGFIAXSSMKHBR-UHFFFAOYSA-N 4-[4-amino-5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)pyrimidin-2-yl]pyridine-2-carbonitrile Chemical compound COC1=CC(=C(C=C1)Cl)OC2=C(N=C(N=C2OCCO)C3=CC(=NC=C3)C#N)N HJGFIAXSSMKHBR-UHFFFAOYSA-N 0.000 description 1
- GNZSFNDVUDNJLJ-UHFFFAOYSA-N 4-[5-(2-methoxyphenoxy)-4,6-dioxo-1h-pyrimidin-2-yl]benzonitrile Chemical compound COC1=CC=CC=C1OC1C(=O)N=C(C=2C=CC(=CC=2)C#N)NC1=O GNZSFNDVUDNJLJ-UHFFFAOYSA-N 0.000 description 1
- IKVRHGPKSBUMIO-UHFFFAOYSA-N 4-cyanobenzenecarboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=CC=C(C#N)C=C1 IKVRHGPKSBUMIO-UHFFFAOYSA-N 0.000 description 1
- VBPFWIJMZIWNMQ-UHFFFAOYSA-N 4-tert-butyl-n-[2-(4-cyanophenyl)-5-(2-methoxyphenoxy)-6-(2-phenylmethoxyethoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=CC(=CC=2)C#N)OCCOCC=2C=CC=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 VBPFWIJMZIWNMQ-UHFFFAOYSA-N 0.000 description 1
- NRQFJZINWNXWSC-UHFFFAOYSA-N 4-tert-butyl-n-[5-(2-chloro-5-methoxyphenoxy)-2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=C(Cl)C(OC=2C(=NC(=NC=2NS(=O)(=O)C=2C=CC(=CC=2)C(C)(C)C)C=2C=C(N=CC=2)C#N)OCCO)=C1 NRQFJZINWNXWSC-UHFFFAOYSA-N 0.000 description 1
- ICLRVCISJHBKTN-UHFFFAOYSA-N 4-tert-butyl-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[3-(2h-tetrazol-5-yl)phenyl]pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(C=CC=2)C=2NN=NN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 ICLRVCISJHBKTN-UHFFFAOYSA-N 0.000 description 1
- JVIAENLKEPCIKM-UHFFFAOYSA-N 4-tert-butyl-n-[6-chloro-5-(2-methoxyphenoxy)-2-(1-oxidopyridin-1-ium-4-yl)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC1=C(Cl)N=C(C=2C=C[N+]([O-])=CC=2)N=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 JVIAENLKEPCIKM-UHFFFAOYSA-N 0.000 description 1
- KYDZEZNYRFJCSA-UHFFFAOYSA-N 4-tert-butylbenzenesulfonamide Chemical compound CC(C)(C)C1=CC=C(S(N)(=O)=O)C=C1 KYDZEZNYRFJCSA-UHFFFAOYSA-N 0.000 description 1
- DJQDHFWHTVTDLR-UHFFFAOYSA-N 5-methylpyrimidine-2-sulfonic acid Chemical class Cc1cnc(nc1)S(O)(=O)=O DJQDHFWHTVTDLR-UHFFFAOYSA-N 0.000 description 1
- BAUXVVCVEDWRGY-UHFFFAOYSA-N 5-propan-2-ylpyrimidine Chemical compound CC(C)C1=CN=CN=C1 BAUXVVCVEDWRGY-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- HRQDNBLMOPRPCV-UHFFFAOYSA-N CC(C)C1=CC(=C(N=C1)S(=O)(=O)N)C2=C(C(=NC(=N2)C3=CC(=NC=C3)C4=NNN=N4)OCCO)OC5=C(C=CC(=C5)OC)Cl Chemical compound CC(C)C1=CC(=C(N=C1)S(=O)(=O)N)C2=C(C(=NC(=N2)C3=CC(=NC=C3)C4=NNN=N4)OCCO)OC5=C(C=CC(=C5)OC)Cl HRQDNBLMOPRPCV-UHFFFAOYSA-N 0.000 description 1
- KLOPHTGYLAFXJK-UHFFFAOYSA-N CC(C=C1)=CN=C1S(O)(=O)=O.COC(C=CC=C1)=C1OC(C(N)=NC(C1=CC(C2=NN=NN2)=NC=C1)=N1)=C1OCCO Chemical compound CC(C=C1)=CN=C1S(O)(=O)=O.COC(C=CC=C1)=C1OC(C(N)=NC(C1=CC(C2=NN=NN2)=NC=C1)=N1)=C1OCCO KLOPHTGYLAFXJK-UHFFFAOYSA-N 0.000 description 1
- IWQYNSKGXYXEAH-UHFFFAOYSA-N CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=C(C=CC(=C4)OC)OC)C5=CC(=NC=C5)C6=NN=NN6 Chemical compound CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=C(C=CC(=C4)OC)OC)C5=CC(=NC=C5)C6=NN=NN6 IWQYNSKGXYXEAH-UHFFFAOYSA-N 0.000 description 1
- FQTXNQRYMKZXSH-UHFFFAOYSA-N CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=NC=C(C=C4)C)C5=CC(=NC=C5)C6=NN=NN6 Chemical compound CCN(C1=CC=CC=N1)C(=O)OOC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=NC=C(C=C4)C)C5=CC(=NC=C5)C6=NN=NN6 FQTXNQRYMKZXSH-UHFFFAOYSA-N 0.000 description 1
- QKBAFBPHVNBDBU-UHFFFAOYSA-N COC1=CC=CC=C1OC2=C(N=CN=C2OCCO)NC3=CC(=NC=C3)C#N Chemical compound COC1=CC=CC=C1OC2=C(N=CN=C2OCCO)NC3=CC(=NC=C3)C#N QKBAFBPHVNBDBU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000005230 Leg Ulcer Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000717965 Pepsis Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 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
- OQSPRJQHUPBRCX-UHFFFAOYSA-N [6-[(4-tert-butylphenyl)sulfonylamino]-5-(2-methoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl] N-ethyl-N-pyridin-2-ylcarbamoperoxoate Chemical compound C(C)N(C(OOC1=NC(=NC(=C1OC1=C(C=CC=C1)OC)NS(=O)(=O)C1=CC=C(C=C1)C(C)(C)C)C1=CC(=NC=C1)C1=NN=NN1)=O)C1=NC=CC=C1 OQSPRJQHUPBRCX-UHFFFAOYSA-N 0.000 description 1
- FPJXTFYUENEVCW-UHFFFAOYSA-N [6-[(4-tert-butylphenyl)sulfonylamino]-5-(2-methoxyphenoxy)-2-[2-(2H-tetrazol-5-yl)-1H-pyridin-2-yl]pyrimidin-4-yl] N-ethyl-N-pyridin-2-ylcarbamoperoxoate Chemical compound C(C)N(C(OOC1=NC(=NC(=C1OC1=C(C=CC=C1)OC)NS(=O)(=O)C1=CC=C(C=C1)C(C)(C)C)C1(NC=CC=C1)C1=NN=NN1)=O)C1=NC=CC=C1 FPJXTFYUENEVCW-UHFFFAOYSA-N 0.000 description 1
- IONKMFGAXKCLMI-UHFFFAOYSA-N [amino(pyridin-4-yl)methylidene]azanium;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=NC=C1 IONKMFGAXKCLMI-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- BHXFKXOIODIUJO-UHFFFAOYSA-N benzene-1,4-dicarbonitrile Chemical compound N#CC1=CC=C(C#N)C=C1 BHXFKXOIODIUJO-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- PLQVNWHRQIGIKW-UHFFFAOYSA-O carbamimidoylazanium;azide Chemical compound [N-]=[N+]=[N-].NC(N)=[NH2+] PLQVNWHRQIGIKW-UHFFFAOYSA-O 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- MOXUSPIFBCWPHJ-UHFFFAOYSA-N diazidoamine Chemical compound [N-]=[N+]=NNN=[N+]=[N-] MOXUSPIFBCWPHJ-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NWJKPSLXLQLUTC-UHFFFAOYSA-N ethane-1,2-diol;sodium Chemical compound [Na].OCCO NWJKPSLXLQLUTC-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- LAQPNDIUHRHNCV-UHFFFAOYSA-N isophthalonitrile Chemical compound N#CC1=CC=CC(C#N)=C1 LAQPNDIUHRHNCV-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- QNRLTJAYWJYZHK-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-5-(2-methoxyphenoxy)-6-(2-phenylmethoxyethoxy)pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCOCC=2C=CC=CC=2)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 QNRLTJAYWJYZHK-UHFFFAOYSA-N 0.000 description 1
- VDFSDWITBOJTED-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=C(C)C=N1 VDFSDWITBOJTED-UHFFFAOYSA-N 0.000 description 1
- IFDFZXKDKJLNSU-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OCCO)=C1NS(=O)(=O)C1=CC=CC=C1 IFDFZXKDKJLNSU-UHFFFAOYSA-N 0.000 description 1
- NEGHGTZIQCZFBE-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]pyridine-3-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C=2NN=NN=2)OCCO)=C1NS(=O)(=O)C1=CC=CN=C1 NEGHGTZIQCZFBE-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- VUENSYJCBOSTCS-UHFFFAOYSA-N tert-butyl-imidazol-1-yl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)N1C=CN=C1 VUENSYJCBOSTCS-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 238000011706 wistar kyoto rat Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Bipolar Transistors (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Lubricants (AREA)
- Surgical Instruments (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH383794 | 1994-12-20 | ||
| CH241995 | 1995-08-24 | ||
| PCT/EP1995/004843 WO1996019459A1 (en) | 1994-12-20 | 1995-12-08 | Novel sulfonamides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CZ187497A3 CZ187497A3 (en) | 1997-10-15 |
| CZ287916B6 true CZ287916B6 (cs) | 2001-03-14 |
Family
ID=25690401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ19971874A CZ287916B6 (cs) | 1994-12-20 | 1995-12-08 | Derivát sulfonamidu, způsob jeho přípravy a jeho použití |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US6004965A (enExample) |
| EP (1) | EP0799209B1 (enExample) |
| JP (1) | JP2989014B2 (enExample) |
| KR (1) | KR100445085B1 (enExample) |
| CN (1) | CN1098254C (enExample) |
| AT (1) | ATE246681T1 (enExample) |
| AU (1) | AU701767B2 (enExample) |
| BR (1) | BR9510104A (enExample) |
| CA (1) | CA2208018C (enExample) |
| CY (1) | CY2495B1 (enExample) |
| CZ (1) | CZ287916B6 (enExample) |
| DE (1) | DE69531457T2 (enExample) |
| DK (1) | DK0799209T3 (enExample) |
| ES (1) | ES2203649T3 (enExample) |
| FI (1) | FI120397B (enExample) |
| HU (1) | HU228619B1 (enExample) |
| IL (1) | IL116385A (enExample) |
| MA (1) | MA23744A1 (enExample) |
| MY (1) | MY131126A (enExample) |
| NO (1) | NO316645B1 (enExample) |
| NZ (1) | NZ297797A (enExample) |
| PT (1) | PT799209E (enExample) |
| SA (1) | SA95160421B1 (enExample) |
| TW (1) | TW313568B (enExample) |
| WO (1) | WO1996019459A1 (enExample) |
Families Citing this family (72)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6063911A (en) * | 1993-12-01 | 2000-05-16 | Marine Polymer Technologies, Inc. | Methods and compositions for treatment of cell proliferative disorders |
| TW555765B (en) | 1996-07-09 | 2003-10-01 | Amgen Inc | Low molecular weight soluble tumor necrosis factor type-I and type-II proteins |
| CA2273852C (en) | 1996-12-06 | 2009-09-29 | Amgen Inc. | Combination therapy using an il-1 inhibitor for treating il-1 mediated diseases |
| DE69824090T2 (de) | 1997-08-19 | 2005-07-07 | F. Hoffmann-La Roche Ag | Verfahren zur Herstellung von 2,5-disubstituierter Pyridine |
| US7517880B2 (en) | 1997-12-22 | 2009-04-14 | Bayer Pharmaceuticals Corporation | Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas |
| US7329670B1 (en) | 1997-12-22 | 2008-02-12 | Bayer Pharmaceuticals Corporation | Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas |
| DE69928610T2 (de) * | 1998-08-10 | 2006-08-10 | F. Hoffmann-La Roche Ag | Verfahren zur Herstellung von 2-Carbamoyl-Pyridinen |
| US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
| EP1140840B1 (en) | 1999-01-13 | 2006-03-22 | Bayer Pharmaceuticals Corp. | -g(v)-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| CA2359244C (en) | 1999-01-13 | 2013-10-08 | Bayer Healthcare Llc | .omega.-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors |
| US7928239B2 (en) | 1999-01-13 | 2011-04-19 | Bayer Healthcare Llc | Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas |
| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| US7351834B1 (en) | 1999-01-13 | 2008-04-01 | Bayer Pharmaceuticals Corporation | ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| TWI284642B (en) * | 1999-01-18 | 2007-08-01 | Hoffmann La Roche | Novel heterocyclic sulfonamides |
| US6417360B1 (en) * | 1999-03-03 | 2002-07-09 | Hoffmann-La Roche Inc. | Heterocyclic sulfonamides |
| AU747596B2 (en) * | 1999-05-22 | 2002-05-16 | Actelion Pharmaceuticals Ltd | Aqueous pharmaceutical composition |
| ZA200002318B (en) * | 1999-05-22 | 2000-11-16 | Actelion Pharmaceuticals Ltd | Aqueous pharmaceutical composition. |
| CA2315614C (en) | 1999-07-29 | 2004-11-02 | Pfizer Inc. | Pyrazoles |
| ES2295048T3 (es) * | 1999-09-03 | 2008-04-16 | Actelion Pharmaceuticals Ltd. | Bis-sulfonamidas. |
| CA2389479A1 (en) * | 1999-12-22 | 2001-06-28 | Christoph Boss | Butyne diol derivatives |
| WO2001081338A1 (en) * | 2000-04-25 | 2001-11-01 | Actelion Pharmaceuticals Ltd | Substituted sulfonylaminopyrimidines |
| US6387915B2 (en) | 2000-05-31 | 2002-05-14 | Pfizer Inc. | Isoxazole-sulfonamide endothelin antagonists |
| US6670362B2 (en) | 2000-09-20 | 2003-12-30 | Pfizer Inc. | Pyridazine endothelin antagonists |
| US8168616B1 (en) | 2000-11-17 | 2012-05-01 | Novartis Ag | Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension |
| WO2002053557A1 (en) * | 2000-12-18 | 2002-07-11 | Actelion Pharmaceuticals Ltd | Novel sulfamides and their use as endothelin receptor antagonists |
| US7235576B1 (en) | 2001-01-12 | 2007-06-26 | Bayer Pharmaceuticals Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| WO2002083650A1 (en) * | 2001-04-11 | 2002-10-24 | Actelion Pharmaceuticals Ltd | Novel sulfonylamino-pyrimidines |
| US7371763B2 (en) | 2001-04-20 | 2008-05-13 | Bayer Pharmaceuticals Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
| SI1580188T1 (sl) | 2002-02-11 | 2012-02-29 | Bayer Healthcare Llc | Aril sečnine kot kinazni inhibitorji |
| EP2324825A1 (en) | 2002-02-11 | 2011-05-25 | Bayer Healthcare LLC | Aryl ureas with angiogenesis inhibiting activity |
| US20030216396A1 (en) | 2002-02-11 | 2003-11-20 | Bayer Corporation | Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors |
| US20040002451A1 (en) | 2002-06-20 | 2004-01-01 | Bruce Kerwin | Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing |
| EP1569914B1 (en) * | 2002-12-02 | 2009-02-18 | Actelion Pharmaceuticals Ltd. | Pyrimidine-sulfamides and their use as endothelian receptor antagonist |
| UY28213A1 (es) | 2003-02-28 | 2004-09-30 | Bayer Pharmaceuticals Corp | Nuevos derivados de cianopiridina útiles en el tratamiento de cáncer y otros trastornos. |
| DE602004007382T2 (de) | 2003-05-20 | 2008-04-17 | Bayer Pharmaceuticals Corp., West Haven | Diaryl-harnstoffe für durch pdgfr vermittelte krankheiten |
| DK1663978T3 (da) | 2003-07-23 | 2008-04-07 | Bayer Pharmaceuticals Corp | Fluorsubstitueret omega-carboxyaryl-diphenylurinstof til behandling og forebyggelse af sygdomme og lidelser |
| GB0327839D0 (en) | 2003-12-01 | 2003-12-31 | Novartis Ag | Organic compounds |
| NZ549535A (en) | 2004-03-17 | 2010-11-26 | Novartis Ag | Use of aliskiren for treating renal and other disorders |
| TW200628467A (en) | 2004-11-11 | 2006-08-16 | Actelion Pharmaceuticals Ltd | Novel sulfamides |
| US7402730B1 (en) | 2005-02-03 | 2008-07-22 | Lexicon Pharmaceuticals, Inc. | Knockout animals manifesting hyperlipidemia |
| GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
| US20090286790A1 (en) | 2006-07-20 | 2009-11-19 | Hidetomo Imase | Organic compounds |
| AR062501A1 (es) | 2006-08-29 | 2008-11-12 | Actelion Pharmaceuticals Ltd | Composiciones terapeuticas |
| WO2008073300A2 (en) | 2006-12-08 | 2008-06-19 | Lexicon Pharmaceuticals, Inc. | Monoclonal antibodies against angptl3 |
| ES2552842T3 (es) | 2007-02-19 | 2015-12-02 | Marine Polymer Technologies, Inc. | Composiciones hemostáticas y regímenes terapéuticos |
| MX2010001837A (es) | 2007-08-17 | 2010-03-10 | Actelion Pharmaceuticals Ltd | Derivados de 4-pirimidinasulfamida. |
| FR2921062A1 (fr) | 2007-09-17 | 2009-03-20 | Commissariat Energie Atomique | Composes utiles comme ligands et notamment comme chromophores organiques de complexation des lanthanides et leurs applications |
| AR069165A1 (es) | 2007-11-05 | 2010-01-06 | Novartis Ag | Derivados de 4-bencilamino-1-carboxacilpiperidina como inhibidores de cetp utiles para el tratamiento de hiperlipidemia |
| PT2404901E (pt) | 2007-12-03 | 2013-08-29 | Novartis Ag | Derivados de 4-benzilamino-pirrolidina 1,2-dissubstituídos como inibidores de cetp úteis para o tratamento de doenças tais como a hiperlipidemia ou a arteriosclerose |
| BRPI1010600A2 (pt) | 2009-05-15 | 2016-03-15 | Novartis Ag | aril piridina como inibidores de aldosterona sintase |
| JP5654572B2 (ja) | 2009-05-15 | 2015-01-14 | ノバルティス アーゲー | アルドステロンシンターゼ阻害剤としてのベンズオキサゾロン誘導体 |
| SG176010A1 (en) | 2009-05-28 | 2011-12-29 | Novartis Ag | Substituted aminobutyric derivatives as neprilysin inhibitors |
| JP5420761B2 (ja) | 2009-05-28 | 2014-02-19 | ノバルティス アーゲー | ネプリリシン阻害剤としての置換アミノプロピオン酸誘導体 |
| ES2663351T3 (es) | 2009-11-17 | 2018-04-12 | Novartis Ag | Derivados de aril-piridina como inhibidores de la aldosterona sintasa |
| JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
| US8575160B2 (en) | 2009-11-30 | 2013-11-05 | Novartis Ag | Imidazole derivatives as aldosterone synthase inhibitors |
| AU2011239466B2 (en) | 2010-04-15 | 2015-01-22 | Marine Polymer Technologies, Inc. | Anti-bacterial applications of poly -N-acetylglucosamine nanofibers |
| US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
| US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
| RU2013123793A (ru) | 2010-11-24 | 2014-12-27 | Лексикон Фармасьютикалз, Инк. | Антитела, связывающиеся с notum пектинацетилэстеразой |
| MX356877B (es) | 2011-04-15 | 2018-06-19 | Marine Polymer Tech Inc | Tratamiento de enfermedades con nanofibras de poli-n-acetil-glucosamina. |
| UY35144A (es) | 2012-11-20 | 2014-06-30 | Novartis Ag | Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca |
| US9383357B2 (en) | 2012-12-07 | 2016-07-05 | Northwestern University | Biomarker for replicative senescence |
| NZ710574A (en) | 2013-02-14 | 2017-11-24 | Novartis Ag | Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors |
| US9266925B2 (en) | 2013-07-25 | 2016-02-23 | Novartis Ag | Cyclic polypeptides for the treatment of heart failure |
| BR112016001376A2 (pt) | 2013-07-25 | 2017-10-24 | Novartis Ag | bioconjugados de polipeptídeos de apelin sintéticos |
| CA2972871A1 (en) | 2015-01-23 | 2016-07-28 | Novartis Ag | Synthetic apelin fatty acid conjugates with improved half-life |
| UY38072A (es) | 2018-02-07 | 2019-10-01 | Novartis Ag | Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos |
| TWI835843B (zh) | 2018-10-03 | 2024-03-21 | 瑞士商亨斯邁紡織染化（瑞士）有限公司 | 新的經吡啶及經嘧啶取代之三ｕｖ吸收劑 |
| CN116456984A (zh) * | 2020-11-05 | 2023-07-18 | 爱杜西亚药品有限公司 | 克拉生坦二钠盐的稳定结晶水合物 |
| KR20240121242A (ko) | 2021-12-17 | 2024-08-08 | 넥세라 파마 씨오., 엘티디. | 클라조센탄 디소듐 염, 이의 제조 및 이를 포함하는 약학 조성물 |
| US20250228835A1 (en) * | 2024-01-12 | 2025-07-17 | Rectify Pharmaceuticals, Inc. | Pyridinyloxypyridines and related compounds and their use in treating medical conditions |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW270116B (enExample) * | 1991-04-25 | 1996-02-11 | Hoffmann La Roche | |
| RU2086544C1 (ru) * | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина |
| TW287160B (enExample) * | 1992-12-10 | 1996-10-01 | Hoffmann La Roche | |
| TW394761B (en) * | 1993-06-28 | 2000-06-21 | Hoffmann La Roche | Novel Sulfonylamino Pyrimidines |
| IL111959A (en) * | 1993-12-17 | 2000-07-16 | Tanabe Seiyaku Co | N-(polysubstituted pyrimidin-4-yl) benzenesulfonamide derivatives their preparation and pharmaceutical compositions containing them |
-
1995
- 1995-11-11 TW TW084111957A patent/TW313568B/zh not_active IP Right Cessation
- 1995-11-29 SA SA95160421A patent/SA95160421B1/ar unknown
- 1995-12-08 DE DE69531457T patent/DE69531457T2/de not_active Expired - Lifetime
- 1995-12-08 AT AT95941706T patent/ATE246681T1/de active
- 1995-12-08 DK DK95941706T patent/DK0799209T3/da active
- 1995-12-08 PT PT95941706T patent/PT799209E/pt unknown
- 1995-12-08 BR BR9510104A patent/BR9510104A/pt not_active IP Right Cessation
- 1995-12-08 CZ CZ19971874A patent/CZ287916B6/cs not_active IP Right Cessation
- 1995-12-08 CN CN95196948A patent/CN1098254C/zh not_active Expired - Lifetime
- 1995-12-08 JP JP8519469A patent/JP2989014B2/ja not_active Expired - Lifetime
- 1995-12-08 NZ NZ297797A patent/NZ297797A/en not_active IP Right Cessation
- 1995-12-08 KR KR1019970704135A patent/KR100445085B1/ko not_active Expired - Lifetime
- 1995-12-08 AU AU43041/96A patent/AU701767B2/en not_active Expired
- 1995-12-08 ES ES95941706T patent/ES2203649T3/es not_active Expired - Lifetime
- 1995-12-08 EP EP95941706A patent/EP0799209B1/en not_active Expired - Lifetime
- 1995-12-08 CA CA002208018A patent/CA2208018C/en not_active Expired - Lifetime
- 1995-12-08 US US08/860,107 patent/US6004965A/en not_active Expired - Lifetime
- 1995-12-08 HU HU9702407A patent/HU228619B1/hu unknown
- 1995-12-08 WO PCT/EP1995/004843 patent/WO1996019459A1/en not_active Ceased
- 1995-12-14 IL IL11638595A patent/IL116385A/xx not_active IP Right Cessation
- 1995-12-15 MA MA24095A patent/MA23744A1/fr unknown
- 1995-12-18 MY MYPI95003923A patent/MY131126A/en unknown
-
1997
- 1997-06-04 NO NO19972538A patent/NO316645B1/no not_active IP Right Cessation
- 1997-06-18 FI FI972628A patent/FI120397B/fi not_active IP Right Cessation
-
2004
- 2004-12-14 CY CY0400089A patent/CY2495B1/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI120397B (fi) | Uudet sulfonamidit | |
| RU2086544C1 (ru) | Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина | |
| KR100478797B1 (ko) | 엔도텔린 수용체 길항제로서의 4-(헤테로사이클릴설폰아미도)-6-메톡시-5-(2-메톡시페녹시)-2-페닐- 또는 -피리딜-피리미딘 | |
| FI112944B (fi) | Menetelmä uusien terapeuttisesti käyttökelpoisten sulfonyyliaminopyrimidiinijohdannaisten valmistamiseksi | |
| JP2003527303A (ja) | グリコーゲンシンターゼキナーゼ３のインヒビター | |
| NO324952B1 (no) | Nye sulfonamider, fremstilling av disse, farmasoytiske preparater inneholdende slike,anvendelse av disse forbindelsene som medikament samt anvendelse av disse for fremstilling av medikament for behandling av lidelser. | |
| RU2162084C2 (ru) | Сульфонамиды и фармацевтический препарат | |
| US7091201B2 (en) | Arylalkane-sulfonamides having endothelin-antagonist activity | |
| JP2723496B2 (ja) | 新規なスルホニルアミノピリミジン類 | |
| RU2151767C1 (ru) | Сульфонамиды и фармацевтическая композиция | |
| PL185692B1 (pl) | Nowe sulfonamidy, sposób ich wytwarzania oraz zawierające je preparaty farmaceutyczne | |
| JPH10194972A (ja) | 医薬組成物 | |
| RU2173317C2 (ru) | Сульфонамидные производные и фармацевтический препарат | |
| HK1001973B (en) | Sulfonamides | |
| MXPA97004587A (es) | Sulfonamidas novedosas | |
| KR100521950B1 (ko) | 설포닐아미노피리미딘 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PD00 | Pending as of 2000-06-30 in czech republic | ||
| MK4A | Patent expired |
Effective date: 20151208 |