AU2003254282A1 - Nitrosated proton pump inhibitors, compositions and methods of use - Google Patents

Info

Publication number

AU2003254282A1

AU2003254282A1 AU2003254282A AU2003254282A AU2003254282A1 AU 2003254282 A1 AU2003254282 A1 AU 2003254282A1 AU 2003254282 A AU2003254282 A AU 2003254282A AU 2003254282 A AU2003254282 A AU 2003254282A AU 2003254282 A1 AU2003254282 A1 AU 2003254282A1

Authority

AU

Australia

Prior art keywords

group

nitrosated

compound

hydrogen

formula

Prior art date

2002-08-01

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• 239000000203 mixture Substances 0.000 title claims description 149
• 238000000034 method Methods 0.000 title claims description 91
• 229940126409 proton pump inhibitor Drugs 0.000 title claims description 91
• 239000000612 proton pump inhibitor Substances 0.000 title claims description 91
• MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 351
• 150000001875 compounds Chemical class 0.000 claims description 328
• 125000000217 alkyl group Chemical group 0.000 claims description 139
• -1 -NR 87 R 87 ' Chemical group 0.000 claims description 134
• 229910052739 hydrogen Inorganic materials 0.000 claims description 111
• 239000001257 hydrogen Substances 0.000 claims description 110
• 125000003118 aryl group Chemical group 0.000 claims description 101
• 150000002431 hydrogen Chemical class 0.000 claims description 73
• 150000002148 esters Chemical class 0.000 claims description 68
• 125000000623 heterocyclic group Chemical group 0.000 claims description 60
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 59
• 239000002253 acid Substances 0.000 claims description 57
• 239000003814 drug Substances 0.000 claims description 57
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 54
• NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 50
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
• 229940124597 therapeutic agent Drugs 0.000 claims description 46
• 125000003545 alkoxy group Chemical group 0.000 claims description 45
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 36
• 239000000758 substrate Substances 0.000 claims description 36
• 238000012546 transfer Methods 0.000 claims description 36
• 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 35
• 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 35
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 35
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 35
• 229910052760 oxygen Inorganic materials 0.000 claims description 35
• 150000003839 salts Chemical class 0.000 claims description 35
• 239000000066 endothelium dependent relaxing factor Substances 0.000 claims description 34
• 239000001301 oxygen Substances 0.000 claims description 34
• 229910002651 NO3 Inorganic materials 0.000 claims description 33
• 239000003112 inhibitor Substances 0.000 claims description 32
• 229910052757 nitrogen Inorganic materials 0.000 claims description 32
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
• 239000003153 chemical reaction reagent Substances 0.000 claims description 28
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 28
• 208000025865 Ulcer Diseases 0.000 claims description 26
• 229940037467 helicobacter pylori Drugs 0.000 claims description 26
• 231100000397 ulcer Toxicity 0.000 claims description 26
• 241000590002 Helicobacter pylori Species 0.000 claims description 24
• MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 24
• 229940069428 antacid Drugs 0.000 claims description 23
• 239000003159 antacid agent Substances 0.000 claims description 23
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
• 229960003174 lansoprazole Drugs 0.000 claims description 22
• 229910052717 sulfur Inorganic materials 0.000 claims description 22
• 238000004519 manufacturing process Methods 0.000 claims description 21
• 239000004215 Carbon black (E152) Substances 0.000 claims description 20
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 20
• 230000000844 anti-bacterial effect Effects 0.000 claims description 19
• 229910052797 bismuth Inorganic materials 0.000 claims description 19
• JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 19
• 229930195733 hydrocarbon Natural products 0.000 claims description 19
• 150000002430 hydrocarbons Chemical class 0.000 claims description 19
• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 19
• 229910052702 rhenium Inorganic materials 0.000 claims description 19
• 108010037462 Cyclooxygenase 2 Proteins 0.000 claims description 18
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 18
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
• 125000004414 alkyl thio group Chemical group 0.000 claims description 18
• 125000004432 carbon atom Chemical group C* 0.000 claims description 18
• 125000005518 carboxamido group Chemical group 0.000 claims description 18
• 229940111134 coxibs Drugs 0.000 claims description 18
• 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 18
• 229910021481 rutherfordium Inorganic materials 0.000 claims description 18
• 239000011593 sulfur Substances 0.000 claims description 18
• 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 17
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 230000001330 gastroprokinetic effect Effects 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 16
• 208000035143 Bacterial infection Diseases 0.000 claims description 15
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 15
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 15
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 15
• 229920006395 saturated elastomer Polymers 0.000 claims description 15
• 208000036142 Viral infection Diseases 0.000 claims description 14
• 229920001184 polypeptide Polymers 0.000 claims description 14
• 230000009385 viral infection Effects 0.000 claims description 14
• 229940122957 Histamine H2 receptor antagonist Drugs 0.000 claims description 13
• 229910004679 ONO2 Inorganic materials 0.000 claims description 13
• 230000003110 anti-inflammatory effect Effects 0.000 claims description 13
• 150000001733 carboxylic acid esters Chemical class 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 230000035876 healing Effects 0.000 claims description 13
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 13
• SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 12
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 12
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 12
• 235000001014 amino acid Nutrition 0.000 claims description 12
• 201000010099 disease Diseases 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
• JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 12
• 125000001931 aliphatic group Chemical group 0.000 claims description 11
• 125000003282 alkyl amino group Chemical group 0.000 claims description 11
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 11
• 150000001767 cationic compounds Chemical class 0.000 claims description 11
• 229910001411 inorganic cation Inorganic materials 0.000 claims description 11
• 229960000381 omeprazole Drugs 0.000 claims description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
• 150000001413 amino acids Chemical class 0.000 claims description 10
• 125000001769 aryl amino group Chemical group 0.000 claims description 10
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
• 230000003247 decreasing effect Effects 0.000 claims description 10
• 125000001424 substituent group Chemical group 0.000 claims description 10
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 9
• 125000005596 alkyl carboxamido group Chemical group 0.000 claims description 9
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 9
• 208000000718 duodenal ulcer Diseases 0.000 claims description 9
• CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 claims description 9
• 230000002496 gastric effect Effects 0.000 claims description 9
• 230000002178 gastroprotective effect Effects 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
• 230000001458 anti-acid effect Effects 0.000 claims description 8
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 8
• 150000002892 organic cations Chemical class 0.000 claims description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 7
• 208000007882 Gastritis Diseases 0.000 claims description 7
• 206010020601 Hyperchlorhydria Diseases 0.000 claims description 7
• FQWRAVYMZULPNK-UHFFFAOYSA-N N(5)-[(Z)-amino(hydroxyimino)methyl]ornithine Chemical compound OC(=O)C(N)CCCNC(N)=NO FQWRAVYMZULPNK-UHFFFAOYSA-N 0.000 claims description 7
• 208000008469 Peptic Ulcer Diseases 0.000 claims description 7
• 125000000747 amidyl group Chemical group [H][N-]* 0.000 claims description 7
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
• KWDSFGYQALRPMG-UHFFFAOYSA-N delta-N-Hydroxy-L-orginin Natural products OC(=O)C(N)CCCN(O)C(N)=N KWDSFGYQALRPMG-UHFFFAOYSA-N 0.000 claims description 7
• 208000010643 digestive system disease Diseases 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• 208000018685 gastrointestinal system disease Diseases 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
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 7
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
• RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 6
• 208000016557 Acute basophilic leukemia Diseases 0.000 claims description 6
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 6
• 208000011231 Crohn disease Diseases 0.000 claims description 6
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• 206010021518 Impaired gastric emptying Diseases 0.000 claims description 6
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
• QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 claims description 6
• QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 claims description 6
• 206010042220 Stress ulcer Diseases 0.000 claims description 6
• 201000008736 Systemic mastocytosis Diseases 0.000 claims description 6
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• 125000004171 alkoxy aryl group Chemical group 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000005001 aminoaryl group Chemical group 0.000 claims description 6
• 230000003872 anastomosis Effects 0.000 claims description 6
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
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• 125000005110 aryl thio group Chemical group 0.000 claims description 6
• 125000004104 aryloxy group Chemical group 0.000 claims description 6
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
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• CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 6
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
• YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 6
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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• ICRHORQIUXBEPA-UHFFFAOYSA-N thionitrous acid Chemical compound SN=O ICRHORQIUXBEPA-UHFFFAOYSA-N 0.000 claims description 5
• PSIREIZGKQBEEO-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfinylmethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CS(=O)C1=NC2=CC=CC=C2N1 PSIREIZGKQBEEO-UHFFFAOYSA-N 0.000 claims description 4
• HBDKFZNDMVLSHM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1S(=O)CC1=CC=CC=N1 HBDKFZNDMVLSHM-UHFFFAOYSA-N 0.000 claims description 4
• FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 claims description 4
• ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 claims description 4
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• SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims description 4
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