ZA200606624B - Pharmaceutical combinations containing benzoxazine for treating respiratory diseases - Google Patents

Info

Publication number

ZA200606624B

ZA200606624B ZA2006/06624A ZA200606624A ZA200606624B ZA 200606624 B ZA200606624 B ZA 200606624B ZA 2006/06624 A ZA2006/06624 A ZA 2006/06624A ZA 200606624 A ZA200606624 A ZA 200606624A ZA 200606624 B ZA200606624 B ZA 200606624B

Authority

ZA

South Africa

Prior art keywords

amino

phenyl

quinazoline

methoxy

chloro

Prior art date

2004-04-22

Links

• Espacenet
• Global Dossier
• Discuss

• CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 title description 2
• 208000023504 respiratory system disease Diseases 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 243
• -1 methyloxy, ethyloxy Chemical group 0.000 claims description 231
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 209
• 239000003814 drug Substances 0.000 claims description 151
• 150000003839 salts Chemical class 0.000 claims description 97
• 229910052739 hydrogen Inorganic materials 0.000 claims description 87
• 239000013543 active substance Substances 0.000 claims description 85
• 239000001257 hydrogen Substances 0.000 claims description 82
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 67
• 239000002253 acid Substances 0.000 claims description 64
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
• 150000004677 hydrates Chemical class 0.000 claims description 60
• 239000012453 solvate Substances 0.000 claims description 58
• 239000000203 mixture Substances 0.000 claims description 56
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 51
• 239000011737 fluorine Substances 0.000 claims description 51
• 229910052731 fluorine Inorganic materials 0.000 claims description 51
• 150000002431 hydrogen Chemical class 0.000 claims description 43
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
• 229910052736 halogen Inorganic materials 0.000 claims description 39
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 39
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 35
• 239000000460 chlorine Substances 0.000 claims description 35
• 229910052801 chlorine Inorganic materials 0.000 claims description 35
• 239000008194 pharmaceutical composition Substances 0.000 claims description 34
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
• 150000002367 halogens Chemical class 0.000 claims description 32
• 230000001078 anti-cholinergic effect Effects 0.000 claims description 31
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 29
• 239000002904 solvent Substances 0.000 claims description 28
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 25
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 23
• 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 23
• 239000000812 cholinergic antagonist Substances 0.000 claims description 23
• 239000000843 powder Substances 0.000 claims description 23
• 239000000443 aerosol Substances 0.000 claims description 21
• 150000001450 anions Chemical class 0.000 claims description 21
• 150000003431 steroids Chemical class 0.000 claims description 21
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
• 229940121647 egfr inhibitor Drugs 0.000 claims description 20
• 239000005557 antagonist Substances 0.000 claims description 19
• 239000003380 propellant Substances 0.000 claims description 19
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 17
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 17
• 229910052794 bromium Inorganic materials 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
• 239000003937 drug carrier Substances 0.000 claims description 14
• 238000009472 formulation Methods 0.000 claims description 14
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 13
• 239000007789 gas Substances 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 13
• 150000007513 acids Chemical class 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 11
• AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 11
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 11
• 230000001225 therapeutic effect Effects 0.000 claims description 11
• 208000006673 asthma Diseases 0.000 claims description 10
• 206010006451 bronchitis Diseases 0.000 claims description 10
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 10
• LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 claims description 10
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 9
• YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 claims description 9
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 8
• ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 8
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 8
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 8
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 8
• CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 claims description 8
• 239000003112 inhibitor Substances 0.000 claims description 8
• OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical class O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 claims description 8
• DPHDSIQHVGSITN-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-2-[1-[(4-fluorophenyl)methyl]-5-hydroxyindol-3-yl]-2-oxoacetamide Chemical compound C1=C(C(=O)C(=O)NC=2C(=CN=CC=2Cl)Cl)C2=CC(O)=CC=C2N1CC1=CC=C(F)C=C1 DPHDSIQHVGSITN-UHFFFAOYSA-N 0.000 claims description 8
• NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical class CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• PYUGFOWNYMLROI-KPKJPENVSA-N 8-[(e)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(2h-tetrazol-5-yl)chromen-4-one Chemical compound C1=CC(F)=CC=C1CCCCOC(C=C1)=CC=C1\C=C\C1=CC=CC2=C1OC(C=1NN=NN=1)=CC2=O PYUGFOWNYMLROI-KPKJPENVSA-N 0.000 claims description 7
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 7
• ANGKOCUUWGHLCE-HKUYNNGSSA-N [(3s)-1,1-dimethylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical class C1[N+](C)(C)CC[C@@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-HKUYNNGSSA-N 0.000 claims description 7
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
• OATDVDIMNNZTEY-DAXLTYESSA-N flutropium Chemical class C[N@@+]1(CCF)[C@H]2CC[C@@H]1C[C@@H](C2)OC(=O)C(O)(C1=CC=CC=C1)C1=CC=CC=C1 OATDVDIMNNZTEY-DAXLTYESSA-N 0.000 claims description 7
• 239000000126 substance Substances 0.000 claims description 7
• 239000000725 suspension Substances 0.000 claims description 7
• OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical class [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 claims description 7
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
• 206010035664 Pneumonia Diseases 0.000 claims description 6
• 208000030934 Restrictive pulmonary disease Diseases 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 230000000241 respiratory effect Effects 0.000 claims description 6
• UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 5
• 229910019142 PO4 Inorganic materials 0.000 claims description 5
• 206010037423 Pulmonary oedema Diseases 0.000 claims description 5
• DHCOPPHTVOXDKU-UHFFFAOYSA-N Tofimilast Chemical compound C1CN2C(C=3SC=CC=3)=NN=C2C2=C1C(CC)=NN2C1CCCC1 DHCOPPHTVOXDKU-UHFFFAOYSA-N 0.000 claims description 5
• YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 claims description 5
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
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• QAIOVDNCIZSSSF-RFAJLIJZSA-N etiprednol dicloacetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](OC(=O)C(Cl)Cl)(C(=O)OCC)[C@@]1(C)C[C@@H]2O QAIOVDNCIZSSSF-RFAJLIJZSA-N 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
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• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 229960004583 pranlukast Drugs 0.000 claims description 5
• UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 claims description 5
• MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 claims description 5
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• JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 5
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• LITNEAPWQHVPOK-FFSVYQOJSA-N 2(1h)-pyrimidinone, 5-[3-[(1s,2s,4r)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl]tetrahydro- Chemical compound C1=C(O[C@@H]2[C@H]3CC[C@H](C3)C2)C(OC)=CC=C1C1CNC(=O)NC1 LITNEAPWQHVPOK-FFSVYQOJSA-N 0.000 claims description 4
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