CA2642239A1

CA2642239A1 - Drug combinations for the treatment of respiratory tract diseases

Drug combinations for the treatment of respiratory tract diseases Download PDF

Info

Publication number: CA2642239A1
Authority: CA; Canada
Prior art keywords: amino; denotes; methyl; contain; quinazoline
Prior art date: 2006-02-16
Legal status : Abandoned

Application number

CA002642239A

Other languages

English (en)

French (fr)

Inventor

Ingo Konetzki

Thierry Bouyssou

Sabine Pestel

Andreas Schnapp

Current Assignee

Boehringer Ingelheim International GmbH

Original Assignee

Individual

Priority date

2006-02-16

Filing date

2007-02-14

Publication date

2007-08-23

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=35983924&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2642239(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2007-02-14 Application filed by Individual filed Critical Individual

2007-08-23 Publication of CA2642239A1 publication Critical patent/CA2642239A1/en

Status Abandoned legal-status Critical Current

Links

239000000890 drug combination Substances 0.000 title abstract 2
208000018569 Respiratory Tract disease Diseases 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 209
239000003814 drug Substances 0.000 claims abstract description 142
-1 methoxy, ethoxy Chemical group 0.000 claims description 100
239000013543 active substance Substances 0.000 claims description 89
150000003839 salts Chemical class 0.000 claims description 81
239000000203 mixture Substances 0.000 claims description 68
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 61
239000002253 acid Substances 0.000 claims description 54
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 50
239000002904 solvent Substances 0.000 claims description 49
239000012453 solvate Substances 0.000 claims description 45
150000004677 hydrates Chemical class 0.000 claims description 41
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
239000000546 pharmaceutical excipient Substances 0.000 claims description 29
150000003431 steroids Chemical class 0.000 claims description 29
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 28
239000011737 fluorine Substances 0.000 claims description 28
229910052731 fluorine Inorganic materials 0.000 claims description 28
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
239000008194 pharmaceutical composition Substances 0.000 claims description 24
230000001078 anti-cholinergic effect Effects 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
229910052736 halogen Inorganic materials 0.000 claims description 20
239000003380 propellant Substances 0.000 claims description 20
229940121647 egfr inhibitor Drugs 0.000 claims description 19
239000005557 antagonist Substances 0.000 claims description 18
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
150000002367 halogens Chemical class 0.000 claims description 16
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
150000007513 acids Chemical class 0.000 claims description 14
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
229910052794 bromium Inorganic materials 0.000 claims description 14
238000009472 formulation Methods 0.000 claims description 14
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
239000000460 chlorine Substances 0.000 claims description 13
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125000000896 monocarboxylic acid group Chemical group 0.000 claims description 9
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125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
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239000000725 suspension Substances 0.000 claims description 7
206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 6
201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 6
206010006451 bronchitis Diseases 0.000 claims description 6
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
230000000241 respiratory effect Effects 0.000 claims description 6
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 5
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
201000003883 Cystic fibrosis Diseases 0.000 claims description 4
206010037423 Pulmonary oedema Diseases 0.000 claims description 4
208000030934 Restrictive pulmonary disease Diseases 0.000 claims description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 4
NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 claims description 4
IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 4
230000033764 rhythmic process Effects 0.000 claims description 4
206010014561 Emphysema Diseases 0.000 claims description 3
208000019693 Lung disease Diseases 0.000 claims description 3
208000011623 Obstructive Lung disease Diseases 0.000 claims description 3
201000009267 bronchiectasis Diseases 0.000 claims description 3
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
150000002016 disaccharides Chemical class 0.000 claims description 3
230000002757 inflammatory effect Effects 0.000 claims description 3
150000002772 monosaccharides Chemical class 0.000 claims description 3
230000000414 obstructive effect Effects 0.000 claims description 3
206010003671 Atrioventricular Block Diseases 0.000 claims description 2
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical class C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical class C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
201000004624 Dermatitis Diseases 0.000 claims description 2
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical class CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 2
206010036600 Premature labour Diseases 0.000 claims description 2
206010040880 Skin irritation Diseases 0.000 claims description 2
206010047141 Vasodilatation Diseases 0.000 claims description 2
230000003288 anthiarrhythmic effect Effects 0.000 claims description 2
239000003416 antiarrhythmic agent Substances 0.000 claims description 2
230000000059 bradycardiac effect Effects 0.000 claims description 2
239000001273 butane Chemical class 0.000 claims description 2
230000005796 circulatory shock Effects 0.000 claims description 2
208000035475 disorder Diseases 0.000 claims description 2
150000005826 halohydrocarbons Chemical class 0.000 claims description 2
229930195733 hydrocarbon Natural products 0.000 claims description 2
150000002430 hydrocarbons Chemical class 0.000 claims description 2
230000004054 inflammatory process Effects 0.000 claims description 2
230000002401 inhibitory effect Effects 0.000 claims description 2
239000001282 iso-butane Substances 0.000 claims description 2
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 2
150000002482 oligosaccharides Polymers 0.000 claims description 2
230000003287 optical effect Effects 0.000 claims description 2
229920001282 polysaccharide Polymers 0.000 claims description 2
239000005017 polysaccharide Substances 0.000 claims description 2
239000001294 propane Chemical class 0.000 claims description 2
230000036556 skin irritation Effects 0.000 claims description 2
231100000475 skin irritation Toxicity 0.000 claims description 2
150000005846 sugar alcohols Polymers 0.000 claims description 2
230000024883 vasodilation Effects 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
150000004676 glycans Chemical class 0.000 claims 1
238000000034 method Methods 0.000 abstract description 24
238000004519 manufacturing process Methods 0.000 abstract description 2
239000004480 active ingredient Substances 0.000 abstract 1
229940079593 drug Drugs 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 74
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
238000004949 mass spectrometry Methods 0.000 description 65
239000000243 solution Substances 0.000 description 65
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 57
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
229910052739 hydrogen Inorganic materials 0.000 description 45
239000001257 hydrogen Substances 0.000 description 38
239000007787 solid Substances 0.000 description 31
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UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
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CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 21
239000012074 organic phase Substances 0.000 description 21
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
239000000543 intermediate Substances 0.000 description 19
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150000001450 anions Chemical class 0.000 description 18
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239000011541 reaction mixture Substances 0.000 description 18
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JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 16
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150000002431 hydrogen Chemical class 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
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ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
239000000047 product Substances 0.000 description 12
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238000007429 general method Methods 0.000 description 11
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239000000741 silica gel Substances 0.000 description 11
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VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 10
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
229910052938 sodium sulfate Inorganic materials 0.000 description 10
235000011152 sodium sulphate Nutrition 0.000 description 10
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PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 9
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239000000706 filtrate Substances 0.000 description 9
239000011780 sodium chloride Substances 0.000 description 9
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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 description 9
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
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DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 8
229910052799 carbon Inorganic materials 0.000 description 8
125000004432 carbon atom Chemical group C* 0.000 description 8
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 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
FGCZLEUESSUCRR-UHFFFAOYSA-N 8-(2-ethoxy-1,2-dihydroxyethyl)-6-phenylmethoxy-4h-1,4-benzoxazin-3-one Chemical compound C=1C=2NC(=O)COC=2C(C(O)C(O)OCC)=CC=1OCC1=CC=CC=C1 FGCZLEUESSUCRR-UHFFFAOYSA-N 0.000 description 7
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 7
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
239000002775 capsule Substances 0.000 description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
238000006243 chemical reaction Methods 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
238000001816 cooling Methods 0.000 description 7
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 7
125000005635 hydromethanesulphonate group Chemical group 0.000 description 7
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 description 7
238000002844 melting Methods 0.000 description 7
230000008018 melting Effects 0.000 description 7
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 description 7
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 description 7
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VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
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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 description 6
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 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
239000002245 particle Substances 0.000 description 6
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FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
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