CA2777245A1 - Compositions for treatment of cystic fibrosis and other chronic diseases - Google Patents
Compositions for treatment of cystic fibrosis and other chronic diseases Download PDFInfo
- Publication number
- CA2777245A1 CA2777245A1 CA2777245A CA2777245A CA2777245A1 CA 2777245 A1 CA2777245 A1 CA 2777245A1 CA 2777245 A CA2777245 A CA 2777245A CA 2777245 A CA2777245 A CA 2777245A CA 2777245 A1 CA2777245 A1 CA 2777245A1
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- CA
- Canada
- Prior art keywords
- compound
- formula
- alkyl
- pharmaceutical composition
- optionally substituted
- Prior art date
- 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
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- 201000003883 Cystic fibrosis Diseases 0.000 title claims abstract description 72
- 239000000203 mixture Substances 0.000 title abstract description 145
- 208000017667 Chronic Disease Diseases 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 315
- 238000000034 method Methods 0.000 claims abstract description 80
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 74
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 claims abstract description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 230000001404 mediated effect Effects 0.000 claims abstract description 21
- 102000003837 Epithelial Sodium Channels Human genes 0.000 claims abstract description 11
- 108090000140 Epithelial Sodium Channels Proteins 0.000 claims abstract description 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 115
- -1 SR' Chemical group 0.000 claims description 99
- 125000000623 heterocyclic group Chemical group 0.000 claims description 84
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 claims description 53
- 239000002713 epithelial sodium channel blocking agent Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 125000001931 aliphatic group Chemical group 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 125000002837 carbocyclic group Chemical group 0.000 claims description 43
- 229940126214 compound 3 Drugs 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- 229940126052 ENaC inhibitor Drugs 0.000 claims description 37
- 125000005843 halogen group Chemical group 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 229940125904 compound 1 Drugs 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 208000006673 asthma Diseases 0.000 claims description 22
- 229940125782 compound 2 Drugs 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 230000035772 mutation Effects 0.000 claims description 18
- 239000001301 oxygen Chemical group 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 239000011593 sulfur Chemical group 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 12
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 claims description 12
- 229960002576 amiloride Drugs 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 9
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 claims description 8
- 230000007812 deficiency Effects 0.000 claims description 8
- 201000010064 diabetes insipidus Diseases 0.000 claims description 8
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 8
- 230000001965 increasing effect Effects 0.000 claims description 8
- 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 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 201000009266 primary ciliary dyskinesia Diseases 0.000 claims description 7
- RXMUPNVSYKGKMY-UHFFFAOYSA-N 3-amino-6-chloro-n-(diaminomethylidene)-5-(dimethylamino)pyrazine-2-carboxamide Chemical compound CN(C)C1=NC(N)=C(C(=O)N=C(N)N)N=C1Cl RXMUPNVSYKGKMY-UHFFFAOYSA-N 0.000 claims description 6
- KXDROGADUISDGY-UHFFFAOYSA-N Benzamil hydrochloride Chemical compound C=1C=CC=CC=1CN=C(N)NC(=O)C1=NC(Cl)=C(N)N=C1N KXDROGADUISDGY-UHFFFAOYSA-N 0.000 claims description 6
- 208000025678 Ciliary Motility disease Diseases 0.000 claims description 6
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 206010014561 Emphysema Diseases 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 4
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 208000007451 chronic bronchitis Diseases 0.000 claims description 4
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 4
- 125000006362 methylene amino carbonyl group Chemical group [H]N(C([*:2])=O)C([H])([H])[*:1] 0.000 claims description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 3
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 3
- 208000015439 Lysosomal storage disease Diseases 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 102100032187 Androgen receptor Human genes 0.000 claims description 2
- 206010003591 Ataxia Diseases 0.000 claims description 2
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 claims description 2
- 206010062264 Congenital hyperthyroidism Diseases 0.000 claims description 2
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 2
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 2
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 2
- 206010013883 Dwarfism Diseases 0.000 claims description 2
- 208000024720 Fabry Disease Diseases 0.000 claims description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 2
- 206010019860 Hereditary angioedema Diseases 0.000 claims description 2
- 208000033981 Hereditary haemochromatosis Diseases 0.000 claims description 2
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 claims description 2
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 claims description 2
- 206010051125 Hypofibrinogenaemia Diseases 0.000 claims description 2
- 208000000038 Hypoparathyroidism Diseases 0.000 claims description 2
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 claims description 2
- 208000019693 Lung disease Diseases 0.000 claims description 2
- 208000002678 Mucopolysaccharidoses Diseases 0.000 claims description 2
- 206010068871 Myotonic dystrophy Diseases 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 206010031243 Osteogenesis imperfecta Diseases 0.000 claims description 2
- 208000035467 Pancreatic insufficiency Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 2
- 208000025237 Polyendocrinopathy Diseases 0.000 claims description 2
- 208000024777 Prion disease Diseases 0.000 claims description 2
- 201000005660 Protein C Deficiency Diseases 0.000 claims description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 2
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 claims description 2
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims description 2
- 208000004622 abetalipoproteinemia Diseases 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- 230000007547 defect Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 201000001386 familial hypercholesterolemia Diseases 0.000 claims description 2
- 208000013746 hereditary thrombophilia due to congenital protein C deficiency Diseases 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 206010028093 mucopolysaccharidosis Diseases 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 108010040003 polyglutamine Proteins 0.000 claims description 2
- 229920000155 polyglutamine Polymers 0.000 claims description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 101000907783 Homo sapiens Cystic fibrosis transmembrane conductance regulator Proteins 0.000 claims 7
- 102000056427 human CFTR Human genes 0.000 claims 7
- 108700028369 Alleles Proteins 0.000 claims 4
- 206010006474 Bronchopulmonary aspergillosis allergic Diseases 0.000 claims 2
- 206010067265 Heterotaxia Diseases 0.000 claims 2
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- 208000001132 Osteoporosis Diseases 0.000 claims 2
- 206010033645 Pancreatitis Diseases 0.000 claims 2
- 208000031733 Situs inversus totalis Diseases 0.000 claims 2
- 208000006778 allergic bronchopulmonary aspergillosis Diseases 0.000 claims 2
- 210000000988 bone and bone Anatomy 0.000 claims 2
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- 102100034452 Alternative prion protein Human genes 0.000 claims 1
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- 208000012904 Bartter disease Diseases 0.000 claims 1
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- 208000006386 Bone Resorption Diseases 0.000 claims 1
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- 206010010356 Congenital anomaly Diseases 0.000 claims 1
- 206010010774 Constipation Diseases 0.000 claims 1
- 208000024940 Dent disease Diseases 0.000 claims 1
- 208000019683 Gorham-Stout disease Diseases 0.000 claims 1
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- 208000007466 Male Infertility Diseases 0.000 claims 1
- 208000029725 Metabolic bone disease Diseases 0.000 claims 1
- 208000010316 Myotonia congenita Diseases 0.000 claims 1
- 206010049088 Osteopenia Diseases 0.000 claims 1
- 108091000054 Prion Proteins 0.000 claims 1
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- 230000008468 bone growth Effects 0.000 claims 1
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- 239000007787 solid Substances 0.000 abstract description 123
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- 102000008371 intracellularly ATP-gated chloride channel activity proteins Human genes 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 297
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 99
- 239000000543 intermediate Substances 0.000 description 98
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- 238000006243 chemical reaction Methods 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 64
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- OCSQJDAUOOHJEI-UHFFFAOYSA-N 3,5-diamino-6-chloropyrazine-2-carboxylic acid Chemical compound NC1=NC(N)=C(C(O)=O)N=C1Cl OCSQJDAUOOHJEI-UHFFFAOYSA-N 0.000 description 54
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Classifications
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-
2010
- 2010-10-22 AU AU2010310449A patent/AU2010310449A1/en not_active Abandoned
- 2010-10-22 EP EP14184159.3A patent/EP2813227A1/en not_active Withdrawn
- 2010-10-22 WO PCT/US2010/053852 patent/WO2011050325A1/en not_active Ceased
- 2010-10-22 CA CA2777245A patent/CA2777245A1/en not_active Abandoned
- 2010-10-22 US US12/910,727 patent/US20110098311A1/en not_active Abandoned
- 2010-10-22 JP JP2012535433A patent/JP2013508414A/ja active Pending
- 2010-10-22 MX MX2012004792A patent/MX2012004792A/es not_active Application Discontinuation
- 2010-10-22 CN CN2010800578878A patent/CN102665715A/zh active Pending
- 2010-10-22 EP EP10773489A patent/EP2490687A1/en not_active Withdrawn
-
2013
- 2013-12-16 US US14/107,700 patent/US20150150879A2/en not_active Abandoned
-
2015
- 2015-04-17 US US14/689,391 patent/US20150231142A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| MX2012004792A (es) | 2013-02-01 |
| CN102665715A (zh) | 2012-09-12 |
| EP2813227A1 (en) | 2014-12-17 |
| US20150231142A1 (en) | 2015-08-20 |
| US20110098311A1 (en) | 2011-04-28 |
| WO2011050325A1 (en) | 2011-04-28 |
| AU2010310449A1 (en) | 2012-05-03 |
| US20140329814A2 (en) | 2014-11-06 |
| US20150150879A2 (en) | 2015-06-04 |
| US20140121208A1 (en) | 2014-05-01 |
| JP2013508414A (ja) | 2013-03-07 |
| EP2490687A1 (en) | 2012-08-29 |
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