WO2012107706A1 - Phenothiazine diaminium salts and their use - Google Patents
Phenothiazine diaminium salts and their use Download PDFInfo
- Publication number
- WO2012107706A1 WO2012107706A1 PCT/GB2011/001221 GB2011001221W WO2012107706A1 WO 2012107706 A1 WO2012107706 A1 WO 2012107706A1 GB 2011001221 W GB2011001221 W GB 2011001221W WO 2012107706 A1 WO2012107706 A1 WO 2012107706A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- disease
- composition according
- treatment
- prophylaxis
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 69
- 229950000688 phenothiazine Drugs 0.000 title description 16
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 255
- 239000000203 mixture Substances 0.000 claims abstract description 220
- 238000011282 treatment Methods 0.000 claims abstract description 83
- -1 C2-4alkenyl Chemical group 0.000 claims abstract description 37
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 27
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 25
- LZILOGCFZJDPTG-UHFFFAOYSA-N 10h-phenothiazine-3,7-diamine Chemical class C1=C(N)C=C2SC3=CC(N)=CC=C3NC2=C1 LZILOGCFZJDPTG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 164
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 85
- 201000010099 disease Diseases 0.000 claims description 78
- 108090000623 proteins and genes Proteins 0.000 claims description 64
- 235000018102 proteins Nutrition 0.000 claims description 63
- 102000004169 proteins and genes Human genes 0.000 claims description 63
- 230000015572 biosynthetic process Effects 0.000 claims description 58
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 57
- 229910001868 water Inorganic materials 0.000 claims description 55
- 239000003826 tablet Substances 0.000 claims description 51
- 230000008569 process Effects 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 42
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 40
- 239000003085 diluting agent Substances 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 38
- 230000002776 aggregation Effects 0.000 claims description 36
- 238000004220 aggregation Methods 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 239000007787 solid Substances 0.000 claims description 33
- 239000000463 material Substances 0.000 claims description 32
- 238000011321 prophylaxis Methods 0.000 claims description 32
- 238000007906 compression Methods 0.000 claims description 26
- 230000006835 compression Effects 0.000 claims description 26
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 239000007909 solid dosage form Substances 0.000 claims description 25
- 208000017004 dementia pugilistica Diseases 0.000 claims description 24
- 239000013078 crystal Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 22
- 239000002245 particle Substances 0.000 claims description 22
- 230000004845 protein aggregation Effects 0.000 claims description 19
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 17
- 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 claims description 17
- 238000007907 direct compression Methods 0.000 claims description 17
- 238000010511 deprotection reaction Methods 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 16
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 15
- 229930195725 Mannitol Natural products 0.000 claims description 15
- 239000000594 mannitol Substances 0.000 claims description 15
- 235000010355 mannitol Nutrition 0.000 claims description 15
- 206010012289 Dementia Diseases 0.000 claims description 14
- 238000007908 dry granulation Methods 0.000 claims description 14
- 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 claims description 13
- 208000034799 Tauopathies Diseases 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 12
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 12
- 208000011580 syndromic disease Diseases 0.000 claims description 12
- 238000002560 therapeutic procedure Methods 0.000 claims description 12
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- 241000710886 West Nile virus Species 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- 230000003612 virological effect Effects 0.000 claims description 11
- 208000023105 Huntington disease Diseases 0.000 claims description 10
- 208000027747 Kennedy disease Diseases 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 125000000732 arylene group Chemical group 0.000 claims description 10
- 239000007888 film coating Substances 0.000 claims description 10
- 238000009501 film coating Methods 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 9
- 230000001580 bacterial effect Effects 0.000 claims description 9
- 210000004556 brain Anatomy 0.000 claims description 9
- 210000000349 chromosome Anatomy 0.000 claims description 9
- 108010040003 polyglutamine Proteins 0.000 claims description 9
- 229920000155 polyglutamine Polymers 0.000 claims description 9
- 201000010374 Down Syndrome Diseases 0.000 claims description 8
- 206010044688 Trisomy 21 Diseases 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 201000004792 malaria Diseases 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 208000004051 Chronic Traumatic Encephalopathy Diseases 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 7
- 125000006242 amine protecting group Chemical group 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 229940032147 starch Drugs 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 6
- 201000008163 Dentatorubral pallidoluysian atrophy Diseases 0.000 claims description 6
- 208000005176 Hepatitis C Diseases 0.000 claims description 6
- 201000002832 Lewy body dementia Diseases 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- 208000018737 Parkinson disease Diseases 0.000 claims description 6
- 208000027089 Parkinsonian disease Diseases 0.000 claims description 6
- 206010034010 Parkinsonism Diseases 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 6
- 230000007850 degeneration Effects 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 208000029402 Bulbospinal muscular atrophy Diseases 0.000 claims description 5
- 206010068597 Bulbospinal muscular atrophy congenital Diseases 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 5
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000009481 moist granulation Methods 0.000 claims description 5
- 208000036709 mucopolysaccharidosis type 3B Diseases 0.000 claims description 5
- 244000052769 pathogen Species 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 4
- 208000025820 Sanfilippo syndrome type B Diseases 0.000 claims description 4
- 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 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008121 dextrose Substances 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 208000005340 mucopolysaccharidosis III Diseases 0.000 claims description 4
- 208000012227 mucopolysaccharidosis type IIIB Diseases 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- 150000008163 sugars Chemical class 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 206010068871 Myotonic dystrophy Diseases 0.000 claims description 3
- 208000014060 Niemann-Pick disease Diseases 0.000 claims description 3
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 claims description 3
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 3
- 229940078495 calcium phosphate dibasic Drugs 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 239000001175 calcium sulphate Substances 0.000 claims description 3
- 235000011132 calcium sulphate Nutrition 0.000 claims description 3
- 230000000415 inactivating effect Effects 0.000 claims description 3
- 230000001717 pathogenic effect Effects 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000011872 intimate mixture Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 208000030381 cutaneous melanoma Diseases 0.000 claims 3
- 201000003708 skin melanoma Diseases 0.000 claims 3
- 229960005261 aspartic acid Drugs 0.000 claims 1
- 229940098895 maleic acid Drugs 0.000 claims 1
- 229960004838 phosphoric acid Drugs 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 68
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract description 2
- 125000006585 (C6-C10) arylene group Chemical group 0.000 abstract description 2
- 108010026424 tau Proteins Proteins 0.000 description 84
- 102000013498 tau Proteins Human genes 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 64
- 235000002639 sodium chloride Nutrition 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 49
- 239000000047 product Substances 0.000 description 46
- 238000004090 dissolution Methods 0.000 description 38
- 230000002829 reductive effect Effects 0.000 description 37
- 230000009467 reduction Effects 0.000 description 35
- 102100040347 TAR DNA-binding protein 43 Human genes 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 34
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 33
- 230000035772 mutation Effects 0.000 description 33
- 101710150875 TAR DNA-binding protein 43 Proteins 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 30
- 238000006722 reduction reaction Methods 0.000 description 27
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 239000004480 active ingredient Substances 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 229940079593 drug Drugs 0.000 description 22
- 239000000523 sample Substances 0.000 description 22
- KCSURCKZGJUTCH-UHFFFAOYSA-N 3,7-dinitro-10h-phenothiazine Chemical compound C1=C([N+]([O-])=O)C=C2SC3=CC([N+](=O)[O-])=CC=C3NC2=C1 KCSURCKZGJUTCH-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 230000000875 corresponding effect Effects 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 18
- 239000002775 capsule Substances 0.000 description 18
- 230000001965 increasing effect Effects 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 125000003277 amino group Chemical group 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 14
- 238000006073 displacement reaction Methods 0.000 description 14
- 238000003860 storage Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 230000006870 function Effects 0.000 description 13
- 235000019359 magnesium stearate Nutrition 0.000 description 13
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 13
- 230000001575 pathological effect Effects 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 239000000314 lubricant Substances 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 150000003871 sulfonates Chemical class 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 0 C[N+](*)(c1cc(*)c2NC(C(*)CC([N+](*)(*)[O-])=C3)=C3Sc2c1)[O-] Chemical compound C[N+](*)(c1cc(*)c2NC(C(*)CC([N+](*)(*)[O-])=C3)=C3Sc2c1)[O-] 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 239000011248 coating agent Substances 0.000 description 9
- 238000000576 coating method Methods 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 231100000331 toxic Toxicity 0.000 description 9
- 230000002588 toxic effect Effects 0.000 description 9
- 238000005550 wet granulation Methods 0.000 description 9
- KPYHKEZPEDJERZ-UHFFFAOYSA-N 10h-phenothiazine-1,2-diamine Chemical class C1=CC=C2NC3=C(N)C(N)=CC=C3SC2=C1 KPYHKEZPEDJERZ-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 230000004931 aggregating effect Effects 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 8
- 208000015122 neurodegenerative disease Diseases 0.000 description 8
- 210000000440 neutrophil Anatomy 0.000 description 8
- 238000012545 processing Methods 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 239000007941 film coated tablet Substances 0.000 description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 7
- 230000001771 impaired effect Effects 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 229960001375 lactose Drugs 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 229960000907 methylthioninium chloride Drugs 0.000 description 7
- 238000006396 nitration reaction Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000009491 slugging Methods 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- VUWDHXCPXJCIJQ-UHFFFAOYSA-N 1-(3,7-dinitrophenothiazin-10-yl)ethanone Chemical compound [O-][N+](=O)C1=CC=C2N(C(=O)C)C3=CC=C([N+]([O-])=O)C=C3SC2=C1 VUWDHXCPXJCIJQ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 208000005870 Lafora disease Diseases 0.000 description 6
- 208000014161 Lafora myoclonic epilepsy Diseases 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 102000008221 Superoxide Dismutase-1 Human genes 0.000 description 6
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 238000002372 labelling Methods 0.000 description 6
- 229960001855 mannitol Drugs 0.000 description 6
- 230000004770 neurodegeneration Effects 0.000 description 6
- 230000007170 pathology Effects 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 238000012430 stability testing Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 5
- 102000015782 Electron Transport Complex III Human genes 0.000 description 5
- 108010024882 Electron Transport Complex III Proteins 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000002518 distortionless enhancement with polarization transfer Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 230000001976 improved effect Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000010348 incorporation Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 208000012268 mitochondrial disease Diseases 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 5
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 238000009490 roller compaction Methods 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 125000000542 sulfonic acid group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 4
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101000979001 Homo sapiens Methionine aminopeptidase 2 Proteins 0.000 description 4
- 101000969087 Homo sapiens Microtubule-associated protein 2 Proteins 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 4
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 4
- 102100023174 Methionine aminopeptidase 2 Human genes 0.000 description 4
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 208000036278 TDP-43 proteinopathy Diseases 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 206010002022 amyloidosis Diseases 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000000132 electrospray ionisation Methods 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 125000004957 naphthylene group Chemical group 0.000 description 4
- 230000000626 neurodegenerative effect Effects 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 230000008506 pathogenesis Effects 0.000 description 4
- 150000002990 phenothiazines Chemical class 0.000 description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 4
- 238000004393 prognosis Methods 0.000 description 4
- 230000000750 progressive effect Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 210000001562 sternum Anatomy 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 3
- 108091006112 ATPases Proteins 0.000 description 3
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 238000005079 FT-Raman Methods 0.000 description 3
- 208000007882 Gastritis Diseases 0.000 description 3
- 241000237858 Gastropoda Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000891092 Homo sapiens TAR DNA-binding protein 43 Proteins 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 208000015439 Lysosomal storage disease Diseases 0.000 description 3
- 108091077621 MAPRE family Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- 102000029749 Microtubule Human genes 0.000 description 3
- 108091022875 Microtubule Proteins 0.000 description 3
- 208000026072 Motor neurone disease Diseases 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- 229910017852 NH2NH2 Inorganic materials 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- 241000282898 Sus scrofa Species 0.000 description 3
- 102000019355 Synuclein Human genes 0.000 description 3
- 108050006783 Synuclein Proteins 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- 102000044159 Ubiquitin Human genes 0.000 description 3
- 108090000848 Ubiquitin Proteins 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- QTWZICCBKBYHDM-UHFFFAOYSA-P [7-(dimethylazaniumyl)-10H-phenothiazin-3-yl]-dimethylazanium Chemical compound C[NH+](C)c1ccc2Nc3ccc(cc3Sc2c1)[NH+](C)C QTWZICCBKBYHDM-UHFFFAOYSA-P 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- KFZNPGQYVZZSNV-UHFFFAOYSA-M azure B Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(NC)=CC=C3N=C21 KFZNPGQYVZZSNV-UHFFFAOYSA-M 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 229960003677 chloroquine Drugs 0.000 description 3
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000012937 correction Methods 0.000 description 3
- 238000013480 data collection Methods 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 229960001031 glucose Drugs 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000002132 lysosomal effect Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 208000005135 methemoglobinemia Diseases 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 210000004688 microtubule Anatomy 0.000 description 3
- 244000309715 mini pig Species 0.000 description 3
- 230000002438 mitochondrial effect Effects 0.000 description 3
- 230000006540 mitochondrial respiration Effects 0.000 description 3
- 210000002161 motor neuron Anatomy 0.000 description 3
- 208000005264 motor neuron disease Diseases 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 3
- 229940067157 phenylhydrazine Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000002797 proteolythic effect Effects 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000001374 small-angle light scattering Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 235000011150 stannous chloride Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 150000003460 sulfonic acids Chemical class 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102100034452 Alternative prion protein Human genes 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 206010007509 Cardiac amyloidosis Diseases 0.000 description 2
- 229910002483 Cu Ka Inorganic materials 0.000 description 2
- 102000012192 Cystatin C Human genes 0.000 description 2
- 108010061642 Cystatin C Proteins 0.000 description 2
- 102100030497 Cytochrome c Human genes 0.000 description 2
- 108010075031 Cytochromes c Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 241000252212 Danio rerio Species 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 239000004150 EU approved colour Substances 0.000 description 2
- 108091006149 Electron carriers Proteins 0.000 description 2
- 208000032274 Encephalopathy Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010053155 Epigastric discomfort Diseases 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 229920001503 Glucan Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102100033468 Lysozyme C Human genes 0.000 description 2
- 108010014251 Muramidase Proteins 0.000 description 2
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 2
- 102100037591 Neuroserpin Human genes 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 206010036105 Polyneuropathy Diseases 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 108010071690 Prealbumin Proteins 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 108091000054 Prion Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 102000009190 Transthyretin Human genes 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- SPCMQFLNOVTUBM-UHFFFAOYSA-N [7-(dimethylazaniumyl)-10h-phenothiazin-3-yl]-dimethylazanium;methanesulfonate Chemical compound CS([O-])(=O)=O.CS([O-])(=O)=O.C1=C([NH+](C)C)C=C2SC3=CC([NH+](C)C)=CC=C3NC2=C1 SPCMQFLNOVTUBM-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 210000004900 c-terminal fragment Anatomy 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 230000027721 electron transport chain Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethanedisulfonate group Chemical group C(CS(=O)(=O)[O-])S(=O)(=O)[O-] AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000013505 freshwater Substances 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002607 hemopoietic effect Effects 0.000 description 2
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 2
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 2
- QTWZICCBKBYHDM-UHFFFAOYSA-N leucomethylene blue Chemical compound C1=C(N(C)C)C=C2SC3=CC(N(C)C)=CC=C3NC2=C1 QTWZICCBKBYHDM-UHFFFAOYSA-N 0.000 description 2
- 239000004325 lysozyme Substances 0.000 description 2
- 229960000274 lysozyme Drugs 0.000 description 2
- 235000010335 lysozyme Nutrition 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 201000000585 muscular atrophy Diseases 0.000 description 2
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 2
- 230000014511 neuron projection development Effects 0.000 description 2
- 108010080874 neuroserpin Proteins 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000007824 polyneuropathy Effects 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- CAXRKYFRLOPCAB-UHFFFAOYSA-N propane-1,1-disulfonic acid Chemical compound CCC(S(O)(=O)=O)S(O)(=O)=O CAXRKYFRLOPCAB-UHFFFAOYSA-N 0.000 description 2
- MGNVWUDMMXZUDI-UHFFFAOYSA-N propane-1,3-disulfonic acid Chemical class OS(=O)(=O)CCCS(O)(=O)=O MGNVWUDMMXZUDI-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 239000007885 tablet disintegrant Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229940033134 talc Drugs 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 238000000003 thermogravimetry coupled to Fourier transform infrared spectroscopy Methods 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- GQMMRLBWXCGBEV-YVMONPNESA-N (nz)-n-[(3-nitrophenyl)methylidene]hydroxylamine Chemical compound O\N=C/C1=CC=CC([N+]([O-])=O)=C1 GQMMRLBWXCGBEV-YVMONPNESA-N 0.000 description 1
- 125000004958 1,4-naphthylene group Chemical group 0.000 description 1
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 1
- JEOGFTYLESYHAM-UHFFFAOYSA-N 1-[3,7-bis(dimethylamino)phenothiazin-10-yl]ethanone Chemical compound C1=C(N(C)C)C=C2SC3=CC(N(C)C)=CC=C3N(C(C)=O)C2=C1 JEOGFTYLESYHAM-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PSDFEFMNSUSZLA-UHFFFAOYSA-N 2-ethylthionine Chemical compound CCC1=CC=CC=CC=CS1 PSDFEFMNSUSZLA-UHFFFAOYSA-N 0.000 description 1
- ZXVONLUNISGICL-UHFFFAOYSA-N 4,6-dinitro-o-cresol Chemical group CC1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1O ZXVONLUNISGICL-UHFFFAOYSA-N 0.000 description 1
- ZGLUKQQSWABKDH-UHFFFAOYSA-N 5-amino-1-methyl-3h-indol-2-one Chemical compound NC1=CC=C2N(C)C(=O)CC2=C1 ZGLUKQQSWABKDH-UHFFFAOYSA-N 0.000 description 1
- 208000023769 AA amyloidosis Diseases 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 102100022987 Angiogenin Human genes 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 102000007592 Apolipoproteins Human genes 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 102000013918 Apolipoproteins E Human genes 0.000 description 1
- 108010025628 Apolipoproteins E Proteins 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 102000007372 Ataxin-1 Human genes 0.000 description 1
- 108010032963 Ataxin-1 Proteins 0.000 description 1
- 102000014461 Ataxins Human genes 0.000 description 1
- 108010078286 Ataxins Proteins 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 208000024806 Brain atrophy Diseases 0.000 description 1
- 201000007120 C1 inhibitor deficiency Diseases 0.000 description 1
- 101150108055 CHMP2B gene Proteins 0.000 description 1
- IJOONAFEBUFVOS-UHFFFAOYSA-N CN1c(c(I)cc([N+]([O-])=O)c2)c2Sc2cc([N+]([O-])=O)cc(N)c12 Chemical compound CN1c(c(I)cc([N+]([O-])=O)c2)c2Sc2cc([N+]([O-])=O)cc(N)c12 IJOONAFEBUFVOS-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102100038279 Charged multivesicular body protein 2b Human genes 0.000 description 1
- 201000000915 Chronic Progressive External Ophthalmoplegia Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 101710197257 E3 ubiquitin-protein ligase NHLRC1 Proteins 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000289695 Eutheria Species 0.000 description 1
- 206010016202 Familial Amyloidosis Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000004878 Gelsolin Human genes 0.000 description 1
- 108090001064 Gelsolin Proteins 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010019860 Hereditary angioedema Diseases 0.000 description 1
- 101000891579 Homo sapiens Microtubule-associated protein tau Proteins 0.000 description 1
- 101000801891 Homo sapiens Thioredoxin, mitochondrial Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 241000282620 Hylobates sp. Species 0.000 description 1
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 1
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 231100000416 LDH assay Toxicity 0.000 description 1
- 101710192391 Laforin Proteins 0.000 description 1
- 102100038889 Laforin, isoform 9 Human genes 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 1
- 208000006136 Leigh Disease Diseases 0.000 description 1
- 208000017507 Leigh syndrome Diseases 0.000 description 1
- 208000035177 MELAS Diseases 0.000 description 1
- 208000035172 MERRF Diseases 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 108010061951 Methemoglobin Proteins 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010058799 Mitochondrial encephalomyopathy Diseases 0.000 description 1
- 241000289390 Monotremata Species 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 102220592550 Neuroserpin_S52R_mutation Human genes 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- 108020003217 Nuclear RNA Proteins 0.000 description 1
- 241000289371 Ornithorhynchus anatinus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000002774 Paraproteinemias Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 108700021402 PrP 27-30 Proteins 0.000 description 1
- 108010036933 Presenilin-1 Proteins 0.000 description 1
- 102000012412 Presenilin-1 Human genes 0.000 description 1
- 108010050254 Presenilins Proteins 0.000 description 1
- 102000015499 Presenilins Human genes 0.000 description 1
- 208000010291 Primary Progressive Nonfluent Aphasia Diseases 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 108010048233 Procalcitonin Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101100240886 Rattus norvegicus Nptx2 gene Proteins 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000018642 Semantic dementia Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 101150014554 TARDBP gene Proteins 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 102100034795 Thioredoxin, mitochondrial Human genes 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102100026145 Transitional endoplasmic reticulum ATPase Human genes 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 108010005705 Ubiquitinated Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- XQAXGZLFSSPBMK-UHFFFAOYSA-M [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride;trihydrate Chemical compound O.O.O.[Cl-].C1=CC(=[N+](C)C)C=C2SC3=CC(N(C)C)=CC=C3N=C21 XQAXGZLFSSPBMK-UHFFFAOYSA-M 0.000 description 1
- HMYOQEBHJQXJTA-UHFFFAOYSA-N [7-(dimethylazaniumyl)-10h-phenothiazin-3-yl]-dimethylazanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1.C1=C([NH+](C)C)C=C2SC3=CC([NH+](C)C)=CC=C3NC2=C1 HMYOQEBHJQXJTA-UHFFFAOYSA-N 0.000 description 1
- JAUPSVVTGFBHTN-UHFFFAOYSA-N [7-(dimethylazaniumyl)-10h-phenothiazin-3-yl]-dimethylazanium;dibromide Chemical compound [Br-].[Br-].C1=C([NH+](C)C)C=C2SC3=CC([NH+](C)C)=CC=C3NC2=C1 JAUPSVVTGFBHTN-UHFFFAOYSA-N 0.000 description 1
- LYZFTAHMAJEAGT-UHFFFAOYSA-N [7-(dimethylazaniumyl)-10h-phenothiazin-3-yl]-dimethylazanium;naphthalene-1,2-disulfonate Chemical compound C1=CC=CC2=C(S([O-])(=O)=O)C(S(=O)(=O)[O-])=CC=C21.C1=C([NH+](C)C)C=C2SC3=CC([NH+](C)C)=CC=C3NC2=C1 LYZFTAHMAJEAGT-UHFFFAOYSA-N 0.000 description 1
- QFHKZASDZUVDPT-UHFFFAOYSA-N [Cl-].CCC1=CC=CC=CC=C[SH+]1 Chemical compound [Cl-].CCC1=CC=CC=CC=C[SH+]1 QFHKZASDZUVDPT-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 231100000354 acute hepatitis Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 description 1
- 108010009380 alpha-N-acetyl-D-glucosaminidase Proteins 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 238000010913 antigen-directed enzyme pro-drug therapy Methods 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 description 1
- 229960003159 atovaquone Drugs 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 102000003799 beta-Synuclein Human genes 0.000 description 1
- 108090000182 beta-Synuclein Proteins 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 125000005488 carboaryl group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- ZXJXZNDDNMQXFV-UHFFFAOYSA-M crystal violet Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1[C+](C=1C=CC(=CC=1)N(C)C)C1=CC=C(N(C)C)C=C1 ZXJXZNDDNMQXFV-UHFFFAOYSA-M 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000001947 dentate gyrus Anatomy 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000008242 dietary patterns Nutrition 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- QXYCYSAGHGKNHM-UHFFFAOYSA-N dodecyl octadecanoate;magnesium Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCC QXYCYSAGHGKNHM-UHFFFAOYSA-N 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DPKGTLUCCMJBQI-UHFFFAOYSA-N ethane-1,2-disulfonic acid;hydrate Chemical compound O.OS(=O)(=O)CCS(O)(=O)=O DPKGTLUCCMJBQI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 208000001759 familial encephalopathy with neuroserpin inclusion bodies Diseases 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 210000001907 heinz body Anatomy 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 102000057063 human MAPT Human genes 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 201000008319 inclusion body myositis Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 206010023497 kuru Diseases 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000002843 lactate dehydrogenase assay Methods 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QQNBSDFGZRIKPZ-UHFFFAOYSA-N methanesulfonic acid;10h-phenothiazine-1,2-diamine Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1=CC=C2NC3=C(N)C(N)=CC=C3SC2=C1 QQNBSDFGZRIKPZ-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 201000011540 mitochondrial DNA depletion syndrome 4a Diseases 0.000 description 1
- 230000006676 mitochondrial damage Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 239000007783 nanoporous material Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000001452 natriuretic effect Effects 0.000 description 1
- 210000000478 neocortex Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000012223 nuclear import Effects 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000010363 phase shift Effects 0.000 description 1
- LTOOVISGEYEBFR-UHFFFAOYSA-N phenothiazin-5-ium Chemical class C1=CC=CC2=NC3=CC=CC=C3[S+]=C21 LTOOVISGEYEBFR-UHFFFAOYSA-N 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000001907 polarising light microscopy Methods 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 210000000976 primary motor cortex Anatomy 0.000 description 1
- CWCXERYKLSEGEZ-KDKHKZEGSA-N procalcitonin Chemical compound C([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)[C@H]1NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@@H](N)CSSC1)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 CWCXERYKLSEGEZ-KDKHKZEGSA-N 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000020978 protein processing Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 210000002763 pyramidal cell Anatomy 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002824 redox indicator Substances 0.000 description 1
- 238000006485 reductive methylation reaction Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 102200036626 rs104893877 Human genes 0.000 description 1
- 102200036620 rs104893878 Human genes 0.000 description 1
- 102200149503 rs121909051 Human genes 0.000 description 1
- 102220007692 rs141804752 Human genes 0.000 description 1
- 102200051507 rs1555689937 Human genes 0.000 description 1
- 102200082935 rs34404985 Human genes 0.000 description 1
- 102220059031 rs374597395 Human genes 0.000 description 1
- 102220004984 rs387906535 Human genes 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000002764 solid phase assay Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 1
- 230000037423 splicing regulation Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000002723 toxicity assay Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 239000000083 urinary anti-infective agent Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920006163 vinyl copolymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 230000003253 viricidal effect Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0029—Radiation
- A61L2/0052—Visible light
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/05—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
- C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
- C07C309/35—Naphthalene sulfonic acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- TECHNICAL FIELD This invention pertains generally to the field of phenothiazine compounds, in particular certain phenothiazine diaminium salts, including uses and formulations thereof.
- the invention relates to bis(sulfonic acid) salts of diaminophenothiazine compounds such as /V,A/,/V', ⁇ /'-tetramethyl-10H-phenothiazine-3,7-diamine.
- the compounds of the invention are useful, for example, in the treatment of tauopathies such as Alzheimer's disease (AD).
- AD Alzheimer's disease
- Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about,” it will be understood that the particular value forms another embodiment.
- Conditions of dementia are frequently characterised by a progressive accumulation of intracellular and/or extracellular deposits of proteinaceous structures such as ⁇ -amyloid plaques and neurofibrillary tangles (NFTs) in the brains of affected patients.
- proteinaceous structures such as ⁇ -amyloid plaques and neurofibrillary tangles (NFTs)
- NFTs neurofibrillary tangles
- both neuritic plaques and NFTs contain paired helical filaments (PHFs), of which a major constituent is the microtubule-associated protein tau (see, e.g., Wischik et al., 1988, PNAS USA, Vol. 85, pp. 4506-4510). Plaques also contain extracellular ⁇ -amyloid fibrils derived from the abnormal processing of amyloid precursor protein (APP) (see, e.g., Kang et al., 1987, Nature, Vol. 325, p. 733).
- APP amyloid precursor protein
- Tau in PHFs is proteolytically processed to a core domain (see, e.g., Wischik, CM., et al., 1988, PNAS USA, Vol. 85, pp. 4884-4888; Wischik et al., 1988, PNAS USA, Vol. 85, pp.
- PHF-like tau aggregates act as seeds for the further capture and provide a template for proteolytic processing of full-length tau protein (see, e.g., Wischik et al., 1996, PNAS USA, Vol. 93, pp. 11213-11218).
- Methythioninium Chloride (also known as Methylene blue (MB); methylthionine chloride; tetramethylthionine chloride; 3,7-bis(dimethylamino) phenothiazin-5-ium chloride; C.I. Basic Blue 9; tetramethylthionine chloride; 3,7-bis(dimethylamino) phenazathionium chloride; Swiss blue; C.I. 52015; C.I. Solvent Blue 8; aniline violet; and Urolene Blue®) is a low molecular weight (319.86), water soluble, tricyclic organic compound of the following formula:
- Methythioninium Chloride is a well known phenothiazine dye and redox indicator and has also been used as an optical probe of biophysical systems, as an intercalator in nanoporous materials, as a redox mediator, and in photoelectrochromic imaging.
- Methythioninium chloride (MTC) and other diaminophenothiazines have been described as inhibitors of protein aggregation in diseases in which proteins aggregate
- diaminopenothiazines including MTC have been shown to inhibit tau protein aggregation and to disrupt the structure of PHFs, and reverse the proteolytic stability of the PHF core (see, e.g., WO 96/30766, Hofmann-La Roche).
- Such compounds were disclosed for use in the treatment or prophylaxis of various diseases, including
- WO2007/1 10630 (WisTa Laboratories Ltd) also discloses certain specific
- diaminophenothiazine compounds related to MTC including ETC, DEMTC, DMETC, DEETC, MTZ, ETZ, MTI, MTILHI, ETI, ETLHI, MTN, and ETN, which are useful as drugs, for example in the treatment of Alzheimer's disease.
- MTC Methythioninium chloride
- MTC has been used to treat malaria, either singly (see, e.g., Guttmann, P. and Ehrlich, P., 1891 , "Uber die rial des methylenblau bei malaria,” Berl. Klin. Woschenr., Vol. 28, pp. 953-956) or in combination with chloroquine (see, e.g., Schirmer, H., et al., 2003, "Methylene blue as an antimalarial agent," Redox Report, Vol. 8, pp. 272-275;
- MTC (under the name Virostat®, from Bioenvision Inc., New York) has also shown potent viricidal activity in vitro. Specifically Virostat® is effective against viruses such as HIV and West Nile Virus in laboratory tests. Virostat® is also currently in clinical trials for the treatment of chronic Hepatitis C, a viral infection of the liver. The virus, HCV, is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and liver cancer. MTC, when combined with light, can also prevent the replication of nucleic acid (DNA or RNA). Plasma, platelets and red blood cells do not contain nuclear DNA or RNA.
- DNA or RNA nucleic acid
- MTC When MTC is introduced into the blood components, it crosses bacterial cell walls or viral membrane then moves into the interior of the nucleic acid structure. When activated with light, the compound then binds to the nucleic acid of the viral or bacterial pathogen, preventing replication of the DNA or RNA. Because MTC can inactivate pathogens, it has the potential to reduce the risk of transmission of pathogens that would remain
- Reduced Cleuco' ) forms MTC a phenothiazin-5-ium salt
- MTC a phenothiazin-5-ium salt
- the “reduced form” (or “leuco form”) is known to be unstable and can be readily and rapidly oxidized to give the corresponding "oxidized” form.
- MTC and similar drugs are taken up in the gut and enter the bloodstream. Unabsorbed drug percolates down the alimentary canal, to the distal gut.
- One important undesired side-effect is the effect of the unabsorbed drug in the distal gut, for example, sensitisation of the distal gut and/or antimicrobial effects of the unabsorbed drug on flora in the distal gut, both leading to diarrhoea. Therefore, it is desirable to minimize the amount of drug that percolates to the distal gut.
- dosage may be reduced, and the undesired side- effects, such as diarrhoea, may be ameliorated.
- WO 02/055720 (The University Court of the University of Aberdeen) discloses the use of reduced forms of certain diaminophenothiazines for the treatment of protein aggregating diseases, primarily tauopathies.
- WO2007/110627 (WisTa Laboratories Ltd) disclosed certain 3,7-diamino-10H- phenothiazinium salts, effective as drugs or pro-drugs for the treatment of diseases including Alzheimer's disease. These compounds are also in the "reduced” or “leuco” form when considered in respect of MTC. These included the following salts:
- Me s N Me HI 3,7-diaminium di(iodide), (LMT.2HI) Me Me Me
- the properties of the compounds are described hereinafter, whereby it can be seen that in preferred embodiments the invention can provide one or more of improved physical, pharmacokinetic, biochemical or other beneficial properties.
- the present inventors also provide novel formulations of 3,7-diamino- 10H-phenothiazinium salts.
- the present invention provides certain compounds, specifically, certain phenothiazine diaminium compounds, as described herein.
- the compound may be selected from compounds of general formula (I):
- each of R 1 and R 9 is independently selected from: -H, C 1-4 alkyl, C 2 - 4 alkenyl, and halogenated Ci- alkyl;
- each of R 3NA and R 3NB is independently selected from: -H, C -4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
- each of R 7NA and R 7NB is independently selected from: -H, C ⁇ alkyl, C 2-4 alkenyl, and halogenated d. 4 alkyl;
- each of R A and R B is independently selected from:
- R A and R B are linked to form a group R AB , wherein R AB is selected from:
- Another aspect of the invention pertains to processes for synthesizing a compound as described above.
- Another aspect of the invention pertains to a pharmaceutical composition
- a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier or diluent.
- Another aspect of the invention pertains to a method of preparing a pharmaceutical composition
- a method of preparing a pharmaceutical composition comprising admixing a compound as described herein and a
- Another aspect of the invention pertains to a pharmaceutical composition in solid dosage form, comprising a compound as described herein and further comprising at least one diluent suitable for dry compression, and optionally one or more other excipients.
- Another aspect of the invention pertains to a process for the manufacture of a pharmaceutical composition in solid dosage form, comprising a compound as described herein and further comprising at least one diluent suitable for dry compression, and optionally one or more other excipients.
- Another aspect of the invention pertains to a process for the manufacture of a
- compositions by a dry compression method, said composition being a solid dosage form comprising a compound as described herein, at least one diluent suitable for dry compression, and optionally one or more other excipients.
- Another aspect of the invention pertains to a free-flowing, cohesive powder, comprising a compound as described herein and at least one diluent suitable for dry compression, and optionally one or more other excipients, said powder being capable of being compressed into a solid dosage form.
- Another aspect of the present invention pertains to a method of reversing and/or inhibiting the aggregation of a protein (e.g., a tau protein, a synuclein, etc.), for example, aggregation of a protein associated with a neurodegenerative disease and/or clinical dementia, comprising contacting the protein with an effective amount of a compound or composition as described herein.
- a protein e.g., a tau protein, a synuclein, etc.
- Such a method may be performed in vitro, or in vivo.
- Another aspect of the present invention pertains to a method of treatment or prophylaxis of a disease condition in a subject comprising administering to said subject a
- prophylactically or therapeutically effective amount of a compound as described herein preferably in the form of a pharmaceutical composition, preferably a pharmaceutical composition in solid dosage form, as further described herein.
- Another aspect of the present invention pertains to a compound or composition as described herein for use in a method of treatment or prophylaxis (e.g., of a disease condition) of the human or animal body by therapy.
- a method of treatment or prophylaxis e.g., of a disease condition
- Another aspect of the present invention pertains to use of a compound or composition as described herein, in the manufacture of a medicament for use in the treatment or prophylaxis of a disease condition.
- the disease condition is a disease of protein aggregation.
- the disease condition is a tauopathy, e.g., a neurodegenerative tauopathy, e.g., Alzheimer's disease or other disease described hereinafter.
- a tauopathy e.g., a neurodegenerative tauopathy, e.g., Alzheimer's disease or other disease described hereinafter.
- the disease condition is skin cancer, e.g., melanoma.
- the disease condition is a viral, bacterial or protozoal disease condition, e.g., Hepatitis C, HIV, West Nile Virus (WNV), or malaria.
- a viral, bacterial or protozoal disease condition e.g., Hepatitis C, HIV, West Nile Virus (WNV), or malaria.
- Another aspect of the present invention pertains to a method of inactivating a pathogen in a sample (for example a blood or plasma sample), comprising the steps of introducing a compound or composition as described herein, into the sample, and then exposing the sample to light.
- a sample for example a blood or plasma sample
- kits comprising (a) a compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound or composition.
- Figure 1 shows the 1 H NMR spectrum of an exemplary compound of the invention (L T.2MsOH) in deuterated methanol (CD 3 OD) at 600 MHz.
- Figure 2 shows the 13 C NMR spectrum of LMT.2MsOH in CD 3 OD at a frequency of 100.56 MHz.
- Figure 3 shows the DEPT-135 spectrum of LMT.2MsOH in CD 3 OD at a frequency of 100.56 MHz.
- Figure 4 shows the HSQC spectrum of LMT.2MsOH in CD 3 OD at a frequency of 100.56 MHz.
- Figure 5 shows the an expanded section of the HSQC spectrum of LMT.2MsOH in CD 3 OD at a frequency of 100.56 MHz.
- Figure 6 shows the infrared (FT-IR) spectrum of LMT.2MsOH (KBr).
- Figure 7 shows the electron impact (El) mass spectrum spectrum of LMT.2MsOH.
- Figure 8 shows the electrospray ionisation (ESI) mass spectrum of LMT.2MsOH.
- Figure 9 shows the UV/Vis spectrum of LMT.2MsOH in de-ionised water.
- FIG. 10 shows the HPLC trace for LMT.2MsOH.
- Figure 1 1 shows a powder X-ray diffractogram for LMT.2MsOH, measured with Cu Ka radiation.
- Figure 12 shows the FT-Raman spectrum for crystalline LMT.2MsOH. The most intense signals are found at 1615 cm “1 , 1588 cm '1 1258 cm “1 , and 1042 cm “1 .
- Figure 13 shows the thermogravimetric profile for crystalline LMT.2MsOH. A constant weight was detected by TG and TG-FTIR up to the beginning of decomposition at 240- 270 °C.
- Figures 15a and 15b show the dynamic vapour sorption (DVS) curve for crystalline LMT.2MsOH measured at 25 °C with 5%/h scanning rate.
- the horizontal dashed lines indicate steps of water uptake of one equivalent.
- a stable weight of the sample (less than 0.5% weight change) was observed in the relative humidity (r.h.) range between 0% and 70%. Above this r.h., the water uptake increased rapidly, and the sample ultimately deliquesced. Upon drying, the water content decreased again to approximately 4 equiv. at 50% r.h.
- the DVS curve of the crystalline dihydrochloride salt (LMT.2HCI) is shown for comparison as a dashed line, the DVS curve of the dihydrobromide salt (LMT.2HBr) as a dotted line.
- Figure 15c shows the dynamic vapour sorption (DVS) curve for crystalline LMT.2MsOH as a function of time. The relative humidity is also indicated (right axis). The horizontal dashed lines indicate steps of one equivalent water uptake.
- Figure 16 shows polarizing microscopy pictures of the LMT.2MsOH (left)
- Figures 17a-c shows the X-ray crystal structures of LMTEsOH, LMT.EDSA.
- Figure 18 shows a comparison of the plasma concentration in pig of the MT moiety over time following dosing of LMT.2HBr , LMT.2HCI and LMT.2MsOH .
- Figure 19 is a diagram of the apparatus used in the dissolution studies (see Formulation Example 12).
- the present inventors have identified a new class of phenothiazine diaminium
- the compounds of the invention may be described as £>/ ' s(sulfonate) salts (or b/s(sulfonic acid) salts) of 3,7-diamino-10/- - phenothiazine compounds.
- the compounds are salts of the corresponding 3,7-diamino-10H-phenothiazine compounds with organic sulfonic acids.
- a compound of the invention is a 6/ ' s(sulfonate) salt of a compound of general formula:
- R ⁇ R 9 , R 3NA , R 3NB , R 7NA and R 7NB are as defined above.
- the salt is a b/s(alkylsulfonate) salt or a b/s(arylsulfonate) salt. ln some embodiments, the salt is selected from a )/s(methanesulfonate) salt, a b s(ethanesulfonate) salt, a )/s(p-toluenesulfonate) salt, a £> s(benzenesulfonate) salt, an ethanedisulfonate salt, a propanedisulfonate salt, or a naphthalenedisulfonate salt.
- the salt is a 6/s(methanesulfonate) salt (which may also be called a bis(mesylate) salt).
- the salt is a 6/ ' s(ethanesulfonate) salt (which may also be called a bis(esylate) salt).
- the salt is a 6/s(p-toluenesulfonate) salt (which may also be called a bis(tosylate) salt).
- the salt is a _?/ ' s(benzenesulfonate) salt.
- the salt is an ethanedisulfonate salt.
- the salt is a propanedisulfonate salt.
- the salt is a naphthalenedisulfonate salt, preferably a
- the compounds of the invention can be considered to be products obtainable from the reaction of a 3,7-diamino-10/-/-phenothiazine compound, for example as set out above, with two organic sulfonic acid moieties (R A S0 3 H and R B S0 3 H).
- the two organic sulfonic acid moieties may optionally be present on the same molecule, i.e. where R A and R B are linked.
- compounds of the invention are selected from compounds of general formula (I):
- each of R 1 and R 9 is independently selected from: -H, C 2 . 4 alkenyl, and halogenated Ci -4 alkyl;
- each of R 3NA and R 3NB is independently selected from: -H, C 1-4 alkyl, Cz ⁇ alkenyl, and halogenated d. 4 alkyl;
- each of R 7NA and R 7NB is independently selected from: -H, C 1- alkyl, C 2-4 alkenyl, and halogenated Ci. 4 alkyl; and wherein: each of R A and R B is independently selected from:
- R A and R B are linked to form a group R AB , wherein R AB is selected from:
- alkylene and C 6 -io arylene and pharmaceutically acceptable salts, solvates, and hydrates thereof.
- the resultant doubly positively-charged species is associated with two sulfonate counterion moieties (which may optionally be present on the same molecule, i.e. where R A and R B are linked):
- C 1 4 alkyl refers to a monovalent moiety obtained by removing a hydrogen atom from a hydrocarbon compound having from 1 to 4 carbon atoms, which may be aliphatic or alicyclic, or a combination thereof.
- C 2 -4alkenyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a C 2-4 alkene compound (i.e. a hydrocarbon compound containing at least one double bond and from 2 to 4 carbon atoms).
- Ci. 6 alkylene refers to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of an aliphatic linear hydrocarbon compound having from 1 to 6 carbon atoms.
- d. 4 alkyl groups may be selected from: linear C 1-4 alkyl groups, such as -Me, -Et, -nPr, -iPr, and -nBu; branched C 3 . 4 alkyl groups, such as -iPr, -iBu, -sBu, and -tBu; and cyclic C 3 . 4 alkyl groups, such as -cPr and -cBu.
- halogenated C 1-4 alkyl groups may be selected from: -CF 3 , -CH 2 CF 3 , and -CF 2 CF 3 .
- C 6 -io aryl refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C 6 -io aromatic compound, said compound having one ring, or two or more rings (e.g., fused), and having from 6 to 10 ring atoms, and wherein at least one of said ring(s) is an aromatic ring.
- C 6 . 10 arylene refers to a bidentate moiety obtained by removing two hydrogen atoms from an aromatic compound having from 6 to 10 carbon atoms.
- C 6 -i 0 aryl groups may be selected from C 6 -i 0 carboaryl groups such as phenyl, and naphthyl.
- C 6 .i 0 arylene groups may be selected from phenylene and naphthylene.
- Said d.4 alkyl and C1.6 alkylene groups may be unsubstituted or may optionally be substituted, for example with one or more groups selected from halo (e.g. F, CI, Br, or I), amino (e.g. -NH 2 , -NHR, or -NR 2 , wherein each R is independently Ci. alkyl), hydroxy (-OH), alkoxy (-OR, wherein R is independently C -4 alkyl), nitro (-N0 2 ), etc.
- halo e.g. F, CI, Br, or I
- amino e.g. -NH 2 , -NHR, or -NR 2 , wherein each R is independently Ci. alkyl), hydroxy (-OH), alkoxy (-OR, wherein R is independently C -4 alkyl), nitro (-N0 2 ), etc.
- Said C 6 .io aryl and C 6 -io arylene groups may be unsubstituted or may optionally be substituted, for example with one or more groups selected from C 1-4 alkyl, for example - Me, halogenated C 1-4 alkyl, for example -CF 3 , halo (e.g. F, CI, Br, or I), amino (e.g. -NH 2 , -NHR, or -NR 2 , wherein each R is independently Ci. 4 alkyl), hydroxy (-OH), alkoxy (-OR, wherein R is independently Ci. 4 alkyl), nitro (-N0 2 ), etc.
- C 1-4 alkyl for example - Me
- halogenated C 1-4 alkyl for example -CF 3
- halo e.g. F, CI, Br, or I
- amino e.g. -NH 2 , -NHR, or -NR 2 , wherein each R is independently Ci.
- R A and R B are independently selected from:
- R A and R B are linked to form a group R AB , wherein R AB is selected from:
- each of R A and R B is independently selected from:
- each of R A and R B is independently C 1-4 alkyl.
- each of R A and R B is independently selected from Me, Et, nPr, iPr, nBu, iBu, tBu.
- each of R A and R B is independently selected from Me and Et.
- each of R A and R B is independently C 6 .i 0 aryl.
- each of R A and R B is independently selected from benzene, 1- naphthalene, 2-naphthalene and p-toluene.
- each of R A and R B is independently selected from Me, Et, benzene and p-toluene.
- R A and R B are the same.
- R A and R B are different.
- R A and R B are the same and are independently Me.
- the compound may then be referred to as a diaminophenothiazine bis(methanesulfonate) salt which is of general formula (la):
- R A and R B are linked to form a group R AB.
- the compounds of the invention may alternately be represented by general formula lb:
- R is selected from C 1-6 alkylene and C 6 -io arylene.
- R AB is a C ⁇ . s alkylene group.
- R AB is a C 1-5 alkylene group selected from -CH 2 -, -CH 2 CH 2 -,
- R AB is a C 1-5 alkylene group selected from methylene (-CH 2 -), ethylene (-CH 2 CH 2 -) and propylene (-CH 2 CH 2 CH 2 -).
- R AB is ethylene
- R AB is a C 6 . 0 arylene group.
- R AB is a C 6 . 10 arylene group selected from phenylene and naphthylene.
- R AB is phenylene
- R AB is selected from 1 ,2-phenylene, 1 ,3-phenylene, and 1 ,4- phenylene.
- R AB is phenylene optionally substituted with one or more substituents, for example selected from ( ⁇ .4 alkyl, halogenated C ⁇ alkyl, and halo. ln some embodiments, R is naphthylene.
- R AB is selected from 1 ,2-naphthylene, 1 ,3-naphthylene, 1 ,4- naphthylene, 1 ,5-naphthylene, 1 ,6-naphthylene, 1 ,7-naphthylene and 1 ,8-naphthylene. In some embodiments, R AB is selected from:
- R is naphthylene optionally substituted with one or more substituents, for example selected from C -4 alkyl, halogenated and halo.
- each of R 1 and R 9 is independently -H, -Me, -Et, or -CF 3 .
- each of R 1 and R 9 is independently -H, -Me, or -Et.
- R 1 and R 9 are the same.
- R 1 and R 9 are different.
- each of R 1 and R 9 is independently -H.
- each of R 1 and R 9 is independently -Me.
- each of R 1 and R 9 is independently -Et.
- Each of R 3NA and R 3NB is independently selected from: -H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C n-4 alkyl.
- each of R 3NA and R 3NB is independently -Me or -Et. In some embodiments, R 3NA and R 3NB are the same.
- R 3NA and R 3NB are different.
- each of R 3NA and R 3NB is independently -Me.
- Each of R 7NA and R 7NB is independently selected from: -H, C 1- alkyl, C 2 . 4 alkenyl, and halogenated C h alky!. In some embodiments, each of R 7NA and R 7NB is independently selected from: C 2 . 4 alkenyl, and halogenated C 1-4 alkyl.
- each of R 7NA and R 7NB is independently -Me or -Et.
- R 7NA and R 7NB are the same.
- R 7NA and R 7NB are different.
- each of R 7NA and R 7NB is independently -Me.
- each of R 3NA and R 3NB is independently C 1- alkyl, C 2 . 4 alkenyl, or halogenated C alkyl; each of R 7NA and R 7NB is independently Ci. 4 alkyl, C 2 . 4 alkenyl, or halogenated C 1-4 alkyl. ln some embodiments:
- each of R 3NA and R 3NB is independently -Me or -Et;
- each of R 7NA and R 7NB is independently -Me or -Et.
- R and R and R and R are all the same.
- R 3NA and R 3NB and R 7NA and R 7NB are the same and are all -Me or all -Et.
- R 3NA and R 3NB and R 7NA and R 7NB are the same and are all -Me. Salts and solvates
- the compounds described herein are themselves salts, they may also be provided in the form of a mixed salt (i.e., the compound of the invention in combination with another salt). Such mixed salts are intended to be encompassed by the term "and pharmaceutically acceptable salts thereof. Unless otherwise specified, a reference to a particular compound also includes salts thereof.
- the compounds of the invention may also be provided in the form of a solvate or hydrate.
- solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, any reference to a compound also includes solvate and hydrate forms thereof. Naturally, solvates or hydrates of salts of the compounds are also encompassed by the present invention.
- one or more carbon atoms of the compound is 11 C, 13 C or 14 C. In some embodiments, one or more carbon atoms of the compound is 11 C.
- one or more carbon atoms of the compound is i3 C.
- one or more carbon atoms of the compound is 1 C.
- one or more nitrogen atoms of the compound is 15 N.
- one or more or all of the carbon atoms of one or more or all of the groups R 3NA , R 3NB , R 7NA , R 7NB , R 1 , R 9 , R A and R B is 11 C, 13 C, or 14 C.
- one or more or all of the carbon atoms of one or more or all of the groups R 3NA , R 3NB , R 7NA and R 7NB is 11 C, 13 C, or 14 C.
- the groups R 3NA , R 3NB , R 7NA , R 7NB , R ⁇ R 9 , R A and R B (and R AB ) are defined as independent variables and it will be recognised by those skilled in the art that any compatible combination of these groups and substituents may be utilised in the compounds and methods of the present invention.
- the compound of the invention may be selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
- One particular compound of the invention is compound 1 :
- This compound may also be referred to as:
- the compounds of the present invention may conveniently be described as being in a "stabilized reduced form".
- the compounds oxidize (e.g., autoxidize) to give the corresponding oxidized forms.
- compositions comprising the compounds of the present invention will contain, as an impurity, at least some of the corresponding oxidized compound.
- another aspect of the present invention pertains to compounds as described herein, in substantially purified form and/or in a form substantially free from contaminants (e.g., the corresponding oxidized compound, other contaminants).
- the substantially purified form is at least 50% by weight pure, e.g., at least 60% by weight pure, e.g., at least 70% by weight pure, e.g., at least 80% by weight pure, e.g., at least 90% by weight pure, e.g., at least 95% by weight pure, e.g., at least 97% by weight pure, e.g., at least 98% by weight pure, e.g., at least 99% by weight pure.
- the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
- Product-b y-Process e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
- the compound is one which is obtained by, or is obtainable by, a method as described herein.
- R 1 , R 9 , R 3NA , R 3NB , R 7NA , and R 7NB are as defined previously.
- R 9 R Prot R 1 wherein R prot is an amine protecting group and R 1 , R 9 , R 3NA , R 3NB , R 7NA , R 7NB , R A and R are as defined previously.
- the compounds of formula (II) may be prepared e.g. by deprotection of the compounds of formula (III), or by other known methods. Conversely, compounds of formula (II) may be produced by protection of compounds of formula (III).
- a suitable phenothiazine can be converted to the corresponding 3,7-dinitro-phenothiazine, for example using sodium nitrite with acetic acid and chloroform.
- the ring amino group may then be protected, for example as the acetate, for example using acetic anhydride and pyridine.
- nitro groups may then be reduced to amino groups, for example using tin (II) chloride with ethanol.
- amino groups may then be substituted, for example disubstituted, for example methyl disubstituted, for example using methyl iodide, sodium hydroxide, DMSO, and tetra-n- butyl ammonium bromide, to provide a /V-acetyl protected 3,7-dialkylamino-10H- phenothiazine.
- Schemes 1a and 1b Examples of such a method are illustrated in Schemes 1a and 1b.
- the use of any one or more of the reagents described herein in the process is of course encompassed by the present invention: Scheme 1 a
- the reduced and acetylated compound (of formula (III)) may then be deprotected (by removing the acetyl group), for example by reaction with a suitable acid, to give a compound of formula (II) or may be used directly.
- this reaction may produce a product with a high degree of purity.
- an appropriate thioninium salt for example, ethyl thioninium semi zinc chloride
- a reducing agent phenylhydrazine, ethanol, acetic anhydride, and pyridine.
- the present invention therefore provides a method of preparing a
- R A , R B , R 1 , R 9 , R 3NA , R 3NB , R 7NA , and R 7NB are as previously defined.
- the method comprises the step of:
- salt formation (SF) comprises treatment of a compound of formula (II) with an appropriate sulfonic acid.
- salt formation comprises treatment of a solution of a compound of formula (II) with an appropriate sulfonic acid, in an organic solvent.
- the present invention provides a method of preparing a 3,7-diamino- 10H-phenothiazine compound of formula (I):
- R A , R B , R 1 , R 9 , R 3NA , R 3NB , R 7NA , and R 7NB are as previously defined and wherein R Prot is an amine protecting group.
- the amine protecting group is an acid-cleavable protecting group.
- the amine protecting group is an acyl group, such as an acetyl group.
- the method comprises the steps of:
- Ring amino deprotection comprises removal of the protecting group to convert the /V-protected ring amine group (-NR Prot -) to a free ring amine group (-NH-).
- Deprotection of a compound of formula (III) produces the corresponding compound of formula (II).
- Methods for the removal of amine protecting groups are known in the art. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
- the step of ring amino deprotection (DP) and the step of salt formation (SF) are performed simultaneously (i.e., as one step). For example:
- simultaneous ring amino deprotection (DP) and salt formation (SF) comprises treatment of the compound of formula (III) with an appropriate sulfonic acid, to produce a £>/ ' s(sulfonate) salt of formula (I).
- simultaneous ring amine deprotection and salt formation may comprise treatment of a solution of a compound of formula (III) in an organic solvent with the sulfonic acid and water.
- the organic solvent is toluene.
- the sulfonic acid may be selected from alkylsuifonic acids and arylsulfonic acids. It may be a sulfonic acid of formula R A S0 3 H or R B S0 3 H, wherein R A and R B are as defined herein.
- the sulfonic acid may be a disulfonic acid. i.e. a compound containing two sulfonic acid moieties per molecule. These sulfonic acid moieties may be linked by e.g. an alkylene or arylene group.
- the sulfonic acid may be selected from: methanesulfonic acid (MsOH), ethanesulfonic acid (EsOH), benzenesulfonic acid (BSA), naphthalenesulfonic acid (NSA), p-toluenesulfonic acid (TsOH), ethanedisulfonic acid (EDSA),
- MsOH methanesulfonic acid
- EsOH ethanesulfonic acid
- BSA benzenesulfonic acid
- NSA naphthalenesulfonic acid
- TsOH p-toluenesulfonic acid
- EDSA ethanedisulfonic acid
- PDSA propanedisulfonic acid
- NDSA naphthalene-1 ,5-disulfonic acid
- the phenothiazine starting material i.e. the compound of formula (III) is first heated in said organic solvent until completely dissolved and the resultant solution is filtered before addition of the reagents (i.e. the sulfonic acid and water). ln some embodiments, the compound is heated in said organic solvent at a temperature of about 60-80 °C, for example at a temperature of about 70 °C.
- the sulfonic acid is added in an amount of at least 2 molar equivalents, for example about 2.2 molar equivalents, relative to the phenothiazine starting material. If a disulfonic acid is used, it will be understood the molar amount of the acid will be at least 1 molar equivalent, for example about 1.1 molar equivalents, so as to achieve the same number of sulfonic acid moieties per molecule of phenothiazine starting material.
- the sulfonic acid may be desirable to add the sulfonic acid slowly to prevent a temperature increase (exotherm). Therefore, in some embodiments, the sulfonic acid is added gradually.
- the sulfonic acid is added at a temperature of about 15-25 °C. In some embodiments, after addition of the sulfonic acid and water, the reaction is heated to a temperature of about 80-90 °C.
- the reaction is maintained at this temperature until judged complete by e.g. chromatographic analysis.
- the solution is treated with a counter solvent to precipitate the product.
- the counter solvent is an alcohol, for example ethanol.
- the resultant mixture is seeded with a small amount of the desired 6 s(sulfonate) salt.
- the seed comprises particles of the desired )/s(sulfonate) salt which have been ground.
- the seed comprises particles of the desired _ /s(sulfonate) salt which have been ground to a size of less than about 100 ⁇ .
- the precipitated product is isolated by filtration.
- salt formation produces the 6 s(sulfonate) salt of formula (I) from the compound of formula (II):
- the b/s(sulfonate) salt may also be prepared directly from a corres onding amino-protected (e.g. N-ace l) compound of formula (III).
- salt formation may be performed at the same time as deprotection, for example by using the appropriate sulfonic acid, e.g. methanesulfonic acid, for the deprotection step.
- sulfonic acid e.g. methanesulfonic acid
- the present invention provides a method of preparing a compound of formula (I):
- R A , R B , R 1 , R 9 , R 3NA , R 3NB , R 7NA , and R 7NB are as previously defined
- preparing said compound of formula (II) or (III) comprises a method as disclosed in WO2007/1 10627.
- preparing said compound of formula (II) or (III) comprises a method as disclosed in WO2008/007074.
- preparing a compound of formula (II) comprises ring amine deprotection (DP) of a compound of formula (III), as set out above.
- preparing a compound of formula (III) comprises one or more steps selected from:
- preparing a compound of formula (III) comprises the steps of reduction (RED), and
- the steps may be performed in any logical order. In some embodiments, the steps are performed in the order listed (i.e., any step in the list is performed at the same time as, or subsequent to, the preceding step in the list).
- nitration comprises:
- nitration is performed using a nitrite, for example, sodium nitrite, for example, sodium nitrite with acetic acid, and a solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitirle, tetrahydrofuran, dimethoxyethane, acetone, dichloromethane or chloroform.
- a nitrite for example, sodium nitrite, for example, sodium nitrite with acetic acid
- a solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitirle, tetrahydrofuran, dimethoxyethane, acetone, dichloromethane or chloroform.
- ring amino protection (AP) comprises:
- ring amino protection wherein the ring amino group (-NH-) of a 3,7-dinitro- 10H-phenothiazine is converted to a protected ring amino group (-NR prot ), for example:
- ring amino protection is achieved as an acetate, for example, using acetic anhydride, for example, using acetic anhydride and a base such as an amine base, for example triethylamine or pyridine.
- nitro reduction (NR) step comprises:
- nitro reduction wherein each of the nitro (-N0 2 ) groups of a protected 3,7-dinitro-10H-phenothiazine is converted to an amino (-NH 2 ) group, for example:
- nitro reduction may be performed using, for example, tin (II) chloride, for example, tin (II) chloride with ethanol.
- nitro reduction may be performed using, for example, palladium on charcoal (Pd/C) and hydrogen in, for example, 2-methyl-tetrahydrofuran.
- Pd/C palladium on charcoal
- hydrogen in, for example, 2-methyl-tetrahydrofuran.
- nitro reduction may be performed using, for example, zinc and aqueous ammonium chloride in methanol and THF
- amine substitution (AS) step comprises:
- amine substitution wherein each of the amino (-NH 2 ) groups of a protected 3,7-diamino-10H-phenothiazine is converted to disubstituted amino group, for example: ln
- amine substitution is performed using an alkyl halide, for example, an alkyl iodide, for example, methyl iodide, for example, methyl iodide with sodium hydroxide, DMSO, toluene and tetra-n-butyl ammonium bromide.
- amine substitution comprises treatment with formaldehyde (e.g. paraformaldehyde, formalin) under reducing conditions.
- formaldehyde e.g. paraformaldehyde, formalin
- reducing conditions for example, treatment with formalin and hydrogen gas, in the presence of a Pd/C catalyst; or treatment with paraformaldehyde in the presence of a reducing agent such as sodium cyanoborohydride and acetic acid.
- the reduction (RED) step is:
- RED 3,7-di(disubstituted amino)-thioninium salt is reduced to give the corresponding 3,7-di(disubstituted amino)-10H-phenothiazine, for example by treatment with a reducing agent, such as hydrazine (NH 2 NH 2 ), methyl hydrazine
- the ring amino protection (AP) step is:
- ring amino protection wherein a 3,7-di(disubstituted amino)-10H- phenothiazine is protected, for example by treatment with acetic anhydride, to give the corresponding protected 3,7-di(disubstituted amino)-10H-phenothiazine, for example the corresponding /V-acetyl 3,7-di(disubstituted amino)-10H-phenothiazine.
- the steps are performed in the order listed (i.e., any step in the list is performed at the same time as, or subsequent to, the preceding step in the list).
- the step of reduction (RED) and the step of ring amino protection (AP) are performed simultaneously (i.e., as one step).
- the combined reduction (RED) step and ring amino protection (AP) step is:
- RED 3,7-di(disubstituted amino)-thioninium salt
- AP ring amino protection
- a 3,7-di(disubstituted amino)-thioninium salt is reduced to give the corresponding 3,7-di(disubstituted amino)- 10H-phenothiazine
- the ring amino group (-NH-) of the 3,7-di(disubstituted amino)- 10H-phenothiazine is converted to a protected ring amino group (-R prot ) to give the corresponding protected 3,7-di(disubstituted amino)-10H-phenothiazine, for example:
- Y is a counterion.
- Y represents CI ' .
- the 3,7-di(disubstituted amino)-thioninium salt is methylthioninium chloride (MTC).
- the combined reduction (RED) step and ring amino protection (AP) step is achieved using a hydrazine, such as phenylhydrazine, MeNHNH 2 , or NH 2 NH 2 .H 2 0 and acetic anhydride.
- a hydrazine such as phenylhydrazine, MeNHNH 2 , or NH 2 NH 2 .H 2 0 and acetic anhydride.
- the step is performed under a nitrogen atmosphere.
- the combined reduction (RED) step and ring amino protection (AP) step is performed using, for example, phenylhydrazine, ethanol, acetic anhydride, and pyridine.
- the combined reduction (RED) step and ring amino protection (AP) step is performed using, for example, hydrazine hydrate, acetonitrile, acetic anhydride, and triethylamine, under a nitrogen atmosphere.
- the protected 3,7-di(disubstituted amino)-10H-phenothiazine undergoes a purification step.
- purification comprises addition of an organic solvent, for example toluene, and an acid, for example acetic acid, to dissolve the compound, followed by a washing step.
- organic solvent for example toluene
- acid for example acetic acid
- washing comprises addition of water and/or aqueous acetic acid to the solution of the compound; agitation and/or heating; and separation of the organic layer.
- washing is repeated, for example up to three times.
- washing is followed by isolation of the purified product.
- isolation of the purified product comprises cooling, precipitation and filtration of the product.
- the compound of the invention is provided in crystalline form.
- the crystalline form is 'Form A' as described herein.
- the crystalline form has the structure depicted in Figure 17 and ⁇ or is characterised by the crystal data shown in an Annex Table 1 and ⁇ or the atomic coordinates shown in an Annex Table 2 and ⁇ or the bond lengths and angles shown in an Annex Table 3 and ⁇ or the anisotropic displacement parameters shown in an Annex Table 4 and ⁇ or the hydrogen coordinates and isotropic displacement parameters shown in an Annex Table 5.
- One aspect of the invention is the use of a compound or composition as described herein, to regulate (e.g., to reverse and/or inhibit) the aggregation of a protein, for example, aggregation of a protein associated with a neurodegenerative disease and/or clinical dementia.
- the aggregation may be in vitro, or in vivo, and may be associated with a disease state as discussed below.
- one aspect of the invention pertains to a method of regulating (e.g., reversing and/or inhibiting) the aggregation of a protein, for example, aggregation of a protein associated with a neurodegenerative disease and/or clinical dementia, comprising contacting the protein with an effective amount of a compound or composition as described herein. The method may be performed in vitro, or in vivo.
- one aspect of the invention pertains to a method of regulating (e.g., reversing and/or inhibiting) the aggregation of a protein in the brain of a mammal, which
- aggregation is associated with a disease state as described herein, the treatment comprising the step of administering to said mammal in need of said treatment, a prophylactically or therapeutically effective amount of a compound or composition as described herein, that is an inhibitor of said aggregation.
- Methods of Treatment Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a prophylactically or therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition.
- a prophylactically or therapeutically effective amount of a compound as described herein preferably in the form of a pharmaceutical composition.
- Another aspect of the present invention pertains to a compound or composition as described herein, for use in a method of treatment (e.g., of a disease condition) of the human or animal body by therapy.
- a method of treatment e.g., of a disease condition
- Another aspect of the present invention pertains to use of a compound or composition as described herein, in the manufacture of a medicament for use in treatment (e.g., of a disease condition).
- the medicament comprises a compound of the invention. In some embodiments, the medicament is a composition as described hereinbelow. Disease Conditions Treated - Diseases of Protein Aggregation
- the compounds and compositions of the present invention are useful in the treatment or prophylaxis of diseases of protein aggregation.
- the disease condition is a disease of protein aggregation
- the treatment is with an amount of a compound or composition as described herein, sufficient to inhibit the aggregation of the protein associated with said disease condition.
- the protein aggregation is that which arises from an induced conformational polymerisation interaction, i.e., one in which a conformational change of the protein, or in a fragment thereof, gives rise to templated binding and aggregation of further (precursor) protein molecules in a self-propagating manner.
- an aggregation cascade may ensue which involves the induced conformational
- the protein aggregates thus formed are thought to be a proximal cause of disease states manifested as neurodegeneration, clinical dementia, and other pathological symptoms.
- Lysozyme 14 Pepys et al. (1993) amyloidosis or without I56T,
- NIDDM amyloid Type II diabetes
- diaminophenothiazines have utility in the inhibition of such protein aggregating diseases.
- tau protein or tau-like proteins e.g., MAP2; see below
- description of embodiments with respect to tau protein or tau-like proteins should be taken as applying equally to the other proteins discussed herein (e.g., ⁇ - amyloid, synuclein, prion, etc.) or other proteins which may initiate or undergo a similar pathological aggregation by virtue of conformational change in a domain critical for propagation of the aggregation, or which imparts proteolytic stability to the aggregate thus formed (see, e.g., the article by Wischik et al. in "Neurobiology of Alzheimer's Disease", 2nd Edition, 2000, Eds. Dawbarn, D. and Allen, S.J., The Molecular and Cellular
- tau-tau aggregation or the like, this may also be taken to be applicable to other “aggregating-protein aggregation", such as ⁇ - amyloid aggregation, prion aggregation, synuclein aggregation, etc. The same applies for “tau proteolytic degradation” etc.
- tau protein refers generally to any protein of the tau protein family. Tau proteins are characterised as being one among a larger number of protein families which co-purify with microtubules during repeated cycles of assembly and disassembly (see, e.g., Shelanski et al., 1973, Proc. Natl. Acad. Sci. USA, Vol. 70, pp. 765-768), and are known as microtubule-associated-proteins (MAPs).
- MAPs microtubule-associated-proteins
- Members of the tau family share the common features of having a characteristic N-terminal segment, sequences of approximately 50 amino acids inserted in the N-terminal segment, which are
- MAP2 is the predominant microtubule-associated protein in the somatodendritic compartment (see, e.g., Matus, A., in “Microtubules” [Hyams and Lloyd, Eds.] pp. 155- 166, John Wiley and Sons, New York, USA).
- MAP2 isoforms are almost identical to tau protein in the tandem repeat region, but differ substantially both in the sequence and extent of the N-terminal domain (see, e.g., Kindler and Garner, 1994, Mol. Brain Res., Vol. 26, pp. 218-224). Nevertheless, aggregation in the tandem-repeat region is not selective for the tau repeat domain.
- any discussion herein in relation to tau protein or tau-tau aggregation should be taken as relating also to tau- MAP2 aggregation, MAP2-MAP2 aggregation, and so on.
- the protein is tau protein. ln some embodiments, the protein is a synuclein, e.g., a- or ⁇ -synuclein. In some embodiments, the protein is TDP-43.
- TDP-43 is a 414 amino acid protein encoded by TARDBP on chromosome 1 p36.2.
- the protein is highly conserved, widely expressed, and predominantly localised to the nucleus but can shuttle between the nucleus and cytoplasm (Mackenzie ef a/ 2010). It is involved in transcription and splicing regulation and may have roles in other processes, such as: microRNA processing, apoptosis, cell division, stabilisation of messenger RNA, regulation of neuronal plasticity and
- TDP-43 is an inherently aggregation-prone protein and aggregates formed in vitro are ultrastructurally similar to the TDP-43 deposits seen in degenerating neurones in ALS patients (Johnson et al 2009). Johnson et al (2008) showed that when TDP-43 is overexpressed in a yeast model only the aggregated form is toxic.
- Mutant TDP-43 expression in cell cultures has repeatedly been reported to result in increased generation of C-terminal fragments, with even greater cytoplasmic aggregation and toxic effects than the wild-type protein (Kabashi et al 2008; Sreedharan et al 2008; Johnson et al 2009; Nonaka et al 2009; Arai et al 2010; Barmarda et al 2010; Kabashi et al 2010).
- protein is tau protein
- a method of inhibiting production of protein aggregates e.g. in the form of paired helical filaments (PHFs), optionally in neurofibrillary tangles (NFTs) in the brain of a mammal, the treatment being as described above.
- PPFs paired helical filaments
- NFTs neurofibrillary tangles
- AD Alzheimer's disease
- tau protein and aberrant function or processing thereof
- PSP progressive supranuclear palsy
- tauopathies fronto- temporal dementia
- FTD FTD with parkinsonism linked to chromosome 17
- DDPAC disinhibition-dementia-parkinsonism-amyotrophy complex
- PPND pallido-ponto-nigral degeneration
- PNLD pallido-nigro-luysian degeneration
- CBD cortico-basal degeneration
- the disease condition is a tauopathy.
- the disease condition is a neurodegenerative tauopathy.
- the disease condition is selected from Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy (PSP), fronto temporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP 17), frontotemporal lobar degeneration (FTLD) syndromes; disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC), pallido-ponto-nigral degeneration (PPND), Guam-ALS syndrome, pallido nigro luysian degeneration (PNLD), cortico-basal degeneration (CBD), dementia with argyrophilic grains (AgD), dementia pugilistica (DP) or chronic traumatic traumatic pulmonary disease, and others.
- AD Alzheimer's disease
- PSP progressive supranuclear palsy
- FTD fronto temporal dementia
- FTD FTD with parkinsonism linked to chromosome 17
- FTLD frontotemporal lobar degeneration
- DDPAC disinhibition
- CTE chronic traumatic encephalopathy
- DS Down's syndrome
- DLB dementia with Lewy bodies
- SSPE subacute sclerosing panencephalitis
- MCI Niemann-Pick disease, type C (NPC), Sanfilippo syndrome type B (mucopolysaccharidosis III B), or myotonic dystrophies (DM), DM1 or DM2, or chronic traumatic encephalopathy (CTE).
- the disease condition is a lysosomal storage disorder with tau pathology.
- NPC is caused by mutations in the gene NPC1, which affects cholesterol metabolism (Love et al 1995) and Sanfilippo syndrome type B is caused by a mutation in the gene NAGLU, in which there is lysosomal accumulation of heparin sulphate (Ohmi et al. 2009).
- tau pathology is observed and its treatment may decrease the progression of the disease.
- Other lysosomal storage disorders may also be characterised by accumulation of tau.
- Use of phenothiazine diaminium salts in the treatment of Parkinson's Disease and MCI is described in more detail in PCT/GB2007/001105 and PCT/GB2008/002066.
- the disease condition is Parkinson's Disease, MCI, or Alzheimer's disease.
- the disease condition is Huntington's Disease or other
- polyglutamine disorder such as spinal bulbar muscular atrophy (or Kennedy disease), and dentatorubropallidoluysian atrophy and various spinocerebellar ataxias.
- the disease condition is an FTLD syndrome (which may for example be a tauopathy or TDP-43 proteinopathy, see below).
- the disease condition is PSP or ALS.
- treatment e.g., treatment of a neurodegenerative tauopathy, e.g., Alzheimer's disease
- one or more cholinesterase inhibitors such as Donepezil (also known as AriceptTM), Rivastigmine (also known as ExelonTM), Galantamine (also known as
- ReminylTM NMDA receptor antagonists
- Memantine also known as EbixaTM, NamendaTM
- muscarinic receptor agonists such as muscarinic receptor agonists, and/or inhibitors of amyloid precursor protein processing that leads to enhanced generation of beta-amyloid.
- TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS; ALS-TDP) and frontotemporal lobar degeneration (FTLD-TDP).
- ALS amyotrophic lateral sclerosis
- FTLD-TDP frontotemporal lobar degeneration
- the role of TDP-43 in neurodegeneration in ALS and other neurodegenerative disorders has been reviewed in several recent publications (Chen-Plotkin et al 2010; Gendron et al 2010; Geser ei al 2010; Mackenzie er a/ 2010).
- ALS is a neurodegenerative disease, characterised by progressive paralysis and muscle wasting, consequent on the degeneration of both upper and lower motor neurones in the primary motor cortex, brainstem and spinal cord. It is sometimes referred to as motor neuron disease (MND) but there are diseases other than ALS which affect either either upper or lower motor neurons.
- MND motor neuron disease
- a definite diagnosis requires both upper and lower motor neurone signs in the bulbar, arm and leg musculature with clear evidence of clinical progression that can not be explained by any other disease process (Wijesekera and Leigh 2009).
- pathological protein differs from TDP-43. Misfolded SOD1 is the pathological protein in ubiquitin-positive inclusions in ALS with SOD1 mutations (Seetharaman et al 2009) and in a very small subset (approximately 3-4%) of familial ALS, due to mutations in FUS (fused in sarcoma protein), the ubiquitinated pathological protein is FUS (Vance ef al 2009; Blair ef al 2010). FUS, like TDP-43, appears to be important in nuclear-cytoplasmic shuttling although the ways in which impaired nuclear import of FUS remains unclear. A new molecular classification of ALS, adapted from Mackenzie et al (2010), reflects the distinct underlying pathological mechanisms in the different subtypes (see Table below).
- TDP-43 is the pathological ubiquitinated protein found in ALS.
- Amyotrophic lateral sclerosis has been recognised as a nosological entity for almost a century and a half and it is recognised in ICD-10 is classified as a subtype of MND in ICD 10 (G12.2).
- Reliable clinical diagnostic are available for ALS, which differ little from Charcot's original description, and neuropathological criteria, reflecting the underlying molecular pathology, have also been agreed.
- ALS is classified pathologically into three subgroups, ALS-TDP, ALS-SOD1 and ALS-FUS, both latter conditions are rare.
- the largest study to date showed all sporadic ALS cases to have TDP-43 pathology (Mackenzie et al 2007). Only around 5% of ALS is familial (Byrne et al 2010) and mutations in SOD1, the commonest mutations found in FALS, account for between 12-23% of cases (Andersen et al 2006). SOD1 may also be implicated in 2-7% of SALS. Mutations in FUS appear to be far less common, accounting for only around 3-4% of FALS (Blair et al 2010).
- TDP-43 is implicated in the pathological processes putatively arising from these mutations (Higashi et al 2010; Ling et al 2010; Elden et al 2010). It is therefore established that TDP-43 has an important, and potentially central role, in the pathogenesis of the vast majority of SALS cases and may be implicated in the pathogenesis of a significant proportion of FALS.
- ALS is now widely considered to be a TDP-43 proteinopathy (Neumann et al 2009) and numerous in vitro, and in vivo studies provide support to the hypothesis that toxic gain of function, due to TDP-43 aggregation is responsible for at least some of the neurotoxicity in the disease.
- FTLD syndromes are insidious onset, inexorably progressive, neurodegenerative conditions, with peak onset in late middle age. There is often a positive family history of similar disorders in a first degree relative.
- FTD Behavioural variant FTD is characterised by early prominent change in social and interpersonal function, often accompanied by repetitive behaviours and changes in eating pattern.
- semantic dementia there are prominent word finding problems, despite otherwise fluent speech, with degraded object knowledge and impaired single word comprehension on cognitive assessment.
- Progressive non-fluent aphasia presents with a combination of motor speech problems and grammatical deficits.
- the core clinical diagnostic features for these three FTLD syndromes are shown in the Table below and the full criteria in Neary et al (1998).
- TARDBP mutations account for approximately 4% of all familial and around 1.5% of sporadic ALS cases.
- Methylthioninium (MT) in TDP-43 proteinopathies MT has a mode of action which targets and can reduce TDP-43 protein aggregation in cells, which is a pathological feature of the vast majority of both familial and sporadic ALS and is also characteristic of FTLD-P.
- the compounds and compositions of the invention may therefore be useful for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
- ALS amyotrophic lateral sclerosis
- FTLD frontotemporal lobar degeneration
- Methylthioninium (MT) in Huntington's disease and polyglutamine disorders MT can reduce polyglutamine protein aggregation in cells, which is a pathological feature of Huntington's disease.
- Huntington's disease is caused by expansion of a translated CAG repeat located in the N-terminus of huntingtin. Wild-type chromosomes contain 6-34 repeats whereas, in Huntington's disease, chromosomes contain 36-121 repeats. The age of onset of disease correlates inversely with the length of the CAG tracts that code for polyglutamine repeats within the protein.
- the compounds and compositions of the invention may therefore be useful for the treatment of Huntington's disease and other polyglutamine disorders such as spinal bulbar muscular atrophy (or Kennedy disease), and dentatorubropallidoluysian atrophy and various spinocerebellar ataxias (Orr & Zoghbi, 2007).
- Mitochondrial Diseases and Lafora Disease The organ most frequently affected in mitochondrial disorders, particularly respiratory chain diseases (RCDs), in addition to the skeletal muscle, is the central nervous system (CNS).
- CNS manifestations of RCDs comprise stroke-like episodes, epilepsy, migraine, ataxia, spasticity, movement disorders, psychiatric disorders, cognitive decline, or even dementia (mitochondrial dementia).
- Compounds and compositions of the invention may also be used to treat mitochondrial diseases which are associated with a deficient and/or impaired complex III function of the respiration chain.
- the compounds have the ability to act as effective electron carrier and/or transfer, as the thioninium moiety has a low redox potential converting between the oxidised and reduced form.
- compounds of the invention are also able to perform the electron transportation and transfer role of complex III because of the ability of the thioninium moiety to shuttle between the oxidised and reduced form, thus acting as an electron carrier in place of sub-optimally functioning complex III, transferring electrons to cytochrome c.
- Compounds and compositions of the invention also have the ability to generate an active thioninium moiety that has the ability to divert misfolded protein/amino acid
- Lafora disease is an autosomal recessive teenage-onset fatal epilepsy associated with a gradual accumulation of poorly branched and insoluble glycogen, termed polyglucosan, in many tissues. In the brain, polyglucosan bodies, or Lafora bodies, form in neurons. Inhibition of Hsp70 ATPase by MT (Jinwal et al. 2009) may upregulate the removal of misfolded proteins.
- Lafora disease is primarily due to a lysosomal ubiquitin- proteasomal system (UPS) defect because of a mutation in either the Laforin or Malin genes, both located on Chromosome 6, which result in inclusions that may accelerate the aggregation of misfolded tau protein. Secondary mitochondrial damage from the impaired UPS may further result in a suppressed mitochondrial activity and impaired electron transport chain leading to further lipofuscin and initiating the seizures that are characteristic of Lafora disease.
- UPS lysosomal ubiquitin- proteasom
- the MT moiety may disaggregate existing tau aggregates, reduce more tau accumulating and enhance lysosomal efficiency by inhibiting Hsp70 ATPase.
- MT may lead to a reduction in tau tangles by enhancing the ubiquitin proteasomal system removal of tau monomers/oligomers, through its inhibitory action on Hsp70 ATPase.
- compositions of the present invention may have utility in the treatment of Lafora disease.
- the disease condition is skin cancer.
- the disease condition is melanoma.
- the disease condition is a viral, bacterial or protozoal disease condition.
- the (protozoal) disease condition is malaria. Treatment may be in combination with one or more antimicrobial agents, for example, chloroquine and/or atovaquone.
- the (viral) disease condition is caused by Hepatitis C, HIV, or West Nile Virus (WNV).
- Another aspect of the present invention pertains to use of a compound as described herein, in a method of inactivating a pathogen in a sample (for example a blood or plasma sample), comprising the steps of introducing the compound into the sample, and exposing the sample to light.
- a sample for example a blood or plasma sample
- the method comprises the steps of introducing the compound into the sample, and then exposing the sample to light.
- the compounds described herein that are capable of inhibiting the aggregation of tau protein will also be capable of acting as ligands or labels of tau protein (or aggregated tau protein).
- the compound of the invention is a ligand of tau protein (or aggregated tau protein).
- Such compounds may incorporate, be conjugated to, be chelated with, or otherwise be associated with, other chemical groups, such as stable and unstable detectable isotopes, radioisotopes, positron-emitting atoms, magnetic resonance labels, dyes, fluorescent markers, antigenic groups, therapeutic moieties, or any other moiety that may aid in a prognostic, diagnostic, or therapeutic application.
- other chemical groups such as stable and unstable detectable isotopes, radioisotopes, positron-emitting atoms, magnetic resonance labels, dyes, fluorescent markers, antigenic groups, therapeutic moieties, or any other moiety that may aid in a prognostic, diagnostic, or therapeutic application.
- the compound is as defined herein, but with the additional limitation that the compound incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels, for example, isotopes, radioisotopes, positron-emitting atoms, magnetic resonance labels, dyes, fluorescent markers, antigenic groups, or therapeutic moieties.
- detectable labels for example, isotopes, radioisotopes, positron-emitting atoms, magnetic resonance labels, dyes, fluorescent markers, antigenic groups, or therapeutic moieties.
- the compound is a ligand as well as a label, e.g., a label for tau protein (or aggregated tau protein), and incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels.
- a label for tau protein or aggregated tau protein
- the compound is as defined above, but with the additional limitation that the compound incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels.
- Labelled compounds may be visualised or detected by any suitable means, and the skilled person will appreciate that any suitable detection means as is known in the art may be used.
- the compound may be suitably detected by incorporating a positron-emitting atom (e.g., 11 C) (e.g., as a carbon atom of one or more alkyl group substituents, e.g., methyl group substituents) and detecting the compound using positron emission tomography (PET) as is known in the art.
- a positron-emitting atom e.g., 11 C
- PET positron emission tomography
- Such 11 C labelled compounds may be prepared by adapting the methods described herein in known ways, for example, in analogy to the methods described in WO
- another aspect of the present invention pertains to a method of labelling tau protein (or aggregated tau protein) comprising the step of: (i) contacting the tau protein (or aggregated tau protein) with a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels.
- the compound may be provided as a composition as described herein.
- Another aspect of the present invention pertains to a method of detecting tau protein (or aggregated tau protein) comprising the steps of: (i) contacting the tau protein (or aggregated tau protein) with a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels, and (ii) detecting the presence and/or amount of said compound bound to tau protein (or aggregated tau protein).
- the compound may be provided as a composition as described herein.
- Another aspect of the present invention pertains to a method of diagnosis or prognosis of a tau proteinopathy in a subject believed to suffer from the disease, comprising the steps of: (i) introducing into the subject a compound capable of labelling tau protein or aggregated tau protein, particularly tau protein (e.g., a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels); (ii) determining the presence and/or amount of said compound bound to tau protein or aggregated tau protein in the brain of the subject; and (iii) correlating the result of the determination made in (ii) with the disease state of the subject.
- the compound may be provided as a composition as described herein.
- Another aspect of the present invention pertains to a compound capable of labelling tau protein or aggregated tau protein (e.g., a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels), for use in a method of diagnosis or prognosis of a tau proteinopathy.
- the compound may be provided as a composition as described herein.
- Another aspect of the present invention pertains to use of a compound of the invention capable of labelling tau protein or aggregated tau protein, particularly tau protein (e.g., a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (e.g., 1 , 2, 3, 4, etc.) detectable labels), in a method of manufacture of a diagnostic or prognostic reagent for use in the diagnosis or prognosis of a tau proteinopathy.
- the compound may be provided as a composition as described herein.
- ligands/labels could be administered in a precursor form, for conversion to the active form (e.g., ligating form, labelling form) by an activating agent present in, or administered to, the same subject.
- active form e.g., ligating form, labelling form
- the ligands disclosed herein may be used as part of a method of diagnosis or prognosis. It may be used to select a patient for treatment, or to assess the effectiveness of a treatment or a therapeutic (e.g., an inhibitor of tau protein aggregation) administered to the subject.
- Treatment e.g., an inhibitor of tau protein aggregation
- treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
- Treatment as a prophylactic measure i.e., prophylaxis, prevention is also included.
- terapéuticaally-effective amount pertains to that amount of a compound of the invention, or a material, composition or dosage from comprising said compound, which is effective for producing some desired therapeutic effect,
- prophylactically effective amount refers to that amount of a compound of the invention, or a material, composition or dosage from comprising said compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- prophylaxis in the context of the present specification should not be understood to circumscribe complete success i.e. complete protection or complete prevention. Rather prophylaxis in the present context refers to a measure which is administered in advance of detection of a symptomatic condition with the aim of preserving health by helping to delay, mitigate or avoid that particular condition.
- treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
- treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in
- prodrugs e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.
- surgery e.g., radiation therapy; and gene therapy.
- a compound as described herein may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies.
- the particular combination would be at the discretion of the physician who would select dosages using his/her common general knowledge and dosing regimens known to a skilled practitioner.
- the agents i.e., a compound as described herein, plus one or more other agents
- the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
- agents i.e., a compound as described here, plus one or more other agents
- the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
- the compound of the invention, or pharmaceutical composition comprising it may be administered to a subject/patient by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
- Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal,
- intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal including, e.g., intracatheter injection into the brain; by implant of a depot or reservoir, for example, subcutaneously or
- compositions are oral compositions, formulated as described in more detail hereinafter.
- the subject/patient may be an animal, a mammal, a placental mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), a monotreme (e.g. platypus), an ape (e.g., gorilla, chimpanzee, orangutang,
- the subject/patient may be any of its forms of development, for example, a foetus.
- the subject/patient is a human.
- the compound of the invention While it is possible for the compound of the invention to be used (e.g., administered) alone, it is often preferable to present it as a composition or formulation.
- compositions comprising a compound as described herein, and a pharmaceutically acceptable carrier or diluent.
- the composition is a pharmaceutical composition (e.g., formulation, preparation, medicament) comprising a compound as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
- a pharmaceutical composition e.g., formulation, preparation, medicament
- a pharmaceutically acceptable carrier e.g., diluent, or excipient.
- the composition is a pharmaceutical composition comprising at least one compound, as described herein, together with one or more other
- pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
- pharmaceutically acceptable carriers including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
- the composition further comprises other active agents, for example, other therapeutic or prophylactic agents.
- Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA),
- Another aspect of the present invention pertains to methods of making a pharmaceutical composition
- a pharmaceutical composition comprising admixing at least one [ 11 C]-radiolabelled compound, as defined herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
- pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
- the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
- carriers e.g., liquid carriers, finely divided solid carrier, etc.
- the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
- Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
- sterile liquids e.g., solutions, suspensions
- Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
- excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
- suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
- the concentration of the compound in the liquid is from about 1 ng/ml to about 10 pg/ml, for example from about 10 ng/ml to about 1 pg/ml.
- the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Examples of Some Preferred Formulations
- One aspect of the present invention pertains to a dosage unit (e.g., a pharmaceutical tablet or capsule) comprising 20 to 300 mg of a compound as described herein (e.g., obtained by, or obtainable by, a method as described herein; having a purity as described herein; etc.), and a pharmaceutically acceptable carrier, diluent, or excipient.
- a dosage unit e.g., a pharmaceutical tablet or capsule
- 20 to 300 mg of a compound as described herein e.g., obtained by, or obtainable by, a method as described herein; having a purity as described herein; etc.
- a pharmaceutically acceptable carrier diluent, or excipient
- the dosage unit is a tablet.
- the dosage unit is a capsule.
- said capsules are gelatine capsules.
- said capsules are HPMC (hydroxypropylmethylcellulose) capsules.
- the amount is 30 to 200 mg.
- the amount is about 30 mg.
- the amount is about 60 mg.
- the amount is about 100 mg.
- the amount is about 150 mg.
- the amount is about 200 mg.
- dosage amounts may refer to the amount of the compound itself or may refer to the amount of free base equivalent (i.e. the amount of LMT moiety) contained in the dosage unit. Both these alternatives are expressly disclosed by the present invention.
- the pharmaceutically acceptable carrier, diluent, or excipient is or comprises one or both of a glyceride (e.g., Gelucire 44/14 ®; lauroyl macrogol-32 glycerides PhEur, USP) and colloidal silicon dioxide (e.g., 2% Aerosil 200 ®; Colliodal Silicon Dioxide PhEur, USP).
- a glyceride e.g., Gelucire 44/14 ®; lauroyl macrogol-32 glycerides PhEur, USP
- colloidal silicon dioxide e.g., 2% Aerosil 200 ®; Colliodal Silicon Dioxide PhEur, USP
- Processes generally used for tablet formulation and film coating often require the use of heat accompanied by low humidity during the drying process.
- LMTM and the other leuco-methylthionium salts are potentially prone to oxidation to methylthioninium moiety (MT) and to degradation e.g. to L Azure B (LAB) (see Scheme, below):
- the principle behind the formulations of the present invention is therefore the provision of a method of manufacture of compressed pharmaceutical formulations and capsules containing leuco-methylthionium salts e.g. bis(methanesulfonate) (LMTM) as the active substance, by direct tablet compression technology or by other unique tabletting techniques, and by encapsulation, in which the active substance exists substantially in a stable form.
- leuco-methylthionium salts e.g. bis(methanesulfonate) (LMTM)
- LMTM leuco-methylthionium salts e.g. bis(methanesulfonate)
- LMTM leuco-methylthionium salts
- the most commonly used method for the preparation of solid dosage forms is wet granulation (also called moist granulation). This involves adding a granulating fluid to a powder.
- the granulating fluid may be water or some other solvent that is sufficiently volatile that can subsequently be removed by drying.
- wet granulation is often preferred over direct compression because wet granulation is more likely to overcome any problems associated with the physical characteristics of various ingredients in the formulation.
- Wet granulation provides material which has the required flow and cohesive properties necessary to obtain an acceptable solid dosage form.
- the content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug.
- Segregation of the drug from excipients is also avoided. ln direct compression, the individual constituents of the composition to be compressed are mixed without previous granulation and then directly compressed. Whilst this appears to be an elegant and simple process, it may be difficult to obtain with it commercially usable tablets which have sufficient strength yet which also disintegrate sufficiently rapidly after administration. Also, many active substances cannot be processed by direct compression since they cannot be compressed without a granulation step.
- methylthioninium (MT) formed can be controlled within the specifications (for example, LAB less than 2% and MT less than 12%). This is in contrast to the behaviour of e.g. LMTM when processed by conventional wet granulation processes.
- LMTM when processed by conventional wet granulation processes.
- LMTM in conventional wet granulation processes LMTM, for instance, may be very unstable and a substantial amount of LAB and MT may be formed.
- a pharmaceutical composition comprising a compound of the invention, in solid dosage form.
- the composition preferably further comprises at least one diluent suitable for dry compression.
- the pharmaceutical composition is characterised in that the compound exists in a
- Another aspect of the invention provides a free-flowing, cohesive powder, comprising a compound of the invention and at least one diluent suitable for dry compression, and optionally one or more other excipients, said powder being capable of being compressed into a solid dosage form.
- compositions and formulations are initially described herein with respect to the bis(sulfonate) salts of the present invention, in particular LMTM.
- advantages of the present formulation methods are equally applicable to other members of the leuco-methylthionium family of salts
- the formulations described herein are applicable also to the 3,7-diamino- 10H-phenothiazinium salts disclosed in WO2007/110627 (WisTa Laboratories Ltd), which were briefly discussed above. These include leuco-methylthionium bis(hydrobromide) (LMT.2HBr, LMTB) and leuco-methylthionium bis(hydrochloride) (LMT.2HCI, LMTC). Therefore, in a broader aspect, the present invention provides a pharmaceutical composition comprisin a compound of the following formula I:
- R 1 , R 9 , R 3NA , R 3NB , R NA and R 7NB are as previously defined; and wherein each of HX 1 and HX 2 is independently a protic acid;
- X 1 and X 2 are the corresponding counterions.
- X 1 and X 2 are independently sulfonate (such as alkylsulfonate or arylsulfonate, for example R A S0 3 or R B S0 3 as defined above) or halide (CI , Br , I ).
- HX 1 and HX 2 are preferably independently sulfonic acids (R A S0 3 H, R B S0 3 H) or hydrohalides (HCI, HBr, HI).
- the term 'active ingredient' refers to the relevant
- leuco(methylthioninium) salt refers to a compound of formula (I), such as a compound of the invention, for example LMTM.
- Another aspect of the invention provides a process for the manufacture of said pharmaceutical compositions, by a dry compression method.
- the process preferably comprises dry compression of an intimate powder mixture of the active compound with at least one diluent suitable for dry compression, and optionally one or more other excipients.
- the process comprises direct compression.
- the process comprises simple direct compression.
- the process comprises dry granulation.
- the process comprises moist granulation of excipients, followed by addition of the active ingredient extra-granularly.
- Solid dosage forms according to the invention advantageously exhibit long-term chemical and physical stability of the active ingredient (compound of the invention - e.g. LMTM).
- the pharmaceutical compositions according to the invention also have fast dissolution rates, even after long-term storage.
- a “substantially stable" form of the active ingredient means, in the present context, a form which does not react to form impurities such as oxidative impurities or other degradation products to any significant extent during the formulation process, or on storage of the formulated product.
- the material may refer to a material which contains, for example, less than 20% w/w, less than 15% w/w, or less than 10% w/w of oxidative impurities or other degradation products.
- the material contains at least 80% w/w, at least 85% w/w, or at least 90% w/w of the pure active ingredient, in its original
- the material containing the active ingredient may contain, for example, less than 20% w/w, less than 15% w/w, less than 12% w/w, or less than 10% w/w of MT. In some embodiments, the material may contain, for example, less than 5% w/w, less than 3% w/w, or less than 2% w/w of LAB.
- a “stable” tablet is, in the context of the present invention, a tablet that remains substantially stable after prolonged storage under controlled conditions of temperature and humidity. Stability testing may be carried out with the solid dosage forms directly exposed to the chosen environmental conditions, or with the solid dosage forms contained within packaging.
- the amount of the active ingredient in the uncoated composition is generally more than about 10% w/w, but can be more than 20%, or more than 30% w/w.
- the amount of the active ingredient is generally less than about 70% w/w, and usually less than 60% or less than 50% w/w in a tablet formulation .
- the amount of the active ingredient in the uncoated tablet core composition is thus from about 10% w/w (or 20% or 30%) to about 70% w/w (or 60% or 50%).
- the active ingredient may not be inherently compressible and thus may require addition of suitable diluents to aid compression.
- compositions of the invention therefore commonly comprise at least 15% w/w, more commonly at least 20%, at least 30%, at least 40% or at least 50% w/w of diluent(s).
- Diluents that may be used include one or more of microcrystalline cellulose, lactose, mannitol, calcium salts such as, calcium phosphate dibasic, calcium sulphate and calcium carbonate, and sugars such as lactose, sucrose, dextrose and maltodextrin.
- Preferred diluents are microcrystalline cellulose, lactose and mannitol. Spray-dried forms of lactose and mannitol are particularly suitable forms of those compounds for direct compression or dry granulation techniques.
- an active ingredientas described herein for example a compound of the present invention, such as LMTM
- dry compression diluents such as one or more of microcrystalline cellulose, spray dried lactose, anhydrous lactose and mannitol
- the resulting solid dosage forms are stable in the sense that the active ingredient remains chemically stable, even after extended storage.
- the invention thus provides a method of preparing low, medium- or high-dose tablets, for example low, medium-, or high-dose LMTM tablets, that are stable and have good dissolution profiles, acceptable degrees of hardness and resistance to chipping, as well as a short disintegration time.
- compositions of the invention Dissolution of compositions of the invention
- present inventors have also surprisingly found that the unique solid dosage forms described herein provide a very fast dissolution rate.
- the active methylthioninium (MT) moiety may preferably be absorbed from the stomach and/or the upper Gl tract.
- a fast-disintegrating and fast-dissolving formulation of the leuco(methylthioninium) salts would therefore be advantageous, since this would deliver the maximum possible amount of drug to the intended point of absorption.
- the fast dissolution rate of the solid dosage forms described herein means that they are capable of dissolving rapidly in the stomach and/or upper Gl tract and hence presenting the active ingredient there effectively, for rapid absorption.
- the formulations of the invention when evaluated using a standard pharmacopeial method, provide at least 80% dissolution within 30 minutes, preferably at least 80% dissolution within 15 minutes, more preferably at least 80% dissolution within 10 minutes.
- the formulations of the invention when evaluated using a standard pharmacopeial method, provide at least 90% dissolution within 30 minutes, preferably at least 90% dissolution within 15 minutes, more preferably at least 90% dissolution within 10 minutes.
- the formulations of the invention when evaluated using a standard pharmacopeial method provide at least 95% dissolution within 30 minutes, preferably at least 95% dissolution within 15 minutes, more preferably at least 95% dissolution within 10 minutes.
- Dissolution rates may be measured by standard pharamcopeial methods as described in United States Pharmacopeia (USP) General Chapter ⁇ 711>.
- USP United States Pharmacopeia
- the current USP is USP 34 (2011 ).
- dissolution rates for the formulations of the invention may be measured using apparatus according to USP Dissolution Apparatus 2 (Paddle).
- the dissolution rates above are evaluated in 0.1 hydrochloric acid at a working concentration of ⁇ 5 pg/ml LMT, with stirring at 50rpm paddle speed.
- the dissolution rates are evaluated by spectrophotometric analysis.
- the formulation methods described herein can provide the active compound with a high degree of bioavailability.
- the fast dissolution rate is maintained after prolonged storage, even if storage is under 'stressed' conditions (i.e. increased temperature and humidity).
- the fast dissolution rate, and hence the good bioavailability, of compositions formulated according to the processes of the present invention is also highly tolerant of variations in the formulation itself.
- Other ingredients i.e. increased temperature and humidity.
- the pharmaceutical composition will generally also include a lubricant.
- lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glycerylbehaptate, polyethylene glycol, ethylene oxide polymers (for example, those available under the registered trademark Carbowax from Union Carbide, Inc., Danbury, CT), sodium lauryl sulphate, magnesium lauryl stearate, mixtures of magnesium stearate with sodium lauryl sulphate, and hydrogenated vegetable oil.
- Preferred lubricants include calcium stearate, magnesium stearate and sodium stearyl fumarate. Most preferred as the lubricant is magnesium stearate.
- Lubricants generally comprise from about 0.5 to about 5.0% of the total (uncoated) tablet weight.
- the amount of lubricant employed is generally from about 1.0 to about 2.0%, preferably 0.5 to 2.0% w/w.
- additional excipients include disintegrants, binders, flavouring agents, colours and glidants. Some excipients can serve multiple functions, for example as both binder and tablet disintegrant. A tablet disintegrant may be present in an amount necessary to achieve rapid dissolution.
- Disintegrants are excipients which oppose the physical forces of particle bonding in a tablet or capsule when the dosage form is placed in an aqueous environment.
- examples of disintegrants include crosslinked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, crosslinked sodium carboxymethyl cellulose (sodium croscarmellose), and pregelatinized starch.
- the amount of disintegrant can be from 0 to about 25% w/w, more commonly from about 1% to about 5% w/w, and usually less than 10% or less than 5% w/w, of the composition.
- Binders are excipients which contribute to particle adhesion in a solid formulation.
- binders include cellulose derivatives (carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, ethylcellulose, microcrystalline cellulose) and sugars such as lactose, sucrose, dextrose, glucose, maltodextrin, and mannitol, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, pregelatinized starch, alginic acids, and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, carrageenan and the like.
- the amount of binder can vary widely, eg from 0% to 95% w/w of the composition.
- excipients may serve multiple functions.
- the tabletting diluent may also serve as a binder.
- Glidants are substances added to a powder to improve its flowability. Examples of glidants include magnesium stearate, colloidal silicon dioxide (such as the grades sold as Aerosil), starch and talc. Glidants may be present in the pharmaceutical composition at a level of from 0 to about 5% w/w. Again, however, it should be noted that excipients may serve multiple functions.
- the lubricant for example magnesium stearate, may also function as a glidant.
- colours examples include titanium dioxide and/or dyes suitable for food such as those known as FD&C dyes and natural colouring agents.
- a colouring agent is unlikely to be used in the powder mixture that is compressed in accordance with the aspects of the invention discussed above, but may form part of a coating applied to the composition, as described below, in which case the colouring agent may be present in the film coat in an amount up to about 2.0% w/w.
- the tablet is desirably coated with a conventional film coating which imparts toughness, ease of swallowing, and an elegant appearance to the final product.
- a conventional film coating which imparts toughness, ease of swallowing, and an elegant appearance to the final product.
- Many polymeric film- coating materials are known in the art.
- a preferred film-coating material is
- HPMC and PVA may be obtained commercially, for example from Colorcon, in coating formulations containing excipients which serve as coating aids, under the registered trademark Opadry. Opadry formulations may also contain talc, polydextrose, triacetin, polyethyleneglycol, polysorbate 80, titanium dioxide, and one or more dyes or lakes. Other suitable film-forming polymers may also be used, including hydroxypropylcellulose, vinyl copolymers such as polyvinyl pyrollidone and polyvinyl acetate, and acrylate- methacrylate copolymers. Use of a film coating is beneficial for ease of handling and because a blue coloured uncoated core may stain the inside of the mouth during swallowing. Coating also improves light stability of the dosage form.
- Coating of the tablets may conveniently be carried out using a conventional coating pan.
- the coating pan is pre-heated using heated inlet air until the exhaust temperature reaches 35°-55°C, more preferably 40-50°C. This may typically require application of heated inlet air at an inlet temperature of 45-75°C, preferably 50-65°C, for 10-15 minutes.
- the tablet cores containing the active ingredient e.g. LMTM
- the spray rate is controlled such that the bed temperature is maintained at 38-48°C, more preferably 42-44°C, until the desired weight gain (coating weight) has been achieved.
- Dry compression refers to compression techniques which do not involve the use of heat or moisture. Dry compression may comprise direct compression of the active ingredient with suitable diluents or it may comprise dry granulation (for example slugging/double compression method or roller compaction).
- Direct compression may comprise simple direct compression of the active ingredient with diluents suitable for direct compression.
- it may comprise granulation, for example moist granulation, of the excipients to produce a dry granular excipient mixture which can then be directly compressed with the dry active ingredient (and optionally further dry excipients). This may be referred to as 'extra-granular incorporation' of the active ingredient.
- the solid dosage forms of the invention may be produced in a manufacturing process which comprises simple direct compression.
- the tablet ingredients i.e. the active ingredient (e.g. LMTM), diluent(s) and other optional excipients, are blended together in solid particulate form to create an intimate mixture, e.g. in a tumbling blender, and are then compressed using a tablet machine.
- the active ingredient e.g. LMTM
- the composition is prepared by a dry granulation process.
- Dry granulation refers to the process of granulating without the use of granulating fluids.
- at least one of its constituents, either the active ingredient or a diluent must have cohesive properties. Dry granulation may be performed by a process known as "slugging".
- slugging the material to be granulated is first made into a large compressed mass or "slug”, typically using a tablet press with large flat-faced tooling (an example of a linear press is illustrated in US 4,880,373).
- a fairly dense slug may be formed by allowing sufficient time for the air to escape from the material to be compacted.
- Compressed slugs are then milled through a desired mesh screen manually or automatically as, for example, by way of a comminuting mill.
- Dry granulation may also be performed using a "roller compactor".
- a roller compactor material particles are consolidated and densified by passing the material between two high-pressure rollers.
- the densified material from a roller compactor is then reduced to a uniform granule size by milling.
- the uniform granules may then be mixed with other substances, such as a lubricant, to tablet the material (as, for example, by way of a rotary tabletting machine).
- roller compaction is used in other industries, such as the food industry, animal feed industry and fertilizer industry.
- Dry granulation is nowadays generally understood to mean roller compaction or slugging, and is well known to those skilled in the art (see, for instance, Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman, and Schwartz (Eds); Marcel Dekker, Inc, 2nd Edition, 1989) and Remington's Pharmaceutical Sciences (A. R. Gennaro (Ed); Mack Publishing Co, Easton, PA, 18th edition, 1990)).
- tablets are prepared by moist granulation of excipients and incorporation of the active ingredient (e.g. LMTM) extra-granularly.
- such a process involves wet massing diluents such as lactose and/or microcrystalline cellulose with water, optionally with the addition of a binder such as polyvinyl pyrrolidone.
- diluents such as lactose and/or microcrystalline cellulose
- a binder such as polyvinyl pyrrolidone.
- the wet mass is dried, then passed through a mesh, to form granules.
- the active ingredient and any remaining excipients, such as a lubricant are then blended with the dry granules and compressed to form tablets.
- compositions containing leuco(methylthioninium) compounds may, in some embodiments, be stabilised by addition of an appropriate amount of certain acids to the bulk substance prior to formulation. These acids may be used to prevent the formation of further MT, both during formulation and throughout the life of the product, thereby providing a stable pharmaceutical composition for the purposes of obtaining regulatory approval with associated cost savings in packaging.
- a pharmaceutical composition comprising an active ingredient as described herein and a pharmaceutically acceptable carrier, characterised in that said formulation additionally comprises an acid in an amount sufficient to prevent the formation of MT.
- a pharmaceutically acceptable carrier characterised in that said formulation additionally comprises an acid in an amount sufficient to prevent the formation of MT.
- acids having a pK1 of greater than 1.5 are preferred.
- the acid is present in an amount of from 5% to 25% w/w.
- the composition is prepared by a dry compression method as described above.
- Preferred acids for the purposes of the invention are maleic acid (pK1 1.9), phosphoric acid (pK1 2.12), ascorbic acid (pK1 4.17), sorbic acid (pK1 4.76), aspartic acid, and sialic acid.
- the stabilising effect of the added acid may be enhanced by the selection of an appropriate carrier.
- the carrier is preferably mannitol, a cellulosic material, or a starch, or mixtures thereof.
- the carrier is typically present in an amount of at least 40% w/w of the formulation.
- composition comprising an active ingredient as described herein and a pharmaceutically acceptable carrier, additionally characterised in that said composition comprises particles of which more than 10% have a size greater than 10 microns.
- composition comprising a leuco(methylthioninium) compound, for example a compound of the invention such as LMTM, and a pharmaceutically acceptable carrier, characterised in that said carrier is Elcema TM , ethylcellulose, mannitol, or Starch 1500 TM .
- a pharmaceutically acceptable carrier characterised in that said carrier is Elcema TM , ethylcellulose, mannitol, or Starch 1500 TM .
- Stabilised dry powder blends in accordance with the invention may be formulated, for example, by compressing into tablets or filling into capsules (with or without prior conversion to a granulated powder by means such as described in Formulation Examples 1 to 4) to give pharmaceutical compositions having excellent shelf life.
- Capsules according to the invention are typically of gelatin or preferably HPMC.
- Preferred excipients include lactose, starch, a cellulose, milk sugar and high MW polyethylene glycols.
- compositions and formulations prepared according to the methods described above are more stable, immediately after completion of manufacture, than formulations produced using conventional aqueous granulation. Furthermore they can demonstrate enhanced stability on storage.
- a pharmaceutical formulation thus prepared with a content of 10 to 50% by weight of LMTM, preferably 15% to 40% by weight of LMTM, makes it possible that in standard stability tests, for example in long term accelerated stability testing, at a temperature of 25 °C and a relative humidity 60 ⁇ 5% the content of L Azure B does not increase by more than 2%, relative to LMTM peak area, within a period of 24 months .
- leuco(methylthioninium) compounds such as LMTM may also oxidise to produce a small amount of MT (see Scheme, above).
- leuco- methylthioninium salts of the present invention may react with oxygen absorbed on the excipients and present within the tablet to give more of the MT particularly in the presence of moisture.
- One advantage of the formulations of this invention is to minimise the amount of MT formed in the tablets, e.g. to less than 12% over 2 years when stored at 25°C at a relative humidity of 60%.
- Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
- Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
- a suitable dose of the compound is in the range of about 100 ng to about 25 mg (more typically about 1 ⁇ g to about 10 mg) per kilogram body weight of the subject per day.
- the compound is administered to a human patient according to the following dosage regime: about 100 mg, 3 times daily.
- the compound is administered to a human patient according to the following dosage regime: about 150 mg, 2 times daily.
- the compound is administered to a human patient according to the following dosage regime: about 200 mg, 2 times daily.
- step i NaN0 2 , DMSO, CH 3 COOH, step ii; (H 3 CCO)0 2 , Et 3 N, D F, step iii; Pd/C, 2- eTHF, H 2 step iv; H 2 CO, H 2 or
- the acetic acid was then added to the RBF in a drop-wise fashion over a 20 minute period.
- the light yellow slurry becomes red in colour and a solid precipitated out of solution.
- the mixture was stirred for 2 hours at ambient temperature (36-20 °C) before increasing the temperature to 95 °C and stirring for 17 hours.
- the mixture was cooled to 50 °C and methanol ( 00 ml) was added and the mixture cooled further to 22 °C.
- the cooled mixture was then filtered and the cake washed with methanol (3 x 25 ml).
- the washed cake was left on the filter with the vacuum applied for 30 minutes before being dried for 15 hours at 50 °C to give the product as a brown solid (MW 289.27 g/mol, 29.45 g, 81 %).
- the synthesis was also successful using dimethylformamide (DMF), acetonitrile (MeCN), tetrahydrofuran (THF), acetone or dimethoxyethane (DME) as the reaction solvent.
- DMF dimethylformamide
- MeCN acetonitrile
- THF tetrahydrofuran
- DME dimethoxyethane
- the crude product was isolated by filtration to give a colourless solid, which was washed with methanol (3 x 5 ml) and dried at 50 °C for 16 hours (MW 327.45 g/mol, 2.26 g, 46 %).
- the filtrate from the isolation process had water added (50 ml), which gave further solid.
- the suspension was stirred at 5 °C for 2 hours before being collected by filtration, washed with methanol (3 x 5 ml) and dried at 50 °C for 13 hours.(MW 327.45 g/mol, 0.83 g, 17 %).
- the total yield of product was (3.09 g, 63 %).
- the retention factor of the dinitro starting material is 0.68 as a yellow spot
- the retention factor of the hydrogenation product is 0.25 as a blue spot
- the retention factor of the methylation product is 0.67 as a light blue spot.
- the mixture was heated to 50 °C after which a warm solution (45-50 °C) of aqueous ammonium chloride (MW 53.49 g/mol, 2.26 g, 42.26 mmol dissolved in 6 ml of water) was added slowly to maintain a gentle reflux. The mixture was then heated to 70 °C and stirred at this temperature for two hours after which it was cooled to ambient temperature (23 °C).
- a warm solution 45-50 °C
- aqueous ammonium chloride MW 53.49 g/mol, 2.26 g, 42.26 mmol dissolved in 6 ml of water
- Synthesis 1 Synthesis of N,N,N',N'-tetramethyl-10H-phenothiazine-3, 7-diaminium bis(methanesulphonate) (LMT.2MsOH)
- volume of water is controlled to ensure product crystallises out as a free flowing precipitate. Seeding the reaction reduces the impact of small variations in water volume.
- incorporation ensures the early precipitation of L T.2 sOH which in turn prevents formation of by-products (such as the alcohol ester EMS a potential genotoxic byproduct - not detected in the synthetic process) and encapsulation of EtOH.
- the seed is also useful as a means of controlling the particle size of the product.
- Rate of cooling has a similar although reduced effect.
- Fast cool down ( ⁇ 1 h) leads to reduction in particle size with a concomitant increase in EtOH levels.
- a slow cool has the opposite effect.
- EtOH is equally effective as MeCN at removing the related substances, however its use is accompanied by a slight increase in the level of retained EtOH.
- the 13 C NMR spectrum was obtained on a Varian 400 MHz NMR instrument at a frequency of 100.56 MHz in deuterated methanol CD 3 OD and is shown in Figure 2.
- the initial assignment of the 3 C-NMR spectrum was based on correlation with charts of known chemical shifts, (Literature Reference: Structure Determination of Organic Compounds: Tables of Spectral Data, Pretsch E., et al., Springer, London, p 122).
- DEPT-135 Disortionless Enhancement by Polarisation Transfer
- HSQC Heteronuclear Single Quantum Coherence
- HMBC Heteronuclear Multiple Bond Correlation
- Mass spectroscopic analysis was carried out using a Waters, LCT Premier XE mass spectrometer. A flow rate of 1 ml / hr was adopted.
- the source used for the analysis of the active component was electron impact ionisation in the positive mode.
- the source used for the analysis of the methanesulphonate counter ion was electrospray ionisation in the positive mode. Using electron impact ionisation a major peak is observed at 285 (see Figure 7). This corresponds to the molecular ion Ci 6 Hi 9 N 3 S.
- a comparison of the exact mass measured and the theoretical value is provided below:
- UV-Vis Ultraviolet-Visible Spectroscopy
- the HPLC trace is shown in Figure 10.
- the organic purity was found to be 99.45 % w/w.
- LMT.2MsOH is produced in crystalline form.
- the crystalline form of LMT.2MsOH is illustrated by the X-ray powder diffraction spectrum shown in Figure 11.
- the XRPD exhibits sharp signals, indicative of a high degree of crystalline order. Variations in relative peak intensity may be observed, which are attributable to orientation effects in combination with differences in particle size. Only slight variations in relative peak intensity (less than 50%) are observed as a function of sample thickness (0.1 mm vs. 1.0 mm).
- the crystal form is further characterised by FT-Raman, thermogravimetric (TG), differential scanning calorimetric (DSC), dynamic vapour sorption (DVS) analysis, and microscopy ( Figures 12-16). This form may conveniently be referred to as 'Form A'.
- Crystals for single crystal X-ray analysis were obtained from ethanol, methanesulfonic acid and water, See Figure 17c.
- the samples were prepared on silicon single crystal sample holders with 0.1 or 1.0 mm depth without any special treatment other than the application of slight pressure to get a flat surface. All samples were rotated during the measurement.
- FT-Raman Spectroscopy Bruker RFS100.
- Nd YAG 1064 nm excitation, 50 mW laser power, Ge-detector, 128 scans, range 50-3500 cm “1 , 2 cm "1 resolution.
- Polarizing Light Microscopy Leitz Orthoplan microscope with Leica OFC280 CCO camera.
- TG TA Instruments TGA Q5000. Open aluminum crucible, N 2 atmosphere, heating rate 10 °C min "1 , range 25-300 °C.
- TG-FTIR Netzsch Thermo-Microbaiance TG 209 with Bruker FT-IR Spectrometer Vector 22.
- this form represents the only stable polymorphic form of LMT.2MsOH.
- Polymorphism studies have shown that Form A is reproduced in nearly all crystallisation systems (studies were performed using degassed solvents, under an inert atmosphere).
- Amorphous LMT.2MsOH can be prepared by evaporation of an aqueous solution of LMT.2MsOH, however the amorphous material recrystallises to Form A upon further drying.
- Methylthioninium chloride trihydrate (MTC.3H 2 0) (150 kg) was added and the
- the batch temperature was then reduced to -5-5 °C over 2 h. and held there for 6 h.
- the solid was collected by filtration.
- the cake was fully de-liquored before water (400 I) was added to R1.
- the temperature in R1 was allowed to rise to 15-25 "C before the water was used in portions to wash the filter cake.
- the product was dried under a stream of nitrogen for 6 h. before being offloaded (Yield: 90-110 kg).
- the lower aqueous layer is removed and fresh water (300 I), 80% aqueous acetic acid (40 I) followed by water rinse (50 I) were then added. The mixture was stirred at 75-85 °C for 1 h before the agitator was stopped and the layers allowed to settle over 30 min. The lower aqueous layer was removed and fresh water (300 I), 80% aqueous acetic acid (40 I) followed by water rinse (50 I) were then added. The mixture was stirred at 75-85 °C for 1 h before the agitator was stopped. The layers were allowed to settle for 30 min before the lower layer was removed and water (390 I) was added and the mixture stirred for 1 h. The agitator was stopped and the layers allowed to settle for 30 min.
- step i H 2 0, MeOH, EsOH, IPA, Acetone
- LMT.2EsOH The synthesis of LMT.2EsOH was carried out by acid hydrolysis of 10-Acetyl- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-10W-phenothiazine-3,7-diamine.
- the acid used was ethanesulfonic acid and the solvent combination was aqueous methanol.
- Synthesis 3 Synthesis and analysis of N,N,N',N'-Tetramethyl-10H-phenothiazine-3, 7- diaminium bis(p-toluenesulfonate) (LMT.2TsOH)
- step i H 2 0, Na 2 C0 3 , THF, Et 2 0, p-TsOH
- LMT.2TsOH The synthesis of LMT.2TsOH was carried out by neutralising ⁇ /, ⁇ /, ⁇ /' /V'-tetramethyl-IO V- phenothiazine-3,7-diaminium dichloride with sodium carbonate and extracting the neutral species into organic solvent. The extract was treated with p-toluenesulphonic acid and the mixture concentrated to dryness.
- step i H 2 0, EtOH, EDSA
- LMT.EDSA The synthesis of LMT.EDSA was carried out by acid hydrolysis of I O-acetyl- ⁇ /, ⁇ /, ⁇ /', ⁇ - tetramethyl-10H-phenothiazine-3,7-diamine.
- the acid used was 1 ,2-ethanedisulfonic acid and the solvent combination was aqueous ethanol.
- the crude was washed with ethanol (3 x 3 ml) and air dried for 15 min before being oven dried for 3.5 hours at 70 °C to give the crude product (1.33 g, 91 %, MW 475.61 g/mol) as a yellow solid.
- Synthesis 5 Synthesis and analysis of N,N,N',N'-Tetramethyl-10H-phenothiazine-3, 7- diaminium naphthalenedisulfonate (LMT.NDSA)
- LMT.NDSA The synthesis of LMT.NDSA was carried out by acid hydrolysis of 10-acetyl- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-10W-phenothiazine-3,7-diamine.
- the acid used was 1 ,5- naphthalenedisulfonic acid and the solvent combination was aqueous ethanol.
- a solution of (0.2 M) potassium chloride (KCI) (0.745 g in 50 mL of deionised water) was initially prepared. From this solution 50 mL was taken and diluted with approximately 80 mL of deionised water. A (0.2 M) hydrochloric acid (HCI) solution was then used to adjust the pH to 2, before further dilution with deionised water to make up to 200 mL. A final pH of 2.00 at 21.6 °C was recorded. pH 3 buffered aqueous solution
- a solution of (0.1 M) potassium hydrogen phthalate (2.042 g in 100 mL of deionised water) was initially prepared. From this solution 100 mL was taken and diluted with approximately 50 mL of deionised water. A 0.2 M HCI solution was then used to adjust the pH to 3, before further dilution with deionised water to make up to 200 mL. A final pH of 2.99 at 21.7 °C was recorded. pH 7 buffered aqueous solution
- a solution of (0.1 M) potassium phosphate monobasic (KH 2 P0 4 ) (1.370 g in 100 mL of deionised water) was initially prepared. From this solution 100 mL was taken and diluted with approximately 80 mL of deionised water. A 0.5 M sodium hydroxide (NaOH) solution was then used to adjust the pH to 7, before further dilution with deionised water to make up to 200 mL. A final pH of 7.07 at 22 °C was recorded.
- KH 2 P0 4 potassium phosphate monobasic
- LMT.2MsOH has better aqueous solubility than MTC (not shown) and enhanced solubility compared to the corresponding chloride and bromide salts. This suggests an increased utility in respect of the treatment and uses described herein.
- the tau-tau aggregation assay uses purified recombinant tau fragments in a solid-phase immunoassay. Methods are described in detail in e.g. WO 96/30766. Briefly, the assay measures the binding of truncated tau (amino acids 297-391) in solution to solid-phase bound truncated tau (residues 297-390). Binding of the former is detected with the antibody mAb 423, which specifically recognises peptides containing a C-terminal Glu- 391 residue.
- the Tau complex formed in vitro is similar to the aggregated complex that forms in Alzheimer's disease as a consequence of the stability of the pathological Tau- Tau binding interaction through a 94/95-amino acid repeat domain (residues 297-390), found in the proteolytically stable core of the paired helical filament.
- the B 50 value (expressed as mean ⁇ SE) is determined as the concentration of compound at which tau-tau binding is decreased by 50%.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Neurology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- AIDS & HIV (AREA)
- Psychology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (25)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR112013020539A BR112013020539A2 (en) | 2011-02-11 | 2011-08-15 | phenothiazine diaminium salts and their use |
AU2011358840A AU2011358840B2 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
CN201180070054.XA CN103649061B (en) | 2011-02-11 | 2011-08-15 | Thiodiphenylamine diamine salts and its purposes |
LTEP11749476.5T LT2673266T (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
DK11749476.5T DK2673266T3 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine DIAMINIUM SALTS AND USE THEREOF |
CA2827027A CA2827027C (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
SI201130992A SI2673266T1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
US13/984,841 US9283230B2 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
ES11749476.5T ES2594703T3 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diamonium salts and their uses |
EP11749476.5A EP2673266B1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
RS20160880A RS55237B1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
EA201391158A EA025033B1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
JP2013553013A JP5898701B2 (en) | 2011-02-11 | 2011-08-15 | Phenothiazinediaminium salts and their use |
KR1020137023810A KR101888713B1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
SG2013060132A SG192666A1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
IL227736A IL227736A (en) | 2011-02-11 | 2013-07-31 | Phenothiazine diaminium salts and their use |
HK13114315.4A HK1186738A1 (en) | 2011-02-11 | 2013-12-27 | Phenothiazine diaminium salts and their use |
US15/056,610 US9907804B2 (en) | 2011-02-11 | 2016-02-29 | Phenothiazine diaminium salts and their use |
HRP20161291TT HRP20161291T1 (en) | 2011-02-11 | 2016-10-06 | Phenothiazine diaminium salts and their use |
CY20161101036T CY1118102T1 (en) | 2011-02-11 | 2016-10-17 | DIAMINIUM SALT FANOTHEIAZINE AND THEIR USE |
SM201600389T SMT201600389B (en) | 2011-02-11 | 2016-10-27 | PHENOTIAZINE DIAMMINE SALTS AND THEIR USE |
IL249056A IL249056B (en) | 2011-02-11 | 2016-11-20 | Phenothiazine diaminium salts and their use |
US15/912,166 US10864216B2 (en) | 2011-02-11 | 2018-03-05 | Phenothiazine diaminium salts and their use |
US16/751,811 US11180464B2 (en) | 2011-02-11 | 2020-01-24 | Phenothiazine diaminium salts and their use |
US17/499,498 US20220098161A1 (en) | 2011-02-11 | 2021-10-12 | Phenothiazine diaminium salts and their use |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SG201101060-0 | 2011-02-11 | ||
SG2011010600 | 2011-02-11 | ||
US201161485880P | 2011-05-13 | 2011-05-13 | |
US61/485,880 | 2011-05-13 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/984,841 A-371-Of-International US9283230B2 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
US15/056,610 Division US9907804B2 (en) | 2011-02-11 | 2016-02-29 | Phenothiazine diaminium salts and their use |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012107706A1 true WO2012107706A1 (en) | 2012-08-16 |
WO2012107706A8 WO2012107706A8 (en) | 2013-09-19 |
Family
ID=44532939
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2011/001221 WO2012107706A1 (en) | 2011-02-11 | 2011-08-15 | Phenothiazine diaminium salts and their use |
Country Status (26)
Country | Link |
---|---|
US (5) | US9283230B2 (en) |
EP (1) | EP2673266B1 (en) |
JP (2) | JP5898701B2 (en) |
KR (1) | KR101888713B1 (en) |
CN (2) | CN105853439A (en) |
AR (2) | AR082699A1 (en) |
AU (1) | AU2011358840B2 (en) |
BR (1) | BR112013020539A2 (en) |
CA (1) | CA2827027C (en) |
CY (1) | CY1118102T1 (en) |
DK (1) | DK2673266T3 (en) |
EA (1) | EA025033B1 (en) |
ES (1) | ES2594703T3 (en) |
HK (1) | HK1186738A1 (en) |
HR (1) | HRP20161291T1 (en) |
HU (1) | HUE031633T2 (en) |
IL (2) | IL227736A (en) |
LT (1) | LT2673266T (en) |
MY (1) | MY165906A (en) |
PL (1) | PL2673266T3 (en) |
PT (1) | PT2673266T (en) |
RS (1) | RS55237B1 (en) |
SG (1) | SG192666A1 (en) |
SI (1) | SI2673266T1 (en) |
SM (1) | SMT201600389B (en) |
WO (1) | WO2012107706A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8785434B2 (en) | 2010-04-30 | 2014-07-22 | Prosetta Antiviral Inc. | Antiviral compounds |
US8828986B2 (en) | 2011-04-20 | 2014-09-09 | Prosetta Antiviral Inc. | Antiviral compounds |
CN105612148A (en) * | 2013-08-15 | 2016-05-25 | 益友制药私人有限公司 | Process for purification of diaminophenothiazinium compounds |
CN106046027A (en) * | 2016-06-30 | 2016-10-26 | 广东工业大学 | Pyrrolo-phenothiazine-1,3-diketone containing derivative as well as preparation method and application thereof |
WO2018019823A1 (en) | 2016-07-25 | 2018-02-01 | Wista Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
WO2018041739A1 (en) | 2016-09-01 | 2018-03-08 | Wista Laboratories Ltd. | Treatment of dementia |
US10323010B2 (en) | 2015-07-20 | 2019-06-18 | Wista Laboratories Ltd. | Methods of chemical synthesis of substituted 10H-phenothiazine-3,7-diamine compounds |
WO2020020751A1 (en) | 2018-07-26 | 2020-01-30 | Wista Laboratories Ltd. | Optimised dosage of diaminophenothiazines in populations |
WO2020048593A1 (en) | 2018-09-05 | 2020-03-12 | Wista Laboratories Ltd. | Network methods for neurodegenerative diseases |
WO2021001306A1 (en) | 2019-07-01 | 2021-01-07 | Wista Laboratories Ltd. | Methylthioninium as enhancers of the cognitive function |
WO2021001380A1 (en) | 2019-07-01 | 2021-01-07 | Wista Laboratories Ltd. | Therapeutic interactions of leucomethylthioninium |
WO2021001326A1 (en) | 2019-07-02 | 2021-01-07 | Wista Laboratories Ltd. | Methylthioninium for use in the treatment of synaptopathies |
US10968174B2 (en) | 2016-12-21 | 2021-04-06 | Wista Laboratories Ltd. | Synthesis of a thiosulfonic acid by a step of periodate mediated oxidative coupling of a thiosulfonic acid with an aniline |
WO2021224146A1 (en) | 2020-05-05 | 2021-11-11 | Wista Laboratories Ltd. | Methylthioninium compounds for use in the treatment of hypoxemia |
WO2021224145A1 (en) | 2020-05-05 | 2021-11-11 | Wista Laboratories Ltd. | Methylthioninium compounds for use in the treatment of covid-19 |
WO2021224144A1 (en) | 2020-05-05 | 2021-11-11 | Wista Laboratories Ltd. | Methylthioninium compounds for use in the treatment of covid-19 |
WO2022008719A1 (en) | 2020-07-10 | 2022-01-13 | Wista Laboratories Ltd. | Anti-tau antibodies |
US11369615B2 (en) | 2017-11-07 | 2022-06-28 | Jichi Medical University | Agent for improving mitochondrial dysfunction, preventative or therapeutic agent for diseases or symptoms caused by mitochondrial dysfunction, and applications therefor |
WO2023180171A1 (en) | 2022-03-24 | 2023-09-28 | Wista Laboratories Ltd | Methylene blue containing compounds for the treatment of methaemoglobinaemia |
WO2023232764A1 (en) | 2022-05-31 | 2023-12-07 | Wista Laboratories Ltd. | Treatment of neurodegenerative disorders utilising methylthioninium (mt)-containing compounds |
WO2024061971A1 (en) | 2022-09-21 | 2024-03-28 | Wista Laboratories Ltd. | Novel formulations and vehicles |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2013191B3 (en) | 2006-03-29 | 2019-02-27 | Wista Laboratories Ltd. | 3,7-diamino-10h-phenothiazine salts and their use |
DK3121169T3 (en) | 2006-07-11 | 2022-02-28 | Wista Lab Ltd | Methods for the synthesis and / or purification of diaminophenothiazinium compounds |
US9925282B2 (en) | 2009-01-29 | 2018-03-27 | The General Hospital Corporation | Cromolyn derivatives and related methods of imaging and treatment |
WO2014066318A1 (en) | 2012-10-25 | 2014-05-01 | The General Hospital Corporation | Combination therapies for the treatment of alzheimer's disease and related disorders |
US10058530B2 (en) | 2012-10-25 | 2018-08-28 | The General Hospital Corporation | Combination therapies for the treatment of Alzheimer's disease and related disorders |
US10525005B2 (en) | 2013-05-23 | 2020-01-07 | The General Hospital Corporation | Cromolyn compositions and methods thereof |
CA2928028A1 (en) | 2013-10-22 | 2015-04-30 | The General Hospital Corporation | Cromolyn derivatives and related methods of imaging and treatment |
WO2015171592A1 (en) * | 2014-05-06 | 2015-11-12 | Milliken & Company | Laundry care compositions |
JP2018514523A (en) * | 2015-04-16 | 2018-06-07 | ノバルティス アーゲー | Ribocyclib tablets |
CN105541756B (en) * | 2015-12-17 | 2018-02-09 | 陕西方舟制药有限公司 | The method that one kind prepares 1 (3,7 pairs of bases of dimethylamino phenthazine 10) ethyl ketone |
JP2019524865A (en) | 2016-08-31 | 2019-09-05 | ザ ジェネラル ホスピタル コーポレイション | Macrophages / microglia in neuroinflammation associated with neurodegenerative diseases |
CA3070386A1 (en) | 2017-07-20 | 2019-01-24 | Aztherapies, Inc. | Powdered formulations of cromolyn sodium and ibuprofen |
AU2019299347A1 (en) | 2018-07-02 | 2021-01-21 | Aztherapies, Inc. | Powdered formulations of cromolyn sodium and alpha-lactose |
KR102396975B1 (en) | 2022-01-11 | 2022-05-12 | 이덕형 | A face lifting device and method therefor |
WO2023202464A1 (en) * | 2022-04-19 | 2023-10-26 | 英科隆生物技术(杭州)有限公司 | Purification method for electron mediator |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880373A (en) | 1988-04-28 | 1989-11-14 | The Upjohn Company | Tablet press |
WO1996030766A1 (en) | 1995-03-27 | 1996-10-03 | F. Hoffmann-La Roche Ag | Inhibition of tau-tau-association |
WO2002055720A2 (en) | 2001-01-15 | 2002-07-18 | Univ Aberdeen | Materials and methods relating to protein aggregation in neurodegenerative disease |
WO2002075318A2 (en) | 2001-03-20 | 2002-09-26 | The University Court Of The University Of Aberdeen | Neurofibrillary labels |
WO2005030676A1 (en) | 2003-09-29 | 2005-04-07 | The University Court Of The University Of Aberdeen | Methods of [11c]-radiolabelling phenothiazine and phenothiazine-like compounds |
WO2007110627A2 (en) | 2006-03-29 | 2007-10-04 | Wista Laboratories Ltd. | 3,7-diamino-10h-phenothiazine salts and their use |
WO2007110630A1 (en) | 2006-03-29 | 2007-10-04 | Wista Laboratories Ltd. | Thioninium compounds and their use |
WO2008007074A2 (en) | 2006-07-11 | 2008-01-17 | Wista Laboratories Ltd. | Methods of synthesis and/or purification of diaminophenothiazinium compounds |
WO2008155533A2 (en) * | 2007-06-19 | 2008-12-24 | Wista Laboratories Ltd | Phenothiazine compounds for treating mild cognitive impairment |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE569430A (en) | 1957-07-17 | |||
US4309255A (en) | 1980-09-10 | 1982-01-05 | International Business Machines Corporation | Electrochromic recording paper |
US4622395A (en) | 1984-10-01 | 1986-11-11 | Minnesota Mining And Manufacturing Company | Phenoxazine and phenothiazine dyes and leuco forms thereof |
US4647525A (en) | 1984-10-01 | 1987-03-03 | Minnesota Mining And Manufacturing Company | Stabilized leuco phenazine dyes and their use in an imaging system |
GB8724412D0 (en) | 1987-10-19 | 1987-11-25 | Medical Res Council | Protein |
US5571666A (en) | 1988-10-28 | 1996-11-05 | Oklahoma Medical Research Foundation | Thiazine dyes used to inactivate HIV in biological fluids |
CA2011116C (en) | 1989-03-06 | 1999-11-16 | Murray A. Kaplan | Lyophilized bmy-28142 dihydrochloride for parenteral use |
US5220009A (en) | 1990-05-03 | 1993-06-15 | Yeda Research And Development Company Limited | Phenothiazinium salts and their use for disinfecting aqueous effluents |
JPH0725786A (en) | 1990-05-16 | 1995-01-27 | Univ Rockefeller | Medical treatment of amyloidosis accompanying alzheimer desease |
AU2414092A (en) | 1991-08-01 | 1993-03-02 | Paul H. Voorheis | Diagnostic method for alzheimer's disease |
WO1993003177A1 (en) | 1991-08-09 | 1993-02-18 | Massachusetts Institute Of Technology | Novel tau/neurofilament protein kinases |
DE4140192C2 (en) | 1991-12-05 | 1996-02-29 | Alfatec Pharma Gmbh | Sol-controlled gelatin-based thermocolloid matrix for peroral sustained release forms |
DE69233723T2 (en) | 1991-12-06 | 2009-02-05 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Use of protein kinases for the diagnosis and treatment of Alzheimer's disease |
JPH06289015A (en) | 1993-03-30 | 1994-10-18 | Sunstar Inc | Stabilized phenothiazine chromogen composition |
GB9316727D0 (en) | 1993-08-12 | 1993-09-29 | Inst Of Psychiatry | Models of alzheimers's disease |
GB9317193D0 (en) | 1993-08-18 | 1993-10-06 | Zeneca Ltd | Method |
EP0778773A1 (en) | 1994-08-08 | 1997-06-18 | Albert Einstein College Of Medicine Of Yeshiva University | Methods for treating and/or preventing alzheimer's disease using phenothiazines and/or thioxanthenes |
DE4430091A1 (en) | 1994-08-25 | 1996-02-29 | Bayer Ag | Use of N-substituted phenothiazines |
US5804601A (en) | 1995-04-10 | 1998-09-08 | Takeda Chemical Industries, Ltd. | Aromatic hydroxamic acid compounds, their production and use |
US5693638A (en) | 1996-02-23 | 1997-12-02 | Myers; Daniel | Method of treating a migraine headache |
US6333322B1 (en) | 1996-03-13 | 2001-12-25 | Eisai Co., Ltd. | Nitrogen-containing tricyclic compounds and drugs containing the same |
EP0973383A4 (en) | 1997-01-21 | 2001-08-22 | American Nat Red Cross | Intracellular and extracellular decontamination of whole blood and blood components by amphiphilic phenothiazin-5-ium dyes plus light |
AU4322999A (en) | 1998-06-01 | 1999-12-20 | Advanced Research And Technology Institute, Inc. | Methods and compositions for diagnosing tauopathies |
FR2788436A1 (en) | 1999-01-14 | 2000-07-21 | Pf Medicament | Composition useful for treating allergic rhinitis contains phenothiazine derivative in aqueous stabilized with sulfur-containing amino acid derivative |
AU2001229619A1 (en) | 2000-01-21 | 2001-07-31 | Pharmacia And Upjohn Company | Transgenic mouse model of human neurodegenerative disease |
GB0017060D0 (en) | 2000-07-11 | 2000-08-30 | Hunter Fleming Ltd | Production, stabilisation and use of reduced forms of pharmaceutical compounds |
GB0100119D0 (en) | 2001-01-03 | 2001-02-14 | Univ Aberdeen | Materials and methods relating to protein aggregation in neurodegenerative disease |
WO2003000714A2 (en) | 2001-06-22 | 2003-01-03 | Panacea Pharmaceuticals, Inc. | Compositions and methods for preventing protein aggregation in neurodegenerative diseases |
GB0117326D0 (en) | 2001-07-16 | 2001-09-05 | Univ Aberdeen | Napthoquinone-type inhibitors of protein aggregation |
US7410965B2 (en) | 2002-05-29 | 2008-08-12 | Gruenenthal Gmbh | Delayed release pharmaceutical composition containing 1-dimethyl-amino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol |
US6953974B2 (en) | 2003-08-26 | 2005-10-11 | Texas Instruments Incorporated | EEPROM device and method for providing lower programming voltage |
JP2007512297A (en) | 2003-11-28 | 2007-05-17 | フォトファーマイカ リミテッド | Development in bioactive methylene blue derivative (2) |
CA2579169C (en) | 2004-09-23 | 2018-03-06 | Wista Laboratories Ltd. | Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (mtc) |
US7790881B2 (en) | 2004-09-23 | 2010-09-07 | Wista Laboratories Ltd. | Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC) |
WO2006091728A2 (en) | 2005-02-24 | 2006-08-31 | The Trustees Of The University Of Pennsylvania | Microtubule stabilizing compounds and methods of their use |
WO2007056439A1 (en) | 2005-11-08 | 2007-05-18 | Collegium Pharmaceutical, Inc. | Salts of methylene blue and its derivatives |
PT2004155T (en) | 2006-03-29 | 2018-05-02 | Wista Lab Ltd | Inhibitors of protein aggregation |
PT2954932T (en) | 2007-10-03 | 2018-12-12 | Wista Lab Ltd | Therapeutic use of diaminophenothiazines |
-
2011
- 2011-08-15 SI SI201130992A patent/SI2673266T1/en unknown
- 2011-08-15 EP EP11749476.5A patent/EP2673266B1/en active Active
- 2011-08-15 EA EA201391158A patent/EA025033B1/en unknown
- 2011-08-15 RS RS20160880A patent/RS55237B1/en unknown
- 2011-08-15 BR BR112013020539A patent/BR112013020539A2/en not_active Application Discontinuation
- 2011-08-15 WO PCT/GB2011/001221 patent/WO2012107706A1/en active Application Filing
- 2011-08-15 KR KR1020137023810A patent/KR101888713B1/en active IP Right Grant
- 2011-08-15 HU HUE11749476A patent/HUE031633T2/en unknown
- 2011-08-15 CN CN201610192816.8A patent/CN105853439A/en active Pending
- 2011-08-15 CA CA2827027A patent/CA2827027C/en active Active
- 2011-08-15 SG SG2013060132A patent/SG192666A1/en unknown
- 2011-08-15 US US13/984,841 patent/US9283230B2/en active Active
- 2011-08-15 JP JP2013553013A patent/JP5898701B2/en active Active
- 2011-08-15 MY MYPI2013002933A patent/MY165906A/en unknown
- 2011-08-15 LT LTEP11749476.5T patent/LT2673266T/en unknown
- 2011-08-15 ES ES11749476.5T patent/ES2594703T3/en active Active
- 2011-08-15 CN CN201180070054.XA patent/CN103649061B/en active Active
- 2011-08-15 DK DK11749476.5T patent/DK2673266T3/en active
- 2011-08-15 PL PL11749476T patent/PL2673266T3/en unknown
- 2011-08-15 PT PT117494765T patent/PT2673266T/en unknown
- 2011-08-15 AU AU2011358840A patent/AU2011358840B2/en active Active
- 2011-08-16 AR ARP110102969A patent/AR082699A1/en not_active Application Discontinuation
-
2013
- 2013-07-31 IL IL227736A patent/IL227736A/en active IP Right Grant
- 2013-12-27 HK HK13114315.4A patent/HK1186738A1/en unknown
-
2016
- 2016-02-26 JP JP2016035263A patent/JP6093890B2/en active Active
- 2016-02-29 US US15/056,610 patent/US9907804B2/en active Active
- 2016-10-06 HR HRP20161291TT patent/HRP20161291T1/en unknown
- 2016-10-17 CY CY20161101036T patent/CY1118102T1/en unknown
- 2016-10-27 SM SM201600389T patent/SMT201600389B/en unknown
- 2016-11-20 IL IL249056A patent/IL249056B/en active IP Right Grant
-
2018
- 2018-03-05 US US15/912,166 patent/US10864216B2/en active Active
-
2020
- 2020-01-24 US US16/751,811 patent/US11180464B2/en active Active
-
2021
- 2021-01-11 AR ARP210100056A patent/AR121016A2/en unknown
- 2021-10-12 US US17/499,498 patent/US20220098161A1/en active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880373A (en) | 1988-04-28 | 1989-11-14 | The Upjohn Company | Tablet press |
WO1996030766A1 (en) | 1995-03-27 | 1996-10-03 | F. Hoffmann-La Roche Ag | Inhibition of tau-tau-association |
WO2002055720A2 (en) | 2001-01-15 | 2002-07-18 | Univ Aberdeen | Materials and methods relating to protein aggregation in neurodegenerative disease |
WO2002075318A2 (en) | 2001-03-20 | 2002-09-26 | The University Court Of The University Of Aberdeen | Neurofibrillary labels |
WO2005030676A1 (en) | 2003-09-29 | 2005-04-07 | The University Court Of The University Of Aberdeen | Methods of [11c]-radiolabelling phenothiazine and phenothiazine-like compounds |
WO2007110627A2 (en) | 2006-03-29 | 2007-10-04 | Wista Laboratories Ltd. | 3,7-diamino-10h-phenothiazine salts and their use |
WO2007110630A1 (en) | 2006-03-29 | 2007-10-04 | Wista Laboratories Ltd. | Thioninium compounds and their use |
WO2008007074A2 (en) | 2006-07-11 | 2008-01-17 | Wista Laboratories Ltd. | Methods of synthesis and/or purification of diaminophenothiazinium compounds |
WO2008155533A2 (en) * | 2007-06-19 | 2008-12-24 | Wista Laboratories Ltd | Phenothiazine compounds for treating mild cognitive impairment |
Non-Patent Citations (99)
Title |
---|
"Handbook of Pharmaceutical Additives", 2001, SYNAPSE INFORMATION RESOURCES, INC. |
"Handbook of Pharmaceutical Excipients", 1994 |
"Pharmaceutical Dosage Forms: Tablets", 1989, MARCEL DEKKER, INC |
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO |
"Remington's Pharmaceutical Sciences", 2000, LIPPINCOTT, WILLIAMS & WILKINS |
ABRAHAMSON, M., JONSDOTTIR, S., OLAFSSON, I., GRUBB, A.: "Hereditary cystatin C amyloid angiopathy identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis", HUMAN GENETICS, vol. 89, 1992, pages 377 - 380 |
ANDERSEN, P.: "Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene", CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, vol. 6, 2006, pages 37 - 46 |
ARAI, T., HASEGAWA, M., NONOKA, T., KAMETANI, F., YAMASHITA, M., HOSOKAWA, M., NIIZATO, K., TSUCHIYA, K., KOBAYASHI, Z., IKEDA, K.: "Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy", NEUROPATHOLOGY, vol. 30, 2010, pages 170 - 181 |
ASKANAS, V., ENGEL, W.K., NOGALSKA, A.: "Inclusion body myositis: a degenerative muscle disease associated with intra-muscle fiber multi-protein aggregates, proteasome inhibition, endoplasmic reticulum stress and decreased lysosomal degradation", BRAIN PATHOLOGY, vol. 19, 2009, pages 493 - 506 |
BARMADA, S.J., SKIBINSKI, G., KORB, E., RAO, E.J., WU, J.Y., FINKBEINER, S.: "Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis", JOURNAL OF NEUROSCIENCE, vol. 30, 2010, pages 639 - 649 |
BLAIR, I.P., WILLIAMS, K.L., WARRAICH, S.T., DURNALL, J.C., THOENG, A.D., MANAVIS, J., BLUMBERGS, P.C., VUCIC, S., KIERNAN, M.C.,: "FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis", JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, vol. 81, 2010, pages 639 - 645 |
BONDAREFF, W. ET AL., J. NEUROPATH. EXPER. NEUROL., vol. 53, no. 2, 1994, pages 158 - 164 |
BOOTH, D.R., SUNDE, M., BELLOTTI, V., ROBINSON, C.V., HUTCHINSON, W.L., FRASER, P.E., HAWKINS, P.N., DOBSON, C.M., RADFORD, S.E.,: "Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis", NATURE, vol. 385, 1997, pages 787 - 793 |
BYRNE, S., WALSH, C., LYNCH, C., BEDE, P., ELAMIN, M., KENNA, K., MCLAUGHLIN, R., HARDIMAN, O.: "Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis", JOURNAL OF NEUROLOGY, NEUROSURGERY & PSYCHIATRY, vol. 82, 2011, pages 623 - 627 |
CARRELL, R.W., GOOPTU, B.: "Conformational changes and disease - serpins, prions and Alzheimer's", CURRENT OPINION IN STRUCTURAL BIOLOGY, vol. 8, 1998, pages 799 - 809 |
CHEN-PLOTKIN, A.S., LEE, V.M.Y., TROJANOWSKI, J.Q.: "TAR DNA-binding protein 43 in neurodegenerative disease", NATURE REVIEWS NEUROLOGY, vol. 6, 2010, pages 211 - 220 |
CHITI, F., WEBSTER, P., TADDEI, N., CLARK, A., STAFANI, M., RAMPONI, G., DOBSON, C.: "Designing conditions for in vitro formation of amyloid protofilaments and fibrils", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA, vol. 96, 1999, pages 3590 - 3594 |
COX, L.E., FERRAIUOLO, L., GOODALL, E.F., HEATH, P.R., HIGGINBOTTOM, A., MORTIBOYS, H., HOLLINGER, H.C., HARTLEY, J.A., BROCKINGTO: "Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS", PLOS ONE, vol. 5, 2010, pages E9872 |
CZECH, C., TREMP, G., PRADIER, L.: "Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms", PROGRESS IN NEUROBIOLOGY, vol. 60, 2000, pages 363 - 384 |
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2010, XP002661598, retrieved from STN Database accession no. 1236208-20-0 * |
DAVIS, RL., SHRIMPTON, AE., HOLOHAN, P.D., BRADSHAW, C., FEIGLIN, D., COLLINS, G.H., SONDEREGGER, P., KINTER, J., BECKER, L.M., LA: "Familial dementia caused by polymerization of mutant neuroserpin", NATURE, vol. 401, 1999, pages 376 - 379 |
DIFIGLIA, M., SAPP, E., CHASE, K.O., DAVIES, S.W., BATES, G.P., VONSATTEL, J.P., ARONIN, N.: "Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain", SCIENCE, vol. 277, 1997, pages 1990 - 1993 |
DISCHE, F.E., WERNSTEDT, C., WESTERMARK, G.T., WESTERMARK, P., PEPYS, M.B., RENNIE, J.A., GILBEY, S.G., WATKINS, P.J.: "Insulin as an amyloid-fibril protein at sites of repeated insulin injections in a diabetic patient", DIABETOLOGIA, vol. 31, 1988, pages 158 - 161 |
ELDEN, A.C., KIM, H.-J., HART, M.P., CHEN-PLOTKIN, A.S., JOHNSON, B.S., FANG, X., ARMAKOLA, M., GESER, F., GREENE, R., LU, M.M.: "Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS", NATURE, vol. 466, 2010, pages 1069 - 1075 |
FINSTERER, J: "Mitochondrial disorders, cognitive impairment and dementia", J. NEUROL. SCI., vol. 283, 2009, pages 143 - 148 |
GASSET, M., BLADWIN, M.A., LLOYD, D.H., ABRIEL, J.-M., HOLTZMAN, D.M., COHEN, F.E., FLETTERICK, R., PRUSINER, S.B.: "Predicted a-helical region of the prion protein when synthesized as peptides form amyloid", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA, vol. 89, 1992, pages 10940 - 10944 |
GENDRON, T.F., JOSEPHS, K.A., PETRUCELLI, L.: "Review: Transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration", NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, vol. 36, 2010, pages 97 - 112 |
GESER, F., LEE, V.M.-Y., TROJANOWSKI, J.Q.: "Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: A spectrum of TDP-43 proteinopathies", NEUROPATHOLOGY, vol. 30, 2010, pages 103 - 112 |
GITCHO, M.A., BALOH, R.H., CHAKRAVERTY, S., MAYO, K., NORTON, J.B., LEVITCH, D., HATANPAA, K.J., WHITE, C.L., III, BIGIO, E.H., CA: "TDP-43 A315T mutation in familial motor neuron disease", ANNALS OF NEUROLOGY, vol. 63, 2008, pages 535 - 538 |
GLENNER, G.G., WONG, C.W.: "Alzheimer's disease: initial report of the purification and characterisation of a novel cerebrovascular amyloid protein", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 120, 1984, pages 885 - 890 |
GOATE, A., CHARTIER-HARLIN, M.-C., MULLAN, M., BROWN, J., CRAWFORD, F., FIDANI, L., GIUFFRA, L., HAYNES, A., IRVING, N., JAMES, L.: "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease", NATURE, vol. 349, 1991, pages 704 - 706 |
GOEDERT, M. ET AL., EMBO J., vol. 8, 1989, pages 393 - 399 |
GOEDERT, M. ET AL., NEURON, vol. 3, 1989, pages 519 - 526 |
GOREVIC, P.D., CASEY, T.T., STONE, W.J., DIRAIMONDO, C.R., PRELLI, F.C., FRANGIONE, B.: "b-2 Microglobulin is an amyloidogenic protein in man", JOURNAL OF CLINICAL INVESTIGATION, vol. 76, 1985, pages 2425 - 2429 |
GUSTAVSSON, A., ENGSTR6M, U., WESTERMARK, P.: "Normal transthyretin and synthetic transthyretin fragments form amyloid-like fibrils in vitro", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 175, 1991, pages 1159 - 1164 |
GUTTMANN, P., EHRLICH, P.: "Uber die wirkung des methylenblau bei malaria", vol. 28, 1891, BERL. KLIN. WOSCHENR., pages: 953 - 956 |
HIGASHI, S., TSUCHIYA, Y., ARAKI, T., WADA, K., KABUTA, T.: "TDP-43 physically interacts with amyotrophic lateral sclerosis-linked mutant CuZn superoxide dismutase", NEUROCHEMISTRY INTERNATIONAL, vol. 57, 2010, pages 906 - 913 |
HUTTON, M., LENDON, C., RIZZU, P., BAKER, M., FROELICH, S., HOULDEN, H., PICKERING-BROWN, S., CHAKRAVERTY, S., ISAACS, A., GROVER,: "Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17", NATURE, vol. 393, 1998, pages 702 - 705 |
IGAZ, L.M., KWONG, L.K., CHEN-PLOTKIN, A., WINTON, M.J., UNGER, T.L., XU, Y., NEUMANN, M., TROJANOWSKI, J.Q., LEE, V.M.Y.: "Expression of TDP-43 C-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, 2009, pages 8516 - 8524 |
JAKES, R ET AL., EMBO J., vol. 10, 1991, pages 2725 - 2729 |
JINWAL, UK, MIYATA, Y, KOREN, J, JONES, JR, TROTTER, JH ET AL.: "Chemical manipulation of Hsp70 ATPase activity regulates tau stability", J. NEUROSCI., vol. 29, 2009, pages 12079 - 12088 |
JOHANSSON, B., WERNSTEDT, C., WESTERMARK, P.: "Atrial natriuretic peptide deposited as atrial amyloid fibrils", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 148, 1987, pages 1087 - 1092 |
JOHNSON, B.S., MCCAFFERY, J.M., LINDQUIST, S., GITLER, AD.: "A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 105, 2008, pages 6439 - 6444 |
JOHNSON, B.S., SNEAD, D., LEE, J.J., MCCAFFERY, J.M., SHORTER, J., GITLER, A.D.: "TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, 2009, pages 20329 - 20339 |
JOHNSON, J.O., MANDRIOLI, J., BENATAR, M., ABRAMZON, Y., VAN DEERLIN, V.M., TROJANOWSKI, J.Q., GIBBS, J.R., BRUNETTI, M., GRONKA,: "Exome sequencing reveals VCP mutations as a cause of familial ALS", NEURON, vol. 68, 2010, pages 857 - 864 |
KABASHI, E., LIN, L., TRADEWELL, M.L., DION, P.A., BERCIER, V., BOURGOUIN, P., ROCHEFORT, D., BEL HADJ, S., DURHAM, H.D., VELDE, C: "Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo", HUMAN MOLECULAR GENETICS, vol. 19, 2010, pages 671 - 683 |
KABASHI, E., VALDMANIS, P.N., DION, P., SPIEGELMAN, D., MCCONKEY, B.J., VELDE, C.V., BOUCHARD, J.-P., LACOMBLEZ, L., POCHIGAEVA, K: "TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis", NATURE GENETICS, vol. 40, 2008, pages 572 - 574 |
KANG ET AL., NATURE, vol. 325, 1987, pages 733 |
KINDLER, GARNER, MOL. BRAIN RES., vol. 26, 1994, pages 218 - 224 |
LAI, R. Y. K. ET AL., NEUROBIOLOGY OF AGEING, vol. 16, no. 3, 1995, pages 433 - 445 |
LING, S.-C., ALBUQUERQUE, C.P., HAN, J.S., LAGIER-TOURENNE, C., TOKUNAGA, S., ZHOU, H., CLEVELAND, D.W.: "ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 107, 2010, pages 13318 - 13323 |
LOMAS, D.A., EVANS, D.L., FINCH, J.T., CARRELL, R.W.: "The mechanism of Z a1-antitrypsin accumulation in the liver", NATURE, vol. 357, 1992, pages 605 - 607 |
LOVE, S., BRIDGES, L.R., CASE, C.P.: "Neurofibrillary tangles in Niemann-Pick disease type C", BRAIN, vol. 118, 1995, pages 119 - 129 |
MACKENZIE, I.R.A., BIGIO, E.H., INCE, P.G., GESER, F., NEUMANN, M., CAIRNS, N.J., KWONG, L.K., FORMAN, M.S., RAVITS, J., STEWART,: "Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations", ANNALS OF NEUROLOGY, vol. 61, 2007, pages 427 - 434 |
MACKENZIE, I.R.A., RADEMAKERS, R., NEUMANN, M.: "TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia", THE LANCET NEUROLOGY, vol. 9, 2010, pages 995 - 1007 |
MATUS, A.: "Microtubules", JOHN WILEY AND SONS, pages: 155 - 166 |
MAURY, C.P., BAUMANN, M.: "Isolation and characterization of cardiac amyloid in familial amyloid polyneuropathy type IV (Finnish): relation of the amyloid protein to variant gelsolin", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1096, 1990, pages 84 - 86 |
MAY ET AL., AM J PHYSIOL CELL PHYSIOL, vol. 286, 2004, pages C1390 - C1398 |
MENA, R ET AL., ACTA NEUROPATHOL., vol. 89, 1995, pages 50 - 56 |
MENA, R. ET AL., ACTA NEUROPATHOL., vol. 91, 1996, pages 633 - 641 |
MUKAETOVA-LADINSKA, E.B. ET AL., AM. J. PATHOL., vol. 157, no. 2, 2000, pages 623 - 636 |
NEARY, D., SNOWDEN, J.S., GUSTAFSON, L., PASSANT, U., STUSS, D., BLACK, S., FREEDMAN, M., KERTESZ, A, ROBERT, P.H., ALBERT, M.: "Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria", NEUROLOGY, vol. 51, 1998, pages 1546 - 1554 |
NEUMANN, M., SAMPATHU, D.M., KWONG, L.K., TRUAX, A.C., MICSENYI, M.C., CHOU, T.T., BRUCE, J., SCHUCK, T., GROSSMAN, M., CLARK, C.M: "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis", SCIENCE, vol. 314, 2006, pages 130 - 133 |
NEUMANN, M.: "Molecular neuropathology of TDP-43 proteinopathies", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 10, 2009, pages 232 - 246 |
NONAKA, T., KAMETANI, F., ARAI, T., AKIYAMA, H., HASEGAWA, M.: "Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43", HUMAN MOLECULAR GENETICS, vol. 18, 2009, pages 3353 - 3364 |
NOVAK, M. ET AL., EMBO J., vol. 12, 1993, pages 365 - 370 |
OHMI, K., KUDO, L.C., RYAZANTSEV, S., ZHAO, H.-Z., KARSTEN, S.L., NEUFELD, E.F.: "Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 106, 2009, pages 8332 - 8337 |
ORR, H.T., ZOGHBI, H.Y.: "Trinucleotide repeat disorders", ANNUAL REVIEW OF NEUROSCIENCE, vol. 30, 2007, pages 575 - 621 |
PAULSON, H.L.: "Human genetics '99: trinucleotide repeats", AMERICAN JOURNAL OF HUMAN GENETICS, vol. 64, 1999, pages 339 - 345 |
PEPYS, M.B., HAWKINS, P.N., BOOTH, D.R., VIGUSHIN, D.M., TENNENT, G.A., SOUTAR, A.K., TOTTY, N., NGUYEN, O., BLAKE, C.C.F., TERRY,: "Human lysozyme gene mutations cause hereditary systemic amyloidosis", NATURE, vol. 362, 1993, pages 553 - 557 |
POLYMEROPOULOS, M.H., LAVEDAN, C., LEROY, E., IDE, S.E., DEHEJIA, A., DUTRA, A., PIKE, B., ROOT, H., RUBENSTEIN, J., BOYER, R.: "Mutation in the a-synuclein gene identified in families with Parkinson's disease", SCIENCE, vol. 276, 1997, pages 2045 - 2047 |
PRETSCH E. ET AL.: "Literature Reference: Structure Determination of Organic Compounds: Tables of Spectral Data", SPRINGER, pages: 122 |
PRUSINER, S.B., SCOTT, M.R., DEARMOND, S.J., COHEN, F.E.: "Prion protein biology", CELL, vol. 93, 1998, pages 337 - 348 |
RENGELSHAUSEN, J. ET AL.: "Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria", EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, vol. 60, 2004, pages 709 - 715 |
SCHIRMER, H. ET AL.: "Methylene blue as an antimalarial agent", REDOX REPORT, vol. 8, 2003, pages 272 - 275 |
SEETHARAMAN, S.V., PRUDENCIO, M., KARCH, C., HOLLOWAY, S.P., BORCHELT, D.R., HART, P.J.: "Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis", EXPERIMENTAL BIOLOGY AND MEDICINE, vol. 234, 2009, pages 1140 - 1154 |
SEILHEAN, D., CAZENEUVE, C., THURIES, V., RUSSAOUEN, O., MILLECAMPS, S., SALACHAS, F., MEININGER, V., LEGUERN, E., DUYCKAERTS, C.: "Accumulation of TDP-43 and a-actin in an amyotrophic lateral sclerosis patient with the K171 ANG mutation", ACTA NEUROPATHOLOGICA, vol. 118, 2009, pages 561 - 573 |
SHELANSKI ET AL., PROC. NATL. ACAD. SCI. USA, vol. 70, 1973, pages 765 - 768 |
SHIBATA, N., HIRANO, A., KOBAYASHI, M., SIDDIQUE, T., DENG, H.X., HUNG, W.Y., KATO, T., ASAYAMA, K.: "Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement", JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, vol. 55, 1996, pages 481 - 490 |
SLETTEN, K., WESTERMARK, P., NATVIG, J.B.: "Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 143, 1976, pages 993 - 998 |
SPILLANTINI, M.G., CROWTHER, R.A., JAKES, R., HASEGAWA, M., GOEDERT, M.: "a-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA, vol. 95, 1998, pages 6469 - 6473 |
SREEDHARAN, J., BLAIR, I.P., TRIPATHI, V.B., HU, X., VANCE, C., ROGELJ, B., ACKERLEY, S., DURNALL, J.C., WILLIAMS, K.L., BURATTI,: "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis", SCIENCE, vol. 319, 2008, pages 1668 - 1672 |
T. GREEN, P. WUTS: "Protective Groups in Organic Synthesis", 2006, JOHN WILEY AND SONS |
UEMICHI, T., LIUEPNICKS, J.J., BENSON, M.D.: "Hereditary renal amyloidosis with a novel variant fibrinogen", JOURNAL OF CLINICAL INVESTIGATION, vol. 93, 1994, pages 731 - 736 |
VAN BEBBER, F., PAQUET, D., HRUSCHA, A., SCHMID, B., HAASS, C.: "Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish", NEUROBIOLOGY OF DISEASE, vol. 39, 2010, pages 265 - 271 |
VANCE, C., ROGELJ, B., HORTOBAGYI, T., DE VOS, K.J., NISHIMURA, A.L., SREEDHARAN, J., HU, X., SMITH, B., RUDDY, D., WRIGHT, P.: "Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6", SCIENCE, vol. 323, 2009, pages 1208 - 1211 |
WESTERMARK, P., ENGSTROM, U., JOHNSON, K.H., WESTERMARK, G.T., BETSHOLTZ, C.: "Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA, vol. 87, 1990, pages 5036 - 5040 |
WESTERMARK, P., JOHNSON, K.H., O'BRIEN, T.D., BETSHOLTZ, C.: "Islet amyloid polypeptide - a novel controversy in diabetes research", DIABETOLOGIA, vol. 35, 1992, pages 297 - 303 |
WESTERMARK, P., JOHNSON, K.H., PITKANEN, P.: "Systemic amyloidosis: A review with emphasis on pathogenesis", APPLIED PHYSIOLOGY, vol. 3, 1985, pages 55 - 68 |
WIJESEKERA, L., LEIGH, P.N.: "Amyotrophic lateral sclerosis", ORPHANET JOURNAL OF RARE DISEASES, vol. 4, 2009, pages 3 |
WISCHIK ET AL., PNAS USA, vol. 85, 1988, pages 4506 - 4510 |
WISCHIK ET AL., PNAS USA, vol. 93, 1996, pages 11213 - 11218 |
WISCHIK ET AL.: "The Molecular and Cellular Neurobiology Series", 2000, BIOS SCIENTIFIC PUBLISHERS, article "Neurobiology of Alzheimer's Disease" |
WISCHIK ET AL.: "The Molecular and Cellular Neurobiology Series", BIOS SCIENTIFIC PUBLISHERS, article "Neurobiology of Alzheimer's Disease" |
WISCHIK, C.M. ET AL., PNAS USA, vol. 85, 1988, pages 4884 - 4888 |
WISCHIK, C.M. ET AL.: "Microtubule-associated proteins: modifications in disease", 1997, HARWOOD ACADEMIC PUBLISHERS, pages: 185 - 241 |
WISCHIK, C.M., NOVAK, M., THOGERSEN, H.C., EDWARDS, P.C., RUNSWICK, M.J., JAKES, R., WALKER, J.E., MILSTEIN, C., M., R. & KLUG, A.: "Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer's disease", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA, vol. 85, 1988, pages 4506 - 4510 |
YAMASHITA, M., NONAKA, T., ARAI, T., KAMETANI, F., BUCHMAN, V.L., NINKINA, N., BACHURIN, S.O., AKIYAMA, H., GOEDERT, M., HASEGAWA,: "Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models", FEBS LETTERS, vol. 583, 2009, pages 2419 - 2424 |
ZHANG, Y.-J., XU, Y.-F., COOK, C., GENDRON, T.F., ROETTGES, P., LINK, C.D., LIN, W.-L., TONG, J., CASTANEDES-CASEY, M., ASH, P.: "Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 106, 2009, pages 7607 - 7612 |
Cited By (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8785434B2 (en) | 2010-04-30 | 2014-07-22 | Prosetta Antiviral Inc. | Antiviral compounds |
US8828986B2 (en) | 2011-04-20 | 2014-09-09 | Prosetta Antiviral Inc. | Antiviral compounds |
CN105612148B (en) * | 2013-08-15 | 2018-09-14 | 益友制药私人有限公司 | Method for purifying diaminophenothiazine compound |
CN105612148A (en) * | 2013-08-15 | 2016-05-25 | 益友制药私人有限公司 | Process for purification of diaminophenothiazinium compounds |
EP3033331A4 (en) * | 2013-08-15 | 2017-01-18 | Eupharma Pty Ltd | Process for the purification of diaminophenothiazinium compounds |
TWI629267B (en) * | 2013-08-15 | 2018-07-11 | 益友製藥私人有限公司 | Process for the purification of diaminophenothiazinium compounds |
US10323010B2 (en) | 2015-07-20 | 2019-06-18 | Wista Laboratories Ltd. | Methods of chemical synthesis of substituted 10H-phenothiazine-3,7-diamine compounds |
CN106046027A (en) * | 2016-06-30 | 2016-10-26 | 广东工业大学 | Pyrrolo-phenothiazine-1,3-diketone containing derivative as well as preparation method and application thereof |
KR20190031552A (en) * | 2016-07-25 | 2019-03-26 | 위스타 레보레이토리스 리미티드 | The administration and dosage of diaminophenothiazines, |
EP4335517A2 (en) | 2016-07-25 | 2024-03-13 | WisTa Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
EP4223297A3 (en) * | 2016-07-25 | 2023-11-15 | WisTa Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
US11065256B2 (en) | 2016-07-25 | 2021-07-20 | Wista Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
KR102592614B1 (en) * | 2016-07-25 | 2023-10-24 | 위스타 레보레이토리스 리미티드 | Administration and Dosage of Diaminophenothiazines |
US11759469B2 (en) | 2016-07-25 | 2023-09-19 | Wista Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
EP4223297A2 (en) | 2016-07-25 | 2023-08-09 | WisTa Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
WO2018019823A1 (en) | 2016-07-25 | 2018-02-01 | Wista Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
KR20230003261A (en) * | 2016-07-25 | 2023-01-05 | 위스타 레보레이토리스 리미티드 | Administration and Dosage of Diaminophenothiazines |
KR102475825B1 (en) * | 2016-07-25 | 2022-12-08 | 위스타 레보레이토리스 리미티드 | Administration and Dosage of Diaminophenothiazines |
AU2017301966B2 (en) * | 2016-07-25 | 2022-09-22 | Wista Laboratories Ltd. | Administration and dosage of diaminophenothiazines |
AU2017318333B2 (en) * | 2016-09-01 | 2023-05-11 | Wista Laboratories Ltd. | Treatment of dementia |
KR102559354B1 (en) | 2016-09-01 | 2023-07-26 | 위스타 레보레이토리스 리미티드 | dementia treatment |
WO2018041739A1 (en) | 2016-09-01 | 2018-03-08 | Wista Laboratories Ltd. | Treatment of dementia |
KR20190045273A (en) * | 2016-09-01 | 2019-05-02 | 위스타 레보레이토리스 리미티드 | Dementia treatment |
US10842796B2 (en) | 2016-09-01 | 2020-11-24 | Wista Laboratories Ltd. | Treatment of dementia |
US10968174B2 (en) | 2016-12-21 | 2021-04-06 | Wista Laboratories Ltd. | Synthesis of a thiosulfonic acid by a step of periodate mediated oxidative coupling of a thiosulfonic acid with an aniline |
US11369615B2 (en) | 2017-11-07 | 2022-06-28 | Jichi Medical University | Agent for improving mitochondrial dysfunction, preventative or therapeutic agent for diseases or symptoms caused by mitochondrial dysfunction, and applications therefor |
EP4364801A2 (en) | 2018-07-26 | 2024-05-08 | WisTa Laboratories Ltd. | Optimised dosage of diaminophenothiazines in populations |
WO2020020751A1 (en) | 2018-07-26 | 2020-01-30 | Wista Laboratories Ltd. | Optimised dosage of diaminophenothiazines in populations |
WO2020048593A1 (en) | 2018-09-05 | 2020-03-12 | Wista Laboratories Ltd. | Network methods for neurodegenerative diseases |
WO2021001306A1 (en) | 2019-07-01 | 2021-01-07 | Wista Laboratories Ltd. | Methylthioninium as enhancers of the cognitive function |
WO2021001380A1 (en) | 2019-07-01 | 2021-01-07 | Wista Laboratories Ltd. | Therapeutic interactions of leucomethylthioninium |
WO2021001326A1 (en) | 2019-07-02 | 2021-01-07 | Wista Laboratories Ltd. | Methylthioninium for use in the treatment of synaptopathies |
WO2021224146A1 (en) | 2020-05-05 | 2021-11-11 | Wista Laboratories Ltd. | Methylthioninium compounds for use in the treatment of hypoxemia |
CN116194107A (en) * | 2020-05-05 | 2023-05-30 | 维斯塔实验室有限公司 | Methylthioninium compounds for the treatment of covd-19 |
CN116056724A (en) * | 2020-05-05 | 2023-05-02 | 维斯塔实验室有限公司 | Methylthioninium compounds for the treatment of covd-19 |
CN115916211A (en) * | 2020-05-05 | 2023-04-04 | 维斯塔实验室有限公司 | Methylthioninium compounds for the treatment of hypoxemia |
WO2021224144A1 (en) | 2020-05-05 | 2021-11-11 | Wista Laboratories Ltd. | Methylthioninium compounds for use in the treatment of covid-19 |
WO2021224145A1 (en) | 2020-05-05 | 2021-11-11 | Wista Laboratories Ltd. | Methylthioninium compounds for use in the treatment of covid-19 |
WO2022008719A1 (en) | 2020-07-10 | 2022-01-13 | Wista Laboratories Ltd. | Anti-tau antibodies |
WO2023180171A1 (en) | 2022-03-24 | 2023-09-28 | Wista Laboratories Ltd | Methylene blue containing compounds for the treatment of methaemoglobinaemia |
WO2023232764A1 (en) | 2022-05-31 | 2023-12-07 | Wista Laboratories Ltd. | Treatment of neurodegenerative disorders utilising methylthioninium (mt)-containing compounds |
WO2024061971A1 (en) | 2022-09-21 | 2024-03-28 | Wista Laboratories Ltd. | Novel formulations and vehicles |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11180464B2 (en) | Phenothiazine diaminium salts and their use | |
US11951110B2 (en) | 3, 7-diamino-10H-phenothiazine salts and their use | |
US9174954B2 (en) | 3,7-diamino-10H-phenothiazine salts and their use | |
AU2013200732B2 (en) | 3,7-diamino-10H-phenothiazine salts and their use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180070054.X Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11749476 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013553013 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2827027 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13984841 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1301004456 Country of ref document: TH |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2011749476 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011749476 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20137023810 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201391158 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 2011358840 Country of ref document: AU Date of ref document: 20110815 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013020539 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: P-2016/0880 Country of ref document: RS |
|
WWE | Wipo information: entry into national phase |
Ref document number: 249056 Country of ref document: IL |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01E Ref document number: 112013020539 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112013020539 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130812 |