JP2007502844A - カテプシンｓの阻害剤 - Google Patents
カテプシンｓの阻害剤 Download PDFInfo
- Publication number
- JP2007502844A JP2007502844A JP2006524107A JP2006524107A JP2007502844A JP 2007502844 A JP2007502844 A JP 2007502844A JP 2006524107 A JP2006524107 A JP 2006524107A JP 2006524107 A JP2006524107 A JP 2006524107A JP 2007502844 A JP2007502844 A JP 2007502844A
- Authority
- JP
- Japan
- Prior art keywords
- group
- substituted
- member selected
- alkyl
- cathepsin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940122805 Cathepsin S inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 108090000613 Cathepsin S Proteins 0.000 claims abstract description 90
- 102100035654 Cathepsin S Human genes 0.000 claims abstract description 90
- 230000005764 inhibitory process Effects 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 54
- 102000005600 Cathepsins Human genes 0.000 claims abstract description 36
- 108010084457 Cathepsins Proteins 0.000 claims abstract description 36
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 71
- -1 benzoimidazolyl Chemical group 0.000 claims description 62
- 229910052717 sulfur Inorganic materials 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 55
- 229910052760 oxygen Inorganic materials 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 125000000623 heterocyclic group Chemical group 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 18
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 13
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 12
- 229920001774 Perfluoroether Polymers 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 239000000651 prodrug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000005062 perfluorophenyl group Chemical group FC1=C(C(=C(C(=C1F)F)F)F)* 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 28
- 108010044467 Isoenzymes Proteins 0.000 abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 173
- 238000006243 chemical reaction Methods 0.000 description 85
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000002904 solvent Substances 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000758 substrate Substances 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000003112 inhibitor Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 102000004190 Enzymes Human genes 0.000 description 15
- 108090000790 Enzymes Proteins 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- 108090000712 Cathepsin B Proteins 0.000 description 12
- 108090000625 Cathepsin K Proteins 0.000 description 12
- 230000001419 dependent effect Effects 0.000 description 12
- 102000004225 Cathepsin B Human genes 0.000 description 11
- 102000004171 Cathepsin K Human genes 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 108090000624 Cathepsin L Proteins 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 102000004172 Cathepsin L Human genes 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 230000002860 competitive effect Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 102000005927 Cysteine Proteases Human genes 0.000 description 5
- 108010005843 Cysteine Proteases Proteins 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000030741 antigen processing and presentation Effects 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001336 alkenes Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
- OJVRHJFNQKFPBY-UHFFFAOYSA-N 5-fluoro-3,3-dimethyl-1,2-dihydroindole Chemical compound C1=C(F)C=C2C(C)(C)CNC2=C1 OJVRHJFNQKFPBY-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 102100036242 HLA class II histocompatibility antigen, DQ alpha 2 chain Human genes 0.000 description 3
- 101000930801 Homo sapiens HLA class II histocompatibility antigen, DQ alpha 2 chain Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- VZSXFJPZOCRDPW-UHFFFAOYSA-N carbanide;trioxorhenium Chemical compound [CH3-].O=[Re](=O)=O VZSXFJPZOCRDPW-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 125000005394 methallyl group Chemical group 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- XEBLJTLDGGRUAV-QMMMGPOBSA-N (2s)-1-(5-fluoro-2,3-dihydroindol-1-yl)propan-2-amine Chemical compound FC1=CC=C2N(C[C@@H](N)C)CCC2=C1 XEBLJTLDGGRUAV-QMMMGPOBSA-N 0.000 description 2
- HURBVFYCLCMKGU-NSHDSACASA-N (2s)-2-cyclopropyl-2-(phenylmethoxycarbonylamino)acetic acid Chemical compound N([C@H](C(=O)O)C1CC1)C(=O)OCC1=CC=CC=C1 HURBVFYCLCMKGU-NSHDSACASA-N 0.000 description 2
- YIYPWNWZNQEQKQ-JTQLQIEISA-N (2s)-4,4-dimethyl-1-morpholin-4-ylpentan-2-ol Chemical compound CC(C)(C)C[C@H](O)CN1CCOCC1 YIYPWNWZNQEQKQ-JTQLQIEISA-N 0.000 description 2
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IPRDZAMUYMOJTA-UHFFFAOYSA-N 5,6-dichloro-1h-benzimidazole Chemical compound C1=C(Cl)C(Cl)=CC2=C1NC=N2 IPRDZAMUYMOJTA-UHFFFAOYSA-N 0.000 description 2
- GKODDAXOSGGARJ-UHFFFAOYSA-N 5-Fluoroisatin Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1 GKODDAXOSGGARJ-UHFFFAOYSA-N 0.000 description 2
- OEHMYBRRXREOEP-UHFFFAOYSA-N 5-fluoro-1-[(4-methoxyphenyl)methyl]indole-2,3-dione Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=C(F)C=C2C(=O)C1=O OEHMYBRRXREOEP-UHFFFAOYSA-N 0.000 description 2
- DJEBQSLSHBSJGM-UHFFFAOYSA-N 5-fluoro-2,2-dimethyl-1,3-dihydroindole Chemical compound FC1=CC=C2NC(C)(C)CC2=C1 DJEBQSLSHBSJGM-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 0 CC=Cc1c(C=C)nc[n]1CC(*)OC(NC(*)CN(*)c1ccccc1)=O Chemical compound CC=Cc1c(C=C)nc[n]1CC(*)OC(NC(*)CN(*)c1ccccc1)=O 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 201000011152 Pemphigus Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- GMTFZFRIEGEBKM-KRWDZBQOSA-N [(2s)-1-cyclopentyl-3-(5,6-dichlorobenzimidazol-1-yl)propan-2-yl] (4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)O[C@H](CN1C2=CC(Cl)=C(Cl)C=C2N=C1)CC1CCCC1 GMTFZFRIEGEBKM-KRWDZBQOSA-N 0.000 description 2
- WJTGGDVYAVMJLD-LBPRGKRZSA-N [(2s)-2-hydroxy-4,4-dimethylpentyl] 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OC[C@@H](O)CC(C)(C)C)C=C1 WJTGGDVYAVMJLD-LBPRGKRZSA-N 0.000 description 2
- SELGXKCPHZBFLY-FQEVSTJZSA-N [(2s)-3-cyclopentyl-2-hydroxypropyl] 2,4,6-tri(propan-2-yl)benzenesulfonate Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1S(=O)(=O)OC[C@@H](O)CC1CCCC1 SELGXKCPHZBFLY-FQEVSTJZSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 2
- DTIFZLWYMOFWRD-HXUWFJFHSA-N benzyl n-[(1s)-1-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2h-indol-1-yl)ethyl]carbamate Chemical compound N([C@H](CN1CC(C2=CC(F)=CC=C21)(C)C)C1CC1)C(=O)OCC1=CC=CC=C1 DTIFZLWYMOFWRD-HXUWFJFHSA-N 0.000 description 2
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 201000001976 pemphigus vulgaris Diseases 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- VELAOFLNAYZVNM-NSHDSACASA-N tert-butyl n-[(2s)-1-(4-methoxyanilino)propan-2-yl]carbamate Chemical compound COC1=CC=C(NC[C@H](C)NC(=O)OC(C)(C)C)C=C1 VELAOFLNAYZVNM-NSHDSACASA-N 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- FHLXUWOHGKLDNF-UHFFFAOYSA-N (2-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=CC=C1OC(Cl)=O FHLXUWOHGKLDNF-UHFFFAOYSA-N 0.000 description 1
- OHTDSWNCIOQBAU-OAHLLOKOSA-N (2r)-1-n-(4-methoxyphenyl)-3-phenylmethoxypropane-1,2-diamine Chemical compound C1=CC(OC)=CC=C1NC[C@@H](N)COCC1=CC=CC=C1 OHTDSWNCIOQBAU-OAHLLOKOSA-N 0.000 description 1
- FXNKFCYDTZQSSP-NSHDSACASA-N (2s)-1-cyclopentyl-3-(5,6-dichlorobenzimidazol-1-yl)propan-2-ol Chemical compound C([C@H](O)CN1C2=CC(Cl)=C(Cl)C=C2N=C1)C1CCCC1 FXNKFCYDTZQSSP-NSHDSACASA-N 0.000 description 1
- BSYPFMFKYAMTDV-QMMMGPOBSA-N (2s)-1-n-(4-methoxyphenyl)propane-1,2-diamine Chemical compound COC1=CC=C(NC[C@H](C)N)C=C1 BSYPFMFKYAMTDV-QMMMGPOBSA-N 0.000 description 1
- OCXXYKJHUOYVLB-ZETCQYMHSA-N (2s)-1-n-[4-(trifluoromethoxy)phenyl]propane-1,2-diamine Chemical compound C[C@H](N)CNC1=CC=C(OC(F)(F)F)C=C1 OCXXYKJHUOYVLB-ZETCQYMHSA-N 0.000 description 1
- 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 1
- OPBFFNZNNJKRCS-YFKPBYRVSA-N (2s)-2-hydroxy-4,4-dimethylpentanoic acid Chemical compound CC(C)(C)C[C@H](O)C(O)=O OPBFFNZNNJKRCS-YFKPBYRVSA-N 0.000 description 1
- LOVPHSMOAVXQIH-UHFFFAOYSA-N (4-nitrophenyl) hydrogen carbonate Chemical compound OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 LOVPHSMOAVXQIH-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XKGUVOKVGSKKPB-UHFFFAOYSA-N 1-(5,6-dichlorobenzimidazol-1-yl)-3,3-dimethylbutan-2-ol Chemical compound ClC1=C(Cl)C=C2N(CC(O)C(C)(C)C)C=NC2=C1 XKGUVOKVGSKKPB-UHFFFAOYSA-N 0.000 description 1
- KYGFNKDGKFAUOI-UHFFFAOYSA-N 1-(5,6-dichlorobenzimidazol-1-yl)-4,4-dimethylpentan-2-ol Chemical compound ClC1=C(Cl)C=C2N(CC(O)CC(C)(C)C)C=NC2=C1 KYGFNKDGKFAUOI-UHFFFAOYSA-N 0.000 description 1
- WVAJJQJALCRFQE-UHFFFAOYSA-N 1-(5-fluoro-3,3-dimethyl-2h-indol-1-yl)ethanone Chemical compound FC1=CC=C2N(C(=O)C)CC(C)(C)C2=C1 WVAJJQJALCRFQE-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- ZULAIBFNHAWBFC-UHFFFAOYSA-N 2,2,5-trifluoro-1,3-dihydroindole Chemical compound FC1=CC=C2NC(F)(F)CC2=C1 ZULAIBFNHAWBFC-UHFFFAOYSA-N 0.000 description 1
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 description 1
- OWIRVNDMYDSKIJ-UHFFFAOYSA-N 2,4-dichloro-1h-benzimidazole Chemical compound C1=CC=C2NC(Cl)=NC2=C1Cl OWIRVNDMYDSKIJ-UHFFFAOYSA-N 0.000 description 1
- JFNMDOCPBNQNQR-UHFFFAOYSA-N 2-(2,2-dimethylpropyl)oxirane Chemical compound CC(C)(C)CC1CO1 JFNMDOCPBNQNQR-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- SHDZTIZBSYDZSH-UHFFFAOYSA-N 2-methylprop-2-enoyl bromide Chemical compound CC(=C)C(Br)=O SHDZTIZBSYDZSH-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- HEAYDCIZOFDHRM-UHFFFAOYSA-N 2-tert-butyloxirane Chemical compound CC(C)(C)C1CO1 HEAYDCIZOFDHRM-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KLCNJIQZXOQYTE-UHFFFAOYSA-N 4,4-dimethylpent-1-ene Chemical compound CC(C)(C)CC=C KLCNJIQZXOQYTE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZDOAFGXOSHMUPG-UHFFFAOYSA-N 5-fluoro-1-[(4-methoxyphenyl)methyl]-3h-indol-2-one Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=C(F)C=C2CC1=O ZDOAFGXOSHMUPG-UHFFFAOYSA-N 0.000 description 1
- UCHMQTCHORUDPS-UHFFFAOYSA-N 5-fluoro-1-[(4-methoxyphenyl)methyl]indole Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=C(F)C=C2C=C1 UCHMQTCHORUDPS-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 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 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108010059081 Cathepsin A Proteins 0.000 description 1
- 102000005572 Cathepsin A Human genes 0.000 description 1
- 108090000267 Cathepsin C Proteins 0.000 description 1
- 108090000258 Cathepsin D Proteins 0.000 description 1
- 108090000611 Cathepsin E Proteins 0.000 description 1
- 108090000610 Cathepsin F Proteins 0.000 description 1
- 108090000617 Cathepsin G Proteins 0.000 description 1
- 108090000619 Cathepsin H Proteins 0.000 description 1
- 101710177066 Cathepsin O Proteins 0.000 description 1
- 108010061112 Cathepsin W Proteins 0.000 description 1
- 108010061117 Cathepsin Z Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 229940126062 Compound A Drugs 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
- 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 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108700033168 EC 3.4.22.28 Proteins 0.000 description 1
- 206010052369 Encephalitis lethargica Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 101000983577 Homo sapiens Cathepsin L2 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 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 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- SZXCCZSGYSSSKJ-KGFAMACYSA-N O=C[C@H](C)NC(=O)OC(C)(C)C.COC1=CC=C(NC[C@H](C)NC(=O)OC(C)(C)C)C=C1 Chemical compound O=C[C@H](C)NC(=O)OC(C)(C)C.COC1=CC=C(NC[C@H](C)NC(=O)OC(C)(C)C)C=C1 SZXCCZSGYSSSKJ-KGFAMACYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical group CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- CHVLPNFLAWFPJA-RXMQYKEDSA-N [(1S)-1-cyclopropyl-2-hydroxyethyl]carbamic acid Chemical compound C1(CC1)[C@@H](CO)NC(O)=O CHVLPNFLAWFPJA-RXMQYKEDSA-N 0.000 description 1
- ZQROPWIHTQRJCS-IBGZPJMESA-N [(2s)-1-(benzimidazol-1-yl)-3-cyclopentylpropan-2-yl] (4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)O[C@H](CN1C2=CC=CC=C2N=C1)CC1CCCC1 ZQROPWIHTQRJCS-IBGZPJMESA-N 0.000 description 1
- KVBPGJCSZPTNED-UHFFFAOYSA-N [1-(5,6-dichlorobenzimidazol-1-yl)-4,4-dimethylpentan-2-yl] (4-nitrophenyl) carbonate Chemical compound C1=NC2=CC(Cl)=C(Cl)C=C2N1CC(CC(C)(C)C)OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 KVBPGJCSZPTNED-UHFFFAOYSA-N 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- NHIDGVQVYHCGEK-UHFFFAOYSA-N allylcyclopentane Chemical compound C=CCC1CCCC1 NHIDGVQVYHCGEK-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000006256 asymmetric dihydroxylation reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001715 carbamic acids Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001727 carbonic acid monoesters Chemical class 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 108010015596 cathepsin J Proteins 0.000 description 1
- 108010015569 cathepsin M Proteins 0.000 description 1
- 108010015561 cathepsin Q Proteins 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- CTTMWKWOBDZOJW-VIFPVBQESA-N n-[(2s)-1-hydroxypropan-2-yl]-2-phenylacetamide Chemical compound OC[C@H](C)NC(=O)CC1=CC=CC=C1 CTTMWKWOBDZOJW-VIFPVBQESA-N 0.000 description 1
- ZLDFVJVAOZOHKB-VIFPVBQESA-N n-[(2s)-1-oxopropan-2-yl]-2-phenylacetamide Chemical compound O=C[C@H](C)NC(=O)CC1=CC=CC=C1 ZLDFVJVAOZOHKB-VIFPVBQESA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000000269 nucleophilic effect 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
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002924 oxiranes Chemical group 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108010009405 ribosomal neutral proteinase Proteins 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- OJVWNENFSPSLRB-UHFFFAOYSA-N tert-butyl n-(4-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(F)C=C1 OJVWNENFSPSLRB-UHFFFAOYSA-N 0.000 description 1
- XXNCCQDANJNGLP-HXUWFJFHSA-N tert-butyl n-[(2r)-1-(5-fluoro-2,3-dihydroindol-1-yl)-3-phenylmethoxypropan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)CN1C2=CC=C(F)C=C2CC1)OCC1=CC=CC=C1 XXNCCQDANJNGLP-HXUWFJFHSA-N 0.000 description 1
- PDAFIZPRSXHMCO-LURJTMIESA-N tert-butyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-LURJTMIESA-N 0.000 description 1
- OEQRZPWMXXJEKU-LURJTMIESA-N tert-butyl n-[(2s)-1-oxopropan-2-yl]carbamate Chemical compound O=C[C@H](C)NC(=O)OC(C)(C)C OEQRZPWMXXJEKU-LURJTMIESA-N 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical class OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P25/28—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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49685803P | 2003-08-20 | 2003-08-20 | |
| US10/922,362 US7256207B2 (en) | 2003-08-20 | 2004-08-18 | Inhibitors of cathepsin S |
| PCT/US2004/027316 WO2005018568A2 (en) | 2003-08-20 | 2004-08-19 | Inhibitors of cathepsin s |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2007502844A true JP2007502844A (ja) | 2007-02-15 |
| JP2007502844A5 JP2007502844A5 (https=) | 2007-10-04 |
Family
ID=34221426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006524107A Pending JP2007502844A (ja) | 2003-08-20 | 2004-08-19 | カテプシンｓの阻害剤 |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US7256207B2 (https=) |
| EP (1) | EP1658274A4 (https=) |
| JP (1) | JP2007502844A (https=) |
| AU (1) | AU2004266151B2 (https=) |
| BR (1) | BRPI0413755A (https=) |
| CA (1) | CA2534489A1 (https=) |
| MX (1) | MXPA06001888A (https=) |
| WO (1) | WO2005018568A2 (https=) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013513569A (ja) * | 2009-12-11 | 2013-04-22 | エフ．ホフマン−ラ ロシュ アーゲー | Ａｍｐｋモジュレーターとして有用なスピロインドール−シクロプロパンインドリノン |
| JP2022518054A (ja) * | 2019-01-22 | 2022-03-11 | アドヴェリオ・ファーマ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | ４－（２，２，３，３－テトラフルオロプロピル）モルホリンを製造する方法 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7256207B2 (en) * | 2003-08-20 | 2007-08-14 | Irm Llc | Inhibitors of cathepsin S |
| TWI389897B (zh) | 2005-02-22 | 2013-03-21 | Chugai Pharmaceutical Co Ltd | 1- (2H) -isoquinolinone derivatives |
| US7751835B2 (en) * | 2005-10-04 | 2010-07-06 | Airvana, Inc. | Non-circular paging areas |
| GB2476823B (en) | 2010-01-11 | 2012-05-02 | Subsea 7 Contracting Uk Ltd | Improvements relating to abandonment and recovery of pipelines |
| WO2020201572A1 (en) | 2019-04-05 | 2020-10-08 | Université De Bretagne Occidentale | Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001068591A1 (en) * | 2000-03-16 | 2001-09-20 | F. Hoffmann-La Roche Ag | Carboxylic acid derivatives as ip antagonists |
| WO2002070517A2 (en) * | 2001-03-02 | 2002-09-12 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
| WO2003031437A1 (en) * | 2001-10-09 | 2003-04-17 | Smithkline Beecham Corporation | Propylcarbamate derivatives as inhibitors of serine and cysteine proteases |
Family Cites Families (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4499295A (en) * | 1983-05-09 | 1985-02-12 | G. D. Searle & Co. | Protease inhibitors |
| US5374623A (en) * | 1992-08-20 | 1994-12-20 | Prototek, Inc. | Cysteine protease inhibitors effective for in vivo use |
| EP0648740B1 (en) * | 1993-04-28 | 1997-10-08 | Kumiai Chemical Industry Co., Ltd. | Amino acid amide derivative, agrohorticultural bactericide, and production process |
| US5648514A (en) | 1994-12-29 | 1997-07-15 | Allergan | Substituted acetylenes having retinoid-like biological activity |
| US5691368A (en) * | 1995-01-11 | 1997-11-25 | Hoechst Marion Roussel, Inc. | Substituted oxazolidine calpain and/or cathepsin B inhibitors |
| US5849711A (en) * | 1995-06-06 | 1998-12-15 | Athena Neurosciences, Inc. | Cathepsin and methods and compositions for inhibition thereof |
| TW438591B (en) * | 1995-06-07 | 2001-06-07 | Arris Pharm Corp | Reversible cysteine protease inhibitors |
| SK48198A3 (en) * | 1995-10-30 | 1998-10-07 | Smithkline Beecham Corp | Cathepsin k molecule, a peptid being bonded to the hollow of active positon of cathepsin k, a composition, method for identification of inhibiting compound and inhibitors being competitively bonded to the active position of cathepsin k |
| WO1997016433A1 (en) * | 1995-10-30 | 1997-05-09 | Smithkline Beecham Corporation | Protease inhibitors |
| DE19610784A1 (de) * | 1996-03-19 | 1997-09-25 | Hoechst Ag | Fluoralkyl- und Fluoralkoxysubstituierte heterocyclische Bradykinin-Antagonisten, Verfahren zu ihrer Herstellung und ihre Verwendung |
| US5840733A (en) | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| US5916887A (en) * | 1996-09-23 | 1999-06-29 | National Research Council Of Canada | 4-substituted-3-(2-amino-2-cycloalkyl methyl)-acetamido azetidin-2-one derivatives as cysteine proteinase regulators |
| US6004933A (en) * | 1997-04-25 | 1999-12-21 | Cortech Inc. | Cysteine protease inhibitors |
| TR199902752T2 (xx) * | 1997-05-08 | 2000-06-21 | Smithkline Beecham Corporation | Proteaz inhibit�rleri. |
| GB9723407D0 (en) * | 1997-11-05 | 1998-01-07 | Ciba Geigy Ag | Organic compounds |
| GB9903548D0 (en) | 1999-02-16 | 1999-04-07 | Novartis Ag | Organic compounds |
| EP1159273A1 (en) * | 1999-03-02 | 2001-12-05 | Boehringer Ingelheim Pharmaceuticals Inc. | Compounds useful as reversible inhibitors of cathepsin s |
| DE60021254T2 (de) * | 1999-03-15 | 2006-04-20 | AXYS Pharmaceuticals, Inc., South San Francisco | N-cyanomethylamide als protease inhibitoren |
| CA2379747C (en) * | 1999-07-30 | 2008-09-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Novel succinate derivative compounds useful as cysteine protease inhibitors |
| US6420364B1 (en) * | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| ES2199856T3 (es) | 1999-09-13 | 2004-03-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | Nuevos compuestos heterociclicos, utiles como inhibidores reversibles de cisteina proteasas. |
| EP1309591B1 (en) | 2000-08-14 | 2007-01-24 | Ortho-McNeil Pharmaceutical, Inc. | Substituted pyrazoles |
| EP1309593B1 (en) | 2000-08-14 | 2006-03-15 | Ortho-McNeil Pharmaceutical, Inc. | Substituted pyrazoles |
| HK1052705B (en) | 2000-08-14 | 2006-09-29 | Ortho-Mcneil Pharmaceutical, Inc. | Substituted pyrazole |
| MXPA03005601A (es) | 2000-12-22 | 2004-12-02 | Axys Pharm Inc | Nuevos compuestos y composiciones como inhibidores de catepsina. |
| CA2439415C (en) | 2001-03-02 | 2011-09-20 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
| WO2002070519A1 (en) | 2001-03-05 | 2002-09-12 | Axys Pharmaceuticals, Inc. | Monobactams as cathepsin k inhibitors |
| EP1411933A1 (en) | 2001-08-03 | 2004-04-28 | SmithKline Beecham Corporation | Alpha-ketoamide derivatives as cathepsin k inhibitors |
| US20030144234A1 (en) | 2001-08-30 | 2003-07-31 | Buxton Francis Paul | Methods for the treatment of chronic pain and compositions therefor |
| US7101880B2 (en) * | 2002-06-24 | 2006-09-05 | Schering Aktiengesellschaft | Peptidic compounds as cysteine protease inhibitors |
| US7256207B2 (en) * | 2003-08-20 | 2007-08-14 | Irm Llc | Inhibitors of cathepsin S |
-
2004
- 2004-08-18 US US10/922,362 patent/US7256207B2/en not_active Expired - Fee Related
- 2004-08-19 BR BRPI0413755-8A patent/BRPI0413755A/pt not_active IP Right Cessation
- 2004-08-19 CA CA002534489A patent/CA2534489A1/en not_active Abandoned
- 2004-08-19 JP JP2006524107A patent/JP2007502844A/ja active Pending
- 2004-08-19 EP EP04781915A patent/EP1658274A4/en not_active Withdrawn
- 2004-08-19 MX MXPA06001888A patent/MXPA06001888A/es active IP Right Grant
- 2004-08-19 AU AU2004266151A patent/AU2004266151B2/en not_active Ceased
- 2004-08-19 WO PCT/US2004/027316 patent/WO2005018568A2/en not_active Ceased
-
2007
- 2007-07-13 US US11/777,879 patent/US7507755B2/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001068591A1 (en) * | 2000-03-16 | 2001-09-20 | F. Hoffmann-La Roche Ag | Carboxylic acid derivatives as ip antagonists |
| WO2002070517A2 (en) * | 2001-03-02 | 2002-09-12 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
| WO2003031437A1 (en) * | 2001-10-09 | 2003-04-17 | Smithkline Beecham Corporation | Propylcarbamate derivatives as inhibitors of serine and cysteine proteases |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013513569A (ja) * | 2009-12-11 | 2013-04-22 | エフ．ホフマン−ラ ロシュ アーゲー | Ａｍｐｋモジュレーターとして有用なスピロインドール−シクロプロパンインドリノン |
| JP2022518054A (ja) * | 2019-01-22 | 2022-03-11 | アドヴェリオ・ファーマ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | ４－（２，２，３，３－テトラフルオロプロピル）モルホリンを製造する方法 |
| JP7471306B2 (ja) | 2019-01-22 | 2024-04-19 | アドヴェリオ・ファーマ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | ４－（２，２，３，３－テトラフルオロプロピル）モルホリンを製造する方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US7256207B2 (en) | 2007-08-14 |
| US7507755B2 (en) | 2009-03-24 |
| CA2534489A1 (en) | 2005-03-03 |
| AU2004266151B2 (en) | 2007-08-02 |
| EP1658274A4 (en) | 2008-11-12 |
| WO2005018568A2 (en) | 2005-03-03 |
| EP1658274A2 (en) | 2006-05-24 |
| US20050107368A1 (en) | 2005-05-19 |
| US20070259873A1 (en) | 2007-11-08 |
| AU2004266151A1 (en) | 2005-03-03 |
| WO2005018568A3 (en) | 2005-09-09 |
| BRPI0413755A (pt) | 2006-10-31 |
| MXPA06001888A (es) | 2006-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW542839B (en) | Bicyclic hydroxamic acid derivatives | |
| AU687558B2 (en) | Substituted sulfonamides as selective beta 3 agonists for the treatment of diabetes and obesity | |
| AU670477B2 (en) | Substituted phenyl sulfonamides as selective Beta3 agonists for the treatment of diabetes and obesity | |
| AU2003297398B2 (en) | Asthma and allergic inflammation modulators | |
| EP2057115B1 (en) | 4-substituted phenoxyphenylacetic acid derivatives | |
| AU2006320621A1 (en) | Compounds for the treatment of inflammatory disorders and microbial diseases | |
| US20040110767A1 (en) | Acyclic amide and sulfonamide ligands for the estrogen receptor | |
| US7507755B2 (en) | Inhibitors of cathepsin s | |
| EP2141147A1 (en) | Ornithine derivative | |
| JP2007522233A (ja) | バニロイド受容体リガンド及び治療におけるそれらの使用 | |
| US7307095B2 (en) | Inhibitors of cathepsin S | |
| US7732449B2 (en) | Inhibitors of cathepsin S | |
| US20080242671A1 (en) | Inhibitors of cathepsin s | |
| KR20080010426A (ko) | 불임 치료용 약제로서의4-페닐-5-옥소-1,4,5,6,7,8-헥사하이드로퀴놀린 유도체 | |
| JP2007527411A (ja) | カテプシンｓの阻害剤 | |
| CN100398522C (zh) | 组织蛋白酶s的抑制剂 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070816 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20070816 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100818 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100824 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20110201 |