CA2516786A1

CA2516786A1 - Treatment of excessive osteolyisis with indolinone compounds

Treatment of excessive osteolyisis with indolinone compounds Download PDF

Info

Publication number: CA2516786A1
Authority: CA; Canada
Prior art keywords: group; alkyl; heteroaryl; aryl; compound
Prior art date: 2003-02-24
Legal status : Abandoned

Application number

CA002516786A

Other languages

English (en)

French (fr)

Inventor

Lesley Murray

Anne-Marie O'farrell

Tinya Abrams

Current Assignee

Sugen LLC

Original Assignee

Individual

Priority date

2003-02-24

Filing date

2004-02-23

Publication date

2004-09-10

2004-02-23 Application filed by Individual filed Critical Individual

2004-09-10 Publication of CA2516786A1 publication Critical patent/CA2516786A1/en

Status Abandoned legal-status Critical Current

Links

238000011282 treatment Methods 0.000 title description 13
JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title description 7
150000001875 compounds Chemical class 0.000 claims abstract description 114
206010028980 Neoplasm Diseases 0.000 claims abstract description 47
208000003076 Osteolysis Diseases 0.000 claims abstract description 33
208000029791 lytic metastatic bone lesion Diseases 0.000 claims abstract description 33
101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims abstract description 19
102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims abstract description 19
102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims abstract description 11
108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims abstract description 11
230000002401 inhibitory effect Effects 0.000 claims abstract description 10
230000026731 phosphorylation Effects 0.000 claims abstract description 10
238000006366 phosphorylation reaction Methods 0.000 claims abstract description 10
125000000217 alkyl group Chemical group 0.000 claims description 105
238000000034 method Methods 0.000 claims description 63
125000003118 aryl group Chemical group 0.000 claims description 56
125000001072 heteroaryl group Chemical group 0.000 claims description 52
125000003545 alkoxy group Chemical group 0.000 claims description 47
125000000623 heterocyclic group Chemical group 0.000 claims description 43
125000000753 cycloalkyl group Chemical group 0.000 claims description 40
-1 amino, monosubstituted amino Chemical group 0.000 claims description 35
210000000988 bone and bone Anatomy 0.000 claims description 30
229910052757 nitrogen Inorganic materials 0.000 claims description 29
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 26
201000011510 cancer Diseases 0.000 claims description 25
229910052739 hydrogen Inorganic materials 0.000 claims description 24
229910052760 oxygen Inorganic materials 0.000 claims description 24
150000003839 salts Chemical class 0.000 claims description 21
229910052717 sulfur Inorganic materials 0.000 claims description 21
239000001257 hydrogen Substances 0.000 claims description 20
229910052799 carbon Inorganic materials 0.000 claims description 19
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
125000006413 ring segment Chemical group 0.000 claims description 13
230000005764 inhibitory process Effects 0.000 claims description 10
125000001188 haloalkyl group Chemical group 0.000 claims description 9
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
208000001132 Osteoporosis Diseases 0.000 claims description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
125000004438 haloalkoxy group Chemical group 0.000 claims description 4
125000004103 aminoalkyl group Chemical group 0.000 claims description 3
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
125000001475 halogen functional group Chemical group 0.000 claims 3
210000002997 osteoclast Anatomy 0.000 abstract description 26
238000011161 development Methods 0.000 abstract description 13
230000001404 mediated effect Effects 0.000 abstract description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 73
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
239000000203 mixture Substances 0.000 description 64
239000007787 solid Substances 0.000 description 45
239000000243 solution Substances 0.000 description 43
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
125000005843 halogen group Chemical group 0.000 description 35
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
238000005160 1H NMR spectroscopy Methods 0.000 description 31
229940125904 compound 1 Drugs 0.000 description 29
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
210000004027 cell Anatomy 0.000 description 27
125000002887 hydroxy group Chemical group [H]O* 0.000 description 27
230000015572 biosynthetic process Effects 0.000 description 26
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
238000003786 synthesis reaction Methods 0.000 description 25
241000699670 Mus sp. Species 0.000 description 24
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 24
239000011541 reaction mixture Substances 0.000 description 24
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
238000006243 chemical reaction Methods 0.000 description 23
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
239000002775 capsule Substances 0.000 description 18
206010006187 Breast cancer Diseases 0.000 description 17
208000026310 Breast neoplasm Diseases 0.000 description 17
230000000694 effects Effects 0.000 description 16
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
239000008194 pharmaceutical composition Substances 0.000 description 15
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
125000004432 carbon atom Chemical group C* 0.000 description 14
125000001424 substituent group Chemical group 0.000 description 14
KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 13
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
239000000047 product Substances 0.000 description 13
239000002904 solvent Substances 0.000 description 13
238000003756 stirring Methods 0.000 description 13
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 12
230000018109 developmental process Effects 0.000 description 12
238000003828 vacuum filtration Methods 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 11
239000003814 drug Substances 0.000 description 11
238000009472 formulation Methods 0.000 description 11
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
206010027476 Metastases Diseases 0.000 description 10
125000004093 cyano group Chemical group *C#N 0.000 description 10
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
LCYXYLLJXMAEMT-SAXRGWBVSA-N Pyridinoline Chemical compound OC(=O)[C@@H](N)CCC1=C[N+](C[C@H](O)CC[C@H](N)C([O-])=O)=CC(O)=C1C[C@H](N)C(O)=O LCYXYLLJXMAEMT-SAXRGWBVSA-N 0.000 description 9
229940079593 drug Drugs 0.000 description 9
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 9
230000000010 osteolytic effect Effects 0.000 description 9
239000000651 prodrug Substances 0.000 description 9
229940002612 prodrug Drugs 0.000 description 9
239000000126 substance Substances 0.000 description 9
238000002560 therapeutic procedure Methods 0.000 description 9
125000004385 trihaloalkyl group Chemical group 0.000 description 9
239000003981 vehicle Substances 0.000 description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
125000002252 acyl group Chemical group 0.000 description 8
150000001299 aldehydes Chemical class 0.000 description 8
239000002585 base Substances 0.000 description 8
239000003795 chemical substances by application Substances 0.000 description 8
238000001727 in vivo Methods 0.000 description 8
230000009401 metastasis Effects 0.000 description 8
125000004433 nitrogen atom Chemical group N* 0.000 description 8
239000000546 pharmaceutical excipient Substances 0.000 description 8
239000012071 phase Substances 0.000 description 8
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
230000008569 process Effects 0.000 description 8
210000002966 serum Anatomy 0.000 description 8
RBHBOUYXUXWCNJ-WDZFZDKYSA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxylic acid Chemical group OC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C RBHBOUYXUXWCNJ-WDZFZDKYSA-N 0.000 description 7
DDIIYGHHUMKDGI-UHFFFAOYSA-N 5-fluoro-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1 DDIIYGHHUMKDGI-UHFFFAOYSA-N 0.000 description 7
108010010803 Gelatin Proteins 0.000 description 7
206010027452 Metastases to bone Diseases 0.000 description 7
239000011575 calcium Substances 0.000 description 7
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
229920000159 gelatin Polymers 0.000 description 7
239000008273 gelatin Substances 0.000 description 7
235000019322 gelatine Nutrition 0.000 description 7
235000011852 gelatine desserts Nutrition 0.000 description 7
230000012010 growth Effects 0.000 description 7
125000005842 heteroatom Chemical group 0.000 description 7
239000000463 material Substances 0.000 description 7
239000001301 oxygen Chemical group 0.000 description 7
230000004614 tumor growth Effects 0.000 description 7
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
YSGPOQDTHDLUGE-UHFFFAOYSA-N 1-amino-3-morpholin-4-ylpropan-2-ol Chemical compound NCC(O)CN1CCOCC1 YSGPOQDTHDLUGE-UHFFFAOYSA-N 0.000 description 6
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
229920002472 Starch Polymers 0.000 description 6
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
239000002253 acid Substances 0.000 description 6
229910021529 ammonia Inorganic materials 0.000 description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
230000029918 bioluminescence Effects 0.000 description 6
238000005415 bioluminescence Methods 0.000 description 6
239000006184 cosolvent Substances 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
150000002431 hydrogen Chemical class 0.000 description 6
239000007788 liquid Substances 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
239000003921 oil Substances 0.000 description 6
235000019198 oils Nutrition 0.000 description 6
229920001223 polyethylene glycol Polymers 0.000 description 6
229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
108090000623 proteins and genes Proteins 0.000 description 6
239000002002 slurry Substances 0.000 description 6
PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 6
239000011593 sulfur Chemical group 0.000 description 6
239000000725 suspension Substances 0.000 description 6
238000004809 thin layer chromatography Methods 0.000 description 6
125000003441 thioacyl group Chemical group 0.000 description 6
229920002554 vinyl polymer Polymers 0.000 description 6
YYBXNWIRMJXEQJ-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine Chemical compound C1CNCCC1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 description 5
102000055006 Calcitonin Human genes 0.000 description 5
108060001064 Calcitonin Proteins 0.000 description 5
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 5
102000004190 Enzymes Human genes 0.000 description 5
108090000790 Enzymes Proteins 0.000 description 5
229930195725 Mannitol Natural products 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
241000021375 Xenogenes Species 0.000 description 5
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 5
229960004015 calcitonin Drugs 0.000 description 5
239000000460 chlorine Substances 0.000 description 5
229910052801 chlorine Inorganic materials 0.000 description 5
125000004663 dialkyl amino group Chemical group 0.000 description 5
201000010099 disease Diseases 0.000 description 5
238000001914 filtration Methods 0.000 description 5
229910052731 fluorine Inorganic materials 0.000 description 5
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
239000012458 free base Substances 0.000 description 5
230000002209 hydrophobic effect Effects 0.000 description 5
239000005457 ice water Substances 0.000 description 5
239000007924 injection Substances 0.000 description 5
238000002347 injection Methods 0.000 description 5
239000000594 mannitol Substances 0.000 description 5
235000010355 mannitol Nutrition 0.000 description 5
230000036470 plasma concentration Effects 0.000 description 5
239000001267 polyvinylpyrrolidone Substances 0.000 description 5
239000002243 precursor Substances 0.000 description 5
239000003586 protic polar solvent Substances 0.000 description 5
235000019698 starch Nutrition 0.000 description 5
235000000346 sugar Nutrition 0.000 description 5
125000000446 sulfanediyl group Chemical group *S* 0.000 description 5
229940124530 sulfonamide Drugs 0.000 description 5
210000004881 tumor cell Anatomy 0.000 description 5
GLHXYSFEVOAOSL-UHFFFAOYSA-N 4-(azetidin-3-yl)morpholine Chemical compound C1NCC1N1CCOCC1 GLHXYSFEVOAOSL-UHFFFAOYSA-N 0.000 description 4
GIARQKRMPGZBGK-ZDLGFXPLSA-N 5-[(z)-(5-chloro-2-oxo-1h-indol-3-ylidene)methyl]-n-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(Cl)=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1CCOCC1 GIARQKRMPGZBGK-ZDLGFXPLSA-N 0.000 description 4
YCIHQDVIAISDPS-UHFFFAOYSA-N 5-formyl-2,4-dimethyl-1h-pyrrole-3-carboxylic acid Chemical compound CC=1NC(C=O)=C(C)C=1C(O)=O YCIHQDVIAISDPS-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
229940122361 Bisphosphonate Drugs 0.000 description 4
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
102000004127 Cytokines Human genes 0.000 description 4
108090000695 Cytokines Proteins 0.000 description 4
BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
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 4
108060001084 Luciferase Proteins 0.000 description 4
239000005089 Luciferase Substances 0.000 description 4
WINHZLLDWRZWRT-UHFFFAOYSA-N N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(C=C2C3=CC(F)=CC=C3NC2=O)=C1C WINHZLLDWRZWRT-UHFFFAOYSA-N 0.000 description 4
MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
125000005631 S-sulfonamido group Chemical group 0.000 description 4
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
239000008186 active pharmaceutical agent Substances 0.000 description 4
229910052783 alkali metal Inorganic materials 0.000 description 4
150000001340 alkali metals Chemical class 0.000 description 4
238000003556 assay Methods 0.000 description 4
125000004429 atom Chemical group 0.000 description 4
150000004663 bisphosphonates Chemical class 0.000 description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
238000004113 cell culture Methods 0.000 description 4
239000012230 colorless oil Substances 0.000 description 4
239000012043 crude product Substances 0.000 description 4
239000008298 dragée Substances 0.000 description 4
GDISALBEIGGPER-UHFFFAOYSA-N ethyl 5-formyl-2,4-dimethyl-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C1=C(C)NC(C=O)=C1C GDISALBEIGGPER-UHFFFAOYSA-N 0.000 description 4
235000019439 ethyl acetate Nutrition 0.000 description 4
238000003384 imaging method Methods 0.000 description 4
239000002502 liposome Substances 0.000 description 4
LIZNIAKSBJKPQC-GDNBJRDFSA-N n-[2-(ethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CCNCCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LIZNIAKSBJKPQC-GDNBJRDFSA-N 0.000 description 4
229910000069 nitrogen hydride Inorganic materials 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
230000011164 ossification Effects 0.000 description 4
150000005623 oxindoles Chemical class 0.000 description 4
239000000843 powder Substances 0.000 description 4
238000002360 preparation method Methods 0.000 description 4
102000004169 proteins and genes Human genes 0.000 description 4
239000011734 sodium Substances 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
239000008107 starch Substances 0.000 description 4
150000008163 sugars Chemical class 0.000 description 4
125000004953 trihalomethyl group Chemical group 0.000 description 4
XLBBKEHLEPNMMF-SSUNCQRMSA-N 129038-42-2 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)[C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCC(O)=O)C1=CC=CC=C1 XLBBKEHLEPNMMF-SSUNCQRMSA-N 0.000 description 3
WYDSIWDKSUOWJN-UHFFFAOYSA-N 2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C WYDSIWDKSUOWJN-UHFFFAOYSA-N 0.000 description 3
GKODDAXOSGGARJ-UHFFFAOYSA-N 5-Fluoroisatin Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1 GKODDAXOSGGARJ-UHFFFAOYSA-N 0.000 description 3
DUZMXWSFRQJXBQ-UHFFFAOYSA-N 5-[(5-bromo-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(C=C2C3=CC(Br)=CC=C3NC2=O)=C1C DUZMXWSFRQJXBQ-UHFFFAOYSA-N 0.000 description 3
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 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
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 3
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 3
206010017076 Fracture Diseases 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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 3
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
241001529936 Murinae Species 0.000 description 3
241000699666 Mus <mouse, genus> Species 0.000 description 3
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
208000002193 Pain Diseases 0.000 description 3
239000002202 Polyethylene glycol Substances 0.000 description 3
102000014128 RANK Ligand Human genes 0.000 description 3
108010025832 RANK Ligand Proteins 0.000 description 3
239000012980 RPMI-1640 medium Substances 0.000 description 3
102100022919 Tartrate-resistant acid phosphatase type 5 Human genes 0.000 description 3
230000002378 acidificating effect Effects 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
150000001408 amides Chemical class 0.000 description 3
150000001412 amines Chemical class 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
125000005110 aryl thio group Chemical group 0.000 description 3
125000004104 aryloxy group Chemical group 0.000 description 3
210000000481 breast Anatomy 0.000 description 3
201000008275 breast carcinoma Diseases 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
229910052791 calcium Inorganic materials 0.000 description 3
238000003965 capillary gas chromatography Methods 0.000 description 3
239000000969 carrier Substances 0.000 description 3
239000001913 cellulose Substances 0.000 description 3
229920002678 cellulose Polymers 0.000 description 3
235000010980 cellulose Nutrition 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
229940125782 compound 2 Drugs 0.000 description 3
229940126214 compound 3 Drugs 0.000 description 3
238000001816 cooling Methods 0.000 description 3
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
108010025752 echistatin Proteins 0.000 description 3
239000000839 emulsion Substances 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
239000012091 fetal bovine serum Substances 0.000 description 3
239000000499 gel Substances 0.000 description 3
230000036541 health Effects 0.000 description 3
DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
229910000041 hydrogen chloride Inorganic materials 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
238000002513 implantation Methods 0.000 description 3
238000000338 in vitro Methods 0.000 description 3
239000004615 ingredient Substances 0.000 description 3
239000003112 inhibitor Substances 0.000 description 3
150000007529 inorganic bases Chemical class 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000010410 layer Substances 0.000 description 3
210000002540 macrophage Anatomy 0.000 description 3
239000011777 magnesium Substances 0.000 description 3
229910052749 magnesium Inorganic materials 0.000 description 3
210000004373 mandible Anatomy 0.000 description 3
BRZYBFNUINXZMJ-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(C=O)=C1C BRZYBFNUINXZMJ-UHFFFAOYSA-N 0.000 description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
125000004430 oxygen atom Chemical group O* 0.000 description 3
239000002953 phosphate buffered saline Substances 0.000 description 3
229920001184 polypeptide Polymers 0.000 description 3
229940069328 povidone Drugs 0.000 description 3
108090000765 processed proteins & peptides Proteins 0.000 description 3
102000004196 processed proteins & peptides Human genes 0.000 description 3
WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 3
229930002330 retinoic acid Natural products 0.000 description 3
239000000600 sorbitol Substances 0.000 description 3
239000003381 stabilizer Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
239000004094 surface-active agent Substances 0.000 description 3
238000013268 sustained release Methods 0.000 description 3
239000012730 sustained-release form Substances 0.000 description 3
230000009885 systemic effect Effects 0.000 description 3
239000003826 tablet Substances 0.000 description 3
238000012360 testing method Methods 0.000 description 3
210000001685 thyroid gland Anatomy 0.000 description 3
210000001519 tissue Anatomy 0.000 description 3
231100000419 toxicity Toxicity 0.000 description 3
230000001988 toxicity Effects 0.000 description 3
238000010792 warming Methods 0.000 description 3
BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 2
JXGVXCZADZNAMJ-LLVKDONJSA-N (2r)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-LLVKDONJSA-N 0.000 description 2
YSGPOQDTHDLUGE-ZETCQYMHSA-N (2s)-1-amino-3-morpholin-4-ylpropan-2-ol Chemical compound NC[C@H](O)CN1CCOCC1 YSGPOQDTHDLUGE-ZETCQYMHSA-N 0.000 description 2
BKBZTIOBCUISCB-OCAPTIKFSA-N (3s,5r)-4-(azetidin-3-yl)-3,5-dimethylmorpholine Chemical compound C[C@H]1COC[C@@H](C)N1C1CNC1 BKBZTIOBCUISCB-OCAPTIKFSA-N 0.000 description 2
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
JOQLZZBYKRJVBI-UHFFFAOYSA-N 1,3,4,5-tetrahydroindol-2-one Chemical compound C1=CCCC2=C1NC(=O)C2 JOQLZZBYKRJVBI-UHFFFAOYSA-N 0.000 description 2
VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
CJXJFSNESZDOGK-UHFFFAOYSA-N 2-o-tert-butyl 4-o-ethyl 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C(=O)OC(C)(C)C)=C1C CJXJFSNESZDOGK-UHFFFAOYSA-N 0.000 description 2
YGGZEPRGJLVRSE-UHFFFAOYSA-N 4-(1-benzylpiperidin-4-yl)morpholine Chemical compound C=1C=CC=CC=1CN(CC1)CCC1N1CCOCC1 YGGZEPRGJLVRSE-UHFFFAOYSA-N 0.000 description 2
KKWQCCPQBCHJBZ-UHFFFAOYSA-N 4-(oxiran-2-ylmethyl)morpholine Chemical compound C1COCCN1CC1CO1 KKWQCCPQBCHJBZ-UHFFFAOYSA-N 0.000 description 2
PSEPXBUKZMCICV-ZDLGFXPLSA-N 5-[(z)-(5-bromo-2-oxo-1h-indol-3-ylidene)methyl]-n-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(Br)=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1CCOCC1 PSEPXBUKZMCICV-ZDLGFXPLSA-N 0.000 description 2
CTNPALGJUAXMMC-ZDLGFXPLSA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-n-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1CCOCC1 CTNPALGJUAXMMC-ZDLGFXPLSA-N 0.000 description 2
KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 2
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
206010065687 Bone loss Diseases 0.000 description 2
101150041968 CDC13 gene Proteins 0.000 description 2
108010001789 Calcitonin Receptors Proteins 0.000 description 2
102100038520 Calcitonin receptor Human genes 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
102000008186 Collagen Human genes 0.000 description 2
108010035532 Collagen Proteins 0.000 description 2
208000032170 Congenital Abnormalities Diseases 0.000 description 2
IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 2
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
238000002965 ELISA Methods 0.000 description 2
BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
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 2
208000002250 Hematologic Neoplasms Diseases 0.000 description 2
241000282412 Homo Species 0.000 description 2
102000006992 Interferon-alpha Human genes 0.000 description 2
108010047761 Interferon-alpha Proteins 0.000 description 2
DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 2
206010025323 Lymphomas Diseases 0.000 description 2
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
CJKRXEBLWJVYJD-UHFFFAOYSA-N N,N'-diethylethylenediamine Chemical compound CCNCCNCC CJKRXEBLWJVYJD-UHFFFAOYSA-N 0.000 description 2
AXDLCFOOGCNDST-UHFFFAOYSA-N N-methyl-DL-tyrosine Natural products CNC(C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-UHFFFAOYSA-N 0.000 description 2
229910017974 NH40H Inorganic materials 0.000 description 2
PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 2
108700020796 Oncogene Proteins 0.000 description 2
241000283973 Oryctolagus cuniculus Species 0.000 description 2
206010033128 Ovarian cancer Diseases 0.000 description 2
206010061535 Ovarian neoplasm Diseases 0.000 description 2
229930012538 Paclitaxel Natural products 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
108091000080 Phosphotransferase Proteins 0.000 description 2
206010035226 Plasma cell myeloma Diseases 0.000 description 2
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
JGPZZSYBKMBVKX-OCAPTIKFSA-N [(2s)-pyrrolidin-2-yl]-[(2r)-pyrrolidin-2-yl]methanone Chemical compound O=C([C@H]1NCCC1)[C@H]1CCCN1 JGPZZSYBKMBVKX-OCAPTIKFSA-N 0.000 description 2
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 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
239000000443 aerosol Substances 0.000 description 2
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
238000010171 animal model Methods 0.000 description 2
239000000010 aprotic solvent Substances 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
230000008901 benefit Effects 0.000 description 2
230000004071 biological effect Effects 0.000 description 2
239000012267 brine Substances 0.000 description 2
239000000872 buffer Substances 0.000 description 2
229910000019 calcium carbonate Inorganic materials 0.000 description 2
AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
239000000920 calcium hydroxide Substances 0.000 description 2
229910001861 calcium hydroxide Inorganic materials 0.000 description 2
239000001506 calcium phosphate Substances 0.000 description 2
229910000389 calcium phosphate Inorganic materials 0.000 description 2
235000011010 calcium phosphates Nutrition 0.000 description 2
239000001569 carbon dioxide Substances 0.000 description 2
229960004424 carbon dioxide Drugs 0.000 description 2
229910002092 carbon dioxide Inorganic materials 0.000 description 2
239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
239000001768 carboxy methyl cellulose Substances 0.000 description 2
230000015556 catabolic process Effects 0.000 description 2
230000001413 cellular effect Effects 0.000 description 2
230000008859 change Effects 0.000 description 2
XENVCRGQTABGKY-ZHACJKMWSA-N chlorohydrin Chemical compound CC#CC#CC#CC#C\C=C\C(Cl)CO XENVCRGQTABGKY-ZHACJKMWSA-N 0.000 description 2
238000000576 coating method Methods 0.000 description 2
229920001436 collagen Polymers 0.000 description 2
230000036569 collagen breakdown Effects 0.000 description 2
238000004440 column chromatography Methods 0.000 description 2
238000009833 condensation Methods 0.000 description 2
230000005494 condensation Effects 0.000 description 2
239000013078 crystal Substances 0.000 description 2
LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
239000008121 dextrose Substances 0.000 description 2
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
230000004069 differentiation Effects 0.000 description 2
238000004821 distillation Methods 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
231100000673 dose–response relationship Toxicity 0.000 description 2
KOWWOODYPWDWOJ-LVBPXUMQSA-N elatine Chemical compound C([C@]12CN(C3[C@@]45OCO[C@]44[C@H]6[C@@H](OC)[C@@H]([C@H](C4)OC)C[C@H]6[C@@]3([C@@H]1[C@@H]5OC)[C@@H](OC)CC2)CC)OC(=O)C1=CC=CC=C1N1C(=O)CC(C)C1=O KOWWOODYPWDWOJ-LVBPXUMQSA-N 0.000 description 2
238000005516 engineering process Methods 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
229960005309 estradiol Drugs 0.000 description 2
229930182833 estradiol Natural products 0.000 description 2
229940011871 estrogen Drugs 0.000 description 2
239000000262 estrogen Substances 0.000 description 2
QWSFDUPEOPMXCV-UHFFFAOYSA-N ethyl 2,4-dimethyl-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C=1C(C)=CNC=1C QWSFDUPEOPMXCV-UHFFFAOYSA-N 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
239000010685 fatty oil Substances 0.000 description 2
239000000945 filler Substances 0.000 description 2
238000003818 flash chromatography Methods 0.000 description 2
239000011737 fluorine Substances 0.000 description 2
238000011010 flushing procedure Methods 0.000 description 2
239000007903 gelatin capsule Substances 0.000 description 2
239000008187 granular material Substances 0.000 description 2
239000003102 growth factor Substances 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
229910052500 inorganic mineral Inorganic materials 0.000 description 2
229910052740 iodine Inorganic materials 0.000 description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
210000005240 left ventricle Anatomy 0.000 description 2
230000000670 limiting effect Effects 0.000 description 2
231100000053 low toxicity Toxicity 0.000 description 2
210000004072 lung Anatomy 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
239000001630 malic acid Substances 0.000 description 2
238000005259 measurement Methods 0.000 description 2
238000010907 mechanical stirring Methods 0.000 description 2
239000002609 medium Substances 0.000 description 2
239000002207 metabolite Substances 0.000 description 2
235000010755 mineral Nutrition 0.000 description 2
239000011707 mineral Substances 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
125000002950 monocyclic group Chemical group 0.000 description 2
210000001616 monocyte Anatomy 0.000 description 2
201000000050 myeloid neoplasm Diseases 0.000 description 2
LDBADIHRPBFQIU-WQRHYEAKSA-N n-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1CCOCC1 LDBADIHRPBFQIU-WQRHYEAKSA-N 0.000 description 2
XNWSIADBVOKMGP-SXGWCWSVSA-N n-[2-hydroxy-3-(triazol-1-yl)propyl]-2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1C=CN=N1 XNWSIADBVOKMGP-SXGWCWSVSA-N 0.000 description 2
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
SBIDUCNDVPSWQT-UHFFFAOYSA-N n-ethyl-n-(oxiran-2-ylmethyl)ethanamine Chemical compound CCN(CC)CC1CO1 SBIDUCNDVPSWQT-UHFFFAOYSA-N 0.000 description 2
229960003753 nitric oxide Drugs 0.000 description 2
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
150000007530 organic bases Chemical class 0.000 description 2
239000003960 organic solvent Substances 0.000 description 2
AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
150000002924 oxiranes Chemical class 0.000 description 2
229960001592 paclitaxel Drugs 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
238000007911 parenteral administration Methods 0.000 description 2
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
239000000825 pharmaceutical preparation Substances 0.000 description 2
230000000144 pharmacologic 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
WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
102000020233 phosphotransferase Human genes 0.000 description 2
239000003880 polar aprotic solvent Substances 0.000 description 2
239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
229940068968 polysorbate 80 Drugs 0.000 description 2
229920000053 polysorbate 80 Polymers 0.000 description 2
239000011591 potassium Substances 0.000 description 2
229910052700 potassium Inorganic materials 0.000 description 2
FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
238000012545 processing Methods 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
210000002307 prostate Anatomy 0.000 description 2
238000000746 purification Methods 0.000 description 2
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
125000001453 quaternary ammonium group Chemical group 0.000 description 2
150000003254 radicals Chemical class 0.000 description 2
230000002829 reductive effect Effects 0.000 description 2
238000007634 remodeling Methods 0.000 description 2
239000011347 resin Substances 0.000 description 2
229920005989 resin Polymers 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
229920006395 saturated elastomer Polymers 0.000 description 2
239000000333 selective estrogen receptor modulator Substances 0.000 description 2
229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
239000000741 silica gel Substances 0.000 description 2
229910002027 silica gel Inorganic materials 0.000 description 2
229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
229910052938 sodium sulfate Inorganic materials 0.000 description 2
235000011152 sodium sulphate Nutrition 0.000 description 2
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
239000012258 stirred mixture Substances 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 2
229960005314 suramin Drugs 0.000 description 2
208000024891 symptom Diseases 0.000 description 2
239000000454 talc Substances 0.000 description 2
229910052623 talc Inorganic materials 0.000 description 2
235000012222 talc Nutrition 0.000 description 2
RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
230000001225 therapeutic effect Effects 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
210000000689 upper leg Anatomy 0.000 description 2
238000001262 western blot Methods 0.000 description 2
YSGPOQDTHDLUGE-SSDOTTSWSA-N (2r)-1-amino-3-morpholin-4-ylpropan-2-ol Chemical compound NC[C@@H](O)CN1CCOCC1 YSGPOQDTHDLUGE-SSDOTTSWSA-N 0.000 description 1
LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-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
MDKHWJFKHDRFFZ-OLQVQODUSA-N (3s,5r)-3,5-dimethylmorpholine Chemical compound C[C@H]1COC[C@@H](C)N1 MDKHWJFKHDRFFZ-OLQVQODUSA-N 0.000 description 1
DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
YLBWRMSQRFEIEB-SECBINFHSA-N 1-[[(2r)-pyrrolidin-2-yl]methyl]pyrrolidine Chemical compound C1CCCN1C[C@H]1CCCN1 YLBWRMSQRFEIEB-SECBINFHSA-N 0.000 description 1
YLBWRMSQRFEIEB-VIFPVBQESA-N 1-[[(2s)-pyrrolidin-2-yl]methyl]pyrrolidine Chemical compound C1CCCN1C[C@@H]1CCCN1 YLBWRMSQRFEIEB-VIFPVBQESA-N 0.000 description 1
AVORXWIYCOTNFE-UHFFFAOYSA-N 1-azabicyclo[1.1.0]butane Chemical compound C1N2CC21 AVORXWIYCOTNFE-UHFFFAOYSA-N 0.000 description 1
YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 1
FOZVXADQAHVUSV-UHFFFAOYSA-N 1-bromo-2-(2-bromoethoxy)ethane Chemical compound BrCCOCCBr FOZVXADQAHVUSV-UHFFFAOYSA-N 0.000 description 1
125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
INWIZUCMCGANRE-UHFFFAOYSA-N 1-chloro-3-(diethylamino)propan-2-ol Chemical compound CCN(CC)CC(O)CCl INWIZUCMCGANRE-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
UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
125000006017 1-propenyl group Chemical group 0.000 description 1
125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
238000004293 19F NMR spectroscopy Methods 0.000 description 1
MMMNUADWVKIOSS-UHFFFAOYSA-N 1H-imidazole oxolane Chemical compound C1CCOC1.c1c[nH]cn1 MMMNUADWVKIOSS-UHFFFAOYSA-N 0.000 description 1
NMIZONYLXCOHEF-UHFFFAOYSA-N 1h-imidazole-2-carboxamide Chemical compound NC(=O)C1=NC=CN1 NMIZONYLXCOHEF-UHFFFAOYSA-N 0.000 description 1
NQVQUJRBCVAMIL-UHFFFAOYSA-N 2,3-dibromopropan-1-amine;hydrobromide Chemical compound Br.NCC(Br)CBr NQVQUJRBCVAMIL-UHFFFAOYSA-N 0.000 description 1
WYDSIWDKSUOWJN-XFFZJAGNSA-N 2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(\C=C/2C3=CC=CC=C3NC\2=O)=C1C WYDSIWDKSUOWJN-XFFZJAGNSA-N 0.000 description 1
ZNFFNNODABCNTK-UHFFFAOYSA-N 2-(2-amino-5-fluorophenyl)acetohydrazide Chemical compound NNC(=O)CC1=CC(F)=CC=C1N ZNFFNNODABCNTK-UHFFFAOYSA-N 0.000 description 1
KBXOBZJVYNAHTD-POHAHGRESA-N 2-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-3,3-dimethyl-1,2-dihydropyrrole-4-carboxylic acid Chemical compound N1C=C(C(O)=O)C(C)(C)C1\C=C/1C2=CC(F)=CC=C2NC\1=O KBXOBZJVYNAHTD-POHAHGRESA-N 0.000 description 1
125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
YMFXRJRQDSSRQP-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine;dihydrochloride Chemical compound Cl.Cl.C1CNCCC1N1CCOCC1 YMFXRJRQDSSRQP-UHFFFAOYSA-N 0.000 description 1
STWODXDTKGTVCJ-UHFFFAOYSA-N 4-pyrrolidin-1-ylpiperidine Chemical compound C1CCCN1C1CCNCC1 STWODXDTKGTVCJ-UHFFFAOYSA-N 0.000 description 1
HGAQQKPBNGSIMU-UHFFFAOYSA-N 5-[(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-n-(2-morpholin-4-ylethyl)-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(C=C2C3=CC(F)=CC=C3NC2=O)=C(C)C=1C(=O)NCCN1CCOCC1 HGAQQKPBNGSIMU-UHFFFAOYSA-N 0.000 description 1
SRSGVKWWVXWSJT-UHFFFAOYSA-N 5-[(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-n-(2-pyrrolidin-1-ylethyl)-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(C=C2C3=CC(F)=CC=C3NC2=O)=C(C)C=1C(=O)NCCN1CCCC1 SRSGVKWWVXWSJT-UHFFFAOYSA-N 0.000 description 1
SURWNIJQSNIEME-PXNMLYILSA-N 5-[(z)-(5-bromo-2-oxo-1h-indol-3-ylidene)methyl]-n-[2-hydroxy-3-(triazol-1-yl)propyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(Br)=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1C=CN=N1 SURWNIJQSNIEME-PXNMLYILSA-N 0.000 description 1
CUMPRQVJAINYRT-WDZFZDKYSA-N 5-[(z)-(5-chloro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(\C=C/2C3=CC(Cl)=CC=C3NC\2=O)=C1C CUMPRQVJAINYRT-WDZFZDKYSA-N 0.000 description 1
ITDIXLGWIYXLSO-PXNMLYILSA-N 5-[(z)-(5-chloro-2-oxo-1h-indol-3-ylidene)methyl]-n-[2-hydroxy-3-(triazol-1-yl)propyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(Cl)=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1C=CN=N1 ITDIXLGWIYXLSO-PXNMLYILSA-N 0.000 description 1
CTNPALGJUAXMMC-PMFHANACSA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-n-[(2s)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound C([C@@H](O)CNC(=O)C=1C(C)=C(\C=C/2C3=CC(F)=CC=C3NC\2=O)NC=1C)N1CCOCC1 CTNPALGJUAXMMC-PMFHANACSA-N 0.000 description 1
KPVYKYXRAWCRQG-PXNMLYILSA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-n-[2-hydroxy-3-(triazol-1-yl)propyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C(C)C=1C(=O)NCC(O)CN1C=CN=N1 KPVYKYXRAWCRQG-PXNMLYILSA-N 0.000 description 1
GAIGHRNVLYOOKS-UHFFFAOYSA-N 5-formyl-2,4-dimethyl-n-(2-pyrrolidin-1-ylethyl)-1h-pyrrole-3-carboxamide Chemical compound N1C(C=O)=C(C)C(C(=O)NCCN2CCCC2)=C1C GAIGHRNVLYOOKS-UHFFFAOYSA-N 0.000 description 1
CHGHIJMLUBUKKO-UHFFFAOYSA-M 7-oxa-4-azoniaspiro[3.5]nonan-2-ol;chloride Chemical compound [Cl-].C1C(O)C[N+]21CCOCC2 CHGHIJMLUBUKKO-UHFFFAOYSA-M 0.000 description 1
244000215068 Acacia senegal Species 0.000 description 1
102000007469 Actins Human genes 0.000 description 1
108010085238 Actins Proteins 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
241000416162 Astragalus gummifer Species 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
206010005949 Bone cancer Diseases 0.000 description 1
208000018084 Bone neoplasm Diseases 0.000 description 1
108091003079 Bovine Serum Albumin Proteins 0.000 description 1
206010006313 Breast tenderness Diseases 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
206010051055 Deep vein thrombosis Diseases 0.000 description 1
206010061619 Deformity Diseases 0.000 description 1
229920002307 Dextran Polymers 0.000 description 1
239000004338 Dichlorodifluoromethane Substances 0.000 description 1
208000030814 Eating disease Diseases 0.000 description 1
LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
241000792859 Enema Species 0.000 description 1
YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
208000010201 Exanthema Diseases 0.000 description 1
208000019454 Feeding and Eating disease Diseases 0.000 description 1
229920000084 Gum arabic Polymers 0.000 description 1
239000007821 HATU Substances 0.000 description 1
238000010268 HPLC based assay Methods 0.000 description 1
101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
208000032843 Hemorrhage Diseases 0.000 description 1
208000033830 Hot Flashes Diseases 0.000 description 1
206010060800 Hot flush Diseases 0.000 description 1
208000037147 Hypercalcaemia Diseases 0.000 description 1
206010020751 Hypersensitivity Diseases 0.000 description 1
208000001953 Hypotension Diseases 0.000 description 1
206010022004 Influenza like illness Diseases 0.000 description 1
102000008070 Interferon-gamma Human genes 0.000 description 1
108010074328 Interferon-gamma Proteins 0.000 description 1
102000014150 Interferons Human genes 0.000 description 1
108010050904 Interferons Proteins 0.000 description 1
YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
239000012097 Lipofectamine 2000 Substances 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
235000019759 Maize starch Nutrition 0.000 description 1
241000124008 Mammalia Species 0.000 description 1
206010027468 Metastases to spine Diseases 0.000 description 1
208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
LBWFXVZLPYTWQI-WNQIDUERSA-N N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid Chemical group O[C@@H](CC(O)=O)C(O)=O.CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(F)cc23)c1C LBWFXVZLPYTWQI-WNQIDUERSA-N 0.000 description 1
NLQCHAUIFBSZPK-UHFFFAOYSA-N N-[2-hydroxy-3-(triazol-1-yl)propyl]-1H-pyrrole-3-carboxamide Chemical compound C1=CN=NN1CC(O)CNC(=O)C=1C=CNC=1 NLQCHAUIFBSZPK-UHFFFAOYSA-N 0.000 description 1
MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
206010028813 Nausea Diseases 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
102000007399 Nuclear hormone receptor Human genes 0.000 description 1
108020005497 Nuclear hormone receptor Proteins 0.000 description 1
WXFHXVCLHRXLGS-UHFFFAOYSA-N O.NN.C(C)N(CCNC(=O)C1=C(NC(=C1C)C=C1C(NC2=CC=C(C=C12)F)=O)C)CC Chemical compound O.NN.C(C)N(CCNC(=O)C1=C(NC(=C1C)C=C1C(NC2=CC=C(C=C12)F)=O)C)CC WXFHXVCLHRXLGS-UHFFFAOYSA-N 0.000 description 1
102000004140 Oncostatin M Human genes 0.000 description 1
108090000630 Oncostatin M Proteins 0.000 description 1
241000906034 Orthops Species 0.000 description 1
208000010191 Osteitis Deformans Diseases 0.000 description 1
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
208000027868 Paget disease Diseases 0.000 description 1
241000254064 Photinus pyralis Species 0.000 description 1
206010036018 Pollakiuria Diseases 0.000 description 1
229920002642 Polysorbate 65 Polymers 0.000 description 1
102000001253 Protein Kinase Human genes 0.000 description 1
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
241000700159 Rattus Species 0.000 description 1
241000283984 Rodentia Species 0.000 description 1
229920002125 Sokalan® Polymers 0.000 description 1
238000000692 Student's t-test Methods 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
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
102000007591 Tartrate-Resistant Acid Phosphatase Human genes 0.000 description 1
108010032050 Tartrate-Resistant Acid Phosphatase Proteins 0.000 description 1
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
229920001615 Tragacanth Polymers 0.000 description 1
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
208000002495 Uterine Neoplasms Diseases 0.000 description 1
206010046788 Uterine haemorrhage Diseases 0.000 description 1
206010046910 Vaginal haemorrhage Diseases 0.000 description 1
206010047249 Venous thrombosis Diseases 0.000 description 1
206010000059 abdominal discomfort Diseases 0.000 description 1
235000010489 acacia gum Nutrition 0.000 description 1
239000000205 acacia gum Substances 0.000 description 1
230000003213 activating effect Effects 0.000 description 1
239000013543 active substance Substances 0.000 description 1
210000000577 adipose tissue Anatomy 0.000 description 1
239000008272 agar Substances 0.000 description 1
235000010419 agar Nutrition 0.000 description 1
229940040563 agaric acid Drugs 0.000 description 1
230000032683 aging Effects 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
235000010443 alginic acid Nutrition 0.000 description 1
239000000783 alginic acid Substances 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
229910001413 alkali metal ion Inorganic materials 0.000 description 1
125000003342 alkenyl group Chemical group 0.000 description 1
125000004414 alkyl thio group Chemical group 0.000 description 1
125000000304 alkynyl group Chemical group 0.000 description 1
208000030961 allergic reaction Diseases 0.000 description 1
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
229910052782 aluminium Inorganic materials 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
230000009435 amidation Effects 0.000 description 1
238000007112 amidation reaction Methods 0.000 description 1
229940024606 amino acid Drugs 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
235000019270 ammonium chloride Nutrition 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
230000001093 anti-cancer Effects 0.000 description 1
229940046836 anti-estrogen Drugs 0.000 description 1
230000001833 anti-estrogenic effect Effects 0.000 description 1
239000000427 antigen Substances 0.000 description 1
102000036639 antigens Human genes 0.000 description 1
108091007433 antigens Proteins 0.000 description 1
229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
238000003782 apoptosis assay Methods 0.000 description 1
230000006907 apoptotic process Effects 0.000 description 1
238000013459 approach Methods 0.000 description 1
239000008135 aqueous vehicle Substances 0.000 description 1
125000003710 aryl alkyl group Chemical group 0.000 description 1
229910052788 barium Inorganic materials 0.000 description 1
DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
230000004888 barrier function Effects 0.000 description 1
239000011324 bead Substances 0.000 description 1
230000009286 beneficial 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
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
125000002619 bicyclic group Chemical group 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
238000004166 bioassay Methods 0.000 description 1
229920000249 biocompatible polymer Polymers 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
230000000740 bleeding effect Effects 0.000 description 1
230000000903 blocking effect Effects 0.000 description 1
238000007664 blowing Methods 0.000 description 1
238000009835 boiling Methods 0.000 description 1
230000037182 bone density Effects 0.000 description 1
230000008468 bone growth Effects 0.000 description 1
210000002798 bone marrow cell Anatomy 0.000 description 1
210000002805 bone matrix Anatomy 0.000 description 1
230000010072 bone remodeling Effects 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
230000001612 cachectic effect Effects 0.000 description 1
230000005907 cancer growth Effects 0.000 description 1
239000007963 capsule composition Substances 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
125000002843 carboxylic acid group Chemical group 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
210000000170 cell membrane Anatomy 0.000 description 1
230000036755 cellular response Effects 0.000 description 1
230000005754 cellular signaling Effects 0.000 description 1
230000000973 chemotherapeutic effect Effects 0.000 description 1
238000002512 chemotherapy Methods 0.000 description 1
WGXZDYPGLJYBJW-UHFFFAOYSA-N chloroform;propan-2-ol Chemical compound CC(C)O.ClC(Cl)Cl WGXZDYPGLJYBJW-UHFFFAOYSA-N 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
238000010367 cloning Methods 0.000 description 1
229940110456 cocoa butter Drugs 0.000 description 1
235000019868 cocoa butter Nutrition 0.000 description 1
238000002648 combination therapy Methods 0.000 description 1
230000002860 competitive effect Effects 0.000 description 1
229940125898 compound 5 Drugs 0.000 description 1
239000013058 crude material Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
125000004966 cyanoalkyl group Chemical group 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
PYRZPBDTPRQYKG-UHFFFAOYSA-N cyclopentene-1-carboxylic acid Chemical compound OC(=O)C1=CCCC1 PYRZPBDTPRQYKG-UHFFFAOYSA-N 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
230000006378 damage Effects 0.000 description 1
230000007423 decrease Effects 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
239000003405 delayed action preparation Substances 0.000 description 1
230000008021 deposition Effects 0.000 description 1
238000001514 detection method Methods 0.000 description 1
230000001627 detrimental effect Effects 0.000 description 1
206010012601 diabetes mellitus Diseases 0.000 description 1
150000004985 diamines Chemical class 0.000 description 1
229940042935 dichlorodifluoromethane Drugs 0.000 description 1
235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
150000001993 dienes Chemical class 0.000 description 1
235000014113 dietary fatty acids Nutrition 0.000 description 1
ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
229940043279 diisopropylamine Drugs 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
235000014632 disordered eating Nutrition 0.000 description 1
239000002270 dispersing agent Substances 0.000 description 1
230000003828 downregulation Effects 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
238000012377 drug delivery Methods 0.000 description 1
229940088679 drug related substance Drugs 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000001804 emulsifying effect Effects 0.000 description 1
239000007920 enema Substances 0.000 description 1
229940079360 enema for constipation Drugs 0.000 description 1
239000000328 estrogen antagonist Substances 0.000 description 1
CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
229940093471 ethyl oleate Drugs 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
210000003527 eukaryotic cell Anatomy 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
201000005884 exanthem Diseases 0.000 description 1
239000000284 extract Substances 0.000 description 1
239000000194 fatty acid Substances 0.000 description 1
229930195729 fatty acid Natural products 0.000 description 1
210000005002 female reproductive tract Anatomy 0.000 description 1
238000011049 filling Methods 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000000834 fixative Substances 0.000 description 1
230000037406 food intake Effects 0.000 description 1
230000022244 formylation Effects 0.000 description 1
238000006170 formylation reaction Methods 0.000 description 1
208000020694 gallbladder disease Diseases 0.000 description 1
239000007789 gas Substances 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
238000003304 gavage Methods 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000003862 glucocorticoid Substances 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
125000005456 glyceride group Chemical group 0.000 description 1
238000000227 grinding Methods 0.000 description 1
230000003394 haemopoietic effect Effects 0.000 description 1
125000004475 heteroaralkyl group Chemical group 0.000 description 1
GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
208000010726 hind limb paralysis Diseases 0.000 description 1
238000001794 hormone therapy Methods 0.000 description 1
102000052833 human CSF1R Human genes 0.000 description 1
238000009396 hybridization Methods 0.000 description 1
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
229920001600 hydrophobic polymer Polymers 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
150000004679 hydroxides Chemical class 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
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 1
230000000148 hypercalcaemia Effects 0.000 description 1
208000030915 hypercalcemia disease Diseases 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
230000028993 immune response Effects 0.000 description 1
238000003018 immunoassay Methods 0.000 description 1
238000011532 immunohistochemical staining Methods 0.000 description 1
238000010324 immunological assay Methods 0.000 description 1
238000001802 infusion Methods 0.000 description 1
229960003130 interferon gamma Drugs 0.000 description 1
229940047124 interferons Drugs 0.000 description 1
230000000968 intestinal effect Effects 0.000 description 1
239000007925 intracardiac injection Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
239000007927 intramuscular injection Substances 0.000 description 1
238000010255 intramuscular injection 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
238000007914 intraventricular administration Methods 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
230000007794 irritation Effects 0.000 description 1
FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
229960003299 ketamine Drugs 0.000 description 1
239000004922 lacquer Substances 0.000 description 1
229940001447 lactate Drugs 0.000 description 1
230000003902 lesion Effects 0.000 description 1
231100000225 lethality Toxicity 0.000 description 1
229940057995 liquid paraffin Drugs 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
230000007774 longterm Effects 0.000 description 1
208000012866 low blood pressure Diseases 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
239000006166 lysate Substances 0.000 description 1
159000000003 magnesium salts Chemical class 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
238000003760 magnetic stirring Methods 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
229940049920 malate Drugs 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
230000036210 malignancy Effects 0.000 description 1
208000027202 mammary Paget disease Diseases 0.000 description 1
230000010534 mechanism of action Effects 0.000 description 1
238000002483 medication Methods 0.000 description 1
230000009245 menopause Effects 0.000 description 1
108020004999 messenger RNA Proteins 0.000 description 1
229910021645 metal ion Inorganic materials 0.000 description 1
206010061289 metastatic neoplasm Diseases 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
229920000609 methyl cellulose Polymers 0.000 description 1
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
239000001923 methylcellulose Substances 0.000 description 1
235000010981 methylcellulose Nutrition 0.000 description 1
230000003278 mimic effect Effects 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
238000002156 mixing Methods 0.000 description 1
230000036651 mood Effects 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
210000005088 multinucleated cell Anatomy 0.000 description 1
UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
SCZVXVGZMZRGRU-UHFFFAOYSA-N n'-ethylethane-1,2-diamine Chemical compound CCNCCN SCZVXVGZMZRGRU-UHFFFAOYSA-N 0.000 description 1
UKHIFWUDEPELAG-UHFFFAOYSA-N n-[2-(ethylamino)ethyl]-5-formyl-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CCNCCNC(=O)C1=C(C)NC(C=O)=C1C UKHIFWUDEPELAG-UHFFFAOYSA-N 0.000 description 1
OCZYWUNAORCGGL-UHFFFAOYSA-N n-[3-(diethylamino)-2-hydroxypropyl]-5-[(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound CCN(CC)CC(O)CNC(=O)C1=C(C)NC(C=C2C3=CC(F)=CC=C3NC2=O)=C1C OCZYWUNAORCGGL-UHFFFAOYSA-N 0.000 description 1
RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
230000008693 nausea Effects 0.000 description 1
239000006199 nebulizer Substances 0.000 description 1
230000027405 negative regulation of phosphorylation Effects 0.000 description 1
208000019382 nerve compression syndrome Diseases 0.000 description 1
FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
229940126701 oral medication Drugs 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
125000001477 organic nitrogen group Chemical group 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
229920000620 organic polymer Polymers 0.000 description 1
239000003791 organic solvent mixture Substances 0.000 description 1
210000000963 osteoblast Anatomy 0.000 description 1
230000002642 osteogeneic effect Effects 0.000 description 1
201000004228 ovarian endometrial cancer Diseases 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
230000007170 pathology Effects 0.000 description 1
230000037361 pathway Effects 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
239000000813 peptide hormone Substances 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
239000002504 physiological saline solution Substances 0.000 description 1
239000000049 pigment Substances 0.000 description 1
239000006187 pill Substances 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
239000004033 plastic Substances 0.000 description 1
239000004014 plasticizer Substances 0.000 description 1
210000003281 pleural cavity Anatomy 0.000 description 1
125000003367 polycyclic group Chemical group 0.000 description 1
229940068886 polyethylene glycol 300 Drugs 0.000 description 1
229920000642 polymer Polymers 0.000 description 1
239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
229920001282 polysaccharide Polymers 0.000 description 1
239000005017 polysaccharide Substances 0.000 description 1
150000004804 polysaccharides Chemical class 0.000 description 1
229940099511 polysorbate 65 Drugs 0.000 description 1
239000013641 positive control Substances 0.000 description 1
229920001592 potato starch Polymers 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002335 preservative effect Effects 0.000 description 1
230000005522 programmed cell death Effects 0.000 description 1
125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
239000003380 propellant Substances 0.000 description 1
108060006633 protein kinase Proteins 0.000 description 1
239000003909 protein kinase inhibitor Substances 0.000 description 1
230000029983 protein stabilization Effects 0.000 description 1
230000002685 pulmonary effect Effects 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
150000003233 pyrroles Chemical class 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
238000001959 radiotherapy Methods 0.000 description 1
206010037844 rash Diseases 0.000 description 1
238000011552 rat model Methods 0.000 description 1
108091006084 receptor activators Proteins 0.000 description 1
238000011084 recovery Methods 0.000 description 1
230000009467 reduction Effects 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000008263 repair mechanism Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
230000004044 response Effects 0.000 description 1
229940100486 rice starch Drugs 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
238000010187 selection method Methods 0.000 description 1
235000011803 sesame oil Nutrition 0.000 description 1
239000008159 sesame oil Substances 0.000 description 1
231100000004 severe toxicity Toxicity 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
231100000046 skin rash Toxicity 0.000 description 1
239000003998 snake venom Substances 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
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229940054269 sodium pyruvate Drugs 0.000 description 1
239000007901 soft capsule Substances 0.000 description 1
239000012439 solid excipient Substances 0.000 description 1
239000012265 solid product Substances 0.000 description 1
239000007921 spray Substances 0.000 description 1
230000000087 stabilizing effect Effects 0.000 description 1
238000003153 stable transfection Methods 0.000 description 1
238000010186 staining Methods 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000001384 succinic acid Substances 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
239000013589 supplement Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000002511 suppository base Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
238000007910 systemic administration Methods 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
235000012976 tarts Nutrition 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
210000000115 thoracic cavity Anatomy 0.000 description 1
210000002303 tibia Anatomy 0.000 description 1
239000004408 titanium dioxide Substances 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
229960001727 tretinoin Drugs 0.000 description 1
150000003626 triacylglycerols Chemical class 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
229940029284 trichlorofluoromethane Drugs 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
229960000281 trometamol Drugs 0.000 description 1
JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
208000022934 urinary frequency Diseases 0.000 description 1
230000036318 urination frequency Effects 0.000 description 1
206010046766 uterine cancer Diseases 0.000 description 1
230000024883 vasodilation Effects 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
229940100445 wheat starch Drugs 0.000 description 1
BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
229960001600 xylazine Drugs 0.000 description 1
229910052727 yttrium Inorganic materials 0.000 description 1