JP2016514705A - ニトロキソリンの塩基付加塩及びその使用 - Google Patents
ニトロキソリンの塩基付加塩及びその使用 Download PDFInfo
- Publication number
- JP2016514705A JP2016514705A JP2016503414A JP2016503414A JP2016514705A JP 2016514705 A JP2016514705 A JP 2016514705A JP 2016503414 A JP2016503414 A JP 2016503414A JP 2016503414 A JP2016503414 A JP 2016503414A JP 2016514705 A JP2016514705 A JP 2016514705A
- Authority
- JP
- Japan
- Prior art keywords
- nitroxoline
- salt
- amine
- base addition
- pharmaceutical composition
- 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.)
- Granted
Links
- 229960005131 nitroxoline Drugs 0.000 title claims abstract description 215
- RJIWZDNTCBHXAL-UHFFFAOYSA-N nitroxoline Chemical compound C1=CN=C2C(O)=CC=C([N+]([O-])=O)C2=C1 RJIWZDNTCBHXAL-UHFFFAOYSA-N 0.000 title claims abstract description 173
- 150000003839 salts Chemical class 0.000 title claims abstract description 114
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 40
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000035475 disorder Diseases 0.000 claims abstract description 20
- 230000005856 abnormality Effects 0.000 claims abstract description 16
- -1 alkali metal salt Chemical class 0.000 claims description 134
- 239000002585 base Substances 0.000 claims description 108
- 239000000203 mixture Substances 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 34
- 150000001412 amines Chemical class 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- 239000004381 Choline salt Substances 0.000 claims description 19
- 235000019417 choline salt Nutrition 0.000 claims description 19
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 19
- 150000003973 alkyl amines Chemical class 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 239000000908 ammonium hydroxide Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 150000004982 aromatic amines Chemical class 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 11
- 208000019206 urinary tract infection Diseases 0.000 claims description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 229920000768 polyamine Polymers 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 8
- 150000002337 glycosamines Chemical class 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 239000012736 aqueous medium Substances 0.000 claims description 7
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004472 Lysine Substances 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 6
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 claims description 5
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical group CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 5
- 150000003863 ammonium salts Chemical group 0.000 claims description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 229950010286 diolamine Drugs 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 5
- 229960000281 trometamol Drugs 0.000 claims description 5
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 4
- 229960001231 choline Drugs 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 3
- 229940031098 ethanolamine Drugs 0.000 claims description 3
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 229940013085 2-diethylaminoethanol Drugs 0.000 claims 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 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 125000003916 ethylene diamine group Chemical group 0.000 claims 1
- 150000003248 quinolines Chemical group 0.000 claims 1
- 210000002700 urine Anatomy 0.000 abstract description 13
- 239000007864 aqueous solution Substances 0.000 abstract description 3
- 230000004962 physiological condition Effects 0.000 abstract description 3
- 230000028327 secretion Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 36
- 125000001424 substituent group Chemical group 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 125000000217 alkyl group Chemical group 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 18
- 239000000725 suspension Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 15
- 238000004949 mass spectrometry Methods 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- 125000002723 alicyclic group Chemical group 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 description 8
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 150000001768 cations Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 150000003335 secondary amines Chemical class 0.000 description 6
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229940075419 choline hydroxide Drugs 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 229910000000 metal hydroxide Inorganic materials 0.000 description 5
- 150000004692 metal hydroxides Chemical class 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000002485 urinary effect Effects 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 230000036325 urinary excretion Effects 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- 229930064664 L-arginine Natural products 0.000 description 3
- 235000014852 L-arginine Nutrition 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000001924 cycloalkanes Chemical class 0.000 description 3
- 150000004985 diamines Chemical class 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 150000002829 nitrogen Chemical group 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- OYQFCKRAZGSTGD-UHFFFAOYSA-N 5-nitroquinolin-8-ol;hydrochloride Chemical class [Cl-].C1=C[NH+]=C2C(O)=CC=C([N+]([O-])=O)C2=C1 OYQFCKRAZGSTGD-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IYGXEHDCSOYNKY-RZHHZEQLSA-N Dinoprost tromethamine Chemical compound OCC(N)(CO)CO.CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O IYGXEHDCSOYNKY-RZHHZEQLSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- 206010037596 Pyelonephritis Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 230000009400 cancer invasion Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 150000001925 cycloalkenes Chemical class 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 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
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 201000003146 cystitis Diseases 0.000 description 2
- 235000006694 eating habits Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- WGESLFUSXZBFQF-UHFFFAOYSA-N n-methyl-n-prop-2-enylprop-2-en-1-amine Chemical compound C=CCN(C)CC=C WGESLFUSXZBFQF-UHFFFAOYSA-N 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- 210000003708 urethra Anatomy 0.000 description 2
- 208000000143 urethritis Diseases 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 125000006049 2-methyl-2-pentenyl group Chemical group 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- OJZYVZNGKDTSFP-UHFFFAOYSA-N 2-morpholin-2-ylethanol Chemical compound OCCC1CNCCO1 OJZYVZNGKDTSFP-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- KSMVBYPXNKCPAJ-UHFFFAOYSA-N 4-Methylcyclohexylamine Chemical compound CC1CCC(N)CC1 KSMVBYPXNKCPAJ-UHFFFAOYSA-N 0.000 description 1
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 208000005440 Basal Cell Neoplasms Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010023424 Kidney infection Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589516 Pseudomonas Species 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
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 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
- 241000282887 Suidae Species 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000012931 Urologic disease Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 229940095602 acidifiers Drugs 0.000 description 1
- 208000009621 actinic keratosis Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006172 buffering agent Substances 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
- 238000007707 calorimetry Methods 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- JQDCIBMGKCMHQV-UHFFFAOYSA-M diethyl(dimethyl)azanium;hydroxide Chemical compound [OH-].CC[N+](C)(C)CC JQDCIBMGKCMHQV-UHFFFAOYSA-M 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- KVFVBPYVNUCWJX-UHFFFAOYSA-M ethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC[N+](C)(C)C KVFVBPYVNUCWJX-UHFFFAOYSA-M 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 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
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 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
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011835 investigation Methods 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000002772 monosaccharides Chemical group 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- SQRXWXCCRCQPKC-UHFFFAOYSA-N n-methyl-n-prop-2-ynylprop-2-yn-1-amine Chemical compound C#CCN(C)CC#C SQRXWXCCRCQPKC-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- SHXLXTUBUWSBRN-UHFFFAOYSA-N nitric acid 5-nitroquinolin-8-ol Chemical class O[N+]([O-])=O.Oc1ccc([N+]([O-])=O)c2cccnc12 SHXLXTUBUWSBRN-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940023490 ophthalmic product Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940126589 solid medicine Drugs 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- RYCLIXPGLDDLTM-UHFFFAOYSA-J tetrapotassium;phosphonato phosphate Chemical compound [K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])([O-])=O RYCLIXPGLDDLTM-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Description
ここでX+は、金属カチオン、アミンカチオン、アンモニウムカチオン(NH4 +)、又は四級アンモニウムカチオンなどのカチオンを示す。
4mL MeOHのニトロキソリン(0.2 g、1.05 mmol)の懸濁液に対して、1.3 eq. 36% HCl水溶液をゆっくりと添加した。オレンジ色の固体がろ過によって得られた(収量:0.15g、63%)。もしくは、ニトロキソリン(0.5g、2.63mmol)を、25mL 36% HCl水溶液中で還流した。透明な溶液が形成され、冷却した。ろ過により、黄色の固体(収量:0.33 g、55%)を得た。mp: 236-240℃;及び1H-NMR (300 MHz、DMSO-d6)δ:9.20 (d、1H)、9.03-9.05 (dd、1H)、8.55-8.58 (d、1H)、7.91-7.95 (m、1H)、7.25-7.28 (d、1H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)の溶液に対して、1.5eq. 40% HBr水溶液をゆっくりと添加した。ろ過により、黄色の固体を得た(収量:0.17g、60%)。もしくは、ニトロキソリン(0.5g、2.63mmol)を、25mL40% HBr水溶液中で還流した。透明な溶液が形成され、冷却した。ろ過により、黄色の固体(収量:0.43g、60%)を得た。mp: 274-276℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.24-9.28 (dd、1H)、9.05-9.07 (dd、1H)、8.56-8.59 (d、1H)、7.95-7.99 (m、1H)、7.24-7.27 (d、1H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)の溶液に対して、2.0eq. 60% HNO3水溶液をゆっくりと添加した。ろ過により、暗黄色の固体を得た(収量:0.21g、79%)。mp: >290℃;及び1H-NMR(300 MHz、DMSO-d6)δ:9.20-9.23 (dd、1H)、9.03-9.05 (dd、1H)、8.55-8.58 (d、1H)、7.91-7.96 (m、1H)、7.21-7.24 (d、1H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)の溶液に対して、1.5eq.のベンゼンスルホン酸をゆっくりと添加した。ろ過により、薄黄色の固体を得た(収量:0.24g、65%)。mp:238-241℃;及び1H-NMR(300MHz、DMSO-d6)δ:9.24-9.27 (dd、1H)、9.05-9.06 (dd、1H)、8.56-8.59 (d、1H)、7.95-7.99 (m、1H)、7.58-7.63 (m、2H)、7.32-7.36 (m、3H)、7.23-7.26 (d、1H)。
4mL EtOHのニトロキソリン(0.2 g、1.05 mmol)の懸濁液に対して、1.5eq. の水酸化ナトリウムをゆっくりと添加した。ろ過により、オレンジ色の固体を得た(収量:0.15g、67%)。mp: >290℃;及び1H-NMR(300MHz、DMSO-d6)δ:9.43-9.46 (dd、1H)、8.53-8.55 (dd、1H)、8.39-8.42 (d、1H)、7.55-7.59 (m、1H)、6.22-6.26 (d、1H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)の溶液に対して、1.5eq.の水酸化カリウムを含む水1mLをゆっくりと添加した。ろ過により、オレンジ色の固体を得た(収量:0.20 g、83%)。mp: >290℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.43-9.46 (dd、1H)、8.51-8.53 (dd、1H)、8.33-8.36 (d、1H)、7.48-7.52 (m、1H)、6.11-6.14 (d、1H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)の溶液に対して、1.4eq. の水酸化アンモニウムをゆっくりと添加した。ろ過により、オレンジ色の固体を得た(収量:0.17g、78%)。mp: 188-192℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.40-9.43 (dd、1H)、8.56-8.57 (dd、1H)、8.37-8.40 (d、1H)、7.52-7.57 (m、1H)、6.21-6.25 (d、1H)。
ニトロキソリン(25g、131.6mmol)とコリン(50%の水溶液、36.5g、150.7 mmol)を含むイソプロピルアルコール(IPA)(350 mL)の懸濁液を1時間還流し、透明な溶液を得た。真空状態で溶媒を除去した後、IPA(110 mL)を付加した。懸濁液を60℃まで加熱し、透明な溶液を得た。室温まで冷却後、ろ過により、黄色の固体(29g)を得た(収率:75.6%)。mp:110-113℃; 1H-NMR (300MHz、DMSO-d6)δ:9.45-9.42 (dd、J=8.7 Hz、1.62 Hz、1H)、8.51-8.50 (dd、J=4.00 Hz、1.55 Hz、1H)、8.35-8.32 (d、J=9.93 Hz、1H)、7.50-7.46 (m、1H)、6.12-6.09 (d、J=9.90 Hz、1H)、5.34-5.31 (t、J=4.55 Hz、1H)、3.84 (m、2H)、3.41-3.38 (t、J=5.25 Hz、2H)、3.10 (s、9H)(図1);LC/MS(M-1):189(図2);DSC:112.50℃(図3);ならびに粉末X線回折(pXRD)2θ及びピーク強度値を図4に示す。
4mL THFのニトロキソリン(0.2g、1.05mmol)溶液に対して、1.8eq.のジエチルアミンをゆっくりと添加した。ろ過により、黄色の固体を得た(収量:0.20g、72%)。mp: 160-168℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.41-9.44 (dd、1H)、8.57-8.59 (dd、1H)、8.37-8.40 (d、1H)、7.53-7.57 (m、1H)、6.22-6.25 (d、1H)、2.92-2.99 (dd、4H)、1.13-1.18 (t、6H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)溶液に対して、1.9eq.のエチレンジアミンをゆっくりと添加した。ろ過により、黄色の固体を得た(収量:0.20g、77%)。mp: 204-206℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.40-9.43 (dd、1H)、8.55-8.57 (dd、1H)、8.37-8.40 (d、1H)、7.52-7.56 (m、1H)、6.22-6.26 (d、1H)、2.84 (s、4H)。
4mL THFのニトロキソリン(0.2g、1.05mmol)溶液に対して、1.5eq.のピペラジンをゆっくりと添加した。ろ過により、黄色の固体を得た(収量:0.25g、86%)。mp: 206-210℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.41-9.44 (dd、1H)、8.58-8.59 (d、1H)、8.36-8.40 (d、1H)、7.53-7.57 (m、1H)、6.23-6.26 (d、1H)、2.91(s、8H)。
ニトロキソリン(0.2g、1.05mmol)及び1.0eq. L-アルギニンを含む4mL IPAの溶液を終夜還流した。室温まで冷却した後、ろ過により、黄色の固体を得た(収量:0.33g、78%)。mp: 198-200℃;及び1H-NMR (300MHz、MeOD-d4)δ:9.46-9.49 (dd、1H)、8.71-8.72 (dd、1H)、8.58-8.61 (d、1H)、7.61-7.70 (m、1H)、6.67-6.70 (d、1H)、3.52-3.56(t、1H)、3.22-3.25 (t、2H), 1.81-1.89 (m、2H), 1.67-1.77 (m、2H)。
CH3CN (100mL)のニトロキソリン水酸化コリン塩(3.5g)の懸濁液を50-60℃まで加熱し、透明な溶液を得た。これを室温まで冷却した後、ろ過により、薄黄色の固体である結晶(2.5g)を得た(収率:71.4%)。mp:110-113℃;及び1H-NMR (300MHz、DMSO-d6)δ:9.46-9.42 (dd、J=8.70 Hz、1.53 Hz、1H)、8.51-8.50 (dd、J=3.99 Hz、1.41 Hz、1H)、8.35-8.32 (d、J=8.33 Hz、1H)、7.50-7.46 (m、1H)、6.12-6.09 (d、J=9.90 Hz、1H)、5.33-5.30 (t、J=4.68 Hz、1H)、3.84 (m、2H)、3.41-3.38 (t、J=5.22 Hz、2H), 3.10 (s、9H) (図5);LC/MS (M-1):189(図6);DSC:113.31℃(図7);ならびに粉末X線回折(pXRD)2θ及びピーク強度値を図8に示す。
THF (20 mL)のニトロキソリン(1.0g、5.26mmol)溶液に対して、1-(2-ヒドロキシエチル)-ピロリジン(1.09g、9.46mmol)を室温で添加した。この混合液を室温で終夜撹拌し、得られた懸濁液を濾過し、黄色の固体を得た(収量:0.8g、50%)。mp: 102-104℃; 1H-NMR (300MHz、DMSO-d6)δ:9.34 (d、1H)、8.69 (d、1H)、8.40-8.43 (d、1H)、7.61-7.65 (m、1H)、6.47-6.50 (d、1H)、3.59-3.63 (m、2H), 2.97-3.03 (m、6H), 1.77-1.84 (m、4H);及びLC/MS (M-1):189.46。
THF (20 mL)のニトロキソリン(1.0g、5.26mmol)溶液に対して、1-(2-ヒドロキシエチル)-ピロリジン(1.09g、9.46mmol)を室温で添加した。この混合液を室温で終夜撹拌し、得られた懸濁液を濾過し、黄色の固体を得た(収量:0.8g、50%)。mp: 102-104℃; 1H-NMR (300 MHz、DMSO-d6)δ:9.34 (d、1H)、8.69 (d、1H)、8.40-8.43 (d、1H)、7.61-7.65 (m、1H)、6.47-6.50 (d、1H)、3.59-3.63 (m、2H), 2.97-3.03 (m、6H), 1.77-1.84 (m、4H);及びLC/MS (M-1):189.46。
THF (20mL)のニトロキソリン(1.0g、5.26mmol)溶液に対して、2-(ジエチルアミノ)エタノール(1.1g、9.46mmol)を室温で添加した。この混合液を室温で終夜撹拌し、得られた懸濁液を濾過し、黄色の固体を得た(収量:0.7g、43%)。mp:76-78℃; 1H-NMR (300MHz、DMSO-d6)δ:9.32 (d、1H)、8.70-8.72 (d、1H)、8.41-8.44 (d、1H)、7.62-7.66 (m、1H)、6.50-6.53(d、1H)、3.59-3.62 (m、2H), 2.87-2.95 (m、6H), 1.07-1.18 (m、6H);及びLC/MS (M-1):189.38。
THF(20mL)のニトロキソリン(1.0g、5.26mmol)溶液に対して、4-(2-ヒドロキシエチル)-モルホリン(0.99g、7.54mmol)を室温で添加した。この混合液を室温で終夜撹拌し、0℃に冷却後、得られた懸濁液を濾過し、黄色の固体を得た(収量:0.8g、47%)。mp:124-128℃; 1H-NMR (300MHz、DMSO-d6)δ:9.18 (d、1H)、8.95-8.96 (d、1H)、8.51-8.54 (d、1H)、7.81-7.86 (m、1H)、7.04-7.07(d、1H)、3.50-3.60 (m、6H)、2.45-2.50 (m、2H);及びLC/MS (M-1):189.44。
イソプロパノール(20mL)のニトロキソリン(1.0g、5.26mmol)溶液に対して、リジン(1.15g、7.87mmol)を室温で添加した。この混合液を加熱還流し、終夜撹拌した。この溶液を室温まで冷却し、得られた懸濁液を濾過して黄色の固体を得た(収量:1.2g、68%)。mp:188-190℃; 1H-NMR (300MHz、DMSO-d6)δ:9.42 (d、1H)、8.56(d、1H)、8.35-8.38(d、1H)、7.51-7.53(m、1H)、6.17-6.20(d、1H)、3.17-3.20(m、2H), 2.76-2.80(t、2H);1.40-1.66(m、6H);及びLC/MS (M-1):189.41。
イソプロパノール(20mL)のニトロキソリン(1.0g、5.26mmol)溶液に対して、トロメタミン(0.95g、7.87mmol)を室温で添加した。この混合液を加熱還流し、1時間撹拌した。この溶液を室温まで冷却し、得られた懸濁液を濾過して黄色の固体を得た(収量:1.0g、61%)。mp:154-158℃;1H-NMR (300MHz、DMSO-d6)δ:9.40-9.43(m、1H)、8.57-8.58(m、1H)、8.35-8.38(m、1H)、7.52-7.56(m、1H)、6.22-6.26(d、1H)、5.10(m、3H)、3.63 (m、6H;及びLC/MS (M-1):189.40。
THF(20mL)のニトロキソリン(3.0g、15.8mmol)溶液に対して、N-メチルグルカミン(5.54g、28.4mmol)を室温で添加した。この混合液を70℃まで加熱し、数時間撹拌した。この溶液を室温まで冷却し、得られた懸濁液を濾過して黄色の固体を得た(収量:4.5g、74%)。mp:173-176℃; 1H-NMR (300MHz、DMSO-d6)δ:9.40 (m、1H)、8.58(dd、J=1.5 Hz、J=3.9 Hz、1H)、8.37 (d、J=9.9 Hz、1H)、7.54 (dd、J=3.9 Hz、J=9.0 Hz、1H)、6.24 (d、J=9.6 Hz、1H)、3.70-3.35 (m、4H)、3.10-2.85 (m、2H)、2.54 (s、3H);及びLC/MS (M-1):189.47。
THF(20mL)のニトロキソリン(3.0g、15.8mmol)溶液に対して、エタノールアミン(1.45g、23.7mmol)を室温で添加した。この混合液を70℃まで加熱し、数時間撹拌した。この溶液を室温まで冷却し、得られた懸濁液を濾過して黄色の固体を得た(収量:3.4g、76%)。mp:178-180℃; 1H-NMR (300MHz、DMSO-d6)δ:9.43 (dd、J=2.5 Hz、J=8.9 Hz、1H)、8.57(dd、J=2.5 Hz、J=4.2 Hz、1H)、8.39 (d、J=9.9 Hz、1H)、7.55 (dd、J=4.2 Hz、J=8.9 Hz、1H)、6.23 (d、J=9.9 Hz、1H)、3.60 (t、J=5.6 Hz、2H)、2.19(t、J=5.6 Hz、2H);及びLC/MS (M-1):189.43。
THF(20mL)のニトロキソリン(3.0g、15.8mmol)溶液に対して、ジオールアミン(2.49g、23.7 mmol)を室温で添加した。この混合液を70℃まで加熱し、数時間撹拌した。この溶液を室温まで冷却し、得られた懸濁液を濾過して黄色の固体を得た(収量:3.39g、62%)。mp: 142-144℃; 1H-NMR(300MHz、DMSO-d6)δ:9.41 (dd、J=1.5 Hz、J=8.7 Hz、1H)、8.61(dd、J=1.5 Hz、J=3.9 Hz、1H)、8.40 (d、 J=9.6 Hz、1H)、7.58 (dd、J=3.9 Hz、J=8.7 Hz、1H)、6.31 (d、J=9.6 Hz、1H)、3.64 (t、J=5.7 Hz、2H)、3.00 (t、J=5.7 Hz、2H);及びLC/MS (M-1):189.51。
ニトロキソリン及びニトロキソリン塩の溶解度を以下のように測定した。その結果が表2にまとめられている。
1)以下に示すように、pHを変えた水性緩衝液を調製した:
i. 水:蒸留水;
ii. pH = 1.2 緩衝液: 7.65mL 36.5%のHCl溶液を水で希釈して1000mLとした;
iii. pH = 4.5 緩衝液:18gの酢酸ナトリウムと9.8mLの酢酸を水で希釈し、1000mLとした;
iv. pH = 5.0 緩衝液:pHが5.0に調節されるまで、0.2mol/Lリン酸一ナトリウム(NaH2PO4)液に水酸化ナトリウムを添加した;
v. pH = 6.0 緩衝液:18gの酢酸ナトリウムを20mLの酢酸(1M)に添加し、混合液を水で希釈し、500mLとした;
vi. pH = 6.8 緩衝液:250mLの0.2M リン酸一カリウム(KH2PO4)液を118mLの0.2M水酸化ナトリウム溶液に添加し、混合液を水で希釈して1000mLとした;
vii. pH = 7.4 緩衝液:1.36gのリン酸一カリウム(KH2PO4)を79mLの0.1M水酸化ナトリウム溶液に添加し、混合液を水で希釈して200mLとした;及び
viii. pH = 8.0 緩衝液:5.59gの重リン酸カリウム(K2HPO4)と0.41gのリン酸一カリウム(KH2PO4)を1000mLの水に添加し、混合した。
温度25±2℃で、各塩の試料を10mg秤量し、100mL容量のボトルに添加した。0.25mLの緩衝液をボトルに入れ、5分おきに30秒間激しく振動させた。30分間で試料の溶解を観察した。試料が完全に溶解したら、その溶解度について、「>30mg/mL」と記録した。
試料が完全に溶解しなかった場合、同じ緩衝液を0.7mL添加し、同様の振動工程により溶解を観察した。試料が完全に溶解したら、その溶解度について「10<<30mg/mL」と記録した。
試料が完全に溶解しなかった場合、同じ緩衝液を8.5mL添加し、同様の振動工程で溶解を観察した。試料が完全に溶解したら、溶解度について「1<<10 mg/mL」と記録した。
試料が、それでも完全に溶解しなかった場合、同じ緩衝液を85mL添加し、同様の振動工程で溶解を観察した。試料が完全に溶解したら、溶解度について「0.1<<1mg/mL」と記録した。
試料が完全に溶解しなかった場合、溶解度について「<0.1mg/mL」と記録した。
10 mgのAPL−1078は、0.25mLの水とpH=8.0の緩衝液に完全に溶解したので、溶解度について>30mg/mLと記録した。第二の試験では、50mgのAPL−1078を100mLの定量ボトルに入れて、0.45mLの水又はpH=8.0の緩衝液を個別に添加した。APL−1078は完全に溶解し、これは、両溶媒において溶解度が>100 mg/mLとなったことを示す。第三の試験では、50mgのAPL−1078を100mL容量のボトルに入れ、0.045mLの水又はpH=8.0の緩衝液を個別に添加した。APL−1078は完全に溶解し、これは、三種類全ての溶媒において溶解度が>1000mg/mLであったことを示す。
体重が10-13kgの3匹の雄のビーグル犬に対し、一晩絶食させた後に75mgのニトロキソリンを含むタブレットを経口投与した。0-2、2-4、4-6、6-8、8-24の時間帯で尿試料を収集した。尿試料はCTC自動回収装置、ABAPI4000質量分析計及びACQUITY UPLC BEH C18(2.1*50mm)を伴うアジレント社製1100 HPLCシステムを利用したLC/MS/MS方法で分析した。デキサメタゾンを内部標準として使用した。ニトロキソリンのピークを、目標とするm/z=190.9及び144.7のフラグメントによりモニタした。線形性の範囲は、25-5000ng/mLとした。様々な時間帯における尿試料中に観察されたニトロキソリンの量について表3にまとめる。
体重が15-20gの範囲の6匹の雄のCD−1ICRマウスそれぞれに対して、終夜絶食後、41.8mg/Kgのニトロキソリンを経口投与した。0-2、2-6、6-24時の各時間帯に尿試料を収集した。マウスの尿は少量なので、ケージ内収集システムは収集時間ごとに水で洗浄された。尿試料及び洗浄試料が、ビーグル犬の実験(実施例24)と同じ方法で分析された。様々な時間帯でのマウスの尿試料から観察されたニトロキソリン量について表5にまとめる。
1. Shim JS, Matsui Y, Bhat S, Nacev BA, Xu J, Bhang HE, Dhara S, Han KC, Chong CR, Pomper MG, So A, Liu JO. Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst. 2010; 102(24):1855-73. Erratum in: J Natl Cancer Inst. 2011; 103(13):1070.
2. Mirkovic B, Renko M, Turk S, Sosic I, Jevnikar Z, Obermajer N, Turk D, Gobec S, Kos J. Novel mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds. ChemMedChem. 2011; 6(8):1351-6
3. Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE, Ding WQ. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline). Cancer Lett. 2011; 312(1):11-7.
4. Bergogne-Berezin E, Berthelot G, Muller-Serieys C. Present status of nitroxoline Pathol Biol (Paris). 1987; 35 (5 Pt 2):873-8.
5. Yatsenko AV, Paseshnichenko KA, Chernysheva VV and Schenkb H Powder diffraction study of the hydrogen bonds in nitroxoline and its hydrochloride Acta Cryst. 2002; C58: 19-21.
6. Gao GY, Lin SY Thermodynamic Investigations of Nitroxoline Sublimation by Simultaneous DSC-FTIR Method and Isothermal TG Analysis J. Pharm. Sciences 2009: 1-7.
Claims (25)
- ニトロキソリンの塩基付加塩。
- 前記塩がアルカリ金属塩である請求項1に記載の塩。
- 前記アルカリ金属がナトリウム又はカリウムである請求項2に記載の塩。
- 前記塩がアンモニウム塩又は四級アンモニウム塩である請求項1に記載の塩。
- 前記四級アンモニウムがコリンである請求項4に記載の塩。
- 前記塩がアミン塩である請求項1に記載の塩。
- 前記アミンが、アルキルアミン、複素環アミン、アリールアミン、ヘテロアリールアミン、塩基性アミノ酸、アミノ糖、ポリアミン、アルケニルアミン、アルキニルアミン及び脂環式アミンからなる群より選択される請求項6に記載の塩。
- 前記アミンが、コリン、ジエチルアミン、2-ジエチルアミノエタノール、N,N-ジメチルエタノールアミン、トロメタミン、エタノールアミン、及びジオールアミンからなる群より選択される置換又は無置換のアルキルアミンである請求項6に記載の塩。
- 前記アミンがピペラジン、ピロリジン、モルホリン、1-(2-ヒドロキシルエチル) -ピロリジン及び4-(2-ヒドロキシエチル)モルホリンからなる群より選択される複素環アミンである請求項6に記載の塩。
- 前記アミンがアルギニン及びリジンからなる群より選択される塩基性アミノ酸である請求項6に記載の塩。
- 前記アミンがN-メチルグルカミンである請求項6に記載の塩。
- 前記アミンがエチレンジアミンである請求項6に記載の塩。
- 前記塩が、アセトン、メチルイソブチルケトン、ジクロロメタン、トルエン、ピリジン、イソブチロニトリル、アセトニトリル、テトラヒドロフラン、メタノール、エタノール、及びイソプロパノールからなる群より選択される1つ以上の溶媒中で、ニトロキソリンとアルカリ金属水酸化物、アミン、水酸化四級アンモニウム、及び水酸化アンモニウムからなる群より選択される塩基とを混合して得られる請求項1に記載の塩。
- 前記塩が、4.5と8との間のpHの水又は水媒体において少なくとも0.1mg/mLの溶解度を有する請求項1〜13のいずれかに記載の塩。
- ニトロキソリンの塩基付加塩の製造方法であって、
(i)溶媒中でニトロキソリンと塩基とを混合してニトロキソリンの前記塩基付加塩を取得すること、及び
(ii)前記溶媒からニトロキソリンの前記塩基付加塩を回収することを含む方法。 - 前記溶媒が、アセトン、メチルイソブチルケトン、ジクロロメタン、トルエン、ピリジン、イソブチロニトリル、アセトニトリル、テトラヒドロフラン、メタノール、エタノール、及びイソプロパノールからなる群より選択される1つ以上の溶媒を含む請求項15に記載の方法。
- 前記回収工程がニトロキソリンの前記塩基付加塩を前記溶媒から結晶化することを含む請求項15に記載の方法。
- 粉末X線回折パターンにおいて、精度±0.2θの回折角(2θ):9.96、12.12、17.72及び20.08にピークを有するニトロキソリンコリン塩の結晶。
- 治療上有効な量の請求項1〜14のいずれか一項に記載のニトロキソリンの塩基付加塩又は請求項18に記載のニトロキソリンコリン塩の結晶と一つ以上の薬学的に許容可能な担体とを含む医薬組成物。
- 前記医薬組成物が徐放性組成物である請求項19に記載の医薬組成物。
- 前記組成物が液体組成物である請求項19に記載の医薬組成物。
- 前記医薬組成物が注射投与のために製剤化されている請求項19に記載の医薬組成物。
- 治療上有効な量のニトロキソリンの前記塩基付加塩と一つ以上の薬学的に許容可能な担体とを組み合わせることを含む請求項19〜22のいずれか一項に記載の医薬組成物の製造方法。
- それを必要とする対象において疾病、障害又は身体異常を治療又は予防する方法であって、請求項19〜22のいずれか一項に記載の医薬組成物を、前記対象に投与することを含み、前記疾病、障害又は身体異常が尿路感染症、血管新生に伴う疾病、腫瘍、及び癌からなる群より選択される方法。
- それを必要とする対象で泌尿器保護効果を与える方法であって、請求項19〜22のいずれか一項に記載の医薬組成物を、前記対象に投与することを含む方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361790059P | 2013-03-15 | 2013-03-15 | |
US61/790,059 | 2013-03-15 | ||
PCT/US2014/030532 WO2014145723A1 (en) | 2013-03-15 | 2014-03-17 | Base addition salts of nitroxoline and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016514705A true JP2016514705A (ja) | 2016-05-23 |
JP6273349B2 JP6273349B2 (ja) | 2018-01-31 |
Family
ID=51538074
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016503414A Active JP6273349B2 (ja) | 2013-03-15 | 2014-03-17 | ニトロキソリンの塩基付加塩及びその使用 |
Country Status (12)
Country | Link |
---|---|
US (1) | US9758484B2 (ja) |
EP (1) | EP2970128B1 (ja) |
JP (1) | JP6273349B2 (ja) |
KR (1) | KR20160021077A (ja) |
CN (1) | CN105228984B (ja) |
AU (2) | AU2014232722B2 (ja) |
BR (1) | BR112015022849B1 (ja) |
CA (1) | CA2907338C (ja) |
ES (1) | ES2766758T3 (ja) |
HK (1) | HK1214589A1 (ja) |
MX (1) | MX357888B (ja) |
WO (1) | WO2014145723A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180129873A (ko) * | 2016-03-31 | 2018-12-05 | 아시이리스 파머수티클 테크놀로지스 코퍼레이션 리미티드 | 암 치료에서 니트록솔린 및 그의 유사체의 화학요법 및 면역요법과의 조합적 사용 |
CN112402388A (zh) * | 2019-08-05 | 2021-02-26 | 江苏亚虹医药科技股份有限公司 | 一种用于治疗膀胱癌的口服固体制剂及其制备方法 |
WO2021136381A1 (zh) | 2019-12-31 | 2021-07-08 | 江苏亚虹医药科技股份有限公司 | 含硝羟喹啉的药物组合物、硝羟喹啉片剂及其制备方法和用途 |
CN111773193A (zh) * | 2020-07-03 | 2020-10-16 | 江苏亚虹医药科技有限公司 | 含硝羟喹啉赖氨酸盐的药物组合物及其制备方法和用途 |
CN111960998A (zh) * | 2020-08-03 | 2020-11-20 | 江苏亚虹医药科技有限公司 | 硝羟喹啉衍生物及其制备方法和用途 |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3872128A (en) * | 1972-03-08 | 1975-03-18 | Union Carbide Corp | Antimicrobial hydroxy quinoline, ethylene-acrylic polymer compositions |
JPS5768831A (en) * | 1980-10-17 | 1982-04-27 | Fuji Photo Film Co Ltd | Heat developable photosensitive material |
US4329185A (en) * | 1981-01-21 | 1982-05-11 | Dso "Pharmachim" | Method for the preparation of a biologically active polyamide net |
JPS57101835A (en) * | 1980-12-17 | 1982-06-24 | Fuji Photo Film Co Ltd | Thermodevelopable photosensitive material |
JPH03284734A (ja) * | 1990-03-31 | 1991-12-16 | Toshiba Corp | 有機非線形光学材料 |
JP2003520814A (ja) * | 2000-01-26 | 2003-07-08 | ニコックス エス エイ | 抗菌剤の硝酸塩 |
US20080207673A1 (en) * | 2005-05-04 | 2008-08-28 | Michel Xilinas | Method for Treating Cancer, Coronary, Inflammatory and Macular Disease, Combining the Modulation of Zinc-and/or Copper Dependent Proteins |
JP2010500875A (ja) * | 2006-08-21 | 2010-01-14 | アイトゲネシシェ・テヒニーシェ・ホッホシューレ・チューリッヒ | Fynキナーゼの改変sh3ドメインを含む特異的かつ高親和性の結合タンパク質 |
JP2010070557A (ja) * | 2009-12-17 | 2010-04-02 | Anacor Pharmaceuticals Inc | 加水分解抵抗性ホウ素含有治療薬および使用法 |
WO2011091973A1 (en) * | 2010-01-28 | 2011-08-04 | University Of Ljubljana | 5-nitro-8-hydroxyquinolines as inhibitors of cathepsin b |
US20110301163A1 (en) * | 2008-10-06 | 2011-12-08 | The Johns Hopkins University | Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders |
JP2012100678A (ja) * | 2005-05-11 | 2012-05-31 | Eidgenoessische Technische Hochschule Zuerich | 原核細胞由来の組み換えn−グリコシル化タンパク質 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2745834A (en) * | 1953-02-09 | 1956-05-15 | Phillips Petroleum Co | Stabilization of certain vinyl-pyridines, vinyl quinolines and vinyl-isoquinolines |
US2745832A (en) * | 1954-03-08 | 1956-05-15 | Nuodex Products Co Inc | Metal quinolinolates and methods of making the same |
US5242892A (en) | 1984-07-27 | 1993-09-07 | The Board Of Trustees Of The University Of Illinois | Chlorophyll biosynthesis modulators |
US7511137B2 (en) * | 2003-12-19 | 2009-03-31 | Rigel Pharmaceuticals, Inc. | Stereoisomers and stereoisomeric mixtures of 1-(2,4-pyrimidinediamino)-2-cyclopentanecarboxamide synthetic intermediates |
TWI328006B (en) | 2003-12-26 | 2010-08-01 | Nissan Chemical Ind Ltd | Crystal form of quinoline compound and process for its production |
EP2435036A2 (en) | 2009-05-28 | 2012-04-04 | Merck Patent GmbH | Ammoniumcarboxylates |
DK2730123T3 (da) * | 2011-07-07 | 2020-03-02 | Ericsson Telefon Ab L M | Overleveringsbeslutning i betjenende basisstation baseret på en første og anden type mobilitetsmekanisme |
-
2014
- 2014-03-17 JP JP2016503414A patent/JP6273349B2/ja active Active
- 2014-03-17 WO PCT/US2014/030532 patent/WO2014145723A1/en active Application Filing
- 2014-03-17 US US14/777,185 patent/US9758484B2/en active Active
- 2014-03-17 CA CA2907338A patent/CA2907338C/en active Active
- 2014-03-17 AU AU2014232722A patent/AU2014232722B2/en active Active
- 2014-03-17 MX MX2015012720A patent/MX357888B/es active IP Right Grant
- 2014-03-17 CN CN201480025681.5A patent/CN105228984B/zh active Active
- 2014-03-17 ES ES14762230T patent/ES2766758T3/es active Active
- 2014-03-17 EP EP14762230.2A patent/EP2970128B1/en active Active
- 2014-03-17 BR BR112015022849-6A patent/BR112015022849B1/pt active IP Right Grant
- 2014-03-17 KR KR1020157028976A patent/KR20160021077A/ko active Search and Examination
-
2016
- 2016-03-02 HK HK16102445.9A patent/HK1214589A1/zh unknown
-
2017
- 2017-02-07 AU AU2017200820A patent/AU2017200820A1/en not_active Abandoned
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3872128A (en) * | 1972-03-08 | 1975-03-18 | Union Carbide Corp | Antimicrobial hydroxy quinoline, ethylene-acrylic polymer compositions |
JPS5768831A (en) * | 1980-10-17 | 1982-04-27 | Fuji Photo Film Co Ltd | Heat developable photosensitive material |
JPS57101835A (en) * | 1980-12-17 | 1982-06-24 | Fuji Photo Film Co Ltd | Thermodevelopable photosensitive material |
US4329185A (en) * | 1981-01-21 | 1982-05-11 | Dso "Pharmachim" | Method for the preparation of a biologically active polyamide net |
JPH03284734A (ja) * | 1990-03-31 | 1991-12-16 | Toshiba Corp | 有機非線形光学材料 |
JP2003520814A (ja) * | 2000-01-26 | 2003-07-08 | ニコックス エス エイ | 抗菌剤の硝酸塩 |
US20080207673A1 (en) * | 2005-05-04 | 2008-08-28 | Michel Xilinas | Method for Treating Cancer, Coronary, Inflammatory and Macular Disease, Combining the Modulation of Zinc-and/or Copper Dependent Proteins |
JP2012100678A (ja) * | 2005-05-11 | 2012-05-31 | Eidgenoessische Technische Hochschule Zuerich | 原核細胞由来の組み換えn−グリコシル化タンパク質 |
JP2010500875A (ja) * | 2006-08-21 | 2010-01-14 | アイトゲネシシェ・テヒニーシェ・ホッホシューレ・チューリッヒ | Fynキナーゼの改変sh3ドメインを含む特異的かつ高親和性の結合タンパク質 |
US20110301163A1 (en) * | 2008-10-06 | 2011-12-08 | The Johns Hopkins University | Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders |
JP2010070557A (ja) * | 2009-12-17 | 2010-04-02 | Anacor Pharmaceuticals Inc | 加水分解抵抗性ホウ素含有治療薬および使用法 |
WO2011091973A1 (en) * | 2010-01-28 | 2011-08-04 | University Of Ljubljana | 5-nitro-8-hydroxyquinolines as inhibitors of cathepsin b |
Non-Patent Citations (3)
Title |
---|
ANTIMICROB. AGENTS CHEMOTHER., vol. 39, JPN6016043189, 1995, pages 707 - 713, ISSN: 0003699680 * |
EUR. POLYM. J., vol. 29, JPN6016043190, 1993, pages 715 - 720, ISSN: 0003699681 * |
MAN-MADE TEXTITLE IN INDIA, vol. 48, JPN6016043188, 2005, pages 216 - 219, ISSN: 0003437136 * |
Also Published As
Publication number | Publication date |
---|---|
ES2766758T3 (es) | 2020-06-15 |
CA2907338C (en) | 2019-09-17 |
EP2970128B1 (en) | 2019-12-04 |
JP6273349B2 (ja) | 2018-01-31 |
KR20160021077A (ko) | 2016-02-24 |
CN105228984B (zh) | 2018-03-23 |
AU2014232722B2 (en) | 2017-03-09 |
MX2015012720A (es) | 2016-06-21 |
US20160031819A1 (en) | 2016-02-04 |
CN105228984A (zh) | 2016-01-06 |
AU2014232722A1 (en) | 2015-09-24 |
WO2014145723A1 (en) | 2014-09-18 |
AU2017200820A1 (en) | 2017-03-02 |
BR112015022849A2 (pt) | 2017-12-26 |
MX357888B (es) | 2018-07-27 |
EP2970128A4 (en) | 2016-11-30 |
HK1214589A1 (zh) | 2016-07-29 |
EP2970128A1 (en) | 2016-01-20 |
CA2907338A1 (en) | 2014-09-18 |
BR112015022849B1 (pt) | 2020-02-18 |
US9758484B2 (en) | 2017-09-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2905993C (en) | Substituted 4-amino-pyrimidinyl-2-amino-phenyl derivatives and pharmaceutical compositions thereof for use as jak2 and alk2 inhibitors | |
JP6273349B2 (ja) | ニトロキソリンの塩基付加塩及びその使用 | |
CA3088927A1 (en) | Biaryl derivative, preparation method therefor and pharmaceutical use thereof | |
JP5826972B2 (ja) | 酸セラミダーゼインヒビターおよびそれらの医薬としての使用 | |
CN107108593B (zh) | 作为类香草素受体配体ii的基于取代的恶唑和噻唑的羧酰胺和脲衍生物 | |
DE102008052943A1 (de) | Azaindolderivate | |
RU2600928C2 (ru) | Цианохинолиновые производные | |
EP3679029B1 (en) | Imidazolidine compounds | |
CN105503827A (zh) | Egfr抑制剂及其制备方法和用途 | |
DE102010034699A1 (de) | Pyrimidinderivate | |
US20220242861A1 (en) | Imidazopyridinyl compounds and use thereof for treatment of proliferative disorders | |
WO2016210345A1 (en) | Composition and methods for inhibiting mammalian sterile 20-like kinase 1 | |
KR101710740B1 (ko) | 2-[[[2-[(히드록시아세틸)아미노]-4-피리디닐]메틸]티오]-n-[4-(트리플루오로메톡시)페닐]-3-피리딘카르복사미드의 벤젠술폰산염, 이의 결정, 이의 결정 다형 및 이들의 제조 방법 | |
KR20010013026A (ko) | 세포 증식 억제제로서의 시아노구아니딘 | |
WO2022017494A1 (zh) | 一种哒嗪类衍生物自由碱的晶型及其制备方法和应用 | |
JP2016539993A (ja) | N−置換ピラゾリルグアニジンf1f0−atpアーゼ阻害剤及びその治療用途 | |
JP2022535870A (ja) | Cdk9阻害剤の結晶多形体及びその製造方法と用途 | |
TW201823236A (zh) | 聯芳組成物和調控激酶級聯之方法 | |
CN115028633A (zh) | 吡咯并嘧啶类化合物的制备及其应用 | |
WO2011145548A1 (ja) | ジ(アリールアミノ)アリール化合物の結晶 | |
TWI720269B (zh) | 用於調節刺蝟途徑之雜芳基胺化合物及其製法及用途 | |
JP7441213B2 (ja) | エストロゲン受容体陽性乳癌の治療のための併用療法 | |
US20160318938A1 (en) | CRYSTALS (2) OF PYRAZINO[2,1-c][1,2,4]TRIAZINE COMPOUND | |
WO2018035950A1 (zh) | 作为酪氨酸蛋白激酶抑制剂的一类化合物 | |
JP2018518515A (ja) | フェニルアミノピリミジン化合物またはその塩の多形物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20161115 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170214 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20170606 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171005 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171031 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20171122 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20171212 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180105 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6273349 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S631 | Written request for registration of reclamation of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313631 |
|
S634 | Written request for registration of reclamation of nationality |
Free format text: JAPANESE INTERMEDIATE CODE: R313634 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |