US20210315886A1 - Imidazotetrazine compounds - Google Patents
Imidazotetrazine compounds Download PDFInfo
- Publication number
- US20210315886A1 US20210315886A1 US17/266,770 US201917266770A US2021315886A1 US 20210315886 A1 US20210315886 A1 US 20210315886A1 US 201917266770 A US201917266770 A US 201917266770A US 2021315886 A1 US2021315886 A1 US 2021315886A1
- Authority
- US
- United States
- Prior art keywords
- tmz
- compound
- alkyl
- cancer
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- LYHRBIAPWZFXBG-UHFFFAOYSA-N 7h-imidazo[4,5-e]tetrazine Chemical class N1=NNC2=NC=NC2=N1 LYHRBIAPWZFXBG-UHFFFAOYSA-N 0.000 title abstract description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 163
- 238000000034 method Methods 0.000 claims description 61
- -1 —C(═O)Ra Chemical group 0.000 claims description 56
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 43
- 208000005017 glioblastoma Diseases 0.000 claims description 38
- 206010028980 Neoplasm Diseases 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 125000006519 CCH3 Chemical group 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 30
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 22
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 231100000226 haematotoxicity Toxicity 0.000 abstract description 8
- 230000002503 metabolic effect Effects 0.000 abstract description 7
- 238000010172 mouse model Methods 0.000 abstract description 7
- 238000011156 evaluation Methods 0.000 abstract description 6
- 238000010189 synthetic method Methods 0.000 abstract description 6
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 124
- 229960004964 temozolomide Drugs 0.000 description 124
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 43
- 241000699670 Mus sp. Species 0.000 description 35
- 210000004556 brain Anatomy 0.000 description 32
- QXYCTGXCOQXVRU-UHFFFAOYSA-N 8-acetyl-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound N1=NN(C)C(=O)N2C1=C(C(=O)C)N=C2 QXYCTGXCOQXVRU-UHFFFAOYSA-N 0.000 description 27
- 238000011282 treatment Methods 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000007787 solid Substances 0.000 description 24
- 150000001408 amides Chemical class 0.000 description 23
- 102100025825 Methylated-DNA-protein-cysteine methyltransferase Human genes 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- 108040008770 methylated-DNA-[protein]-cysteine S-methyltransferase activity proteins Proteins 0.000 description 22
- 238000001727 in vivo Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 229940002612 prodrug Drugs 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 210000004369 blood Anatomy 0.000 description 18
- 239000008280 blood Substances 0.000 description 18
- 238000000132 electrospray ionisation Methods 0.000 description 18
- 238000004896 high resolution mass spectrometry Methods 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 230000001093 anti-cancer Effects 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 210000002966 serum Anatomy 0.000 description 16
- 230000008499 blood brain barrier function Effects 0.000 description 15
- 210000001218 blood-brain barrier Anatomy 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 210000003169 central nervous system Anatomy 0.000 description 13
- 239000002552 dosage form Substances 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 108020004414 DNA Proteins 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 230000001965 increasing effect Effects 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 0 *N1N=NC2=C([1*])N=C([3*])N2C1=C Chemical compound *N1N=NC2=C([1*])N=C([3*])N2C1=C 0.000 description 10
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 10
- 239000013543 active substance Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 210000001853 liver microsome Anatomy 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241000124008 Mammalia Species 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229960005524 O6-benzylguanine Drugs 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 241000894007 species Species 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000002349 favourable effect Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000004113 cell culture Methods 0.000 description 7
- 125000000664 diazo group Chemical class [N-]=[N+]=[*] 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- BXJHWYVXLGLDMZ-UHFFFAOYSA-N 6-O-methylguanine Chemical compound COC1=NC(N)=NC2=C1NC=N2 BXJHWYVXLGLDMZ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 210000000265 leukocyte Anatomy 0.000 description 6
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 102200082402 rs751610198 Human genes 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- SLYAKFNETBOCEE-UHFFFAOYSA-N 3,8-dimethylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound N1=NN(C)C(=O)N2C1=C(C)N=C2 SLYAKFNETBOCEE-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 5
- 210000001589 microsome Anatomy 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- JIKHCVGEYSELGY-UHFFFAOYSA-N 3-methyl-8-phenylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound C1(=O)N2C=NC(C3=CC=CC=C3)=C2N=NN1C JIKHCVGEYSELGY-UHFFFAOYSA-N 0.000 description 4
- KSEFBYAEHWXHLM-UHFFFAOYSA-N 5-bromo-4-nitro-1h-imidazole Chemical compound [O-][N+](=O)C=1N=CNC=1Br KSEFBYAEHWXHLM-UHFFFAOYSA-N 0.000 description 4
- 206010065553 Bone marrow failure Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- ILCWPURMMPQERK-UHFFFAOYSA-N S-ethyl 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioate Chemical compound CN1N=NC=2N(C1=O)C=NC=2C(SCC)=O ILCWPURMMPQERK-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000003349 alamar blue assay Methods 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 4
- 229960002216 methylparaben Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- GRRYSIXDUIAUGY-UHFFFAOYSA-N n-methylcarbamoyl chloride Chemical compound CNC(Cl)=O GRRYSIXDUIAUGY-UHFFFAOYSA-N 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 231100000057 systemic toxicity Toxicity 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- YQNRVGJCPCNMKT-LFVJCYFKSA-N 2-[(e)-[[2-(4-benzylpiperazin-1-ium-1-yl)acetyl]hydrazinylidene]methyl]-6-prop-2-enylphenolate Chemical group [O-]C1=C(CC=C)C=CC=C1\C=N\NC(=O)C[NH+]1CCN(CC=2C=CC=CC=2)CC1 YQNRVGJCPCNMKT-LFVJCYFKSA-N 0.000 description 3
- JRPIJYQHDFBYRU-UHFFFAOYSA-N 3-methyl-4-oxo-N-(2-oxopropyl)imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide Chemical compound C1(=O)N2C=NC(C(=O)NCC(=O)C)=C2N=NN1C JRPIJYQHDFBYRU-UHFFFAOYSA-N 0.000 description 3
- UNCSYWYTUBIMHD-UHFFFAOYSA-N 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide Chemical compound O=C1N(C)N=NC2=C(C(N)=S)N=CN21 UNCSYWYTUBIMHD-UHFFFAOYSA-N 0.000 description 3
- MLCWJTSOCRDKDJ-UHFFFAOYSA-N 8-(4-chlorophenyl)-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound C1(=O)N2C=NC(C3=CC=C(Cl)C=C3)=C2N=NN1C MLCWJTSOCRDKDJ-UHFFFAOYSA-N 0.000 description 3
- FFJZXGSDLVYHQH-UHFFFAOYSA-N 8-(4-fluorophenyl)-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound N12C(=O)N(N=NC2=C(N=C1)C1=CC=C(F)C=C1)C FFJZXGSDLVYHQH-UHFFFAOYSA-N 0.000 description 3
- WUDTXRDBMSKXEU-UHFFFAOYSA-N 8-chloro-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound ClC=1N=CN2C=1N=NN(C2=O)C WUDTXRDBMSKXEU-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
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 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
- RRJZCACJJKZDNV-UHFFFAOYSA-N Methyldiazonium ion Chemical compound C[N+]#N RRJZCACJJKZDNV-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000011717 athymic nude mouse Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000004820 blood count Methods 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000001721 carbon Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000007917 intracranial administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- QXYYYPFGTSJXNS-UHFFFAOYSA-N mitozolomide Chemical compound N1=NN(CCCl)C(=O)N2C1=C(C(=O)N)N=C2 QXYYYPFGTSJXNS-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 238000003305 oral gavage Methods 0.000 description 3
- 239000001301 oxygen Chemical group 0.000 description 3
- 238000010979 pH adjustment Methods 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002203 pretreatment Methods 0.000 description 3
- 150000003140 primary amides Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 150000007970 thio esters Chemical class 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000001521 two-tailed test Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- FPHTXVLCFRUKHV-UHFFFAOYSA-N 2-diazoimidazole Chemical compound [N-]=[N+]=C1N=CC=N1 FPHTXVLCFRUKHV-UHFFFAOYSA-N 0.000 description 2
- WWDMZNMQLRYMPJ-UHFFFAOYSA-N 2h-tetrazin-5-one Chemical compound O=C1C=NNN=N1 WWDMZNMQLRYMPJ-UHFFFAOYSA-N 0.000 description 2
- BVQQVSPFQSNCHV-UHFFFAOYSA-N 3-methyl-8-(5-methyl-1,3-oxazol-2-yl)imidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound C1(=O)N2C=NC(=C2N=NN1C)C=1OC(C)=CN=1 BVQQVSPFQSNCHV-UHFFFAOYSA-N 0.000 description 2
- PTBOOAFVLVVLAM-UHFFFAOYSA-N 3-methyl-8-(pyrrolidine-1-carbonyl)imidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound C1(=O)N2C=NC(C(=O)N3CCCC3)=C2N=NN1C PTBOOAFVLVVLAM-UHFFFAOYSA-N 0.000 description 2
- JLYJQBRFULDMTN-UHFFFAOYSA-N 3-methyl-8-[4-(trifluoromethyl)phenyl]imidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound C1(=O)N2C=NC(C3=CC=C(C(F)(F)F)C=C3)=C2N=NN1C JLYJQBRFULDMTN-UHFFFAOYSA-N 0.000 description 2
- MMOHXPNJNVCMRT-UHFFFAOYSA-N 4-diazoimidazole Chemical compound [N-]=[N+]=C1C=NC=N1 MMOHXPNJNVCMRT-UHFFFAOYSA-N 0.000 description 2
- IYLDMQGTZVDXLH-UHFFFAOYSA-N 4-nitro-5-phenyl-1h-imidazole Chemical compound N1=CNC(C=2C=CC=CC=2)=C1[N+](=O)[O-] IYLDMQGTZVDXLH-UHFFFAOYSA-N 0.000 description 2
- NPULRJKDSGAKML-UHFFFAOYSA-O 5-carbamoyl-1h-imidazole-4-diazonium Chemical compound NC(=O)C=1NC=NC=1[N+]#N NPULRJKDSGAKML-UHFFFAOYSA-O 0.000 description 2
- CSFVEPQJWIQXGP-UHFFFAOYSA-N 8-bromo-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound BrC=1N=CN2C=1N=NN(C2=O)C CSFVEPQJWIQXGP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- LEBARYKLRCDOEU-UHFFFAOYSA-N C#CCN1N=N/C2=C(Cl)/N=C\N2C1=O Chemical compound C#CCN1N=N/C2=C(Cl)/N=C\N2C1=O LEBARYKLRCDOEU-UHFFFAOYSA-N 0.000 description 2
- SOZDFISOHTYWTN-UHFFFAOYSA-N CC1=C2NC=NC2=NC=[N+]1[O-] Chemical compound CC1=C2NC=NC2=NC=[N+]1[O-] SOZDFISOHTYWTN-UHFFFAOYSA-N 0.000 description 2
- WOQMHICIAPIYGD-UHFFFAOYSA-N CN(C)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CNC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1 Chemical compound CN(C)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CNC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1 WOQMHICIAPIYGD-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000012624 DNA alkylating agent Substances 0.000 description 2
- 229940126161 DNA alkylating agent Drugs 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- CDEXEOGPGLULPU-UHFFFAOYSA-N N,N-dibutyl-3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide Chemical compound N12C(=O)N(C)N=NC2=C(N=C1)C(=O)N(CCCC)CCCC CDEXEOGPGLULPU-UHFFFAOYSA-N 0.000 description 2
- IUYYOXPPTQJMSH-UHFFFAOYSA-N N,N-diethyl-3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide Chemical compound C1(=O)N2C=NC(C(=O)N(CC)CC)=C2N=NN1C IUYYOXPPTQJMSH-UHFFFAOYSA-N 0.000 description 2
- XMNGSPOWUCNRMO-UHFFFAOYSA-N N-succinimidyl N-methylcarbamate Chemical compound CNC(=O)ON1C(=O)CCC1=O XMNGSPOWUCNRMO-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000004611 cancer cell death Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 201000007455 central nervous system cancer Diseases 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 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
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 125000005265 dialkylamine group Chemical group 0.000 description 2
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000003467 diminishing effect Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000009545 invasion Effects 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
- 230000003902 lesion Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000013160 medical therapy Methods 0.000 description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000033607 mismatch repair Effects 0.000 description 2
- 229950005967 mitozolomide Drugs 0.000 description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- VJMRKWPMFQGIPI-UHFFFAOYSA-N n-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide Chemical compound OCC1=C(C(=O)NCCO)C(C)=NN1C1=CC=CC2=C1SC(CC=1C=C(C=CC=1)C(F)(F)F)=C2 VJMRKWPMFQGIPI-UHFFFAOYSA-N 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000004783 oxidative metabolism Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229940100611 topical cream Drugs 0.000 description 2
- 229940042129 topical gel Drugs 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IKZLMSPFYNDYIL-UHFFFAOYSA-N (5E)-5-diazoimidazole-4-carboxamide Chemical compound NC(=O)C1=NC=NC1=[N+]=[N-] IKZLMSPFYNDYIL-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- XVZKKIYWHYCKLD-UHFFFAOYSA-N 5-methyl-1h-imidazol-4-amine Chemical compound CC=1NC=NC=1N XVZKKIYWHYCKLD-UHFFFAOYSA-N 0.000 description 1
- WHBHETKRJOEQIG-UHFFFAOYSA-N 5-methyl-1h-imidazol-4-amine;dihydrochloride Chemical compound Cl.Cl.CC=1NC=NC=1N WHBHETKRJOEQIG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 description 1
- GLANOOJJBKXTMI-UHFFFAOYSA-N 9-(9-formylfluoren-9-yl)fluorene-9-carbaldehyde Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1(C=O)C1(C=O)C2=CC=CC=C2C2=CC=CC=C21 GLANOOJJBKXTMI-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- JHGYHIRPZKSABQ-UHFFFAOYSA-N C#CCN1N=N/C2=C(C(N)=O)/N=C\N2C1=O Chemical compound C#CCN1N=N/C2=C(C(N)=O)/N=C\N2C1=O JHGYHIRPZKSABQ-UHFFFAOYSA-N 0.000 description 1
- UINJAFGFDHYXHX-UHFFFAOYSA-N C#CCN1N=NC2=C(C(N)=O)N=CN2C1=O.C#CCN1N=NC2=C(Cl)N=CN2C1=O Chemical compound C#CCN1N=NC2=C(C(N)=O)N=CN2C1=O.C#CCN1N=NC2=C(Cl)N=CN2C1=O UINJAFGFDHYXHX-UHFFFAOYSA-N 0.000 description 1
- VAVQISHQCKNOMN-UHFFFAOYSA-N C.C.C.C.C.CC(=O)C1=C2N=NN(C)C(=O)N2C=N1.CC1=CN=C(C2=C3N=NN(C)C(=O)N3C=N2)O1.CN(C)C(=O)C1=C2N=NN(C)C(=O)N2C=N1.CN1N=NC2=C(C(N)=O)N=CN2C1=O.CNC(=O)C1=C2N=NN(C)C(=O)N2C=N1 Chemical compound C.C.C.C.C.CC(=O)C1=C2N=NN(C)C(=O)N2C=N1.CC1=CN=C(C2=C3N=NN(C)C(=O)N3C=N2)O1.CN(C)C(=O)C1=C2N=NN(C)C(=O)N2C=N1.CN1N=NC2=C(C(N)=O)N=CN2C1=O.CNC(=O)C1=C2N=NN(C)C(=O)N2C=N1 VAVQISHQCKNOMN-UHFFFAOYSA-N 0.000 description 1
- KZUXXYREDYMUCQ-UHFFFAOYSA-N C.CC(=O)C1=C(N)NC=N1.CC(=O)C1=C2N=NN(C)C(=O)N2C=N1.CCC(=O)N1C=NC(C(C)=O)=C1N.Cl.ClC1=C2N=CN(C3CCCCO3)C2=NC=N1.ClC1=C2N=CNC2=NC=N1.[O-]N1=CN=C2NC=NC2=C1Cl Chemical compound C.CC(=O)C1=C(N)NC=N1.CC(=O)C1=C2N=NN(C)C(=O)N2C=N1.CCC(=O)N1C=NC(C(C)=O)=C1N.Cl.ClC1=C2N=CN(C3CCCCO3)C2=NC=N1.ClC1=C2N=CNC2=NC=N1.[O-]N1=CN=C2NC=NC2=C1Cl KZUXXYREDYMUCQ-UHFFFAOYSA-N 0.000 description 1
- WBIPHNQVEXVROL-KXXNUFKCSA-N C.CC.CC/N=N/C1=C(C(N)=O)N=CN1.CN1N=NC2=C(C(N)=O)N=CN2C1=O.C[AlH2].NC(=O)C1=C(N)NC=N1.O.[N-]=[N+]=C1C=NC=N1.[N-]=[N+]=C1N=CN=C1C(N)=O Chemical compound C.CC.CC/N=N/C1=C(C(N)=O)N=CN1.CN1N=NC2=C(C(N)=O)N=CN2C1=O.C[AlH2].NC(=O)C1=C(N)NC=N1.O.[N-]=[N+]=C1C=NC=N1.[N-]=[N+]=C1N=CN=C1C(N)=O WBIPHNQVEXVROL-KXXNUFKCSA-N 0.000 description 1
- XLRXVXJQGQGZOS-UHFFFAOYSA-N C.CC1=C(=[N+]=[N-])NC=N1.CC1=C(N)NC=N1.CC1=C2N=NN(C)C(=O)N2C=N1.CNC(=O)Cl Chemical compound C.CC1=C(=[N+]=[N-])NC=N1.CC1=C(N)NC=N1.CC1=C2N=NN(C)C(=O)N2C=N1.CNC(=O)Cl XLRXVXJQGQGZOS-UHFFFAOYSA-N 0.000 description 1
- VHLJYSWYRHRBNR-UHFFFAOYSA-N CC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CC1=CN=C(C2=C3\N=NN(C)C(=O)N3/C=N\2)O1 Chemical compound CC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CC1=CN=C(C2=C3\N=NN(C)C(=O)N3/C=N\2)O1 VHLJYSWYRHRBNR-UHFFFAOYSA-N 0.000 description 1
- FQYVEAGHXXVZGI-UHFFFAOYSA-N CC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CCCCN(CCCC)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CCN(CC)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CN(C)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CN1N=N/C2=C(C(=O)N3CCCC3)/N=C\N2C1=O.CNC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1 Chemical compound CC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CCCCN(CCCC)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CCN(CC)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CN(C)C(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1.CN1N=N/C2=C(C(=O)N3CCCC3)/N=C\N2C1=O.CNC(=O)C1=C2\N=NN(C)C(=O)N2/C=N\1 FQYVEAGHXXVZGI-UHFFFAOYSA-N 0.000 description 1
- BSTVSZQIECVASQ-UHFFFAOYSA-N CC(=O)CBr.CC1=CSC(C2=C3N=NN(C)C(=O)N3C=N2)=N1.CN1N=NC2=C(C(=O)O)N=CN2C1=O.CN1N=NC2=C(C(N)=S)N=CN2C1=O Chemical compound CC(=O)CBr.CC1=CSC(C2=C3N=NN(C)C(=O)N3C=N2)=N1.CN1N=NC2=C(C(=O)O)N=CN2C1=O.CN1N=NC2=C(C(N)=S)N=CN2C1=O BSTVSZQIECVASQ-UHFFFAOYSA-N 0.000 description 1
- JCNDTVRMXOXZQM-UHFFFAOYSA-N CC(=O)CN.CC(=O)CNC(=O)C1=C2N=NN(C)C(=O)N2C=N1.CC1=CN=C(C2=C3N=NN(C)C(=O)N3C=N2)O1.CN1N=NC2=C(C(=O)Cl)N=CN2C1=O.Cl.O=P(Cl)(Cl)Cl Chemical compound CC(=O)CN.CC(=O)CNC(=O)C1=C2N=NN(C)C(=O)N2C=N1.CC1=CN=C(C2=C3N=NN(C)C(=O)N3C=N2)O1.CN1N=NC2=C(C(=O)Cl)N=CN2C1=O.Cl.O=P(Cl)(Cl)Cl JCNDTVRMXOXZQM-UHFFFAOYSA-N 0.000 description 1
- FGRGBONLLVDVGC-UHFFFAOYSA-N CC(C)C1=CC=NN1.CC(C)C1=CC=NO1.CC(C)C1=CC=NS1.CC(C)C1=CN=CN1.CC(C)C1=CN=CO1.CC(C)C1=CN=CS1.CC(C)C1=CN=NN1.CC(C)C1=CN=NO1.CC(C)C1=CN=NS1.CC(C)C1=NC=CN1.CC(C)C1=NC=CO1.CC(C)C1=NC=CS1.CC(C)C1=NC=NO1.CC(C)C1=NC=NS1.CC(C)C1=NN=CN1.CC(C)C1=NN=CO1.CC(C)C1=NN=CS1.CC(C)C1=NN=NN1.CC(C)C1=NN=NO1.CC(C)C1=NN=NS1 Chemical compound CC(C)C1=CC=NN1.CC(C)C1=CC=NO1.CC(C)C1=CC=NS1.CC(C)C1=CN=CN1.CC(C)C1=CN=CO1.CC(C)C1=CN=CS1.CC(C)C1=CN=NN1.CC(C)C1=CN=NO1.CC(C)C1=CN=NS1.CC(C)C1=NC=CN1.CC(C)C1=NC=CO1.CC(C)C1=NC=CS1.CC(C)C1=NC=NO1.CC(C)C1=NC=NS1.CC(C)C1=NN=CN1.CC(C)C1=NN=CO1.CC(C)C1=NN=CS1.CC(C)C1=NN=NN1.CC(C)C1=NN=NO1.CC(C)C1=NN=NS1 FGRGBONLLVDVGC-UHFFFAOYSA-N 0.000 description 1
- KHPNYRTVISGFBO-UHFFFAOYSA-N CC(C)C1=C[Y]=[V][W]1 Chemical compound CC(C)C1=C[Y]=[V][W]1 KHPNYRTVISGFBO-UHFFFAOYSA-N 0.000 description 1
- CEOXGZXZIQMISC-UHFFFAOYSA-N CC(C)C1=NC=CN1.CC(C)C1=NC=CO1.CC(C)C1=NC=CS1 Chemical compound CC(C)C1=NC=CN1.CC(C)C1=NC=CO1.CC(C)C1=NC=CS1 CEOXGZXZIQMISC-UHFFFAOYSA-N 0.000 description 1
- IVFIUQYXOJPSOI-UHFFFAOYSA-N CC.CC.CC.CC.CC.CC.CC1=C[Y]C(C2=C3N=NN(C)C(=O)N3C=N2)C1.CN1N=NC2=C(C3=CC=CC=C3)N=CN2C1=O.CN1N=NC2=C([Ar])N=CN2C1=O.CO.NC1=C(C2=CC=CC=C2)N=CN1.O=[N+]([O-])C1=C(Br)N=CN1.O=[N+]([O-])C1=C(C2=CC=CC=C2)N=CN1 Chemical compound CC.CC.CC.CC.CC.CC.CC1=C[Y]C(C2=C3N=NN(C)C(=O)N3C=N2)C1.CN1N=NC2=C(C3=CC=CC=C3)N=CN2C1=O.CN1N=NC2=C([Ar])N=CN2C1=O.CO.NC1=C(C2=CC=CC=C2)N=CN1.O=[N+]([O-])C1=C(Br)N=CN1.O=[N+]([O-])C1=C(C2=CC=CC=C2)N=CN1 IVFIUQYXOJPSOI-UHFFFAOYSA-N 0.000 description 1
- IYGGCJWAPLFFCI-UHFFFAOYSA-N CC1=CC=C(C2=C3\N=NN(C)C(=O)N3/C=N\2)C=C1 Chemical compound CC1=CC=C(C2=C3\N=NN(C)C(=O)N3/C=N\2)C=C1 IYGGCJWAPLFFCI-UHFFFAOYSA-N 0.000 description 1
- CJPZWQQIEHDPMA-UHFFFAOYSA-N CC1=CC=C(N2N=NC3=C(C(N)=O)N=CN3C2=O)C=C1 Chemical compound CC1=CC=C(N2N=NC3=C(C(N)=O)N=CN3C2=O)C=C1 CJPZWQQIEHDPMA-UHFFFAOYSA-N 0.000 description 1
- KQFMTNSJYMHLBI-UHFFFAOYSA-N CC1=CC=C(N2N=NC3=C(C(N)=O)N=CN3C2=O)C=C1.CC1=CC=C(OC#N)C=C1.N=C1N=CN=C1C(N)=O Chemical compound CC1=CC=C(N2N=NC3=C(C(N)=O)N=CN3C2=O)C=C1.CC1=CC=C(OC#N)C=C1.N=C1N=CN=C1C(N)=O KQFMTNSJYMHLBI-UHFFFAOYSA-N 0.000 description 1
- SXEDXGFLFXYNOQ-AZQMUMGESA-N CN(C)/N=N/C1=C(C(N)=O)N=CN1.CN1N=NC2=C(C(N)=O)N=CN2C1=O Chemical compound CN(C)/N=N/C1=C(C(N)=O)N=CN1.CN1N=NC2=C(C(N)=O)N=CN2C1=O SXEDXGFLFXYNOQ-AZQMUMGESA-N 0.000 description 1
- UDHVJROWSSIFMK-UHFFFAOYSA-N CN1N=NC2=C(Br)N=CN2C1=O.CN1N=NC2=C(C(=O)O)N=CN2C1=O Chemical compound CN1N=NC2=C(Br)N=CN2C1=O.CN1N=NC2=C(C(=O)O)N=CN2C1=O UDHVJROWSSIFMK-UHFFFAOYSA-N 0.000 description 1
- HXAVVEZGHAKNDJ-UHFFFAOYSA-N CN1N=NC2=C(C(=O)O)N=CN2C1=O.CN1N=NC2=C(Cl)N=CN2C1=O Chemical compound CN1N=NC2=C(C(=O)O)N=CN2C1=O.CN1N=NC2=C(Cl)N=CN2C1=O HXAVVEZGHAKNDJ-UHFFFAOYSA-N 0.000 description 1
- DOGXLWFEUGJQLZ-UHFFFAOYSA-N CN1N=NC2=C(C3=CC=CC=C3)N=CN2C1=O.CO.NC1=C(C2=CC=CC=C2)N=CN1.O=[N+]([O-])C1=C(Br)N=CN1.O=[N+]([O-])C1=C(C2=CC=CC=C2)N=CN1 Chemical compound CN1N=NC2=C(C3=CC=CC=C3)N=CN2C1=O.CO.NC1=C(C2=CC=CC=C2)N=CN1.O=[N+]([O-])C1=C(Br)N=CN1.O=[N+]([O-])C1=C(C2=CC=CC=C2)N=CN1 DOGXLWFEUGJQLZ-UHFFFAOYSA-N 0.000 description 1
- VVTMIOYTNALQAW-UHFFFAOYSA-N CN1N=Nc2c(C(O)=O)nc[n]2C1=O Chemical compound CN1N=Nc2c(C(O)=O)nc[n]2C1=O VVTMIOYTNALQAW-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- SFJKUSZCQMSHCX-UHFFFAOYSA-N Cc1c[s]c(-c(nc[n]23)c2N=NN(C)C3=O)n1 Chemical compound Cc1c[s]c(-c(nc[n]23)c2N=NN(C)C3=O)n1 SFJKUSZCQMSHCX-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 108020005124 DNA Adducts Proteins 0.000 description 1
- 230000007064 DNA hydrolysis Effects 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000838335 Homo sapiens Dual specificity protein phosphatase 2 Proteins 0.000 description 1
- 101001080401 Homo sapiens Proteasome assembly chaperone 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- BCKDNMPYCIOBTA-RRKCRQDMSA-N O(6)-methyl-2'-deoxyguanosine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 BCKDNMPYCIOBTA-RRKCRQDMSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229960005552 PAC-1 Drugs 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 201000007288 Pleomorphic xanthoastrocytoma Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100027583 Proteasome assembly chaperone 1 Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 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
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000004479 aerosol dispenser 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
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229940082484 carbomer-934 Drugs 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- NMMPMZWIIQCZBA-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylethanamine Chemical compound [Pd+]Cl.NCCC1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 NMMPMZWIIQCZBA-UHFFFAOYSA-M 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007819 coupling partner Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- YQGOWXYZDLJBFL-UHFFFAOYSA-N dimethoxysilane Chemical class CO[SiH2]OC YQGOWXYZDLJBFL-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000005782 double-strand break Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000592 heterocycloalkyl 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000013383 initial experiment Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 201000010893 malignant breast melanoma Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- DYPGZSGGVOBXGN-UHFFFAOYSA-N n,3-dimethyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide Chemical compound N1=NN(C)C(=O)N2C1=C(C(=O)NC)N=C2 DYPGZSGGVOBXGN-UHFFFAOYSA-N 0.000 description 1
- ITCSSQHXIMMGKH-UHFFFAOYSA-N n,n,3-trimethyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide Chemical compound N1=NN(C)C(=O)N2C1=C(C(=O)N(C)C)N=C2 ITCSSQHXIMMGKH-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- UOKZUTXLHRTLFH-UHFFFAOYSA-N o-phenylhydroxylamine Chemical group NOC1=CC=CC=C1 UOKZUTXLHRTLFH-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- CVXGFPPAIUELDV-UHFFFAOYSA-N phenacylazanium;chloride Chemical compound [Cl-].[NH3+]CC(=O)C1=CC=CC=C1 CVXGFPPAIUELDV-UHFFFAOYSA-N 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000004624 phenarsazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3[As]=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000019525 primary metabolic process Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000005783 single-strand break Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 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 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000001425 triazolyl 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
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- GBM Glioblastoma multiforme
- TMZ temozolomide
- TMZ beneficial properties of TMZ are favorable pharmacokinetics (including 100% oral bioavailability 7 ), non-enzymatic prodrug activation, and some accumulation in the brain (cerebral spinal fluid:blood ratio of 17:83 in human cancer patients 8,9 ).
- TMZ provides a significant therapeutic benefit to a subset of GBM patients. For example, in patients whose tumors do not express O 6 -methylguanine DNA methyltransferase (MGMT), an enzyme that removes O 6 -methylguanine lesions, TMZ extends median survival to approximately two years.
- MGMT O 6 -methylguanine DNA methyltransferase
- TMZ Even in the era of personalized anticancer therapy, TMZ remains frontline therapy for oligodendrogliomas, diffuse astrocytic gliomas, and pleomorphic xanthoastrocytomas in addition to GBM. 11 However, given the ineffectiveness of TMZ against tumors expressing MGMT and the inevitable recurrence of GBM after multimodal combination therapy, there remains a significant clinical need for better treatment strategies.
- TMZ is a prodrug activated in aqueous solutions that ultimately releases methyldiazonium, the active alkylating component (Scheme 1(a)).
- the half-life of TMZ is ⁇ 2 hours in vivo and in aqueous solutions in vitro, and it has been suggested that the drug has an increased rate of hydrolysis in the more alkaline environment of gliomas, providing some selectivity for cancerous vs. non-cancerous cells.
- TMZ has been FDA approved for two decades, more efficacious drugs for glioblastoma that have lower systemic toxicity would be desirable. Therapeutic compounds that can reach the entirety of the diffuse tumor in sufficient concentrations to be effective are sought. Accordingly, there is a need for new compounds that possess the desirable properties of TMZ, but have better brain penetration, lower toxicity, and provide improved patient survival rates.
- X is O or S
- R 1 is halo, —CN, —NO 2 , —(C 1 -C 6 )alkyl, —C( ⁇ O)R a , phenyl, or a 5- or 6-membered heterocycle, wherein R a is H, halo, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, OR b , SR b , or —NR b R c ;
- R 2 is —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, propargyl, phenyl, or a 5- or 6-membered heterocycle;
- R 3 is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl;
- each —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, propargyl, phenyl, and 5- or 6-membered heterocycle are optionally substituted with one or more substituents, and each —(C 1 -C 6 )alkyl is unbranched or optionally branched.
- This disclosure also provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed above, wherein the cancer is thereby treated.
- the invention provides novel compounds of Formulas I-III(A/B/C), intermediates for the synthesis of compounds of Formulas I-III, as well as methods of preparing compounds of Formulas I-III.
- the invention also provides compounds of Formulas I-III that are useful as intermediates for the synthesis of other useful compounds.
- the invention provides for the use of compounds of Formulas I-III for the manufacture of medicaments useful for the treatment of bacterial infections in a mammal, such as a human.
- the invention provides for the use of the compositions described herein for use in medical therapy.
- the medical therapy can be treating cancer, for example, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer or brain cancers such as glioblastoma.
- the invention also provides for the use of a composition as described herein for the manufacture of a medicament to treat a disease in a mammal, for example, cancer in a human.
- the medicament can include a pharmaceutically acceptable diluent, excipient, or carrier.
- FIG. 1 Hydrolytic stability of C8-substituted imidazotetrazines.
- (a) The percentage of compound remaining after 2 hours plotted against the Hammett constant of its C8 substituent.
- Compounds with hydrolytic stability similar to TMZ are enclosed in the oval (see Table 1c).
- FIG. 3 Assessment of the hematological toxicity of imidazotetrazines in vivo. Mice were administered a single IV dose of 125 mg/kg imidazotetrazine. After 7 days, whole blood was collected, and a complete blood count was obtained for each individual mouse.
- FIG. 4 Imidazotetrazines were added to T98G cells with or without 3 h pre-treatment of O6BG (100 ⁇ M). IC50 values after 7-day incubation and fold changes between (+/ ⁇ ) O6BG treatments are reported. P-values between IC50 values (+/ ⁇ ) O6BG ⁇ 0.02 for all compounds. Error is SEM, n ⁇ 3. Statistical significance was determined by using a two-sample Student's t-test (two-tailed test, assuming equal variance).
- FIG. 5 Evaluation of imidazotetrazines in intracranial mouse models of GBM.
- GBM Br23c oncospheres were intracranially implanted into female athymic nude mice. Treatment was started 5 days post implantation.
- Mice were administered 15 mg/kg TMZ or an equimolar dose of Me-TMZ (16.1 mg/kg) or DiMe-TMZ (17.2 mg/kg) orally once-per-day, 5 ⁇ /week for 7 weeks.
- Control vs. TMZ: P 0.0014
- TMZ vs. DiMe-TMZ: P 0.061
- TMZ vs. Me-TMZ: P 0.016.
- mice were administered 15 mg/kg TMZ or an equimolar dose of DiMe-TMZ (17.2 mg/kg) or K-TMZ (14.9 mg/kg) orally once-per-day for 5 total doses.
- Control vs. TMZ: P 0.0007
- DiMe-TMZ vs. TMZ: P 0.7
- K-TMZ vs. TMZ: P 0.055.
- Compounds were formulated in 10% PEG in PBS immediately prior to each treatment. Number of mice per treatment cohort ⁇ 5. Survival curves were compared using log-rank test.
- FIG. 6 Western blot for MGMT status of all cell lines used.
- FIG. 7 The hydrolytic stabilities of TMZ and K-TMZ assessed in saline at pH 7.0, 7.4, and 8.0 by calculating the percentage of parent compound remaining after 2 h at 37° C.
- FIG. 8 Assessment of the hematological toxicity of imidazotetrazines in vivo. Mice were treated with a single IV dose of 125 mg/kg imidazotetrazine and a complete blood count was obtained for each mouse after 7 days. (a) Neutrophil concentrations (b) RBC concentrations (c) Platelet concentrations (see Table 2b).
- FIG. 9 GBM oncosphere Br23c cells were intracranially implanted into female athymic nude mice. Treatment was started 5 days post implantation. Mice were administered compound 14 (12.8 mg/kg, equimolar to 15 mg/kg TMZ) orally once-per-day for 5 doses. Compound was formulated in 10% PEG in PBS. n ⁇ 5. This experiment was run alongside that presented in FIG. 5 b ; the control group is the same for FIG. 5 b and FIG. 9 .
- FIG. 10 Development pathway of MGMT-Independent Imidazotetrazines.
- Graph of brain:serum ratio mice were administered 25 mg/kg compound IV. After 15 min, mice were sacrificed, and blood and brain were collected. The concentration of drug in each was quantified by LC-MS/MS. N ⁇ 3 mice per cohort, error is SEM. *P ⁇ 0.05, **P ⁇ 0.01.
- TMZ temozolomide
- GBM glioblastoma
- TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Therefore, discerning the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance was sought.
- BBB blood-brain barrier
- references in the specification to “one embodiment”, “an embodiment”, etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.
- the term “and/or” means any one of the items, any combination of the items, or all of the items with which this term is associated.
- the phrases “one or more” and “at least one” are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit.
- one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is disubstituted.
- the terms “about” and “approximately” are used interchangeably. Both terms can refer to a variation of ⁇ 5%, +10%, +20%, or +25% of the value specified. For example, “about 50” percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim.
- the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range.
- the terms “about” and “approximately” are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment.
- the terms “about” and “approximately” can also modify the endpoints of a recited range as discussed above in this paragraph.
- ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range.
- a recited range e.g., weight percentages or carbon groups
- any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths.
- each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
- all language such as “up to”, “at least”, “greater than”, “less than”, “more than”, “or more”, and the like include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above.
- all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
- contacting refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.
- an “effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
- an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art.
- the term “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
- an “effective amount” generally means an amount that provides the desired effect.
- an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
- an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
- An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations.
- the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).
- treating include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
- the terms “treat”, “treatment”, and “treating” can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated.
- treatment can include medical, therapeutic, and/or prophylactic administration, as appropriate.
- subject or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy.
- a patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein.
- patient may include either adults or juveniles (e.g., children).
- patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein.
- mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
- non-mammals include, but are not limited to, birds, fish and the like.
- the mammal is a human.
- compositions of the disclosure are used interchangeably herein and refer to the placement of the compositions of the disclosure into a subject by a method or route which results in at least partial localization of the composition to a desired site.
- the compositions can be administered by any appropriate route which results in delivery to a desired location in the subject.
- the compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs.
- inhibitor refers to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells.
- the inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.
- substantially is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified.
- the term could refer to a numerical value that may not be 100% the full numerical value.
- the full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%.
- substituted or “substituent” is intended to indicate that one or more (for example, 1-20 in various embodiments, 1-10 in other embodiments, 1, 2, 3, 4, or 5; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a selection from the indicated group(s), or with a suitable group known to those of skill in the art, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- Suitable indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, and cyano.
- substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, CF 3 , OCF 3 , R′, O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R′) 2 , SR′, SOR′, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 NHC(O)R′, N(R′)N(R′)C(O)R′, N(R′)
- a substituent When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
- a substituent When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C ⁇ O, wherein the C and the O are double bonded.
- a divalent substituent such as O, S, C(O), S(O), or S(O) 2 can be connected by two single bonds to two different carbon atoms.
- O a divalent substituent
- the O can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system.
- any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 )n or (CR′ 2 ) n wherein n is 1, 2, 3, or more, and each R′ is independently selected.
- halo or “halide” refers to fluoro, chloro, bromo, or iodo.
- halogen refers to fluorine, chlorine, bromine, and iodine.
- alkyl refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms or a range in between (such as 2-8 or 3-8 carbons), and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below.
- Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (iso-propyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like.
- the alkyl can be unsubstituted or substituted, for example, with a substituent described below.
- the alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include both alkenyl and alkynyl groups.
- the alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene).
- cycloalkyl refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like.
- the cycloalkyl can be unsubstituted or substituted.
- the cycloalkyl group can be monovalent or divalent, and can be optionally substituted as described for alkyl groups.
- the cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like.
- heterocycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring.
- Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
- heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane.
- the group may be a terminal group or a bridging group.
- aryl refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system.
- the radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system.
- the aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. In other embodiments, the aryl group can have 6 to 60 carbons atoms, 6 to 120 carbon atoms, or 6 to 240 carbon atoms.
- the aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl).
- Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted.
- heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring.
- the heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of “substituted”.
- Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms.
- heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, ⁇ -carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
- heteroaryl denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (C 1 -C 6 )alkylaryl.
- heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
- X is O or S
- R 1 is halo, —CN, —NO 2 , —(C 1 -C 6 )alkyl, —C( ⁇ O)R a , phenyl, or a 5- or 6-membered heterocycle, wherein R a is H, halo, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, OR b , SR b , or —NR b R c ; wherein
- R 2 is —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, propargyl, phenyl, or a 5- or 6-membered heterocycle;
- R 3 is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl;
- each —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, propargyl, phenyl, and 5- or 6-membered heterocycle are optionally substituted with one or more substituents, and each —(C 1 -C 6 )alkyl is unbranched or optionally branched.
- the phenyl and —(C 1 -C 6 )alkyl are each independently substituted with, for example but not limited to, halo (e.g., one or more chloro or fluoro), alkoxy, or aminoalkyl.
- the substituents do not include a phenyl group, or the molecular weight of the substituent is less than about 100, about 90, about 80, about 70, about 60, or about 50.
- both R b and R c cannot be H.
- R 1 is —C( ⁇ O)—(C 1 -C 6 )alkyl, —C( ⁇ O)—NH(C 1 -C 6 )alkyl, or —C( ⁇ O)—N[(C 1 -C 6 )alkyl] 2 .
- X is O
- R 3 is H and R 1 is —C( ⁇ O)—(C 1 -C 6 )alkyl, —C( ⁇ O)—NH(C 1 -C 6 )alkyl, or —C( ⁇ O)—N[(C 1 -C 6 )alkyl] 2 .
- X is O and R 1 is —C( ⁇ O)—(C 1 -C 6 )alkyl.
- X is O
- R 2 is —(C 1 -C 6 )alkyl
- R 3 is H.
- R 2 is —(C 1 -C 6 )alkyl and R 3 is H.
- R 2 is propargyl or a substituted phenyl.
- X is O and R 3 is H.
- R 1 is a moiety of Formula IB:
- R 1 is one of:
- R 1 is optionally substituted (at one or the other of the carbon atoms CH, thereby modifying that carbon to C-substituent, wherein the substituent is a substituent as defined herein).
- R 1 is i, ii, or iii:
- R 1 is a para-substituted phenyl, wherein the molecular weight of each substituent is less than about 300, about 200 or about 100 daltons.
- the para-substituent is halo, —CN, —CF 3 , —CF 2 CF 3 , or —(C 1 -C 6 )alkyl.
- R 1 is halo, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl.
- the substituted phenyl is substituted with halo, alkyl, alkoxy, phenoxy, amine, alkylamine, dialkylamine, or combination thereof.
- the compound is:
- the compound of Formula I is a compound of Formula IC:
- G 1 is halo, alkyl, alkoxy, phenoxy, or dialkylamine.
- G 1 is OCH 3 , OCH 2 CH 3 , OPh, or N(CH 3 ) 2 .
- the compound of Formula I is a compound of Formula II:
- R 2 is —(C 1 -C 6 )alkyl and R 3 is H.
- the compound is K-TMZ:
- R a is CH 3 , CH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 ) 2 , N[(CH 2 CH 2 ) 2 O], OCH 3 , OCH 2 CH 3 , SCH 3 , or SCH 2 CH 3 .
- the compound is:
- the compound of Formula I is a compound of Formula IIIA or IIIB:
- R z is H, halo, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl.
- R z is CH 3 or CH 2 CH 3 .
- the compound is:
- This disclosure additionally provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 - 19 , wherein the cancer is thereby treated.
- the cancer is glioblastoma (GBM).
- a composition comprises the compounds disclosed above and a second active agent.
- the second active agent is a procaspase-3 activator, for example PAC-1:
- the disclosed compounds herein and the second active agent are administered to a subject concurrently or sequentially for the treatment of a cancer.
- the disclosed compound and the second active agent are concurrently administered to the subject.
- the disclosed compound and the second active agent are sequentially administered to the subject.
- the disclosed compound is administered to the subject before the second active agent.
- the disclosed compound is administered to the subject after the second active agent.
- the concentration of the disclosed compounds herein is about 1 nM to about 10 ⁇ M. In yet other embodiments, the concentration of the second active agent is about 1 nM to about 1 ⁇ M.
- a range such as “number1” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers.
- 1 to 10 means 1, 2, 3, 4, 5, . . . 9, 10. It also means 1.0, 1.1, 1.2. 1.3, . . . , 9.8, 9.9, 10.0, and also means 1.01, 1.02, 1.03, and so on.
- the variable disclosed is a number less than “number10”, it implies a continuous range that includes whole numbers and fractional numbers less than number10, as discussed above.
- the variable disclosed is a number greater than “number10”, it implies a continuous range that includes whole numbers and fractional numbers greater than number10.
- Challenges of replacing C8 amide include: aqueous sensitivity; base sensitivity; diazoimidazole degradation; and poor substitutes for CH 3 NCO.
- the privileged 4-diazoimidazole-5-carboxamide (1, Scheme 1b) readily precipitates out of solution as a pure, stable compound; however, other 4-diazoimidazoles (such as 2) remain in aqueous solution, are exceptionally prone to decomposition, and are sensitive to heat, shock, and often light.
- installation of the N3-methyl group in the initial route to TMZ was achieved via cyclization with methyl isocyanate. 25 Methyl isocyanate, however, is a poisonous gas and no longer commercially available.
- alternate routes 27 or less effective alternatives to methyl isocyanate such as N-succinimidyl N-methylcarbamate or N-methylcarbamic chloride must be used that reduce the yield of the cyclizations.
- heterocyclic compounds 27 and 28 (Scheme 2e) were synthesized upon cyclization of the C8 amide or thioamide, respectively; an analogous route had been utilized to introduce bulkier 4-substituted oxazoles and thiazoles at the C8 position, 19 but not smaller methyl groups.
- TMZ Hydrolytic stability of C8 substituted imidazotetrazines.
- the principal aspect governing the anticancer activity of imidazotetrazines is the hydrolytic activation of the prodrug.
- Scheme 1(a) TMZ has a half-life of ⁇ 2 hours in humans. 7 This timeline allows the intact prodrug to reach the brain and release the active methylating component prior to elimination. Beyond TMZ, the relationship between imidazotetrazine stability and anticancer activity is unknown; that is, while hydrolytic activation is required for cancer cell death, the optimal timing of this event is unclear both in vitro and in vivo.
- Methyl and phenyl derivatives 14 and 23 were consistently the most potent compounds in each of the tested cell lines (Table 1a). Interestingly, they also possessed electron-donating substituents and, accordingly, the greatest aqueous stability ( FIG. 1 ), suggesting that a longer-lived prodrug is favorable for efficacy in cell culture. The opposite effect was observed for compound 11, which was the least stable in solution. Even in U87 cells lacking MGMT, it exhibited a ten-fold loss of activity compared to TMZ, suggesting that there is a critical threshold of aqueous stability below which hydrolysis occurs too quickly to methylate target DNA.
- TMZ hydrolytic stabilities similar to TMZ such as 4, 5, 17, 19, and 27 retained activity in culture.
- ketone derivative 17 was equipotent to TMZ even with a shorter aqueous half-life, indicating that compounds with ⁇ p ⁇ 0.50 can still retain marked anticancer activity.
- TMZ Liver microsome stability.
- TMZ fortuitously possesses several ideal pharmacokinetic properties including avoidance of primary metabolism. 7
- the stabilities of select compounds were assessed after 2 hours in the presence of mouse liver microsomes. Prodrug hydrolysis was accounted for by including control runs that did not contain liver microsomes. The slightly acidic pH of the working solution resulted in enhanced stability of TMZ compared to incubation in PBS alone. Predictably, TMZ was insensitive to metabolic perturbation as its instability was entirely accounted for by hydrolysis (Table 2a).
- CNS MPO scores span from 0 to 6.0 based on the optimal ranges of 6 physicochemical properties. Though TMZ has an agreeable MPO of 4.9, higher scores were achieved for the C8 analogs, which in several cases reached the top desirability value (Table 2a). The more favorable c Log BB and CNS MPO values predicted for the panel suggests that certain derivatives may achieve higher drug concentrations in the brain than TMZ.
- TMZ had a relative brain:serum ratio of 0.23 ⁇ 0.03 ng/g:ng/mL, comparable to the few other TMZ biodistribution experiments in murine systems. 41,42 Assigning average mouse blood volumes to equate units, TMZ had an absolute brain:serum ratio of 8:92, while Ox-TMZ and K-TMZ boasted brain:serum ratios of 55:45 and 69:31, respectively.
- FIG. 2 d The dramatic differences in drug partitioning suggest that replacing the amide at C8 is a viable strategy to significantly increase local drug concentration in the brain relative to the blood, which may increase effectiveness against brain tumors and also reduce hematological toxicity.
- Novel imidazotetrazines induce alkylation-mediated cancer cell death.
- the cytotoxicity of TMZ is mediated by methylation of O 6 guanine; subsequent single- and double-strand breaks and apoptosis are facilitated by the mismatch repair system.
- 2-6 To assess if the novel imidazotetrazines kill through the same mechanism, O 6 -methylguanine adducts were quantitated in U87 cells treated with 100 or 1000 ⁇ M of each imidazotetrazine. After 8 hours of incubation with compound, the genomic DNA was isolated, quantified, and hydrolyzed to its constituent deoxyribonucleosides, which were quantitated via LC-MS/MS analysis.
- O6BG O 6 -benzylguanine
- O6BG is a pseudosubstrate for MGMT that quenches cellular stores of the enzyme, leading to the persistence of O 6 -methylguanine DNA adducts.
- Pre-incubation of MGMT-expressing T98G cells with O6BG (100 ⁇ M) led to an eight-fold enhancement in cytotoxicity for TMZ ( FIG. 4 ), consistent with literature reports. 45,46 Similarly, DiMe-TMZ, Ox-TMZ, and K-TMZ demonstrated a significant increase in activity when administered after O6BG, suggesting that O 6 -methylguanine lesions are the cause of cell death.
- Novel imidazotetrazines have superior activity in mouse models of GBM.
- the increased BBB penetrance observed for amide derivatives (Me-TMZ and DiMe-TMZ) relative to TMZ suggested that greater drug concentrations in the brain might lead to greater efficacy in an intracranial tumor model.
- GBM oncosphere lines were chosen for these studies as they more accurately recapitulate the genetic and histopathological features of human GBM than traditional adherent cell lines, which are passaged in serum and typically grow as compact masses in vivo. 47
- the Br23c GBM oncosphere cell line does not express MGMT, was sensitive to TMZ and the novel C8-substituted imidazotetrazines (Table 2d), and was thus chosen as the model system.
- mice implanted intracranially with these cells were administered 15 mg/kg TMZ or the equimolar equivalent of Me-TMZ or DiMe-TMZ once-per-day, 5 ⁇ /week via oral gavage.
- TMZ significantly increased median survival compared with vehicle ( FIG. 5 a ).
- Mice treated with both Me-TMZ and DiMe-TMZ however, outperformed TMZ and increased median survival by 24% and 46%, respectively, suggesting that increasing the BBB-permeability of imidazotetrazine prodrugs is a viable strategy to improve efficacy.
- K-TMZ was selected for evaluation due to its most favorable brain:blood ratio ( FIG. 2 d ).
- mice intracranially implanted with Br23c cells were treated with K-TMZ (via oral gavage), which led to an extended median survival of more than 50 days past TMZ-treated mice, and showed greater efficacy even compared to DiMe-TMZ ( FIG. 5 b ).
- methyl derivative 14 which has excellent efficacy in cell culture but an extended (40 hour) half-life in aqueous solution, had no effect in this in vivo model ( FIG. 9 ) suggesting that dramatically elongated half-lives are detrimental in vivo, likely due to compound clearance prior to hydrolytic activation.
- TMZ remains the only approved imidazotetrazine anticancer drug; this likely stems from the lack of generalized syntheses for this class of compounds prohibiting conventional medicinal chemistry campaigns.
- Herein is reported new synthetic methods that enable the construction of novel C8-substituted imidazotetrazines that were previously inaccessible. Evaluation of these compounds in systematic, head-to-head assays led to the definitive conclusion that the C8 amide is not required for anticancer activity, and indeed compounds lacking an H-bond donor or acceptor (or both) at C8 can still retain activity comparable to TMZ against cancer cells in culture.
- TMZ remains the gold-standard for treating the most aggressive brain tumors, shows promise against brain metastases from other cancers, 54 and its predictable activity (based on clinical biomarkers) has recently led to advocation for an expanded use of TMZ in the management of diverse cancer types. 55 As such, the novel imidazotetrazines reported here could hold considerable promise for treatment of GBM and other cancers.
- the invention also relates to methods of making the compounds and compositions of the invention.
- the compounds and compositions can be prepared by any of the applicable techniques of organic synthesis, for example, the techniques described herein. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
- reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
- the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
- the temperatures will be ⁇ 100° C. to 200° C.
- solvents will be aprotic or protic depending on the conditions required
- reaction times will be 1 minute to 10 days.
- Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separation of the layer containing the product.
- Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C. Heating can also be used when appropriate.
- Solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
- Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
- Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
- Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
- protecting group refers to any group which, when bound to a hydroxy or other heteroatom prevents undesired reactions from occurring at this group and which can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl group.
- removable protecting group employed is not always critical and preferred removable hydroxyl blocking groups include conventional substituents such as, for example, allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidene, phenacyl, methyl methoxy, silyl ethers (e.g., trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), or t-butyldimethylsilyl (TBS)) and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
- silyl ethers e.g., trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), or t-butyldimethylsilyl (TBS)
- TMS trimethylsilyl
- TDPS t-butyl-
- Suitable hydroxyl protecting groups are known to those skilled in the art and disclosed in more detail in T. W. Greene, Protecting Groups In Organic Synthesis ; Wiley: New York, 1981 (“Greene”) and the references cited therein, and Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), both of which are incorporated herein by reference.
- Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds by the methods of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis.
- the compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier.
- the compounds may be added to a carrier in the form of a salt or solvate.
- a pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
- Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.
- salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound.
- a sufficiently basic compound such as an amine
- a suitable acid for example, a sufficiently basic compound such as an amine
- Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.
- the compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a vertebrate or mammalian host, such as a human patient, in a variety of forms.
- the forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes.
- the compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier.
- a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
- compounds can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet.
- Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- Such compositions and preparations typically contain at least 0.1% of active compound.
- compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form.
- amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained.
- the tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate.
- binders such as gum tragacanth, acacia, corn starch or gelatin
- excipients such as dicalcium phosphate
- a disintegrating agent such as corn starch, potato starch, alginic acid and the like
- a lubricant such as magnesium stearate.
- a sweetening agent such as sucrose, fructose, lactose or aspartame
- a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring
- the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
- a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the active compound may be incorporated into sustained-release preparations and devices.
- the active compound may be administered intravenously or intraperitoneally by infusion or injection.
- Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
- Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms.
- compositions suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
- the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
- the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and/or gelatin.
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization.
- methods of preparation can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution.
- compounds may be applied in pure form, e.g., when they are liquids.
- a dermatologically acceptable carrier which may be a solid, a liquid, a gel, or the like.
- Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like.
- Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
- Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
- the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.
- Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
- compositions for delivering active agents to the skin are known to the art; for example, see U.S. Pat. No. 4,992,478 (Geria), 4,820,508 (Wortzman), 4,608,392 (Jacquet et al.), and 4,559,157 (Smith et al.).
- Such dermatological compositions can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition.
- Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949 (Borch et al.).
- the amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician.
- a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
- the compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
- the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
- the compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg/m 2 , conveniently 10 to 750 mg/m 2 , most conveniently, 50 to 500 mg/m 2 of active ingredient per unit dosage form.
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
- the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
- the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
- the compounds described herein can be effective anti-tumor agents and have higher potency and/or reduced toxicity as compared to TMZ.
- compounds of the invention are more potent and less toxic than TMZ, and/or avoid a potential site of catabolic metabolism encountered with TMZ, i.e., have a different metabolic profile than TMZ.
- the invention provides therapeutic methods of treating cancer in a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein.
- a mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like.
- Cancer refers to any various type of malignant neoplasm, for example, colon cancer, breast cancer, melanoma and leukemia, and in general is characterized by an undesirable cellular proliferation, e.g., unregulated growth, lack of differentiation, local tissue invasion, and metastasis.
- the ability of a compound of the invention to treat cancer may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, quantification of tumor cell-kill, and the biological significance of the use of transplantable tumor screens are known.
- HGCC patient-derived cell line U3054MG 1 was cultured under serum-free stem cell conditions (1:1 neurobasal: DMEM/F12 media supplemented with B27, N2, hEGF, and hFGF).
- GBM oncosphere cell line Br23c 2 was cultured with the NeuroCult NS-A proliferation kit (Stem Cell Technologies) supplemented with 0.0002% heparin, hEGF, and hFGF.
- Temozolomide (TMZ) was purchased from AK Scientific. TMZ analogs were synthesized as described below. Compounds were dissolved in DMSO (1% final concentration, Fisher Chemical) for cell culture studies.
- Mouse Liver Microsome Stability Assay A mixture of PBS (pH 7.4), NADPH regenerating system solution A (Corning Life Sciences), and NADPH regenerating system solution B (Corning Life Sciences) was incubated at 37° C. in a shaking incubator for 5 min. Next, compound was added in DMSO (final concentration 50 ⁇ M, 0.5% DMSO) before ice-cold mouse liver microsomes (Thermo Fisher, male CD-1 mice, pooled) were added (final protein concentration of 1 mg/mL).
- DMSO final concentration 50 ⁇ M, 0.5% DMSO
- U87 cells were plated at 1 ⁇ 10 6 c/w in a 6-well plate before they were treated with compound at the indicated concentration (1% final concentration DMSO). After 8 h incubation, the cells were harvested and pelleted. Genomic DNA was extracted using the DNeasy Blood & Tissue Kit (Qiagen, ID: 69504). DNA was then precipitated using the following procedure: 1/10 v/v 3M sodium acetate (pH 5.2) and 2.5 ⁇ v/v ethanol was added to each sample which was then kept at ⁇ 80° C. for 1 h. The mixture was centrifuged at max at 4° C.
- CD-1 IGS mice were administered compound in 1% DMSO ( FIG. 2 a ) or 10% DMSO ( FIG. 2 b - d ) in PBS at 25 mg/kg via lateral tail vein injection. Five minutes post injection, mice were sacrificed, and blood was collected by lacerating the right auricle with iris scissors. An 18-gauge angiocatheter was inserted through the left ventricle, and all residual circulatory volume was removed by perfusing 0.9% saline solution via an analog peristaltic pump.
- Brains were harvested from the cranial vault, acidified with 0.3% aqueous H 3 PO 4 and flash frozen. Homogenized brain samples were centrifuged twice at 13,000 rcf for ten minutes and supernatant and tissue debris were separated. The resultant supernatant was analyzed, along with plasma, by LC-MS/MS to determine compound concentrations. In order to calculate absolute brain:serum ratios (ng drug brain :ng drug serum ), a mouse blood volume of 58.5 mL/kg was assumed for each mouse.
- Human GBM Br23c stem-like neurosphere cells were intracranially implanted in female athymic nude mice (150,000 cells/mouse). Beginning day 5 after implantation of the tumor cells, drugs were formulated in 10% PEG 400 in saline and 15 mg/kg TMZ (or equimolar dose of C8 analog) was administered via oral gavage once-per-day for 7 weeks ( FIG. 5 a ) or once-per-day for 5 total treatments ( FIG. 5 b ). TMZ and C8 analogs were dissolved fresh for each use. Mice were observed daily for any signs of deterioration, neurotoxicity, or movement disorders. They were inspected for signs of pain and distress, as in accordance with the Johns Hopkins Animal Care and Use Guidelines. If the symptoms persisted and resulted in debilitation, the animals were euthanized according to protocol.
- G 1 is OCH 3 , OCH 2 CH 3 , OPh, N(CH 3 ) 2 , propargyl, or a substituent as defined herein.
- TMZ is a non-explosive, weighable surrogate for diazomethane.
- TMZ and other imidazotetrazines can be used as synthetic diazoalkane precursors as illustrated below.
- compositions illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as ‘Compound X’):
- Aerosol mg/can ‘Compound X’ 20 Oleic acid 10 Trichloromonofluoromethane 5,000 Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000
- Topical Cream 1 wt. % ‘Compound X’ 5%
- White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5%
- Purified water q.s. to 100 g
- Topical Cream 2 wt. % ‘Compound X’ 5% Stearic acid 10% Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5% Isopropyl palmitate 2% Methyl Paraben 0.2% Purified water q.s. to 100 g
- compositions may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient ‘Compound X’. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
- This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Nos. 62/716,390 filed on Aug. 9, 2018, 62/778,750 filed on Dec. 12, 2018, and 62/873,669 filed on Jul. 12, 2019, each of which are incorporated herein by reference in their entirety.
- This invention was made with government support under Grant No. R21-CA195149 awarded by the National Institutes of Health. The government has certain rights in the invention.
- Glioblastoma multiforme (GBM) is the most prevalent, infiltrative, and lethal primary malignant brain tumor, with only 10% of patients surviving five years.1 The current standard-of-care for GBM is gross surgical resection followed by radiotherapy combined with temozolomide (TMZ), a small molecule DNA alkylating agent. The antitumor effect of TMZ is ultimately mediated through methylation of the O6-position of guanine residues and subsequent mismatch repair-dependent cell death.2-6 Among the beneficial properties of TMZ are favorable pharmacokinetics (including 100% oral bioavailability7), non-enzymatic prodrug activation, and some accumulation in the brain (cerebral spinal fluid:blood ratio of 17:83 in human cancer patients8,9). TMZ provides a significant therapeutic benefit to a subset of GBM patients. For example, in patients whose tumors do not express O6-methylguanine DNA methyltransferase (MGMT), an enzyme that removes O6-methylguanine lesions, TMZ extends median survival to approximately two years.10 Even in the era of personalized anticancer therapy, TMZ remains frontline therapy for oligodendrogliomas, diffuse astrocytic gliomas, and pleomorphic xanthoastrocytomas in addition to GBM.11 However, given the ineffectiveness of TMZ against tumors expressing MGMT and the inevitable recurrence of GBM after multimodal combination therapy, there remains a significant clinical need for better treatment strategies.
- TMZ is a prodrug activated in aqueous solutions that ultimately releases methyldiazonium, the active alkylating component (Scheme 1(a)). The half-life of TMZ is ˜2 hours in vivo and in aqueous solutions in vitro, and it has been suggested that the drug has an increased rate of hydrolysis in the more alkaline environment of gliomas, providing some selectivity for cancerous vs. non-cancerous cells.12-15 While this 2 hour half-life enables TMZ to reach the central nervous system (CNS) and release methyldiazonium, there is scarce information on the relationship between half-life and anticancer activity; specifically, it is unclear if 2 hours is optimal to maximize therapeutic efficacy or if shorter (or longer) half-lives may bolster its effect. Given the advantageous features of TMZ, an understanding of the relationship between its structure, hydrolytic stability, and anticancer activity.
- While TMZ has been FDA approved for two decades, more efficacious drugs for glioblastoma that have lower systemic toxicity would be desirable. Therapeutic compounds that can reach the entirety of the diffuse tumor in sufficient concentrations to be effective are sought. Accordingly, there is a need for new compounds that possess the desirable properties of TMZ, but have better brain penetration, lower toxicity, and provide improved patient survival rates.
- Herein is described the development of a model for that accurately predicts the hydrolytic stability and half-life of imidazotetrazines. This model was used to discover novel imidazotetrazines with exceptional BBB penetration and superior anticancer activity compared to TMZ, including in a murine model of GBM.
- Accordingly, this disclosure provides a compound of Formula I:
- or a salt thereof;
wherein - X is O or S;
- R1 is halo, —CN, —NO2, —(C1-C6)alkyl, —C(═O)Ra, phenyl, or a 5- or 6-membered heterocycle, wherein Ra is H, halo, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, ORb, SRb, or —NRbRc;
- wherein
-
- Rb is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- Rc is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or
- when Ra is —NRbRc, Rb and Rc taken together optionally forms a heterocycle;
- R2 is —(C1-C6)alkyl, —(C3-C6)cycloalkyl, propargyl, phenyl, or a 5- or 6-membered heterocycle; and
- R3 is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- wherein each —(C1-C6)alkyl, —(C3-C6)cycloalkyl, propargyl, phenyl, and 5- or 6-membered heterocycle are optionally substituted with one or more substituents, and each —(C1-C6)alkyl is unbranched or optionally branched.
- This disclosure also provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound disclosed above, wherein the cancer is thereby treated.
- The invention provides novel compounds of Formulas I-III(A/B/C), intermediates for the synthesis of compounds of Formulas I-III, as well as methods of preparing compounds of Formulas I-III. The invention also provides compounds of Formulas I-III that are useful as intermediates for the synthesis of other useful compounds. The invention provides for the use of compounds of Formulas I-III for the manufacture of medicaments useful for the treatment of bacterial infections in a mammal, such as a human.
- The invention provides for the use of the compositions described herein for use in medical therapy. The medical therapy can be treating cancer, for example, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer or brain cancers such as glioblastoma. The invention also provides for the use of a composition as described herein for the manufacture of a medicament to treat a disease in a mammal, for example, cancer in a human. The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier.
- The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention.
-
FIG. 1 . Hydrolytic stability of C8-substituted imidazotetrazines. (a) The percentage of compound remaining after 2 hours plotted against the Hammett constant of its C8 substituent. Compounds with hydrolytic stability similar to TMZ are enclosed in the oval (see Table 1c). -
FIG. 2 . (a) Relevant brain:serum ratios of TMZ, Me-TMZ, and DiMe-TMZ (25 mg/kg) were measured 5 minutes after IV injection into mice. Values are the fold change of brain:serum ratio relative to TMZ. In a second experiment, brain (b) and serum (c) concentrations of TMZ and C8 analogs (25 mg/kg) were quantitated 5 minutes after IV injection into mice. (d) Brain:serum ratios were calculated based on (b) and (c) assuming a mouse blood volume of 58.5 mL/kg (see Scheme 2b). Error is SEM, number of mice per cohort=3. Statistical significance was determined by using a two-sample Student's t-test (two-tailed test, assuming equal variance). -
FIG. 3 . Assessment of the hematological toxicity of imidazotetrazines in vivo. Mice were administered a single IV dose of 125 mg/kg imidazotetrazine. After 7 days, whole blood was collected, and a complete blood count was obtained for each individual mouse. (a) Total WBC count. Control vs. Ox-TMZ: P=0.7, Control vs. K-TMZ: P=0.9. (b) Lymphocyte concentrations. Control vs. Ox-TMZ: P=0.5, Control vs. K-TMZ: P=0.9. Error is SEM, number of mice per cohort=4. Statistical significance was determined by using a two-sample Student's t-test (two-tailed test, assuming equal variance). The concentrations of other relevant blood constituents are shown inFIG. 8 . -
FIG. 4 . Imidazotetrazines were added to T98G cells with or without 3 h pre-treatment of O6BG (100 μM). IC50 values after 7-day incubation and fold changes between (+/−) O6BG treatments are reported. P-values between IC50 values (+/−) O6BG<0.02 for all compounds. Error is SEM, n≥3. Statistical significance was determined by using a two-sample Student's t-test (two-tailed test, assuming equal variance). -
FIG. 5 . Evaluation of imidazotetrazines in intracranial mouse models of GBM. GBM Br23c oncospheres were intracranially implanted into female athymic nude mice. Treatment was started 5 days post implantation. (a) Mice were administered 15 mg/kg TMZ or an equimolar dose of Me-TMZ (16.1 mg/kg) or DiMe-TMZ (17.2 mg/kg) orally once-per-day, 5×/week for 7 weeks. Control vs. TMZ: P=0.0014, TMZ vs. DiMe-TMZ: P=0.061, TMZ vs. Me-TMZ: P=0.016. (b) Mice were administered 15 mg/kg TMZ or an equimolar dose of DiMe-TMZ (17.2 mg/kg) or K-TMZ (14.9 mg/kg) orally once-per-day for 5 total doses. Control vs. TMZ: P=0.0007, DiMe-TMZ vs. TMZ: P=0.7, K-TMZ vs. TMZ: P=0.055. Compounds were formulated in 10% PEG in PBS immediately prior to each treatment. Number of mice per treatment cohort ≥5. Survival curves were compared using log-rank test. -
FIG. 6 . Western blot for MGMT status of all cell lines used. -
FIG. 7 . The hydrolytic stabilities of TMZ and K-TMZ assessed in saline at pH 7.0, 7.4, and 8.0 by calculating the percentage of parent compound remaining after 2 h at 37° C. -
FIG. 8 . Assessment of the hematological toxicity of imidazotetrazines in vivo. Mice were treated with a single IV dose of 125 mg/kg imidazotetrazine and a complete blood count was obtained for each mouse after 7 days. (a) Neutrophil concentrations (b) RBC concentrations (c) Platelet concentrations (see Table 2b). -
FIG. 9 . GBM oncosphere Br23c cells were intracranially implanted into female athymic nude mice. Treatment was started 5 days post implantation. Mice were administered compound 14 (12.8 mg/kg, equimolar to 15 mg/kg TMZ) orally once-per-day for 5 doses. Compound was formulated in 10% PEG in PBS. n≥5. This experiment was run alongside that presented inFIG. 5b ; the control group is the same forFIG. 5b andFIG. 9 . -
FIG. 10 . Development pathway of MGMT-Independent Imidazotetrazines. Graph of brain:serum ratio: mice were administered 25 mg/kg compound IV. After 15 min, mice were sacrificed, and blood and brain were collected. The concentration of drug in each was quantified by LC-MS/MS. N≥3 mice per cohort, error is SEM. *P<0.05, **P<0.01. - Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Therefore, discerning the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance was sought.
- This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.
- While the amide at C8 of TMZ had been suggested in the past to be essential for activity,2,16 conflicting reports have since indicated that alternate functionality may be tolerated at this position.17-19 Indeed, an analysis led to a belief that strategic substitutions at C8 could be used to tune the hydrolytic stability of imidazotetrazines, and that in doing so a suite of compounds with a range of half-lives could be constructed. In addition to varying the stability of the prodrug, alterations at the C8 position could lead to compounds that retain the favorable pharmacokinetic properties of TMZ but have increased CNS penetrance. An imidazotetrazine with enhanced blood-brain barrier (BBB) penetrance will exhibit lower systemic toxicity and allow for higher and more efficacious dosing regimens since the dose-limiting toxicity of TMZ (myelosuppression) is not CNS-related.7,20,21
- The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley's
Condensed Chemical Dictionary 14th Edition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001. - References in the specification to “one embodiment”, “an embodiment”, etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.
- The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a compound” includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as “solely,” “only,” and the like, in connection with any element described herein, and/or the recitation of claim elements or use of “negative” limitations.
- The term “and/or” means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases “one or more” and “at least one” are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is disubstituted.
- As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term “about.” These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value without the modifier “about” also forms a further aspect.
- The terms “about” and “approximately” are used interchangeably. Both terms can refer to a variation of ±5%, +10%, +20%, or +25% of the value specified. For example, “about 50” percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms “about” and “approximately” are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms “about” and “approximately” can also modify the endpoints of a recited range as discussed above in this paragraph.
- As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as “up to”, “at least”, “greater than”, “less than”, “more than”, “or more”, and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
- One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.
- The term “contacting” refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.
- An “effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an “effective amount” generally means an amount that provides the desired effect.
- Alternatively, the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).
- The terms “treating”, “treat” and “treatment” include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms “treat”, “treatment”, and “treating” can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term “treatment” can include medical, therapeutic, and/or prophylactic administration, as appropriate.
- As used herein, “subject” or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods provided herein, the mammal is a human.
- As used herein, the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of the compositions of the disclosure into a subject by a method or route which results in at least partial localization of the composition to a desired site. The compositions can be administered by any appropriate route which results in delivery to a desired location in the subject. The compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs.
- The terms “inhibit”, “inhibiting”, and “inhibition” refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.
- The term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%.
- As used herein, the term “substituted” or “substituent” is intended to indicate that one or more (for example, 1-20 in various embodiments, 1-10 in other embodiments, 1, 2, 3, 4, or 5; in some
embodiments - The term “halo” or “halide” refers to fluoro, chloro, bromo, or iodo. Similarly, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.
- The term “alkyl” refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms or a range in between (such as 2-8 or 3-8 carbons), and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (iso-propyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted, for example, with a substituent described below. The alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include both alkenyl and alkynyl groups. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene).
- The term “cycloalkyl” refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent, and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like.
- The term “heterocycloalkyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group.
- The term “aryl” refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system. The radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system. The aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. In other embodiments, the aryl group can have 6 to 60 carbons atoms, 6 to 120 carbon atoms, or 6 to 240 carbon atoms. The aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted.
- The term “heteroaryl” refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. The heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of “substituted”. Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl. In one embodiment the term “heteroaryl” denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (C1-C6)alkylaryl. In some embodiments, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
- This disclosure provides a compound of Formula I:
- or a salt thereof;
wherein - X is O or S;
- R1 is halo, —CN, —NO2, —(C1-C6)alkyl, —C(═O)Ra, phenyl, or a 5- or 6-membered heterocycle, wherein Ra is H, halo, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, ORb, SRb, or —NRbRc; wherein
-
- Rb is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- Rc is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or
- when Ra is —NRbRc, Rb and Rc taken together optionally forms a heterocycle;
- R2 is —(C1-C6)alkyl, —(C3-C6)cycloalkyl, propargyl, phenyl, or a 5- or 6-membered heterocycle; and
- R3 is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- wherein each —(C1-C6)alkyl, —(C3-C6)cycloalkyl, propargyl, phenyl, and 5- or 6-membered heterocycle are optionally substituted with one or more substituents, and each —(C1-C6)alkyl is unbranched or optionally branched.
- In some embodiments, the phenyl and —(C1-C6)alkyl are each independently substituted with, for example but not limited to, halo (e.g., one or more chloro or fluoro), alkoxy, or aminoalkyl. In some other embodiments the substituents do not include a phenyl group, or the molecular weight of the substituent is less than about 100, about 90, about 80, about 70, about 60, or about 50. In yet other embodiments, both Rb and Rc cannot be H.
- In other embodiments, R1 is —C(═O)—(C1-C6)alkyl, —C(═O)—NH(C1-C6)alkyl, or —C(═O)—N[(C1-C6)alkyl]2. In further In other embodiments, X is O, R3 is H and R1 is —C(═O)—(C1-C6)alkyl, —C(═O)—NH(C1-C6)alkyl, or —C(═O)—N[(C1-C6)alkyl]2. In yet other embodiments, X is O and R1 is —C(═O)—(C1-C6)alkyl. In additional embodiments, X is O, R2 is —(C1-C6)alkyl, and R3 is H. In some other embodiments, R2 is —(C1-C6)alkyl and R3 is H. In various other embodiments, R2 is propargyl or a substituted phenyl. In some embodiments, X is O and R3 is H.
- In various embodiments, R1 is a moiety of Formula IB:
- wherein
-
- W is O, S, or NRd; wherein Rd is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- V is N or CRx, wherein Rx is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl;
- Y is N or CRy, wherein Ry is H, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; and
- Z is N or CH.
- In various other embodiments, R1 is one of:
- wherein the 5-membered heterocyclic moiety R1 is optionally substituted (at one or the other of the carbon atoms CH, thereby modifying that carbon to C-substituent, wherein the substituent is a substituent as defined herein).
- In further embodiments, R1 is i, ii, or iii:
- wherein (i), (ii) and (iii) are optionally substituted at
position - In additional embodiments, R1 is a para-substituted phenyl, wherein the molecular weight of each substituent is less than about 300, about 200 or about 100 daltons. In yet other embodiments, the para-substituent is halo, —CN, —CF3, —CF2CF3, or —(C1-C6)alkyl. In some other embodiments, R1 is halo, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl.
- In various additional embodiments, the substituted phenyl is substituted with halo, alkyl, alkoxy, phenoxy, amine, alkylamine, dialkylamine, or combination thereof.
- In other embodiments, the compound is:
- In additional embodiments, the compound of Formula I is a compound of Formula IC:
- wherein G1 is halo, alkyl, alkoxy, phenoxy, or dialkylamine. In some embodiments G1 is OCH3, OCH2CH3, OPh, or N(CH3)2.
- In various other embodiments, the compound of Formula I is a compound of Formula II:
- In additional embodiments, R2 is —(C1-C6)alkyl and R3 is H. In yet other embodiments, the compound is K-TMZ:
- In further embodiments, Ra is CH3, CH2CH3, NHCH3, NHCH2CH3, N(CH3)2, N(CH2CH3)2, N(CH2CH2CH3)2, N(CH2CH2CH2CH3)2, N(CH2CH2)2, N[(CH2CH2)2O], OCH3, OCH2CH3, SCH3, or SCH2CH3. In other embodiments, the compound is:
- In additional embodiments, the compound of Formula I is a compound of Formula IIIA or IIIB:
- wherein Rz is H, halo, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl. In other embodiments, Rz is CH3 or CH2CH3. In yet other embodiments, the compound is:
- This disclosure additionally provides a method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-19, wherein the cancer is thereby treated. In other additional embodiments, the cancer is glioblastoma (GBM).
- In some embodiments, a composition comprises the compounds disclosed above and a second active agent. In other embodiments, the second active agent is a procaspase-3 activator, for example PAC-1:
- In yet further embodiments, the disclosed compounds herein and the second active agent are administered to a subject concurrently or sequentially for the treatment of a cancer. In some additional embodiments, the disclosed compound and the second active agent are concurrently administered to the subject. In other embodiments, the disclosed compound and the second active agent are sequentially administered to the subject. In some other embodiments, the disclosed compound is administered to the subject before the second active agent. In yet more embodiments, the disclosed compound is administered to the subject after the second active agent.
- In some embodiments, the concentration of the disclosed compounds herein is about 1 nM to about 10 μM. In yet other embodiments, the concentration of the second active agent is about 1 nM to about 1 μM.
- This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “number1” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10
means - Construction of C8-substituted imidazotetrazines. The inclusion of an amide at the C8 position of TMZ is largely an artifact of the original synthesis of imidazotriazenes and imidazotetrazines. Both dacarbazine and TMZ are derived from precursor 4-diazoimidazole-5-carboxamide (1, Scheme 1b). The remarkable stability of this diazo species, reportedly >2.5 years at room temperature,22 permitted its use for exploratory chemistry where other diazoimidazole species (such as 4-diazoimidazole (2)) simply decomposed.23 Thus, the initial synthesis of dacarbazine in 1962 and TMZ in 1984 involved the quenching of 1 with dimethylamine24 or the cyclization of 1 with methyl isocyanate,25 respectively, and the primary amide moiety remained. Over time, there have been suggestions that this amide is critical for anticancer activity. Such claims were supported by theoretical studies suggesting that a hydrogen bond donor at C8 is required for activity,2,16 but clouding the picture is a conflicting structure-activity relationship (SAR) adopted from derivatives of a related compound (mitozolomide) in non-CNS cancer models.26 There are considerable challenges to establishing a general synthetic route that can be used to construct novel derivatives at the C8 position; these synthetic challenges have hindered the development of new imidazotetrazines, and in the absence of new compounds and biological data, the outdated SAR has persisted.
- Challenges of replacing C8 amide include: aqueous sensitivity; base sensitivity; diazoimidazole degradation; and poor substitutes for CH3NCO.
- Key challenges to making novel imidazotetrazines include sensitivity to protic solvents or basic reagents, instability of intermediate diazo species, and the lack of efficient reagents to install the N3 methyl. The sensitivity of the prodrug to conditions involving base or water (at pH>6) renders the tetrazinone unstable to many practical cross-coupling or reducing conditions. Another challenge, as alluded to above, is the instability of intermediate diazo species. The privileged 4-diazoimidazole-5-carboxamide (1, Scheme 1b) readily precipitates out of solution as a pure, stable compound; however, other 4-diazoimidazoles (such as 2) remain in aqueous solution, are exceptionally prone to decomposition, and are sensitive to heat, shock, and often light.23 Finally, installation of the N3-methyl group in the initial route to TMZ was achieved via cyclization with methyl isocyanate.25 Methyl isocyanate, however, is a poisonous gas and no longer commercially available. As such, alternate routes27 or less effective alternatives to methyl isocyanate such as N-succinimidyl N-methylcarbamate or N-methylcarbamic chloride must be used that reduce the yield of the cyclizations.
- To provide access to certain derivatives of the C8 amide, an exploration of these types of compounds was begun by modifying an established route, largely developed for mitozolomide.28 This sequence begins with a hydrolysis of the amide of TMZ to carboxylic acid 3 (Scheme 2a), which can then be converted to the acid chloride. From this intermediate, substitution with various nucleophiles provides products in high yields. This route was used to synthesize amide, ester, and thioester derivatives 4-10 (Scheme 2a). Additionally, an established reaction was employed to install a cyano group (11) directly from TMZ (Scheme 2a).29 The creation of a structurally diverse panel of C8 analogs, however, would require novel synthetic routes, especially for those with aliphatic, ketone, halogen, and aryl groups; such substituents have not been described at this position in the ˜35 year history of TMZ. Thus, an aliphatic group at C8 was introduced via diazotization of 5-amino-4-methylimidazole 12 to diazo species 13 and subsequent cyclization with methyl isocyanate surrogate N-methylcarbamoyl chloride to afford C8-methyl derivative 14 (Scheme 2b).
- Although various amides, esters, and thioamides had been installed at C8, ketones were entirely absent, perhaps unsurprisingly since initial attempts to use Grignard or alkyllithium reagents led to complete degradation of the tetrazinone ring. Thus, a stepwise cyclization was utilized to synthesize methyl ketone derivative 17 from its disubstituted precursor 16, obtained upon hydrolytic degradation of 6-methylpurine N-oxide (15)30 (Scheme 2c). Bromine and chlorine substituents were directly incorporated at C8 in moderate yields upon a decarboxylative halogenation of intermediate 3 employing Dess-Martin periodinane and the respective tetraethylammonium salt (
compounds heterocyclic compounds 27 and 28 (Scheme 2e) were synthesized upon cyclization of the C8 amide or thioamide, respectively; an analogous route had been utilized to introduce bulkier 4-substituted oxazoles and thiazoles at the C8 position,19 but not smaller methyl groups. - Anticancer activity of C8 substituted imidazotetrazines. With a suite of imidazotetrazines in hand, each compound was evaluated against a panel of human GBM cell lines (Table 1a, Table 1b). Cell lines were selected to include those expressing and lacking MGMT (
FIG. 6 ) and, consistent with literature reports, those with negligible MGMT expression were sensitive to TMZ (IC50˜50 μM or less) whereas those with significant MGMT expression were resistant (IC50>300 μM). Amide-substituted derivatives 4-8 as well as ester (9) and thioester (10) derivatives had activity comparable to TMZ in the MGMT-deficient U87 and D54 cell lines. Notably, the retention of activity for disubstituted amide (5-8) and ester (9) imidazotetrazines confirms that a hydrogen bond donor is not required at C8. In U118MG and T98G MGMT-expressing GBM cells, more potent activity was observed for these derivatives compared to TMZ.Ketone analog 17 was also effective against MGMT-deficient cell lines, demonstrating that an amide is not required at the C8 position. - Compounds completely lacking a carbonyl, such as 14, 19, 23, and 27 proved to be as (or more) potent than TMZ in the absence of MGMT and significantly more potent in cell lines expressing MGMT. Methyl (14) and phenyl (23) substitutions were the most active across all cell lines. Cyano derivative 11 and
carboxylic acid derivative 3 were inactive in all tested cell lines (>7-fold less potent than TMZ), even in the absence of MGMT. In addition to these canonical adherent GBM cell lines, most analogs were more active than TMZ in the patient-derived U3054MG GBM cell line cultured under serum-free stem cell conditions.31 -
TABLE 1a Panel of C8-substituted imidazotetrazines and associated IC50 values (μM) in multiple GBM cell lines. Cell lines were incubated with compound for 7 days then viability was assessed using the Alamar Blue assay. Error is SEM, n ≥3. Prl = pyrrolidine. A table with additional compounds (Table 1b) and a Western blot for MGMT status of all cell lines used (FIG. 6) are disclosed herein. MGMT − − + + + Compound R U87 D54 U118MG T98G U3054MG TMZ CONH2 51 ± 8 12 ± 1 322 ± 7 660 ± 10 370 ± 40 3 COO− 320 ± 7 130 ± 8 370 ± 20 321 ± 8 ND 4 (Me-TMZ) CONHMe 49 ± 7 11 ± 1 280 ± 20 580 ± 20 290 ± 20 5 (DiMe-TMZ) CONMe2 40 ± 20 12 ± 5 130 ± 30 250 ± 60 132 ± 6 6 CONEt2 80 ± 30 13 ± 2 80 ± 10 160 ± 40 ND 7 CON(n-Bu)2 27 ± 6 11 ± 2 62 ± 2 140 ± 20 ND 8 CO(PrI) 17 ± 3 12 ± 4 136 ± 8 186 ± 5 ND 9 COOEt 66 ± 3 7 ± 1 180 ± 20 236 ± 10 ND 10 COSEt 64 ± 21 8 ± 1 165 ± 4 327 ± 4 ND 11 CN 500 ± 60 91 ± 6 670 ± 20 >1000 870 ± 60 14 Me 3 ± 1 6 ± 3 7 ± 1 6 ± 1 ND 17 (K-TMZ) COMe 44 ± 6 18 ± 1 115 ± 9 240 ± 20 125 ± 4 19 Cl 15 ± 4 21 ± 4 60 ± 20 60 ± 10 87 ± 4 23 Ph 9 ± 1 7 ± 1 3 ± 1 14 ± 1 18 ± 1 27 (Ox-TMZ) 5-Me-Oxaz 27 ± 4 9 ± 1 70 ± 20 100 ± 20 123 ± 6 28 4-Me-Thiaz 9 ± 1 8 ± 1 12 ± 2 31 ± 4 ND - Hydrolytic stability of C8 substituted imidazotetrazines. The principal aspect governing the anticancer activity of imidazotetrazines is the hydrolytic activation of the prodrug. As depicted in Scheme 1(a), TMZ has a half-life of ˜2 hours in humans.7 This timeline allows the intact prodrug to reach the brain and release the active methylating component prior to elimination. Beyond TMZ, the relationship between imidazotetrazine stability and anticancer activity is unknown; that is, while hydrolytic activation is required for cancer cell death, the optimal timing of this event is unclear both in vitro and in vivo. Towards this end, the hydrolytic stability of each new compound was assessed in buffered saline, which mimics in vivo conditions (in pH 7.4 PBS TMZ has a half-life of 119 minutes,
FIG. 1 ). A HPLC assay was developed to quantify the fraction of intact prodrug remaining in solution after 2 hours at pH 7.4, 37° C. The results of this experiment suggest that electronic substituent effects at C8 directly translate through the bicycle to C4, the site of hydrolysis. The magnitude of this effect was dramatic, with stabilities ranging from 0% to 97% remaining after 2 hours depending on the substituent at the C8 position (FIG. 1 ). Since the group at C8 appeared to have such a clear influence on the aqueous stability of the prodrug, its Hammett constant (σp) was plotted against the percent remaining after 2 hours. - As shown in
FIG. 1 , an obvious relationship exists between these two parameters, suggesting that σp can be used to accurately predict the stability of C8-substituted imidazotetrazines. Among those compounds possessing substituents with similar electronics (0.23<δp<0.50) to a primary amide (σp=0.36) wereamide derivatives ketone derivative 17, andchloro derivative 19. Each had measured half-lives within an hour of TMZ in PBS at pH 7.4 (Table 1c). On either extreme were cyano analog 11 (σp=0.66), with a half-life of 0.5 h, and methyl derivative 14 (σp=−0.17), which remained in its prodrug form the longest with a half-life of 40 hours. The same assay was used to confirm that hydrolysis remained pH-dependent for C8-substituted derivatives (e.g. K-TMZ 17,FIG. 7 ). -
TABLE 1b Panel of C8-substituted imidazotetrazines and associated 7-day IC50 values (μM) in multiple GBM cell lines; the four compounds below were tested, and this supporting table is a complement to Table 1a. Cell viability was assessed using the Alamar Blue assay. Error is SEM, n ≥3. MGMT − − + + Compound R U87 D54 U118MG T98G TMZ CONH2 51 ± 8 12 ± 1 322 ± 7 660 ± 10 18 Br 26 ± 7 20 ± 1 80 ± 20 60 ± 10 24 C6H4-4-F 13 ± 2 ND ND 18 ± 2 25 C6H4-4-CF3 16 ± 1 ND ND >100 26 C6H4-4- Cl 9 ± 1 7 ± 1 5 ± 1 19 ± 3 -
TABLE 1c Half-lives of select C8 derivatives in PBS (pH 7.4, 37° C.). Compound t1/2 (h) 11 0.57 ± 0.03 17 (K-TMZ) 1.20 ± 0.10 TMZ 1.98 ± 0.01 4 (Me-TMZ) 2.70 ± 0.10 5 (DiMe-TMZ) 2.80 ± 0.20 25 2.90 ± 0.30 27 (Ox-TMZ) 3.00 ± 0.10 19 3.10 ± 0.10 23 27 ± 3 14 40 ± 1 - Relationship between hydrolytic stability and anticancer activity. Methyl and
phenyl derivatives FIG. 1 ), suggesting that a longer-lived prodrug is favorable for efficacy in cell culture. The opposite effect was observed forcompound 11, which was the least stable in solution. Even in U87 cells lacking MGMT, it exhibited a ten-fold loss of activity compared to TMZ, suggesting that there is a critical threshold of aqueous stability below which hydrolysis occurs too quickly to methylate target DNA. Compounds with hydrolytic stabilities similar to TMZ such as 4, 5, 17, 19, and 27 retained activity in culture. Notably,ketone derivative 17 was equipotent to TMZ even with a shorter aqueous half-life, indicating that compounds with σp˜0.50 can still retain marked anticancer activity. - Liver microsome stability. TMZ fortuitously possesses several ideal pharmacokinetic properties including avoidance of primary metabolism.7 To assess whether modification or replacement of the amide at C8 would lead to significant metabolic liabilities, the stabilities of select compounds were assessed after 2 hours in the presence of mouse liver microsomes. Prodrug hydrolysis was accounted for by including control runs that did not contain liver microsomes. The slightly acidic pH of the working solution resulted in enhanced stability of TMZ compared to incubation in PBS alone. Predictably, TMZ was insensitive to metabolic perturbation as its instability was entirely accounted for by hydrolysis (Table 2a). The addition of methyl(s) to the amide (compounds 4 and 5) resulted in some susceptibility to the effects of the microsomes, and this effect was amplified for larger amide substitutions (compound 7), which demonstrated improved aqueous stability but markedly less stability in liver microsomes.
Ketone 17 andchloro 19 were generally stable to oxidative metabolism, suggesting that for these compounds the hydrolysis could drive the pharmacokinetics in vivo, similar to TMZ. - Blood-brain barrier penetrance. It has been reported that >98% of small molecule drugs do not penetrate the BBB,32 making TMZ unusual, especially amongst anticancer agents. In humans, TMZ is rapidly absorbed and reaches the brain in minutes with cerebral spinal fluid concentrations averaging 20% of those in the plasma;8,9 the accumulation of even more drug in the brain by increasing the BBB penetrance may be a viable strategy to increase efficacy against CNS-based tumors. To predict the BBB penetrance of the novel imidazotetrazines, log BB values were calculated (c Log BB) based on a formula utilizing c Log P and total polar surface area.33 When applied across a consistent drug scaffold, these types of in silico metrics have been used reliably to predict relative changes in BBB penetrance as well as other biological phenomenon,34-38 though not always reflective of absolute concentrations. The c Log BB value for TMZ is −1.58 (Table 2a). Replacing the primary amide led to marked increases in the c Log BB and larger predicted brain:blood ratios relative to TMZ. Importantly, c Log BB does not account for molecular weight, making one wary of analogs with large, hydrophobic functionality (e.g. 7) even if they possess attractive predicted values. A more comprehensive metric, the CNS multiparameter optimization (MPO) tool39,40 was also employed to gauge prospective BBB permeabilities. CNS MPO scores span from 0 to 6.0 based on the optimal ranges of 6 physicochemical properties. Though TMZ has an agreeable MPO of 4.9, higher scores were achieved for the C8 analogs, which in several cases reached the top desirability value (Table 2a). The more favorable c Log BB and CNS MPO values predicted for the panel suggests that certain derivatives may achieve higher drug concentrations in the brain than TMZ.
- The BBB penetrance of top compounds (those with favorable anticancer activity, appropriate hydrolytic and liver microsome stability, and predicted BBB penetrance, Scheme 2b) was thus assessed in vivo. In an initial experiment, Me-TMZ (4) and DiMe-TMZ (5) were tested head-to-head with TMZ to explore whether alkylation of the C8 amide could confer increased brain:blood ratios. Mice were administered 25 mg/kg drug intravenously and sacrificed 5 minutes after injection. The serum and perfused brain samples were immediately acidified to prevent prodrug degradation before the drug concentration within each compartment was quantitated by LC-MS/MS. After 5 minutes, drug concentrations in the brain were significantly elevated for analogs Me-TMZ and DiMe-TMZ versus TMZ, a >3-fold increase in brain:serum ratio for each compound (
FIG. 2a ). The equivalent brain:serum ratios for Me-TMZ and DiMe-TMZ is likely due to the fast metabolism of the dimethylated amide to its monomethylated counterpart. This preliminary experiment suggested that other derivatives with higher predicted BBB penetrance may lead to greater brain permeability in vivo. Accordingly, compounds Ox-TMZ (27) and K-TMZ (17) were evaluated head-to-head with DiMe-TMZ and TMZ. After 5 minutes, each derivative had accumulated numerically higher concentrations in the brain than TMZ (FIG. 2b ). When paired with the corresponding serum concentrations (FIG. 2c ), TMZ had a relative brain:serum ratio of 0.23±0.03 ng/g:ng/mL, comparable to the few other TMZ biodistribution experiments in murine systems.41,42 Assigning average mouse blood volumes to equate units, TMZ had an absolute brain:serum ratio of 8:92, while Ox-TMZ and K-TMZ boasted brain:serum ratios of 55:45 and 69:31, respectively. (FIG. 2d ). The dramatic differences in drug partitioning suggest that replacing the amide at C8 is a viable strategy to significantly increase local drug concentration in the brain relative to the blood, which may increase effectiveness against brain tumors and also reduce hematological toxicity. -
TABLE 2a Metabolic stability, cLogBB, and CNS MPO values for relevant C8 analogs. The metabolic stability was assessed in mouse liver microsomes. Compounds were incubated in microsomes for 2 h, then the percentage remaining was quantified relative to t0. Experiments assessing stability in the absence of microsomes were identical but replaced liver microsomes with PBS. Error is SEM, n ≥ 2. Internal standard = N3-propyl TMZ. CNS MPO = Central Nervous System Multiparameter Optimization Score. Stability Stability (2 h, (2 h, No Compound Microsomes) Microsomes) cLogBB CNS MPO Propranolol 68 ± 2% 102 ± 3% ND ND TMZ 87 ± 6% 86 ± 4% −1.58 4.9 4 (Me-TMZ) 86 ± 1% 93 ± 1% −1.34 5.7 5 (DiMe-TMZ) 81 ± 2% 92 ± 3% −1.18 6.0 6 81 ± 1% 95 ± 2% −1.07 6.0 7 1 ± 1% 98 ± 3% −0.78 5.6 17 (K-TMZ) 70 ± 1% 77 ± 3% −1.08 6.0 19 91 ± 3% 91 ± 1% −0.72 6.0 23 44 ± 2% 103 ± 5% −0.56 5.7 27 (Ox-TMZ) 71 ± 1% 95 ± 4% −1.19 5.9 - Assessment of hematological toxicity. The elevated brain concentrations and dramatically decreased serum concentrations (
FIG. 2b ,FIG. 2c ) observed upon treatment with Ox-TMZ and K-TMZ compared to TMZ indicated that these C8-modified imidazotetrazines attenuate the dose-limiting hematological toxicity observed for TMZ in the clinic. To test this hypothesis, mice were treated with a single dose of 125 mg/kg TMZ, Ox-TMZ, or K-TMZ intravenously; this dose of TMZ induces non-lethal toxicity in mice.43,44 Seven days post-treatment, whole blood was collected and complete blood counts were obtained for each individual mouse. Expectedly, a dose of 125 mg/kg TMZ led to white blood cell (WBC) depletion relative to control mice (FIG. 3a ), suggestive of drug-induced myelosuppression. Both lymphocyte (FIG. 3b ) and neutrophil (FIG. 8a ) concentrations were decreased in TMZ-treated mice. Conversely, treatment with 125 mg/kg of Ox-TMZ or K-TMZ did not produce myelosuppression. Total WBC, lymphocyte, and neutrophil counts for mice treated with these compounds were equivalent to those of control mice. Notably, the novel imidazotetrazines did not give rise to other hematological symptoms such as red blood cell (RBC) toxicity (FIG. 8b ) or thrombocytopenia (FIG. 8c ) and did not lead to weight loss 7 days post-treatment (Table 2b). -
TABLE 2b Cohort weights of mice prior to treatment and at the time of blood collection 7 days post-treatment. Error is SEM, number of mice per cohort = 4 (see FIG. 8). Compound Pre-treatment (g) 7 days Post (g) Control 31 ± 1 32 ± 1 TMZ 31 ± 1 32 ± 1 K- TMZ 30 ± 1 31 ± 1 Ox-TMZ 30.7 ± 0.1 31.6 ± 0.3 - Novel imidazotetrazines induce alkylation-mediated cancer cell death. The cytotoxicity of TMZ is mediated by methylation of O6 guanine; subsequent single- and double-strand breaks and apoptosis are facilitated by the mismatch repair system.2-6 To assess if the novel imidazotetrazines kill through the same mechanism, O6-methylguanine adducts were quantitated in U87 cells treated with 100 or 1000 μM of each imidazotetrazine. After 8 hours of incubation with compound, the genomic DNA was isolated, quantified, and hydrolyzed to its constituent deoxyribonucleosides, which were quantitated via LC-MS/MS analysis. Dose dependent increases in the concentration of O6-methylated deoxyguanosine were observed for TMZ as well as each of the lead compounds (Table 2c), indicating that DNA methylation is occurring. Further confirmation that the novel compounds remain DNA alkylators was obtained upon pre-treatment with MGMT inhibitor O6-benzylguanine (O6BG). O6BG is a pseudosubstrate for MGMT that quenches cellular stores of the enzyme, leading to the persistence of O6-methylguanine DNA adducts. Pre-incubation of MGMT-expressing T98G cells with O6BG (100 μM) led to an eight-fold enhancement in cytotoxicity for TMZ (
FIG. 4 ), consistent with literature reports.45,46 Similarly, DiMe-TMZ, Ox-TMZ, and K-TMZ demonstrated a significant increase in activity when administered after O6BG, suggesting that O6-methylguanine lesions are the cause of cell death. - Novel imidazotetrazines have superior activity in mouse models of GBM. The increased BBB penetrance observed for amide derivatives (Me-TMZ and DiMe-TMZ) relative to TMZ suggested that greater drug concentrations in the brain might lead to greater efficacy in an intracranial tumor model. GBM oncosphere lines were chosen for these studies as they more accurately recapitulate the genetic and histopathological features of human GBM than traditional adherent cell lines, which are passaged in serum and typically grow as compact masses in vivo.47 The Br23c GBM oncosphere cell line does not express MGMT, was sensitive to TMZ and the novel C8-substituted imidazotetrazines (Table 2d), and was thus chosen as the model system. Mice implanted intracranially with these cells were administered 15 mg/kg TMZ or the equimolar equivalent of Me-TMZ or DiMe-TMZ once-per-day, 5×/week via oral gavage. As expected, TMZ significantly increased median survival compared with vehicle (
FIG. 5a ). Mice treated with both Me-TMZ and DiMe-TMZ, however, outperformed TMZ and increased median survival by 24% and 46%, respectively, suggesting that increasing the BBB-permeability of imidazotetrazine prodrugs is a viable strategy to improve efficacy. In a second experiment, K-TMZ was selected for evaluation due to its most favorable brain:blood ratio (FIG. 2d ). Mice intracranially implanted with Br23c cells were treated with K-TMZ (via oral gavage), which led to an extended median survival of more than 50 days past TMZ-treated mice, and showed greater efficacy even compared to DiMe-TMZ (FIG. 5b ). Importantly,methyl derivative 14, which has excellent efficacy in cell culture but an extended (40 hour) half-life in aqueous solution, had no effect in this in vivo model (FIG. 9 ) suggesting that dramatically elongated half-lives are detrimental in vivo, likely due to compound clearance prior to hydrolytic activation. -
TABLE 2c The concentration of O6-methylguanine was measured in U87 cells (10 μg DNA) after treatment with 100 or 1000 μM of imidazotetrazine for 8 hours. IC50 Values (μM) Compound (−) O6BG (+) O6BG Fold Change TMZ 660 ± 10 81 ± 8 8 DiMe-TMZ 250 ± 60 25 ± 9 10 Ox- TMZ 100 ± 20 5 ± 1 20 K-TMZ 240 ± 20 32 ± 4 8 - Despite being known since 1984, FDA approved since 1999, and reaching $1 billion in sales in 2009, TMZ remains the only approved imidazotetrazine anticancer drug; this likely stems from the lack of generalized syntheses for this class of compounds prohibiting conventional medicinal chemistry campaigns. Herein is reported new synthetic methods that enable the construction of novel C8-substituted imidazotetrazines that were previously inaccessible. Evaluation of these compounds in systematic, head-to-head assays led to the definitive conclusion that the C8 amide is not required for anticancer activity, and indeed compounds lacking an H-bond donor or acceptor (or both) at C8 can still retain activity comparable to TMZ against cancer cells in culture. Unmoored from the necessity of an amide at C8, a panel of imidazotetrazines was synthesized, varying this position. Strikingly, the electronic properties of the substituent at C8 has a dramatic effect on the activation of the corresponding prodrug, a previously undefined phenomenon. The relationship derived herein between the hydrolytic stability of imidazotetrazines and the electronics at C8 allows the stability of the prodrug to be tuned by employing easily accessible σp values, enabling the rational design of TMZ derivatives that have similar stabilities in vivo and facilitating investigation into the optimal timing of imidazotetrazine prodrug activation.
- From this work it appears that compounds with very short half-lives (such as 11, t1/2=0.57 h) simply hydrolyze too rapidly, releasing methyl diazonium prior to accumulation in the DNA microenvironment and diminishing anticancer activity. Thus, for activity against cancer cells in culture, a half-life of 1 h or greater is optimal. Conversely, compounds that have very long half-lives (such as 14 or 23, t1/2>20 h) can be distinctly more potent than TMZ in cell culture as the prodrug has ample time to distribute to the nucleus before conversion to the active methylating agent. However, these compounds with markedly increased hydrolytic stabilities are less likely to be useful in vivo as elimination through alternate pathways (excretion of the intact prodrug, oxidative metabolism, etc.) will occur before activation to the alkylating species. This hypothesis accounts for the lack of in vivo efficacy of
compound 14. - A hallmark of GBM is its invasion into surrounding brain tissue at an early stage, making cure via surgical resection unachievable. As such, there is an obvious clinical need for improved compounds that can reach the entirety of the diffuse tumor in sufficient concentrations to be effective. Importantly, the data herein shows that the BBB-penetrance of imidazotetrazines can be improved through modifications at the C8 position. The dramatically enhanced brain:serum distribution of Ox-TMZ and K-TMZ, in particular, could provide substantial improvement over TMZ for treatment of CNS cancers. Both of these compounds retain the favorable features of TMZ (timely prodrug activation, stability to liver microsomes) while also accumulating higher drug concentration in the brain and reduced concentration in the blood. It was hypothesized that partitioning the imidazotetrazine more to the site of the tumor and less to the compartment responsible for adverse effects would expand the therapeutic window by enhancing anticancer activity while simultaneously reducing systemic toxicity. Myelotoxicity occurs in ˜20% of TMZ-treated patients, is the major dose-limiting toxicity,48 and is exacerbated in elderly and female GBM patients.49,50 Ox-TMZ and K-TMZ demonstrated significantly less in vivo toxicity to WBCs compared to TMZ, likely a direct result of the increased partitioning to the CNS. Imidazotetrazines such as these with lower toxicity profiles could permit elevated dosing schedules and additional anticancer efficacy, and/or make this drug class accessible to more patients.
- Other imidazotetrazines of various composition in the literature have failed to improve median survival head-to-head compared to TMZ in preclinical models, despite promising results in cell culture.42,51,52 Only one derivative has outperformed TMZ in an intracranial murine model of GBM, bestowing a modest 10% increase in median survival.53 Clearly, the interplay between retaining the favorable properties that have kept TMZ as frontline treatment for GBM and modulating its structure is not trivial. The data reported herein now suggest that imidazotetrazines may be substantially modified without losing these advantages, and indeed such new compounds can have dramatically enhanced in vivo efficacy. TMZ remains the gold-standard for treating the most aggressive brain tumors, shows promise against brain metastases from other cancers,54 and its predictable activity (based on clinical biomarkers) has recently led to advocation for an expanded use of TMZ in the management of diverse cancer types.55 As such, the novel imidazotetrazines reported here could hold considerable promise for treatment of GBM and other cancers.
-
TABLE 2d 7-day IC50 values (μM) for TMZ and lead C8-substituted imidazotetrazines in the Br23c GBM oncosphere cell line. Cell viability was assessed using the Alamar Blue assay. Error is SEM, n ≥3. MGMT − Compound R Br23C TMZ CONH2 5.2 ± 0.2 4 (Me-TMZ) CONHMe 6 ± 1 5 (DiMe-TMZ) CONMe2 6 ± 1 17 (K-TMZ) COMe 5.2 ± 0.3 - The invention also relates to methods of making the compounds and compositions of the invention. The compounds and compositions can be prepared by any of the applicable techniques of organic synthesis, for example, the techniques described herein. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed. by M. B. Smith and J. March (John Wiley & Sons, New York, 2001), Comprehensive Organic Synthesis; Selectivity, Strategy & Efficiency in Modern Organic Chemistry, in 9 Volumes, Barry M. Trost, Ed.-in-Chief (Pergamon Press, New York, 1993 printing)); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983); Protecting Groups in Organic Synthesis, Second Edition, Greene, T. W., and Wutz, P. G. M., John Wiley & Sons, New York; and Comprehensive Organic Transformations, Larock, R. C., Second Edition, John Wiley & Sons, New York (1999).
- A number of exemplary methods for the preparation of the compounds of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.
- Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically, the temperatures will be −100° C. to 200° C., solvents will be aprotic or protic depending on the conditions required, and reaction times will be 1 minute to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separation of the layer containing the product.
- Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to −100° C. Heating can also be used when appropriate. Solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
- Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to −100° C.) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
- Protecting Groups. The term “protecting group” refers to any group which, when bound to a hydroxy or other heteroatom prevents undesired reactions from occurring at this group and which can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl group. The particular removable protecting group employed is not always critical and preferred removable hydroxyl blocking groups include conventional substituents such as, for example, allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidene, phenacyl, methyl methoxy, silyl ethers (e.g., trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), or t-butyldimethylsilyl (TBS)) and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
- Suitable hydroxyl protecting groups are known to those skilled in the art and disclosed in more detail in T. W. Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981 (“Greene”) and the references cited therein, and Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), both of which are incorporated herein by reference.
- Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds by the methods of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis.
- The compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier. The compounds may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and β-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.
- Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.
- The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a vertebrate or mammalian host, such as a human patient, in a variety of forms. The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes.
- The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained.
- The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
- The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms.
- Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and/or gelatin.
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution.
- For topical administration, compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer the active agent to the skin as a composition or formulation, for example, in combination with a dermatologically acceptable carrier, which may be a solid, a liquid, a gel, or the like.
- Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.
- Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
- Examples of dermatological compositions for delivering active agents to the skin are known to the art; for example, see U.S. Pat. No. 4,992,478 (Geria), 4,820,508 (Wortzman), 4,608,392 (Jacquet et al.), and 4,559,157 (Smith et al.). Such dermatological compositions can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition.
- Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician.
- In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
- The compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
- The compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg/m2, conveniently 10 to 750 mg/m2, most conveniently, 50 to 500 mg/m2 of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
- The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
- The compounds described herein can be effective anti-tumor agents and have higher potency and/or reduced toxicity as compared to TMZ. Preferably, compounds of the invention are more potent and less toxic than TMZ, and/or avoid a potential site of catabolic metabolism encountered with TMZ, i.e., have a different metabolic profile than TMZ.
- The invention provides therapeutic methods of treating cancer in a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein. A mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like. Cancer refers to any various type of malignant neoplasm, for example, colon cancer, breast cancer, melanoma and leukemia, and in general is characterized by an undesirable cellular proliferation, e.g., unregulated growth, lack of differentiation, local tissue invasion, and metastasis.
- The ability of a compound of the invention to treat cancer may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, quantification of tumor cell-kill, and the biological significance of the use of transplantable tumor screens are known.
- The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention.
- Cell Culture and Reagents. All cell lines were grown in a 37° C., 5% C02, humidified environment, in media containing 1% penicillin/streptomycin. Cell culture conditions are as follows: traditional cell lines U87 and T98G were grown in EMEM with 10% FBS.
- Traditional cell lines D54 and U118MG were grown in DMEM with 10% FBS. HGCC patient-derived cell line U3054MG1 was cultured under serum-free stem cell conditions (1:1 neurobasal: DMEM/F12 media supplemented with B27, N2, hEGF, and hFGF). GBM oncosphere cell line Br23c2 was cultured with the NeuroCult NS-A proliferation kit (Stem Cell Technologies) supplemented with 0.0002% heparin, hEGF, and hFGF. Temozolomide (TMZ) was purchased from AK Scientific. TMZ analogs were synthesized as described below. Compounds were dissolved in DMSO (1% final concentration, Fisher Chemical) for cell culture studies.
- Cell Viability Assays. Cells were harvested, seeded in a 96-well plate and allowed to adhere. After three hours, compound was added to each well in DMSO (1% final concentration). Cells were incubated for seven days before viability was assessed by the Alamar Blue Assay. Raptinal (20 μM) was used as a dead control.
- Mouse Liver Microsome Stability Assay. A mixture of PBS (pH 7.4), NADPH regenerating system solution A (Corning Life Sciences), and NADPH regenerating system solution B (Corning Life Sciences) was incubated at 37° C. in a shaking incubator for 5 min. Next, compound was added in DMSO (
final concentration 50 μM, 0.5% DMSO) before ice-cold mouse liver microsomes (Thermo Fisher, male CD-1 mice, pooled) were added (final protein concentration of 1 mg/mL). An aliquot was immediately removed, quenched with an equal volume of 100 μM internal standard and 0.5% hydrochloric acid in ice-cold acetonitrile, and centrifuged at 13,000 rcf for 3 min. The supernatant was diluted 1:5 in ddH2O and analyzed by LC-MS. The reactions were incubated at 37° C. in a shaking incubator for 2 h. A second aliquot was removed, quenched and diluted as before and analyzed by LC-MS. The ratio of the areas of analyte: internal standard at 2 hours was compared to the ratio at t0 to determine the percentage of compound remaining. Analysis was performed on an Agilent 6230 LC/MS TOF system with a 1.8 μm, 2.1×50 mm Agilent ZORBAX Eclipse Plus C18 column. Internal standard=N3-propyl TMZ. - O6-Methyldeoxyguanosine Quantitation. U87 cells were plated at 1×106 c/w in a 6-well plate before they were treated with compound at the indicated concentration (1% final concentration DMSO). After 8 h incubation, the cells were harvested and pelleted. Genomic DNA was extracted using the DNeasy Blood & Tissue Kit (Qiagen, ID: 69504). DNA was then precipitated using the following procedure: 1/10 v/v 3M sodium acetate (pH 5.2) and 2.5× v/v ethanol was added to each sample which was then kept at −80° C. for 1 h. The mixture was centrifuged at max at 4° C. for 30 min and decanted to afford a pellet of DNA, which was re-suspended in ddH2O containing 10 mM tris base (pH 7.5) and 1 mM EDTA. The concentration of DNA in each sample was quantified measuring absorbance on a NanoDrop 2000 UV-Vis Spectrophotometer (Thermo Fisher). DNA (10 μg) from each sample was added to DNA hydrolysis buffer3 and incubated at 37° C. for 6 h. Hydrolyzed samples were then submitted for LC-MS/MS quantitation. Samples were analyzed with a 5500 QTRAP LC/MS/MS system (AB Sciex) with a 1200 series HPLC system (Agilent).
- in vivo Blood-Brain Barrier Permeability. All experimental procedures were reviewed and approved by the University of Illinois Institutional Animal Care and Use Committee. CD-1 IGS mice were administered compound in 1% DMSO (
FIG. 2a ) or 10% DMSO (FIG. 2b-d ) in PBS at 25 mg/kg via lateral tail vein injection. Five minutes post injection, mice were sacrificed, and blood was collected by lacerating the right auricle with iris scissors. An 18-gauge angiocatheter was inserted through the left ventricle, and all residual circulatory volume was removed by perfusing 0.9% saline solution via an analog peristaltic pump. Blood samples were immediately centrifuged at 13,000 rcf for five minutes and the supernatant collected and acidified with 8.5% aqueous H3PO4. Brains were harvested from the cranial vault, acidified with 0.3% aqueous H3PO4 and flash frozen. Homogenized brain samples were centrifuged twice at 13,000 rcf for ten minutes and supernatant and tissue debris were separated. The resultant supernatant was analyzed, along with plasma, by LC-MS/MS to determine compound concentrations. In order to calculate absolute brain:serum ratios (ng drugbrain:ng drugserum), a mouse blood volume of 58.5 mL/kg was assumed for each mouse. - in vivo Efficacy Models. Human GBM Br23c stem-like neurosphere cells were intracranially implanted in female athymic nude mice (150,000 cells/mouse). Beginning
day 5 after implantation of the tumor cells, drugs were formulated in 10% PEG 400 in saline and 15 mg/kg TMZ (or equimolar dose of C8 analog) was administered via oral gavage once-per-day for 7 weeks (FIG. 5a ) or once-per-day for 5 total treatments (FIG. 5b ). TMZ and C8 analogs were dissolved fresh for each use. Mice were observed daily for any signs of deterioration, neurotoxicity, or movement disorders. They were inspected for signs of pain and distress, as in accordance with the Johns Hopkins Animal Care and Use Guidelines. If the symptoms persisted and resulted in debilitation, the animals were euthanized according to protocol. - Assessment of Hematological Toxicity. Male CD-1 IGS mice (n=4 mice/group) were administered a single dose of 125 mg/kg compound intravenously. Imidazotetrazines were formulated with SBEβCD in sterile water immediately prior to injection. Seven days post-treatment, mice were humanely sacrificed and whole blood was collected for assessment of total white blood cells, lymphocytes, neutrophils, platelets, and red blood cells.
- Materials and Methods. Chemical reagents were purchased from commercial sources and used without further purification. Flash chromatography was performed using silica gel (230-400 mesh). Anhydrous solvents were dried after being passed through columns packed with activated alumina under positive pressure of nitrogen. Unless otherwise noted, all reactions were carried out in oven-dried glassware with magnetic stirring under nitrogen atmosphere. 1H and 13C NMR spectra were recorded on Bruker 500 (500 MHz, 1H; 125 MHz, 13C) or Varian Unity Inova 500 (500 MHz, 1H) MHz spectrometers. Spectra are referenced to residual chloroform (δ=7.26 ppm, 1H; 77.16 ppm, 13C) or dimethyl sulfoxide (δ=2.50 ppm, 1H; 39.52 ppm, 13C). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Coupling constants J are reported in Hertz (Hz). High resolution mass spectrometry (HRMS) was performed on a Waters Q-Tof Ultima or Waters Synapt G2-Si instrument with electrospray ionization (ESI) or electron impact ionization (EI).
- Preparation and Characterization of C8 Analogs. Experimental information for
compounds -
- General procedure for preparation of 4-10. In an oven-dried 25 mL round bottom flask, acyl chloride 29 (148.6 mg, 0.70 mmol, 1 eq.) was dissolved in anhydrous THE (2.8 mL, 0.25 M). Methylamine (33% w/w in ethanol, 0.09 mL, 0.73 mL, 1.05 eq.) was then added and the reaction was stirred for 3 h at room temperature. When complete, the reaction was stopped and the solvent was evaporated. The crude solid was purified by flash silica gel chromatography (100% ethyl acetate) to yield 98.3 mg (68%) of pure 4 as a white solid.
- Experimental data for
compounds - 1H NMR (500 MHz, d-DMSO) δ 8.84 (s, 1H), 8.45 (d, J=4.9 Hz, 1H), 3.86 (s, 3H), 2.81 (d, J=4.8 Hz, 3H). 13C (125 MHz, d-DMSO) δ 160.13, 139.23, 134.27, 130.54, 128.44, 36.14, 25.80. HRMS (ESI) calc. for C7H8N6O2Na, [M+Na]+: 231.0606, found: 231.0608.
- 76% yield as a white solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.81 (s, 1H), 3.85 (s, 3H), 3.06 (s, 6H). 13C NMR (125 MHz, d-DMSO) δ 161.76, 139.22, 133.57, 132.05, 128.59, 38.12, 36.05, 34.84. HRMS (ESI) calc. for C8H11N6O2, [M+H]: 223.0938, found: 223.0943.
- 91% as a white solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.81 (s, 1H), 3.84 (s, 3H), 3.49 (q, J=7.1 Hz, 2H), 3.38 (q, J=7.0 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.11 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, d-DMSO) δ 161.35, 139.24, 133.54, 132.72, 128.45, 42.53, 36.01, 14.43, 12.80.
- HRMS (ESI) calc. for C10H15N6O2, [M+H]+: 251.1256, found: 251.1250.
- 85% yield as a white solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.80 (s, 1H), 3.84 (s, 3H), 3.45 (m, 2H), 3.34 (m, 2H), 1.59 (m, 2H), 1.49 (m, 2H), 1.35 (h, J=7.4 Hz, 2H), 1.11 (h, J=7.4 Hz, 2H), 0.94 (t, J=7.4 Hz, 3H), 0.76 (t, J=7.4 Hz, 3H). 13C NMR (125 MHz, d-DMSO) δ 161.74, 139.23, 133.35, 132.80, 128.42, 47.66, 44.41, 35.99, 30.54, 29.20, 19.65, 19.17, 13.79, 13.55. HRMS (ESI) calc. for C14H23N6O2, [M+H]+: 307.1882, found: 307.1881.
- 55% yield as pale-yellow solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.81 (s, 1H), 3.85 (s, 3H), 3.63 (m, 2H), 3.53 (m, 2H), 1.88 (m, 4H). 13C NMR (125 MHz, d-DMSO) δ 159.73, 139.21, 134.07, 132.54, 128.33, 48.05, 46.09, 36.05, 25.80, 23.63. HRMS (ESI) calc. for C10H13N6O2, [M+H]+: 249.1100, found: 249.1105.
- 92% as a white solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.86 (s, 1H), 3.89 (s, 3H), 3.02 (q, J=7.4 Hz, 2H), 1.28 (t, J=7.4 Hz, 3H). 13C NMR (125 MHz, d-DMSO) δ 184.57, 138.95, 133.80, 131.55, 129.19, 36.50, 22.15, 14.70. HRMS (ESI) calc. for C8H10N5O2S, [M+H]+: 240.0555, found: 240.0551.
-
- Procedure. To a 15 mL round bottom flask, 4-methyl-1H-imidazol-5-amine dihydrochloride 12 (44.2 mg, 0.3 mmol, 1 eq.) was added and dissolved in 1M HCl (0.4 mL, 0.65 M) before sodium nitrite (26.2 mg, 0.4 mmol, 1.5 eq.) in water (0.4 mL, 0.65 M) was added at 0° C. in the dark. The solution was stirred 30 minutes then concentrated and azeotroped twice with toluene to afford crude diazo 13. To the crude diazo suspended in ethyl acetate (1.3 mL, 0.2 M), anhydrous triethylamine (0.08 mL, 0.6 mmol, 2.2 eq.) and methylcarbamic chloride (79 mg, 0.8 mmol, 3.2 eq.) were added in the dark. The reaction was stirred overnight before being purified via flash silica gel chromatography (4:1 hexanes: ethyl acetate) to afford 2.4 mg (6%) 14 as a pale yellow solid. Note: To minimize decomposition of the crude diazo species, concentration was done (without heating) in the dark as quickly as possible.
- 1H NMR (500 MHz, d-CHCl3) δ 8.35 (s, 1H), 3.94 (s, 3H), 2.66 (s, 3H). 13C NMR (125 MHz, d-CHCl3) δ 139.71, 139.64, 132.51, 127.94, 35.76, 12.53. HRMS (EI) calc. for C6H7N5O, [M]+: 165.0651, found: 165.0654.
-
- Procedure. To an oven-dried 25 mL round bottom flask, 16 (186 mg, 0.89 mmol, 1 eq.) and N-succinimidyl N-methylcarbamate (321 mg, 1.86 mmol, 2.1 eq.) were added and suspended in anhydrous acetonitrile (1.5 mL, 0.6 M). Next, under nitrogen, dry triethylamine (0.34 mL, 2.4 mmol, 2.7 eq.) was added slowly and the solution was stirred overnight at room temperature. Upon completion, the mixture was concentrated and purified by silica gel flash chromatography (100% dichloromethane to 4:1 dichloromethane: methanol) to afford 106 mg (66%) of intermediate 16a as a gold solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.17 (br s, 1H), 7.97 (s, 1H), 7.56 (s, 2H), 3.36 (d, J=4.5 Hz, 3H), 2.73 (s, 3H).
- In a 15 mL round bottom flask, LiCl (802 mg, 19 mmol, 36 eq.) was dissolved in distilled water (1.3 mL, 0.4 M) and AcOH (0.10 mL, 5.3 M) and stirred for thirty minutes until the exotherm dissipated. Intermediate 16a (96.3 mg, 0.53 mmol, 1 eq.) was added in one portion and stirred for thirty minutes. The suspension was then cooled to 0° C. in an ice bath before a solution of NaNO2 (57 mg, 0.8 mmol, 1.5 eq.) in a minimal amount of distilled water was added dropwise. The resultant mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred an additional 5 hours. Upon completion, the reaction mixture was diluted with CH2Cl2 and the organic layer was separated. The aqueous layer was extracted with dichloromethane (×6) and the combined organic layers were dried over sodium sulfate and concentrated to yield crude solid which was purified by flash silica chromatography (1:1 ethyl acetate: hexanes) to afford 36 mg (35%) of 17 as a white solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.86 (s, 1H), 3.90 (s, 3H), 2.68 (s, 3H). 13C NMR (125 MHz, d-DMSO) δ 191.47, 139.01, 135.56, 133.35, 129.11, 36.43, 28.31. HRMS (ESI) calc. for C7H8N502, [M+H]*: 194.0678, found: 194.0683.
- Experimental data for
intermediates 31, 15, and 16 has been published.7,8,10 -
- Procedure. To a stirred suspension of Dess-Martin periodinane (477 mg, 1.12 mmol, 2.2 eq) in anhydrous CH3CN (2.6 mL, 0.2 M), tetraethylammonium bromide (240 mg, 1.12 mmol, 2.2 eq) was added. Reaction was stirred 5 min at room temperature before 3 (100 mg, 0.51 mmol, 1 eq) was added. The resultant reaction mixture was heated at 50° C. for 2 h. Upon completion, the solvent was concentrated under reduced pressure to give the crude product that was purified by flash silica gel chromatography (9:1 hexanes: ethyl acetate) to afford 73 mg (58%) of 18 as a white solid.
- 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 3.98 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 138.74, 133.32, 128.56, 117.16, 36.43. HRMS (ESI) calc. for C5H5N5OBr, [M+H]+: 229.9677, found: 229.9684.
-
- Procedure. To a stirred suspension of Dess-Martin periodinane (477 mg, 1.12 mmol, 2.2 eq.) in anhydrous CH3CN (2.6 mL, 0.2 M), tetramethylammonium chloride (123 mg, 1.12 mmol, 2.2 eq.) was added. The reaction was stirred 5 min at room temperature before 3 (100 mg, 0.51 mmol, 1 eq.) was added. The resultant reaction mixture was heated at 50° C. for 2 hours. Upon completion, the solvent was concentrated under reduced pressure to give the crude product that was purified by flash silica chromatography (9:1 hexanes: ethyl acetate) to afford 43 mg (45%) of 19 as a white solid.
- 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 11H), 3.98 (s, 31). 13C NMR (125 MHz, CDCl3) δ 138.74, 130.84, 129.81, 127.25, 36.37. HRMS (ESI) calc. for C5H5N5OCl, [M+H]+: 186.0183, found: 186.0186.
-
- General Procedure for Preparation of 23-26. (a) Suzuki Coupling. A mixture of 4-bromo-5-nitro-1H-imidazole 20 (400 mg, 2.08 mmol, 1 eq.), phenyl boronic acid (507 mg, 4.17 mmol, 2 eq.), XPhosPdG1(164 mg, 0.2 mmol, 0.1 eq.) and K3PO4 (1.32 g, 6.24 mmol, 3 eq.) under nitrogen was suspended in degassed 1:1 H2O: dioxane (16 mL, 0.13 M). The resulting mixture was stirred at 110° C. for 16 h. The reaction was cooled to room temperature and H2O was added. The aqueous layer was extracted ×3 with ethyl acetate and the combined organic layers were dried over Na2SO4 and concentrated. The residue obtained was purified by flash silica gel chromatography (100% ethyl acetate) to afford
crude product 21 that was used for next step without further purification. - (b) Nitro Reduction.
Crude 21 was dissolved in dry MeOH (10 mL, 0.2 M) containing 10% Pd/C before H2 (1 atm) was introduced. The reaction was stirred for 16 h at room temperature before the catalyst was filtered over Celite. The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography (95:5 DCM: MeOH) providing compound 22 that was used for next step without further purification. - (c) Cyclization. To a suspension of intermediate 22 in 1 M HCl (2.9 mL, 0.7 M) at 0° C. was added a pre-formed solution of NaNO2 (186 mg, 2.7 mmol, 1.3 eq.) in H2O (2.9 mL, 0.9 M) dropwise. The resultant mixture was stirred at 0° C. in the dark for 30 min. Upon completion, the solvent was evaporated, and the crude diazo compound was dissolved in ethyl acetate (9.6 mL, 0.2 M) before triethylamine (544 μL, 4.6 mmol, 2 eq.) and methylcarbamic chloride (1010 mg, 10.8 mmol, 5.2 eq.) were added. The reaction mixture was stirred at room temperature for 16 h protected from light. Upon reaction completion, the solvent was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (9:1 hexanes: ethyl acetate) to afford 28 mg (6%) of pure 23 as a white solid.
-
- Product was obtained using general procedure. White solid, 6% yield (4 steps).
- 1H NMR (500 MHz, d-DMSO) δ 8.84 (s, 1H), 8.31-8.29 (m, 2H), 7.57-7.53 (m, 2H), 7.44 (tt, J=7.4, 1.3 Hz, 1H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 140.02, 137.02, 132.30, 131.88, 129.86, 129.48, 129.43, 127.07, 36.29. HRMS (ESI) calc. for C11H10N5O, [M+H]+: 228.0885, found: 228.0878.
-
- Product was obtain using general procedure. Yellow solid, 3% yield (4 steps).
- 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 8.44-8.40 (m, 2H), 7.24-7.19 (m, 2H), 4.01 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 164.57, 162.58, 139.20 (d, J=86.4 Hz, 1C), 131.00, 129.43 (d, J=8.3 Hz, 1C), 128.56, 127.26 (d, J=3.3 Hz, 1C), 116.00 (d, J=21.6 Hz, 1C), 35.97. HRMS (ESI) calc. for C11H9FN5O, [M+H]+: 246.0791, found: 246.0788.
-
- Product was obtained using the general procedure. Yellow solid, 5% yield (4 steps).
- 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J=8.2 Hz, 2H), 8.48 (s, 1H), 7.75 (d, J=8.2 Hz, 2H), 4.02 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 139.34, 137.89, 134.30, 131.91, 131.03 (q, J=32.3 Hz, 1C), 128.77, 127.61, 125.80 (q, J=3.8 Hz, 1C), 122.96, 36.15. HRMS (ESI) calc. for C12H9N5OF3, [M+H]+: 296.0759, found: 296.0754.
-
- Product was obtained using the general procedure. Yellow solid, 1.2% yield (4 steps).
- 1H NMR (500 MHz, d-DMSO) δ 8.86 (s, 1H), 8.30 (dt, J=9.25, 2.5 Hz, 2H), 7.62 (dt, J=9.25, 2.5 Hz, 2H), 3.86 (s, 3H). 13C NMR (125 MHz, d-DMSO) δ 139.92, 135.67, 133.97, 132.45, 130.75, 130.00, 129.63, 128.62, 36.37. HRMS (ESI) calc. for C11H9N5OCl, [M+H]+: 262.0496, found: 262.0489.
-
- Procedure. To 29 (447 mg, 2.09 mmol, 1 eq.) and 2-aminoacetophenone hydrochloride (229 mg, 2.09 mmol, 1 eq.) was added DMF (4.4 mL, 0.47 M) and pyridine (0.9 mL). The reaction mixture was stirred for 16 h at room temperature. Water was added and the aqueous layer was extracted ×5 with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The residue obtained was purified by flash silica gel chromatography (100% ethyl acetate) to afford 266 mg (51%) of 32 as an orange solid.
- 1H NMR (500 MHz, d-DMSO) δ 8.87 (s, 1H), 8.59 (t, J=5.7 Hz, 1H), 4.17 (d, J=5.7 Hz, 2H), 3.88 (s, 3H), 2.15 (s, 3H). 13C NMR (125 MHz, d-DMSO) δ 204.55, 160.15, 139.65, 135.10, 130.18, 129.09, 49.57, 36.67, 27.52. LC-MS (ESI) calc. for C9H11N6O3 [M+H]+: 251.0893, found: 251.09.
- Procedure: Intermediate 32 (266 mg, 1.06 mmol, 1 eq.) was added to phosphoryl chloride (6.5 mL, 0.16 M) and the stirred mixture was heated at 110° C. for 3 h. Upon completion, ice water was added, and the aqueous layer was extracted ×4 with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The residue obtained was purified by flash silica gel chromatography (100% ethyl acetate) to afford 80 mg (32%) of the
product 27 as a yellow solid. - 1H NMR (500 MHz, d-DMSO) δ 8.89 (s, 1H), 7.13 (br d, J=1.2 Hz, 1H), 3.87 (s, 3H), 2.44 (d, J=1.2 Hz, 3H). 13C NMR (125 MHz, d-DMSO) δ 154.15, 150.47, 139.64, 133.64, 130.43, 126.15, 125.36, 36.56, 11.17. HRMS (ESI) calc. for C9H9N6O2, [M+H]+: 233.0782, found: 233.0787.
- The route to 4-substituted oxazol-2-yls at the C8 position of imidazotetrazines is known,11 however, the synthesis of
compound 27 via intermediate 32 had never been reported. -
- Procedure. To a solution of 33 (550 mg, 2.6 mmol, 1 eq.) in acetonitrile (40 mL, 0.07 M) was added α-Bromo acetone (220 μL, 2.6 mmol, 1 eq.) and the solution was stirred at room temperature for 18 h. Upon completion, the reaction was stopped, and the precipitate was filtered and purified by flash silica gel chromatography (4:6 hexanes: ethyl acetate) to afford 167 mg (26%) of the desired
product 28 as a yellow solid. - 1H NMR (500 MHz, d-DMSO) δ 8.87 (s, 1H), 7.46 (d, J=0.9 Hz, 1H), 3.86 (s, 3H), 2.48 (d, J=0.9 Hz, 3H). 13C NMR (125 MHz, d-DMSO) δ 158.63, 154.58, 139.75, 131.84, 131.80, 130.24, 116.56, 36.52, 17.45. HRMS (ESI) calc. for C9H9N6OS, [M+H]+: 249.0559, found: 249.0559.
- The route to 4-substituted thiazol-2-yls at the C8 position of imidazotetrazines is known,11 however, the synthesis of
compound 28 had never been reported. Experimental data for intermediate 33 has been published.6 - Arene and propargyl substituted imidazotetrazines can be prepared as follows.
- wherein G1 is OCH3, OCH2CH3, OPh, N(CH3)2, propargyl, or a substituent as defined herein.
- TMZ is a non-explosive, weighable surrogate for diazomethane. TMZ and other imidazotetrazines can be used as synthetic diazoalkane precursors as illustrated below.
- The following formulations illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as ‘Compound X’):
-
(i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 -
(ii) Tablet 2mg/tablet ‘Compound X’ 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ‘Compound X’ 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 -
(iv) Injection 1 (1 mg/mL) mg/mL ‘Compound X’ (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL -
(v) Injection 2 (10 mg/mL) mg/mL ‘Compound X’ (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400200.0 0.1N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL -
(vi) Aerosol mg/can ‘Compound X’ 20 Oleic acid 10 Trichloromonofluoromethane 5,000 Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000 -
(vii) Topical Gel 1 wt. % ‘Compound X’ 5% Carbomer 934 1.25% Triethanolamine q.s. (pH adjustment to 5-7) Methyl paraben 0.2% Purified water q.s. to 100 g -
(viii) Topical Gel 2wt. % ‘Compound X’ 5 % Methylcellulose 2% Methyl paraben 0.2% Propyl paraben 0.02% Purified water q.s. to 100 g -
(ix) Topical Ointment wt. % ‘Compound X’ 5% Propylene glycol 1% Anhydrous ointment base 40 % Polysorbate 80 2% Methyl paraben 0.2% Purified water q.s. to 100 g -
(x) Topical Cream 1 wt. % ‘Compound X’ 5% White bees wax 10 % Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s. to 100 g -
(xi) Topical Cream 2wt. % ‘Compound X’ 5 % Stearic acid 10% Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5 % Isopropyl palmitate 2% Methyl Paraben 0.2% Purified water q.s. to 100 g - These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient ‘Compound X’. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest.
-
- (1) Stupp, R.; Mason, W.; van den Bent, M. J.; Weller, M.; Fisher, B. M.; Taphoorn, M. J. B.; Belanger, K.; Brandes, A. A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R. C.; Ludwin, S. K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J. G.; Eisenhauer, E.; Mirimanoff, R. O. (2005) Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 352, 987-996.
- (2) Denny, B. J.; Wheelhouse, R. T.; Stevens, M. F.; Tsang, L. L.; Slack, J. a. (1994) NMR and Molecular Modeling Investigation of the Mechanism of Activation of the Antitumor Drug Temozolomide and Its Interaction with DNA. Biochemistry 33, 9045-9051.
- (3) Karran, P.; Macpherson, P.; Ceccotti, S.; Dogliotti, E.; Griffin, S.; Bignami, M. (1993) O6-Methylguanine Residues Elicit DNA Repair Synthesis by Human Cell Extracts. J. Biol. Chem. 268, 15878-15886.
- (4) Ceccotti, S.; Aquilina, G.; Macpherson, P.; Yamada, M.; Karran, P.; Bignami, M. (1996) Processing of O6-Methylguanine by Mismatch Correction in Human Cell Extracts. Curr. Biol. 6, 1528-1531.
- (5) Margison, G. P.; Santibanez Koref, M. F.; Povey, A. C. (2002) Mechanisms of Carcinogenicity/Chemotherapy by 06-Methylguanine.
Mutagenesis 17, 483-487. - (6) Tisdale, M. J. (1987) Antitumour Imidazotetrazines-XV. Role of Guanine O6 Alkylation in the Mechanism of Cytotoxicity of Imidazotetrazinones. Biochem. Pharmacol. 36, 457-462.
- (7) Newlands, E. S.; Blackledge, G. R.; Slack, J. A.; Rustin, G. J.; Smith, D. B.; Stuart, N. S.; Quarterman, C. P.; Hoffman, R.; Stevens, M. F.; Brampton, M. H.; Gibson, A. C. (1992) Phase I Trial of Temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br. J. Cancer 65, 287-291.
- (8) Ostermann, S.; Csajka, C.; Buclin, T.; Leyvraz, S.; Lejeune, F.; Decosterd, L. a; Stupp, R. (2004) Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients. Clin. Cancer Res. 10, 3728-3736.
- (9) Portnow, J.; Badie, B.; Chen, M.; Liu, A.; Blanchard, S.; Synold, T. W. (2009) The Neuropharmacokinetics of Temozolomide in Patients with Resectable Brain Tumors: Potential Implications for the Current Approach to Chemoradiation. Clin. Cancer Res. 15, 7092-7098.
- (10) Stupp, R.; Hegi, M. E.; Mason, W. P.; van den Bent, M. J.; Taphoorn, M. J.; Janzer, R. C.; Ludwin, S. K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; Brandes, A. A.; Gijtenbeek, J.; Marosi, C.; Vecht, C. J.; Mokhtari, K.; Wesseling, P.; Villa, S.; Eisenhauer, E.; Gorlia, T.; Weller, M.; Lacombe, D.; Cairncross, J. G.; Mirimanoff, R. O. (2009) Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial. Lancet Oncol. 10, 459-466.
- (11) Reifenberger, G.; Wirsching, H.-G.; Knobbe-Thomsen, C. B.; Weller, M. (2017) Advances in the Molecular Genetics of Gliomas Implications for Classification and Therapy. Nat. Rev. Clin. Oncol. 14, 434-452.
- (12) Vaupel, P.; Kallinowski, F.; Okunieff, P. (1989) Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review. Cancer Res. 49, 6449-6465.
- (13) Rottenberg, D. A., Ginos, J. Z., Kearfott, K. J., Junck, L., and Bigner, D. D. (1984) In Vivo Measurement of Regional Brain Tissue PH Using Positron Emission Tomography. Ann. Neurol. 15, S98-S102.
- (14) Arnold, James B, Kraig, Richard P, Rottenberg, D. A. (1986) In Vivo Measurement of Regional Brain and Tumor pH Using [14 C]Dimethyloxazolidinedione and Quantitative Autoradiography. II: Characterization of the Extracellular Fluid Compartment Using PH-Sensitive Microelectrodes and [14 C]Sucrose. J. Cereb. Blood Flow Metab. 6, 435-440.
- (15) McLean, L. A.; Roscoe, J.; Jorgensen, N. K.; Gorin, F. A.; Cala, P. M. (2000) Malignant Gliomas Display Altered pH Regulation by NHE1 Compared with Nontransformed Astrocytes. Am. J. Physiol. Cell Physiol. 278, C676-88.
- (16) Lowe, P. R.; Sansom, C. E.; Schwalbe, C. H.; Stevens, M. F. G.; Clark, A. S. (1992) Antitumor Imidazotetrazines. 25. Crystal Structure of 8-Carbamoyl-3-Methylimidazo[5,1-d]-1,2,3,5-Tetrazin-4(3H)-One (Temozolomide) and Structural Comparisons with the Related Drugs Mitozolomide and DTIC. J. Med. Chem. 35, 3377-3382.
- (17) Suppasansatorn, P.; Wang, G.; Conway, B. R.; Wang, W.; Wang, Y. (2006) Skin Delivery Potency and Antitumor Activities of Temozolomide Ester Prodrugs. Cancer Lett. 244, 42-52.
- (18) Liu, D.; Yang, J. G.; Cheng, J.; Zhao, L. X. (2010) Synthesis and Antitumor Activity of 3-Methyl-4-Oxo-3,4-Dihydroimidazo [5,1-d][1,2,3,5]Tetrazine-8-Carboxylates and -Carboxamides.
Molecules 15, 9427-9436. - (19) Hummersone, M. G.; Stevens, M. F. G.; Cousin, D. Preparation of 3-Substituted-3H-Imidazo[5,1-d][1,2,3,5]Tetrazin-4-One Compounds for Treating Proliferative Disorders. WO 2010149968, 2010.
- (20) O'Reilly, S. M.; Newlands, E. S.; Brampton, M.; Glaser, M. G.; Rice-Edwards, J. M.; Illingworth, R. D.; Richards, P. G.; Kennard, C.; Colquhoun, I. R.; Lewis, P.; Stevens, M. F. G. (1993) Temozolomide: A New Oral Cytotoxic Chemotherapeutic Agent with Promising Activity against Primary Brain Tumours. Eur. J. Cancer 29, 940-942.
- (21) Bleehen, N. M.; Newlands, E. S.; Lee, S. M.; Thatcher, N.; Selby, P.; Calvert, A. H.; Rustin, G. J. S.; Brampton, M.; Stevens, M. F. G. (1995) Cancer Research Campaign Phase II Trial of Temozolomide in Metastatic Melanoma. J. Clin. Oncol. 13, 910-913.
- (22) Shealy, Y. F.; Struck, R. F.; Holum, L. B.; Montgomery, J. A. (1961) Synthesis of Potential Anticancer Agents. XXIX. 5-Diazoimidazole-4-Carboxamide and 5-Diazo-v-Triazole-4-Carboxamide. J. Org. Chem. 26, 2396-2401.
- (23) Shechter, H.; Magee, W. L.; Rao, C. B.; Glinka, J.; Hui, H.; Amick, T. J.; Fiscus, D.; Kakodkar, S.; Nair, M. (1987) Dipolar Cycloaddition Reactions of Diazoazoles with Electron-Rich and with Strained Unsaturated Compounds. J. Org. Chem. 52, 5538-5548.
- (24) Fulmer Shealy, Y.; Krauth, C. A.; Montgomery, J. A. (1962) Imidazoles. I. Coupling Reactions of 5-Diazoimidazole-4-Carboxamide. J. Org. Chem. 27, 2150-2154.
- (25) Stevens, M. F.; Hickman, J. A.; Stone, R.; Gibson, N. W.; Baig, G. U.; Lunt, E.; Newton, C. G. (1984) Antitumor Imidazotetrazines. 1. Synthesis and Chemistry of 8-Carbamoyl-3-(2-Chloroethyl)Imidazo[5,1-d]-1,2,3,5-Tetrazin-4(3H)-One, a Novel Broad-Spectrum Antitumor Agent. J. Med. Chem. 27, 196-201.
- (26) Lunt, E.; Newton, C. G.; Smith, C.; Stevens, G. P.; Stevens, M. F. G.; Straw, C. G.; Walsh, R. J. A.; Warren, P. J.; Fizames, C.; Lavelle, F.; Langdon, S. P.; Vickers, L. M. (1987) Antitumor Imidazotetrazines. 14. Synthesis and Antitumor Activity of 6- and 8-Substituted Imidazo[5,1-d]-1,2,3,5-Tetrazinones and 8-Substituted Pyrazolo[5,1-d]-1,2,3,5-Tetrazinones. J. Med. Chem. 30, 357-366.
- (27) Moseley, C. K.; Carlin, S. M.; Neelamegam, R.; Hooker, J. M. (2012) An Efficient and Practical Radiosynthesis of [11C]Temozolomide. Org. Lett. 14, 5872-5875.
- (28) Horspool, K. R.; Stevens, M. F. G.; Baig, G. U.; Newton, C. G.; Lunt, E.; Walsh, R. J. A.; Pedgrift, B. L.; Lavelle, F.; Fizames, C. (1990) Antitumor Imidazotetrazines. 20. Preparation of the 8-Acid Derivative of Mitozolomide and Its Utility in the Preparation of Active Antitumor Agents. J. Med. Chem. 33, 1393-1399.
- (29) Langnel, D. A. F.; Arrowsmith, J.; Stevens, M. F. G. (2000) Antitumor Imidazotetrazines. 38. New 8-Substituted Derivatives of the Imidazo[5,1-d]-1,2,3,5-Tetrazines Temozolomide and Mitozolomide. ARKIVOC No. iii, 421-437.
- (30) Stevens, M. A.; Giner-Sorolla, A.; Smith, H. W.; Bosworth Brown, G. (1962) Purine N-Oxides. X. The Effect of Some Substituents on Stability and Reactivity. J. Org. Chem. 27, 567-572.
- (31) Xie, Y.; Bergstrom, T.; Jiang, Y.; Johansson, P.; Marinescu, V. D.; Lindberg, N.; Segerman, A.; Wicher, G.; Niklasson, M.; Baskaran, S.; Sreedharan, S.; Everlien, I.; Kastemar, M.; Hermansson, A.; Elfineh, L.; Libard, S.; Holland, E. C.; Hesselager, G.; Alafuzoff, I.; Westermark, B.; Nelander, S.; Forsberg-Nilsson, K.; Uhrbom, L. (2015) The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes.
EBioMedicine 2, 1351-1363. - (32) Pardridge, W. M. (2005) The Blood-Brain Barrier: Bottleneck in Brain Drug Development.
NeuroRX 2, 3-14. - (33) Norinder, U.; Haeberlein, M. (2002) Computational Approaches to the Prediction of the Blood-Brain Distribution. Adv. Drug Deliv. Rev. 54, 291-313.
- (34) West, D. C.; Qin, Y.; Peterson, Q. P.; Thomas, D. L.; Palchaudhuri, R.; Morrison, K. C.; Lucas, P. W.; Palmer, A. E.; Fan, T. M.; Hergenrother, P. J. (2012) Differential Effects of Procaspase-3 Activating Compounds in the Induction of Cancer Cell Death. Mol. Pharm. 9, 1425-1434.
- (35) Egan, W. J.; Merz, K. M.; Baldwin, J. J. (2000) Prediction of Drug Absorption Using Multivariate Statistics. J. Med. Chem. 43, 3867-3877.
- (36) Tian, S.; Wang, J.; Li, Y.; Li, D.; Xu, L.; Hou, T. (2015) The Application of in Silico Drug-Likeness Predictions in Pharmaceutical Research. Adv. Drug Deliv. Rev. 86, 2-10.
- (37) Daina, A.; Zoete, V. (2016) A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules.
ChemMedChem 11, 1117-1121. - (38) Alifrangis, L. H.; Christensen, I. T.; Berglund, A.; Sandberg, M.; Hovgaard, L.; Frokjaer, S. (2000) Structure-Property Model-for Membrane Partitioning of Oligopeptides. J. Med. Chem. 43, 103-113.
- (39) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. (2010) Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach to Enable Alignment of Druglike Properties. ACS Chem. Neurosci. 1, 435-449.
- (40) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. (2016) Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery. ACS Chem. Neurosci. 7, 767-775.
- (41) Reyderman, L.; Statkevich, P.; Thonoor, C. M.; Patrick, J.; Batra, V. K.; Wirth, M. (2004) Disposition and Pharmacokinetics of Temozolomide in Rat. Xenobiotica 34, 487-500.
- (42) Rai, R.; Banerjee, M.; Wong, D. H.; McCullagh, E.; Gupta, A.; Tripathi, S.; Riquelme, E.; Jangir, R.; Yadav, S.; Raja, M.; Melkani, P.; Dixit, V.; Patil, U.; Shrivastava, R.; Middya, S.; Olivares, F.; Guerrero, J.; Surya, A.; Pham, S. M.; Bernales, S.; Protter, A. A.; Hung, D. T.; Chakravarty, S. (2016) Temozolomide Analogs with Improved Brain/Plasma Ratios—Exploring the Possibility of Enhancing the Therapeutic Index of Temozolomide. Bioorganic Med. Chem. Lett. 26, 5103-5109.
- (43) Kim, S. S.; Rait, A.; Kim, E.; DeMarco, J.; Pirollo, K. F.; Chang, E. H. (2015) Encapsulation of Temozolomide in a Tumor-Targeting Nanocomplex Enhances Anti-Cancer Efficacy and Reduces Toxicity in a Mouse Model of Glioblastoma. Cancer Lett. 369, 250-258.
- (44) Stevens, M. F.; Hickman, J. A.; Langdon, S. P.; Chubb, D.; Vickers, L.; Stone, R.; Baig, G.; Goddard, C.; Gibson, N. W.; Slack, J. A. (1987) Antitumor Activity and Pharmacokinetics in Mice of 8-Carbamoyl-3-Methyl-Imidazo[5,1-d]-1,2,3,5-Tetrazin-4(3H)-One (CCRG 81045; M & B 39831), a Novel Drug with Potential as an Alternative to Dacarbazine. Cancer Res. 47, 5846-5852.
- (45) Bobola, M. S.; Tseng, S. H.; Blank, a; Berger, M. S.; Silber, J. R. (1996) Role of 06-Methylguanine-DNA Methyltransferase in Resistance of Human Brain Tumor Cell Lines to the Clinically Relevant Methylating Agents Temozolomide and Streptozotocin. Clin. Cancer Res. 2, 735-741.
- (46) Kanzawa, T.; Bedwell, J.; Kondo, Y.; Kondo, S.; Germano, I. M. (2003) Inhibition of DNA Repair for Sensitizing Resistant Glioma Cells to Temozolomide. J. Neurosurg. 99, 1047-1052.
- (47) Binder, Z. A.; Wilson, K. M.; Salmasi, V.; Orr, B. A.; Eberhart, C. G.; Siu, I M.; Lim, M.; Weingart, J. D.; Quinones-Hinojosa, A.; Bettegowda, C.; Kassam, A. B.; Olivi, A.; Brem, H.; Riggins, G. J.; Gallia, G. L. (2016) Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.
PLoS One 11, e0150271. - (48) Scaringi, C.; De Sanctis, V.; Minniti, G.; Enrici, R. M. (2013) Temozolomide-Related Hematologic Toxicity. Onkologie 36, 444-449.
- (49) Thomas, R. P.; Recht, L.; Nagpal, S. (2013) Advances in the Management of Glioblastoma: The Role of Temozolomide and MGMT Testing. Clin. Pharmacol., 5, 1-9.
- (50) Chamberlain, M. C. (2010) Temozolomide: Therapeutic Limitations in the Treatment of Adult High-Grade Gliomas. Expert Rev. Neurother. 10, 1537-1544.
- (51) Li, R.; Tang, D.; Zhang, J.; Wu, J.; Wang, L.; Dong, J. (2014) The Temozolomide Derivative 2T-P400 Inhibits Glioma Growth via Administration Route of Intravenous Injection. J. Neurooncol. 116, 25-30.
- (52) Cheng, Y.; Sk, U. H.; Zhang, Y.; Ren, X.; Zhang, L.; Huber-Keener, K. J.; Sun, Y. W.; Liao, J.; Amin, S.; Sharma, A. K.; Yang, J. M. (2012) Rational Incorporation of Selenium into Temozolomide Elicits Superior Antitumor Activity Associated with Both Apoptotic and Autophagic Cell Death. PLoS One 7, e35104.
- (53) Cho, H.-Y.; Wang, W.; Jhaveri, N.; Lee, D. J.; Sharma, N.; Dubeau, L.; Schonthal, A. H.; Hofman, F. M.; Chen, T. C. (2014) NE0212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas. Mol. Cancer Ther. 13, 2004-2017.
- (54) Owonikoko, T. K.; Arbiser, J.; Zelnak, A.; Shu, H.-K. G.; Shim, H.; Robin, A. M.; Kalkanis, S. N.; Whitsett, T. G.; Salhia, B.; Tran, N. L.; Ryken, T.; Moore, M. K.; Egan, K. M.; Olson, J. J. (2014) Current Approaches to the Treatment of Metastatic Brain Tumours. Nat. Rev. Clin. Oncol. 11, 203-222.
- (55) Thomas, A.; Tanaka, M.; Trepel, J.; Reinhold, W. C.; Rajapakse, V. N.; Pommier, Y. (2017) Temozolomide in the Era of Precision Medicine. Cancer Res., 77, 823-826.
-
- (1) Xie, Y.; Bergstrom, T.; Jiang, Y.; Johansson, P.; Marinescu, V. D.; Lindberg, N.; Segerman, A.; Wicher, G.; Niklasson, M.; Baskaran, S.; et al. (2015) The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes.
EBioMedicine 2, 1351-1363. - (2) Binder, Z. A.; Wilson, K. M.; Salmasi, V.; Orr, B. A.; Eberhart, C. G.; Siu, I. M.; Lim, M.; Weingart, J. D.; Quinones-Hinojosa, A.; Bettegowda, C.; et al. (2016) Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.
PLoS One 11, e0150271. - (3) Quinlivan, E. P.; Gregory, J. F. (2008) DNA Digestion to Deoxyribonucleoside: A Simplified One-Step Procedure. Anal. Biochem. 373, 383-385.
- (4) Arrowsmith, J.; Jennings, S. A.; Clark, A. S.; Stevens, M. F. G. (2002) Antitumor Imidazotetrazines. 41.1 Conjugation of the Antitumor Agents Mitozolomide and Temozolomide to Peptides and Lexitropsins Bearing DNA Major and Minor Groove-Binding Structural Motifs. J. Med. Chem. 45, 5458-5470.
- (5) Wang, Y.; Conway, B.; Suppasansatorn, P. Synthesis of Temozolomide Esters as Potent Anticancer Pro-Drugs for Topical and Transdermal Applications in Treatments of Cancers. US 2006/0047117 A1, 2006.
- (6) Langnel, D. A. F.; Arrowsmith, J.; Stevens, M. F. G. (2000) Antitumor Imidazotetrazines. 38. New 8-Substituted Derivatives of the Imidazo[5,1-d]-1,2,3,5-Tetrazines Temozolomide and Mitozolomide. ARKIVOC No. iii, 421-437.
- (7) Jiao, Y. G.; Yu, H. T. (2001) Methyltrioxorhenium (MeReO3) Catalyzed Selective Oxidation of Purine and Related Compounds into Their N-Oxides. Synlett No. 1, 73-74.
- (8) Stevens, M. A.; Giner-Sorolla, A.; Smith, H. W.; Bosworth Brown, G. (1962) Purine N-Oxides. X. The Effect of Some Substituents on Stability and Reactivity1. J. Org. Chem. 27, 567-572.
- (9) Liu, D.; Yang, J. G.; Cheng, J.; Zhao, L. X. (2010) Synthesis and Antitumor Activity of 3-Methyl-4-Oxo-3,4-Dihydroimidazo [5,1-d][1,2,3,5]Tetrazine-8-Carboxylates and -Carboxamides.
Molecules 15, 9427-9436. - (10) Marasco, C. J.; Pera, P. J.; Spiess, A. J.; Bernacki, R.; Sufrin, J. R. (2005) Improved Synthesis of β-D-6-Methylpurine Riboside and Antitumor Effects of the β-D- and α-D-Anomers.
Molecules 10, 1015-1020. - (11) Hummersone, Marc Geoffery; Stevens, Malcolm Francis Graham; Cousin, D. Preparation of 3-Substituted-3H-Imidazo[5,1-d][1,2,3,5]Tetrazin-4-One Compounds for Treating Proliferative Disorders. WO 2010/149968, 2010.
- While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.
- All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
Claims (23)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/266,770 US20210315886A1 (en) | 2018-08-09 | 2019-08-09 | Imidazotetrazine compounds |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862716390P | 2018-08-09 | 2018-08-09 | |
US201862778750P | 2018-12-12 | 2018-12-12 | |
US201962873669P | 2019-07-12 | 2019-07-12 | |
US17/266,770 US20210315886A1 (en) | 2018-08-09 | 2019-08-09 | Imidazotetrazine compounds |
PCT/US2019/045986 WO2020033880A1 (en) | 2018-08-09 | 2019-08-09 | Imidazotetrazine compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20210315886A1 true US20210315886A1 (en) | 2021-10-14 |
Family
ID=69415152
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/266,770 Pending US20210315886A1 (en) | 2018-08-09 | 2019-08-09 | Imidazotetrazine compounds |
US17/017,475 Abandoned US20210002286A1 (en) | 2018-08-09 | 2020-09-10 | Imidazotetrazine compounds |
US18/067,531 Pending US20240124462A9 (en) | 2018-08-09 | 2022-12-16 | SUBSTITUTED IMIDAZO[5,1-d][1,2,3,5]TETRAZINES FOR THE TREATMENT OF CANCER |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/017,475 Abandoned US20210002286A1 (en) | 2018-08-09 | 2020-09-10 | Imidazotetrazine compounds |
US18/067,531 Pending US20240124462A9 (en) | 2018-08-09 | 2022-12-16 | SUBSTITUTED IMIDAZO[5,1-d][1,2,3,5]TETRAZINES FOR THE TREATMENT OF CANCER |
Country Status (12)
Country | Link |
---|---|
US (3) | US20210315886A1 (en) |
EP (1) | EP3833342A4 (en) |
JP (1) | JP7487949B2 (en) |
KR (1) | KR20210042941A (en) |
CN (1) | CN113271939A (en) |
AU (1) | AU2019316635A1 (en) |
BR (1) | BR112021002293A2 (en) |
CA (1) | CA3109191A1 (en) |
IL (1) | IL280700A (en) |
MX (1) | MX2021001567A (en) |
WO (1) | WO2020033880A1 (en) |
ZA (1) | ZA202100813B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023150569A1 (en) * | 2022-02-01 | 2023-08-10 | The Board Of Trustees Of The University Of Illinois | Imidazotetrazine compounds and treatment of tmz-resistant cancers |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB201907813D0 (en) * | 2019-05-31 | 2019-07-17 | Univ Nottingham | Therapeutic compounds |
WO2023049806A1 (en) * | 2021-09-23 | 2023-03-30 | Yale University | Compounds and methods for treating cancers that are mgmt deficient regardless of mmr status |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0252682A2 (en) * | 1986-07-02 | 1988-01-13 | May & Baker Limited | Tetrazines |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5260291A (en) * | 1981-08-24 | 1993-11-09 | Cancer Research Campaign Technology Limited | Tetrazine derivatives |
CN1752088A (en) | 2004-09-22 | 2006-03-29 | 天津市金士力药物研究开发有限公司 | Medicinal composition containing timeazoamine ester |
DE102006007309B4 (en) * | 2005-02-17 | 2012-11-29 | Chemagis Ltd. | Improved process for the preparation of temozolomide |
CN101190917B (en) | 2006-11-30 | 2011-07-13 | 天津天士力集团有限公司 | 3,4-dihydro-3-methyl-4-oxomidazo[5,1-d]-1,2,3,5-tetrazine-8-formic acid benzenesulfonyl furoxan esters compound, preparation method and use thereof |
PE20091101A1 (en) | 2007-12-18 | 2009-07-26 | Pharminox Ltd | 3-SUBSTITUTED-4-OXO-3,4-DIHYDRO-IMIDAZO [5,1-d] [1,2,3,5-TETRACINE-8-CARBOXYL ACID AMIDES AND ITS USE |
CN102803264A (en) | 2009-06-23 | 2012-11-28 | 法米诺克斯有限公司 | 3-substituted-8-substituted-3h imidazo[5,1-d][1,2,3,5-tetrazin-4-one compounds and their use |
-
2019
- 2019-08-09 KR KR1020217006694A patent/KR20210042941A/en active Search and Examination
- 2019-08-09 MX MX2021001567A patent/MX2021001567A/en unknown
- 2019-08-09 EP EP19848070.9A patent/EP3833342A4/en active Pending
- 2019-08-09 CN CN201980065948.6A patent/CN113271939A/en active Pending
- 2019-08-09 BR BR112021002293-7A patent/BR112021002293A2/en unknown
- 2019-08-09 CA CA3109191A patent/CA3109191A1/en active Pending
- 2019-08-09 JP JP2021506472A patent/JP7487949B2/en active Active
- 2019-08-09 US US17/266,770 patent/US20210315886A1/en active Pending
- 2019-08-09 WO PCT/US2019/045986 patent/WO2020033880A1/en unknown
- 2019-08-09 AU AU2019316635A patent/AU2019316635A1/en active Pending
-
2020
- 2020-09-10 US US17/017,475 patent/US20210002286A1/en not_active Abandoned
-
2021
- 2021-02-05 ZA ZA2021/00813A patent/ZA202100813B/en unknown
- 2021-02-07 IL IL280700A patent/IL280700A/en unknown
-
2022
- 2022-12-16 US US18/067,531 patent/US20240124462A9/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0252682A2 (en) * | 1986-07-02 | 1988-01-13 | May & Baker Limited | Tetrazines |
Non-Patent Citations (4)
Title |
---|
Furiassi, L. Medicinal Chemistry Approaches to Widen Therapeutic Potential for Melatonin and Temozolomide Derivatives. University of Urbino, created April 25, 2018. Retrieved from internet: 1-123 (Year: 2018) * |
Gyanani, V. et al. Challenges of Current Anticancer Treatment Approaches with Focus on Liposomal Drug Delivery Systems. Pharmaceuticals (Basel, Switzerland), 2021; Vol. 14(9), article ID 835: 1-27. (Year: 2021) * |
Kaestner, S.A. et al. Chemotherapy dosing part I: scientific basis for current practice and use of body surface area. Clin Oncol (R Coll Radiol). 2007; Vol.19(1):23-37 (Year: 2007) * |
Larsson, P. et al. Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens. Sci Rep, 2020. Vol. 10, article ID 5798: 1-12. (Year: 2020) * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023150569A1 (en) * | 2022-02-01 | 2023-08-10 | The Board Of Trustees Of The University Of Illinois | Imidazotetrazine compounds and treatment of tmz-resistant cancers |
Also Published As
Publication number | Publication date |
---|---|
JP2021533164A (en) | 2021-12-02 |
CA3109191A1 (en) | 2020-02-13 |
WO2020033880A1 (en) | 2020-02-13 |
JP7487949B2 (en) | 2024-05-21 |
BR112021002293A2 (en) | 2021-05-04 |
CN113271939A (en) | 2021-08-17 |
US20240124462A9 (en) | 2024-04-18 |
EP3833342A4 (en) | 2022-07-13 |
MX2021001567A (en) | 2021-04-29 |
KR20210042941A (en) | 2021-04-20 |
ZA202100813B (en) | 2021-10-27 |
IL280700A (en) | 2021-03-25 |
EP3833342A1 (en) | 2021-06-16 |
US20230183252A1 (en) | 2023-06-15 |
US20210002286A1 (en) | 2021-01-07 |
AU2019316635A1 (en) | 2021-03-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20240124462A9 (en) | SUBSTITUTED IMIDAZO[5,1-d][1,2,3,5]TETRAZINES FOR THE TREATMENT OF CANCER | |
US11299512B2 (en) | Cyclic di-nucleotide compounds and methods of use | |
US11345707B2 (en) | Atropisomerism for increased kinase inhibitor selectivity | |
US9370515B2 (en) | Mixed lineage kinase inhibitors and method of treatments | |
US20110237606A1 (en) | 3-Deazaneplanocin Derivatives | |
US20130281398A1 (en) | Treatment of diseases by epigenetic regulation | |
US9381172B2 (en) | Small molecule choline kinase inhibitors, screening assays, and methods for treatment of neoplastic disorders | |
CN101932569A (en) | Indoles, its derivative and analogue and uses thereof | |
US10934300B2 (en) | Atropisomerism for enhanced kinase inhibitor selectivity | |
US7902359B2 (en) | Decahydronaphthalene compounds | |
US20220306638A1 (en) | Selective btk irreversible inhibitors | |
US20150274742A1 (en) | Treating Brain Cancer using Agelastatin A (AA) and Analogues Thereof | |
CZ20032287A3 (en) | Treatment methods of inflammatory and immune diseases by making use of IkB kinase inhibitors (IKK) | |
US20200123165A1 (en) | Kinase inhibitors | |
US8518901B2 (en) | Fused diimidazodiazepine compounds and methods of use and manufacture thereof | |
KR20140112489A (en) | Acyl-hydrazone and oxadiazole compounds, pharmaceutical compositions containing the same and uses thereof | |
JP2011521986A (en) | 4,6-Diphenylpyrid-2-one for cancer | |
US20220162184A1 (en) | Quinolyl-containing compound and pharmaceutical composition, and use thereof | |
US11274106B2 (en) | Topoisomerase inhibitors with antibacterial and anticancer activity | |
CA2956464C (en) | Bisamidinium-based inhibitors for the treatment of myotonic dystrophy | |
US11400079B2 (en) | Antibacterial monobactams | |
US20170240531A1 (en) | Aminomethylene pyrazolones with therapeutic activity | |
US20060148848A1 (en) | Compounds and methods for treating cancer and inflammation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS, ILLINOIS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HERGENROTHER, PAUL J.;FAN, TIMOTHY M.;SVEC, RILEY L.;SIGNING DATES FROM 20190813 TO 20191121;REEL/FRAME:056160/0980 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT, MARYLAND Free format text: CONFIRMATORY LICENSE;ASSIGNOR:UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN;REEL/FRAME:061877/0355 Effective date: 20200117 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |