EA007983B1 - Индолизины в качестве ингибиторов киназных белков - Google Patents

Info

Publication number

EA007983B1

EA007983B1 EA200400447A EA200400447A EA007983B1 EA 007983 B1 EA007983 B1 EA 007983B1 EA 200400447 A EA200400447 A EA 200400447A EA 200400447 A EA200400447 A EA 200400447A EA 007983 B1 EA007983 B1 EA 007983B1

Authority

EA

Eurasian Patent Office

Prior art keywords

phenyl

compounds

optionally substituted

formula

group

Prior art date

2001-09-19

Links

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• Global Dossier
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• 108091000080 Phosphotransferase Proteins 0.000 title claims abstract description 40
• 102000020233 phosphotransferase Human genes 0.000 title claims abstract description 40
• 150000002478 indolizines Chemical class 0.000 title abstract 2
• 229940121649 protein inhibitor Drugs 0.000 title 1
• 239000012268 protein inhibitor Substances 0.000 title 1
• -1 cyclic amine Chemical class 0.000 claims abstract description 696
• 150000001875 compounds Chemical class 0.000 claims abstract description 496
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 123
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 112
• 150000003839 salts Chemical class 0.000 claims abstract description 109
• 125000003118 aryl group Chemical group 0.000 claims abstract description 96
• 229940002612 prodrug Drugs 0.000 claims abstract description 91
• 239000000651 prodrug Substances 0.000 claims abstract description 91
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 78
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 73
• 239000001257 hydrogen Substances 0.000 claims abstract description 72
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 63
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 61
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 59
• 150000004677 hydrates Chemical class 0.000 claims abstract description 46
• 239000012453 solvate Substances 0.000 claims abstract description 45
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 37
• 150000002367 halogens Chemical class 0.000 claims abstract description 37
• 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 30
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 28
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 25
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims abstract description 24
• 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 23
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 22
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 15
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
• 125000003435 aroyl group Chemical group 0.000 claims abstract description 11
• 125000002252 acyl group Chemical group 0.000 claims abstract description 10
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 10
• 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 10
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 8
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims abstract description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 6
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims abstract description 5
• 239000003937 drug carrier Substances 0.000 claims abstract description 4
• 150000001408 amides Chemical class 0.000 claims description 329
• 238000000034 method Methods 0.000 claims description 253
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 192
• HWGYCYYNKQMGNG-UHFFFAOYSA-N 7-chloro-6-phenyl-3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid Chemical compound C1N(C(=O)O)CCN2C1=C(C(O)=O)C(Cl)=C2C1=CC=CC=C1 HWGYCYYNKQMGNG-UHFFFAOYSA-N 0.000 claims description 56
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 38
• 238000011282 treatment Methods 0.000 claims description 38
• 125000004076 pyridyl group Chemical group 0.000 claims description 36
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 35
• 125000001424 substituent group Chemical group 0.000 claims description 35
• 201000011510 cancer Diseases 0.000 claims description 31
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 30
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 29
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 27
• 125000001847 2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1([H])C([H])([H])C1([H])* 0.000 claims description 26
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 26
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 24
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 24
• 125000004432 carbon atom Chemical group C* 0.000 claims description 24
• 125000003107 substituted aryl group Chemical group 0.000 claims description 24
• 239000003814 drug Substances 0.000 claims description 23
• 229910052801 chlorine Inorganic materials 0.000 claims description 21
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• 239000003112 inhibitor Substances 0.000 claims description 19
• 239000000460 chlorine Substances 0.000 claims description 17
• 238000004519 manufacturing process Methods 0.000 claims description 17
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 14
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 238000002360 preparation method Methods 0.000 claims description 12
• 229920006395 saturated elastomer Polymers 0.000 claims description 12
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 239000003795 chemical substances by application Substances 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000002541 furyl group Chemical group 0.000 claims description 9
• 150000007522 mineralic acids Chemical class 0.000 claims description 9
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 9
• MRZDZERGURQSBI-UHFFFAOYSA-N 4-[(8-carbamoyl-7-chloro-6-phenyl-3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2-carbonyl)amino]benzoic acid Chemical compound N12CCN(C(=O)NC=3C=CC(=CC=3)C(O)=O)CC2=C(C(=O)N)C(Cl)=C1C1=CC=CC=C1 MRZDZERGURQSBI-UHFFFAOYSA-N 0.000 claims description 8
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
• 208000029742 colonic neoplasm Diseases 0.000 claims description 8
• 125000004122 cyclic group Chemical group 0.000 claims description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000002950 monocyclic group Chemical group 0.000 claims description 8
• 150000007524 organic acids Chemical class 0.000 claims description 8
• 235000005985 organic acids Nutrition 0.000 claims description 8
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 8
• 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 7
• 206010006187 Breast cancer Diseases 0.000 claims description 7
• 208000026310 Breast neoplasm Diseases 0.000 claims description 7
• 125000001931 aliphatic group Chemical group 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 238000002512 chemotherapy Methods 0.000 claims description 7
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 230000007062 hydrolysis Effects 0.000 claims description 7
• 238000006460 hydrolysis reaction Methods 0.000 claims description 7
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 7
• 150000007529 inorganic bases Chemical class 0.000 claims description 7
• 208000020816 lung neoplasm Diseases 0.000 claims description 7
• 150000007530 organic bases Chemical class 0.000 claims description 7
• 125000001544 thienyl group Chemical group 0.000 claims description 7
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 6
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 6
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
• 206010009944 Colon cancer Diseases 0.000 claims description 6
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 239000002246 antineoplastic agent Substances 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 201000005202 lung cancer Diseases 0.000 claims description 6
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
• 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 6
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 6
• 125000003367 polycyclic group Chemical group 0.000 claims description 6
• 150000003254 radicals Chemical class 0.000 claims description 6
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
• HUQMWYWVHCVJBX-UHFFFAOYSA-N NC1CCCC1.N#CC1=C(C2=CC=CC=C2)N(CCN(C2)C(O)=O)C2=C1C(O)=O Chemical compound NC1CCCC1.N#CC1=C(C2=CC=CC=C2)N(CCN(C2)C(O)=O)C2=C1C(O)=O HUQMWYWVHCVJBX-UHFFFAOYSA-N 0.000 claims description 5
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 5
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 5
• 239000000654 additive Substances 0.000 claims description 5
• 230000000996 additive effect Effects 0.000 claims description 5
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
• UBLYEVLMRSPMOG-UHFFFAOYSA-N cyclopentylmethanamine Chemical compound NCC1CCCC1 UBLYEVLMRSPMOG-UHFFFAOYSA-N 0.000 claims description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 210000002307 prostate Anatomy 0.000 claims description 5
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
• TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 claims description 4
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
• 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 4
• 125000004864 4-thiomethylphenyl group Chemical group 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims description 4
• 125000005936 piperidyl group Chemical group 0.000 claims description 4
• 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• 229940124597 therapeutic agent Drugs 0.000 claims description 4
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
• MMAHJYLVXZFMBA-UHFFFAOYSA-N ethyl 2-[(8-carbamoyl-7-chloro-6-phenyl-3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2-carbonyl)amino]acetate Chemical compound C1N(C(=O)NCC(=O)OCC)CCN2C1=C(C(N)=O)C(Cl)=C2C1=CC=CC=C1 MMAHJYLVXZFMBA-UHFFFAOYSA-N 0.000 claims description 3
• 229940043355 kinase inhibitor Drugs 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 239000011593 sulfur Substances 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• FOSWAWDYQGCPOD-UHFFFAOYSA-N 2-[4-[(8-carbamoyl-7-chloro-6-phenyl-3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2-carbonyl)amino]phenoxy]acetic acid Chemical compound N12CCN(C(=O)NC=3C=CC(OCC(O)=O)=CC=3)CC2=C(C(=O)N)C(Cl)=C1C1=CC=CC=C1 FOSWAWDYQGCPOD-UHFFFAOYSA-N 0.000 claims description 2
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
• GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
• 206010033128 Ovarian cancer Diseases 0.000 claims description 2
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
• 206010043515 Throat cancer Diseases 0.000 claims description 2
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
• 229940122803 Vinca alkaloid Drugs 0.000 claims description 2
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
• 125000005157 alkyl carboxy group Chemical group 0.000 claims description 2
• 239000002168 alkylating agent Substances 0.000 claims description 2
• 229940100198 alkylating agent Drugs 0.000 claims description 2
• 229940045799 anthracyclines and related substance Drugs 0.000 claims description 2
• 230000001093 anti-cancer Effects 0.000 claims description 2
• 230000000340 anti-metabolite Effects 0.000 claims description 2
• 229940100197 antimetabolite Drugs 0.000 claims description 2
• 239000002256 antimetabolite Substances 0.000 claims description 2
• 125000002619 bicyclic group Chemical group 0.000 claims description 2
• 201000006491 bone marrow cancer Diseases 0.000 claims description 2
• 238000004113 cell culture Methods 0.000 claims description 2
• 229940044683 chemotherapy drug Drugs 0.000 claims description 2
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 229940127089 cytotoxic agent Drugs 0.000 claims description 2
• 239000002254 cytotoxic agent Substances 0.000 claims description 2
• 231100000599 cytotoxic agent Toxicity 0.000 claims description 2
• 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 claims description 2
• 229960002949 fluorouracil Drugs 0.000 claims description 2
• 206010017758 gastric cancer Diseases 0.000 claims description 2
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
• 239000000138 intercalating agent Substances 0.000 claims description 2
• 210000004324 lymphatic system Anatomy 0.000 claims description 2
• 230000003211 malignant effect Effects 0.000 claims description 2
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
• 230000002503 metabolic effect Effects 0.000 claims description 2
• 125000001624 naphthyl group Chemical group 0.000 claims description 2
• 201000002528 pancreatic cancer Diseases 0.000 claims description 2
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
• 201000001514 prostate carcinoma Diseases 0.000 claims description 2
• 230000004952 protein activity Effects 0.000 claims description 2
• 238000001959 radiotherapy Methods 0.000 claims description 2
• 201000011549 stomach cancer Diseases 0.000 claims description 2
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 4
• AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims 2
• CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims 1
• 101710183280 Topoisomerase Proteins 0.000 claims 1
• 229940009456 adriamycin Drugs 0.000 claims 1
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims 1
• VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims 1
• CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 1
• DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims 1
• 229960004316 cisplatin Drugs 0.000 claims 1
• 229960004397 cyclophosphamide Drugs 0.000 claims 1
• 125000003944 tolyl group Chemical group 0.000 claims 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 31
• 201000010099 disease Diseases 0.000 abstract description 23
• 230000005764 inhibitory process Effects 0.000 abstract description 9
• 150000001204 N-oxides Chemical class 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 369
• 239000007787 solid Substances 0.000 description 294
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 204
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 113
• 238000000921 elemental analysis Methods 0.000 description 85
• 239000011541 reaction mixture Substances 0.000 description 84
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• 239000000243 solution Substances 0.000 description 77
• 238000003756 stirring Methods 0.000 description 58
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
• 239000002253 acid Substances 0.000 description 49
• 239000000203 mixture Substances 0.000 description 48
• 239000000047 product Substances 0.000 description 45
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
• 238000006243 chemical reaction Methods 0.000 description 44
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• 239000000725 suspension Substances 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 36
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