IL105264A

IL105264A - History of pyrimidine processes for their preparation and pharmaceutical preparations containing them

History of pyrimidine processes for their preparation and pharmaceutical preparations containing them

Info

Publication number: IL105264A
Authority: IL; Israel
Prior art keywords: phenyl; lower alkyl; pyridyl; formula; compound
Prior art date: 1992-04-03

Application number

IL10526493A

Other languages

English (en)

Hebrew (he)

Other versions

IL105264A0 (en

Original Assignee

Novartis Ag

Priority date

1992-04-03

Filing date

1993-04-01

Publication date

1999-04-11

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=4202064&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IL105264(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1993-04-01 Application filed by Novartis Ag filed Critical Novartis Ag

1993-08-18 Publication of IL105264A0 publication Critical patent/IL105264A0/xx

1999-04-11 Publication of IL105264A publication Critical patent/IL105264A/en

Links

238000000034 method Methods 0.000 title claims description 53
230000008569 process Effects 0.000 title claims description 22
238000002360 preparation method Methods 0.000 title claims description 15
239000008194 pharmaceutical composition Substances 0.000 title claims description 9
229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 3
150000003230 pyrimidines Chemical class 0.000 title description 2
-1 4-pyrazinyl Chemical group 0.000 claims abstract description 161
150000001875 compounds Chemical class 0.000 claims abstract description 138
125000000217 alkyl group Chemical group 0.000 claims abstract description 90
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 66
239000001257 hydrogen Substances 0.000 claims abstract description 64
150000002431 hydrogen Chemical class 0.000 claims abstract description 35
125000003545 alkoxy group Chemical group 0.000 claims abstract description 33
229910052799 carbon Inorganic materials 0.000 claims abstract description 30
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 27
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 27
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 24
125000003277 amino group Chemical group 0.000 claims abstract description 23
125000004076 pyridyl group Chemical group 0.000 claims abstract description 22
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 21
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 20
229910052760 oxygen Inorganic materials 0.000 claims abstract description 20
239000001301 oxygen Substances 0.000 claims abstract description 20
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
125000004043 oxo group Chemical group O=* 0.000 claims abstract description 16
125000001589 carboacyl group Chemical group 0.000 claims abstract description 15
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 15
125000003118 aryl group Chemical group 0.000 claims abstract description 11
206010028980 Neoplasm Diseases 0.000 claims abstract description 10
125000002757 morpholinyl group Chemical class 0.000 claims abstract description 10
125000003386 piperidinyl group Chemical class 0.000 claims abstract description 10
125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 8
125000000719 pyrrolidinyl group Chemical class 0.000 claims abstract description 8
125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract description 8
125000005277 alkyl imino group Chemical group 0.000 claims abstract description 7
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
150000003839 salts Chemical class 0.000 claims description 88
125000001424 substituent group Chemical group 0.000 claims description 32
238000006243 chemical reaction Methods 0.000 claims description 26
150000001721 carbon Chemical group 0.000 claims description 21
229910052736 halogen Inorganic materials 0.000 claims description 18
150000002367 halogens Chemical class 0.000 claims description 18
125000006239 protecting group Chemical group 0.000 claims description 17
125000003282 alkyl amino group Chemical group 0.000 claims description 15
125000000524 functional group Chemical group 0.000 claims description 11
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 8
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
241001465754 Metazoa Species 0.000 claims description 7
239000000460 chlorine Chemical group 0.000 claims description 7
229910052801 chlorine Inorganic materials 0.000 claims description 7
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 5
125000004423 acyloxy group Chemical group 0.000 claims description 5
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
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 5
125000001544 thienyl group Chemical group 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 4
239000011737 fluorine Substances 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
125000005236 alkanoylamino group Chemical group 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
239000007800 oxidant agent Substances 0.000 claims description 3
239000011593 sulfur Substances 0.000 claims description 3
125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 2
125000004193 piperazinyl group Chemical group 0.000 claims description 2
LLJRXVHJOJRCSM-UHFFFAOYSA-N 3-pyridin-4-yl-1H-indole Chemical group C=1NC2=CC=CC=C2C=1C1=CC=NC=C1 LLJRXVHJOJRCSM-UHFFFAOYSA-N 0.000 claims 1
102100035189 GPI ethanolamine phosphate transferase 1 Human genes 0.000 claims 1
101710120219 GPI ethanolamine phosphate transferase 1 Proteins 0.000 claims 1
DTCFXYVLDFXFEA-UHFFFAOYSA-N n-(3-nitrophenyl)-4-pyridin-2-ylpyrimidin-2-amine Chemical compound [O-][N+](=O)C1=CC=CC(NC=2N=C(C=CN=2)C=2N=CC=CC=2)=C1 DTCFXYVLDFXFEA-UHFFFAOYSA-N 0.000 claims 1
125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 18
238000002560 therapeutic procedure Methods 0.000 abstract description 2
150000004046 2-(N-anilino)pyrimidines Chemical class 0.000 abstract 1
125000002883 imidazolyl group Chemical group 0.000 abstract 1
125000001041 indolyl group Chemical group 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 113
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
239000002253 acid Substances 0.000 description 50
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
150000003254 radicals Chemical class 0.000 description 38
239000000203 mixture Substances 0.000 description 35
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
239000007858 starting material Substances 0.000 description 22
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
108090000315 Protein Kinase C Proteins 0.000 description 18
102000003923 Protein Kinase C Human genes 0.000 description 18
239000004480 active ingredient Substances 0.000 description 16
239000000243 solution Substances 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
239000000725 suspension Substances 0.000 description 14
150000008064 anhydrides Chemical class 0.000 description 13
210000004027 cell Anatomy 0.000 description 13
239000003795 chemical substances by application Substances 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
238000001816 cooling Methods 0.000 description 11
230000002401 inhibitory effect Effects 0.000 description 11
150000002148 esters Chemical class 0.000 description 10
229960004592 isopropanol Drugs 0.000 description 10
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
229920002472 Starch Polymers 0.000 description 9
235000011114 ammonium hydroxide Nutrition 0.000 description 9
238000001035 drying Methods 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
238000010992 reflux Methods 0.000 description 9
XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 8
108091008606 PDGF receptors Proteins 0.000 description 8
102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
239000002904 solvent Substances 0.000 description 8
229940100445 wheat starch Drugs 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 7
108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 7
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 7
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 7
201000010099 disease Diseases 0.000 description 7
230000000694 effects Effects 0.000 description 7
238000001914 filtration Methods 0.000 description 7
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
150000001718 carbodiimides Chemical class 0.000 description 6
239000003054 catalyst Substances 0.000 description 6
238000009833 condensation Methods 0.000 description 6
230000005494 condensation Effects 0.000 description 6
238000006722 reduction reaction Methods 0.000 description 6
RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 6
235000012239 silicon dioxide Nutrition 0.000 description 6
239000000454 talc Substances 0.000 description 6
235000012222 talc Nutrition 0.000 description 6
229910052623 talc Inorganic materials 0.000 description 6
238000012360 testing method Methods 0.000 description 6
238000005406 washing Methods 0.000 description 6
MZLRFUCMBQWLNV-UHFFFAOYSA-N 3-(dimethylamino)-1-pyridin-3-ylprop-2-en-1-one Chemical compound CN(C)C=CC(=O)C1=CC=CN=C1 MZLRFUCMBQWLNV-UHFFFAOYSA-N 0.000 description 5
102000004190 Enzymes Human genes 0.000 description 5
108090000790 Enzymes Proteins 0.000 description 5
125000001931 aliphatic group Chemical group 0.000 description 5
239000012298 atmosphere Substances 0.000 description 5
239000002585 base Substances 0.000 description 5
150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
239000007795 chemical reaction product Substances 0.000 description 5
239000003814 drug Substances 0.000 description 5
230000007062 hydrolysis Effects 0.000 description 5
238000006460 hydrolysis reaction Methods 0.000 description 5
229910052763 palladium Inorganic materials 0.000 description 5
239000011541 reaction mixture Substances 0.000 description 5
230000009467 reduction Effects 0.000 description 5
239000002002 slurry Substances 0.000 description 5
201000001320 Atherosclerosis Diseases 0.000 description 4
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
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 4
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
102000001253 Protein Kinase Human genes 0.000 description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
125000002252 acyl group Chemical group 0.000 description 4
229910052783 alkali metal Inorganic materials 0.000 description 4
125000004466 alkoxycarbonylamino group Chemical group 0.000 description 4
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
230000001419 dependent effect Effects 0.000 description 4
229940079593 drug Drugs 0.000 description 4
239000000543 intermediate Substances 0.000 description 4
239000008101 lactose Substances 0.000 description 4
235000019359 magnesium stearate Nutrition 0.000 description 4
VBYYPCNNGNGURO-UHFFFAOYSA-N nitric acid;2-(3-nitrophenyl)guanidine Chemical compound O[N+]([O-])=O.NC(N)=NC1=CC=CC([N+]([O-])=O)=C1 VBYYPCNNGNGURO-UHFFFAOYSA-N 0.000 description 4
239000004033 plastic Substances 0.000 description 4
229920003023 plastic Polymers 0.000 description 4
108060006633 protein kinase Proteins 0.000 description 4
238000011160 research Methods 0.000 description 4
238000003797 solvolysis reaction Methods 0.000 description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
ZQTRXPRIWRFHRY-UHFFFAOYSA-N 3-n-(4-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine Chemical compound NC1=CC=CC(NC=2N=C(C=CN=2)C=2C=NC=CC=2)=C1 ZQTRXPRIWRFHRY-UHFFFAOYSA-N 0.000 description 3
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 3
NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
239000005711 Benzoic acid Substances 0.000 description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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 3
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
238000006136 alcoholysis reaction Methods 0.000 description 3
235000010233 benzoic acid Nutrition 0.000 description 3
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
239000003153 chemical reaction reagent Substances 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
238000003818 flash chromatography Methods 0.000 description 3
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
238000005984 hydrogenation reaction Methods 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
238000011065 in-situ storage Methods 0.000 description 3
229910052500 inorganic mineral Inorganic materials 0.000 description 3
229910052749 magnesium Inorganic materials 0.000 description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
239000011707 mineral Substances 0.000 description 3
235000010755 mineral Nutrition 0.000 description 3
239000012299 nitrogen atmosphere Substances 0.000 description 3
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
230000026731 phosphorylation Effects 0.000 description 3
238000006366 phosphorylation reaction Methods 0.000 description 3
239000000047 product Substances 0.000 description 3
HFAFXVOPGDBAOK-UHFFFAOYSA-M pyridine-2-carboxylate;hydrochloride Chemical compound [Cl-].OC(=O)C1=CC=CC=N1 HFAFXVOPGDBAOK-UHFFFAOYSA-M 0.000 description 3
102000005962 receptors Human genes 0.000 description 3
108020003175 receptors Proteins 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
241000894007 species Species 0.000 description 3
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
229920001567 vinyl ester resin Polymers 0.000 description 3
RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 2
NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
CVKKTGQSXNZVKW-UHFFFAOYSA-N 2-(3-methyl-5-nitrophenyl)guanidine;nitric acid Chemical compound O[N+]([O-])=O.CC1=CC(N=C(N)N)=CC([N+]([O-])=O)=C1 CVKKTGQSXNZVKW-UHFFFAOYSA-N 0.000 description 2
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 2
RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 2
WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
KNBRFZWWCBSGDU-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]benzoyl chloride Chemical compound C1CN(C)CCN1CC1=CC=C(C(Cl)=O)C=C1 KNBRFZWWCBSGDU-UHFFFAOYSA-N 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
238000006418 Brown reaction Methods 0.000 description 2
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
102000009024 Epidermal Growth Factor Human genes 0.000 description 2
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238000005809 transesterification reaction Methods 0.000 description 1
PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 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
230000001173 tumoral effect Effects 0.000 description 1
238000010518 undesired secondary reaction Methods 0.000 description 1
208000010570 urinary bladder carcinoma Diseases 0.000 description 1
238000001262 western blot Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
229940001158 ximino Drugs 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1