AP89A - Heterocyclic compounds. - Google Patents

Heterocyclic compounds. Download PDF

Info

Publication number: AP89A
Authority: AP; ARIPO
Prior art keywords: group; carbamate; imidazo; methyl; compound
Prior art date: 1987-08-15

Application number

APAP/P/1988/000098A

Other languages

English (en)

Other versions

AP8800098A0 (en

Inventor

Simon Teanby Hodgson

Original Assignee

The Wellcome Foundation Ltd

Priority date (The priority date 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 date listed.)

1987-08-15

Filing date

1988-08-10

Publication date

1990-06-14

1988-08-01 Publication of AP8800098A0 publication Critical patent/AP8800098A0/xx

1988-08-10 Application filed by The Wellcome Foundation Ltd filed Critical The Wellcome Foundation Ltd

1990-06-14 Application granted granted Critical

1990-06-14 Publication of AP89A publication Critical patent/AP89A/en

Links

150000002391 heterocyclic compounds Chemical class 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 166
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 58
125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 claims description 34
-1 3-methylbenzyloxy Chemical group 0.000 claims description 26
150000003839 salts Chemical class 0.000 claims description 23
125000003118 aryl group Chemical group 0.000 claims description 20
230000000259 anti-tumor effect Effects 0.000 claims description 16
239000003795 chemical substances by application Substances 0.000 claims description 16
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
125000000623 heterocyclic group Chemical group 0.000 claims description 14
125000000217 alkyl group Chemical group 0.000 claims description 13
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
125000002837 carbocyclic group Chemical group 0.000 claims description 9
229910052760 oxygen Inorganic materials 0.000 claims description 9
239000001301 oxygen Substances 0.000 claims description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
125000005842 heteroatom Chemical group 0.000 claims description 6
229910052739 hydrogen Inorganic materials 0.000 claims description 6
239000001257 hydrogen Substances 0.000 claims description 6
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
125000003342 alkenyl group Chemical group 0.000 claims description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000001624 naphthyl group Chemical group 0.000 claims description 4
229910052757 nitrogen Inorganic materials 0.000 claims description 4
125000000547 substituted alkyl group Chemical group 0.000 claims description 4
239000005864 Sulphur Chemical group 0.000 claims description 3
125000003710 aryl alkyl group Chemical group 0.000 claims description 3
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical group CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 2
125000003107 substituted aryl group Chemical group 0.000 claims 1
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 99
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 65
239000000203 mixture Substances 0.000 description 57
239000007787 solid Substances 0.000 description 52
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 48
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
239000000543 intermediate Substances 0.000 description 43
238000000034 method Methods 0.000 description 37
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 27
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
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RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
239000000243 solution Substances 0.000 description 21
230000000694 effects Effects 0.000 description 20
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 19
238000005481 NMR spectroscopy Methods 0.000 description 17
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239000000843 powder Substances 0.000 description 17
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239000002904 solvent Substances 0.000 description 15
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 description 14
238000003756 stirring Methods 0.000 description 13
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239000002253 acid Substances 0.000 description 11
WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 11
239000000377 silicon dioxide Substances 0.000 description 11
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
238000001727 in vivo Methods 0.000 description 10
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JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 10
210000004881 tumor cell Anatomy 0.000 description 10
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
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239000002585 base Substances 0.000 description 9
125000004432 carbon atom Chemical group C* 0.000 description 9
239000000460 chlorine Substances 0.000 description 9
239000004615 ingredient Substances 0.000 description 9
238000002360 preparation method Methods 0.000 description 9
PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
102000004243 Tubulin Human genes 0.000 description 8
108090000704 Tubulin Proteins 0.000 description 8
238000003556 assay Methods 0.000 description 8
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OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 8
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 8
CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 7
108010092160 Dactinomycin Proteins 0.000 description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
241001465754 Metazoa Species 0.000 description 7
229940009456 adriamycin Drugs 0.000 description 7
229910052681 coesite Inorganic materials 0.000 description 7
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239000003814 drug Substances 0.000 description 7
239000011734 sodium Substances 0.000 description 7
229910052682 stishovite Inorganic materials 0.000 description 7
239000000725 suspension Substances 0.000 description 7
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UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 6
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RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 6
229960000640 dactinomycin Drugs 0.000 description 6
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238000000338 in vitro Methods 0.000 description 6
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229940041181 antineoplastic drug Drugs 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
150000001540 azides Chemical class 0.000 description 1
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
210000004204 blood vessel Anatomy 0.000 description 1
239000011575 calcium Substances 0.000 description 1
150000001669 calcium Chemical class 0.000 description 1
208000035269 cancer or benign tumor Diseases 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
210000003710 cerebral cortex Anatomy 0.000 description 1
230000008859 change Effects 0.000 description 1
238000002512 chemotherapy Methods 0.000 description 1
229940110456 cocoa butter Drugs 0.000 description 1
235000019868 cocoa butter Nutrition 0.000 description 1
201000010897 colon adenocarcinoma Diseases 0.000 description 1
208000029742 colonic neoplasm Diseases 0.000 description 1
230000005757 colony formation Effects 0.000 description 1
239000007891 compressed tablet Substances 0.000 description 1
238000007906 compression Methods 0.000 description 1
230000006835 compression Effects 0.000 description 1
239000012050 conventional carrier Substances 0.000 description 1
239000002178 crystalline material Substances 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
239000012228 culture supernatant Substances 0.000 description 1
229960004397 cyclophosphamide Drugs 0.000 description 1
230000002939 deleterious effect Effects 0.000 description 1
XUDOZULIAWNMIU-UHFFFAOYSA-N delta-hexenoic acid Chemical compound OC(=O)CCCC=C XUDOZULIAWNMIU-UHFFFAOYSA-N 0.000 description 1
239000011928 denatured alcohol Substances 0.000 description 1
230000001627 detrimental effect Effects 0.000 description 1
239000008121 dextrose Substances 0.000 description 1
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
230000007646 directional migration Effects 0.000 description 1
239000002270 dispersing agent Substances 0.000 description 1
239000012153 distilled water Substances 0.000 description 1
VHJLVAABSRFDPM-ZXZARUISSA-N dithioerythritol Chemical compound SC[C@H](O)[C@H](O)CS VHJLVAABSRFDPM-ZXZARUISSA-N 0.000 description 1
UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
239000003684 drug solvent Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
KNHPZFQUZAMWBV-UHFFFAOYSA-N ethyl n-[5-amino-3-[(n-methylanilino)methyl]-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamate Chemical compound N=1C=2C(N)=NC(NC(=O)OCC)=CC=2NCC=1CN(C)C1=CC=CC=C1 KNHPZFQUZAMWBV-UHFFFAOYSA-N 0.000 description 1
238000001914 filtration Methods 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
239000012520 frozen sample Substances 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
239000007903 gelatin capsule Substances 0.000 description 1
125000001188 haloalkyl group Chemical group 0.000 description 1
150000008282 halocarbons Chemical class 0.000 description 1
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
150000004678 hydrides Chemical class 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
239000007943 implant Substances 0.000 description 1
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
238000001802 infusion Methods 0.000 description 1
239000003112 inhibitor Substances 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
JORABGDXCIBAFL-UHFFFAOYSA-M iodonitrotetrazolium chloride Chemical compound [Cl-].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C=CC=CC=2)=N1 JORABGDXCIBAFL-UHFFFAOYSA-M 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
239000012948 isocyanate Substances 0.000 description 1
150000002513 isocyanates Chemical class 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
201000005296 lung carcinoma Diseases 0.000 description 1
208000019420 lymphoid neoplasm Diseases 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
239000000463 material Substances 0.000 description 1
239000012528 membrane Substances 0.000 description 1
210000002418 meninge Anatomy 0.000 description 1
SYWSERLZKPGKDI-UHFFFAOYSA-N methyl n-(2-chloroacetyl)carbamate Chemical compound COC(=O)NC(=O)CCl SYWSERLZKPGKDI-UHFFFAOYSA-N 0.000 description 1
CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
229960000907 methylthioninium chloride Drugs 0.000 description 1
231100000782 microtubule inhibitor Toxicity 0.000 description 1
238000002156 mixing Methods 0.000 description 1
VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
HSZCJVZRHXPCIA-UHFFFAOYSA-N n-benzyl-n-ethylaniline Chemical compound C=1C=CC=CC=1N(CC)CC1=CC=CC=C1 HSZCJVZRHXPCIA-UHFFFAOYSA-N 0.000 description 1
229950006344 nocodazole Drugs 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
238000010979 pH adjustment Methods 0.000 description 1
239000008188 pellet Substances 0.000 description 1
239000012466 permeate Substances 0.000 description 1
239000012071 phase Substances 0.000 description 1
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
239000004033 plastic Substances 0.000 description 1
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
229920000053 polysorbate 80 Polymers 0.000 description 1
150000003109 potassium Chemical class 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
PLUFUQWYWZOOFQ-UHFFFAOYSA-N propyl n-(2-chloroacetyl)carbamate Chemical compound CCCOC(=O)NC(=O)CCl PLUFUQWYWZOOFQ-UHFFFAOYSA-N 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
238000000746 purification Methods 0.000 description 1
SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 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
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
239000013074 reference sample Substances 0.000 description 1
BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
229940016590 sarkosyl Drugs 0.000 description 1
108700004121 sarkosyl Proteins 0.000 description 1
229910052711 selenium Inorganic materials 0.000 description 1
239000011669 selenium Substances 0.000 description 1
238000007493 shaping process Methods 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
239000002002 slurry Substances 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
239000000600 sorbitol Substances 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
239000007858 starting material Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
150000005846 sugar alcohols Polymers 0.000 description 1
125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
239000000829 suppository Substances 0.000 description 1
KCDXJAYRVLXPFO-UHFFFAOYSA-N syringaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1O KCDXJAYRVLXPFO-UHFFFAOYSA-N 0.000 description 1
COBXDAOIDYGHGK-UHFFFAOYSA-N syringaldehyde Natural products COC1=CC=C(C=O)C(OC)=C1O COBXDAOIDYGHGK-UHFFFAOYSA-N 0.000 description 1
NIMXTWQFXZXEBG-UHFFFAOYSA-N tert-butyl n-[6-[(3,4,5-trimethoxyphenyl)methoxy]imidazo[1,2-b]pyridazin-2-yl]carbamate Chemical compound COC1=C(OC)C(OC)=CC(COC2=NN3C=C(NC(=O)OC(C)(C)C)N=C3C=C2)=C1 NIMXTWQFXZXEBG-UHFFFAOYSA-N 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
239000002562 thickening agent Substances 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
239000003104 tissue culture media Substances 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
238000007817 turbidimetric assay Methods 0.000 description 1
229960003048 vinblastine Drugs 0.000 description 1
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1

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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Plural Heterocyclic Compounds (AREA)

APAP/P/1988/000098A 1987-08-15 1988-08-10 Heterocyclic compounds. AP89A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
GB878719368A GB8719368D0 (en)	1987-08-15	1987-08-15	Heterocyclic compounds

Publications (2)

Publication Number	Publication Date
AP8800098A0 AP8800098A0 (en)	1988-08-01
AP89A true AP89A (en)	1990-06-14

Family

ID=10622364

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
APAP/P/1988/000098A AP89A (en)	1987-08-15	1988-08-10	Heterocyclic compounds.

Country Status (28)

Country	Link
US (5)	US5091531A (fr)
EP (1)	EP0305093B1 (fr)
JP (1)	JPS6468375A (fr)
KR (1)	KR890003764A (fr)
CN (2)	CN1031532A (fr)
AP (1)	AP89A (fr)
AT (1)	ATE103919T1 (fr)
AU (1)	AU613392B2 (fr)
CA (1)	CA1336432C (fr)
DD (1)	DD289529A5 (fr)
DE (1)	DE3888897T2 (fr)
DK (1)	DK168954B1 (fr)
ES (1)	ES2063039T3 (fr)
FI (1)	FI89600C (fr)
GB (1)	GB8719368D0 (fr)
HU (1)	HU204052B (fr)
IL (1)	IL87435A (fr)
MC (1)	MC1969A1 (fr)
MX (1)	MX12655A (fr)
MY (1)	MY103602A (fr)
NO (1)	NO168305C (fr)
NZ (1)	NZ225808A (fr)
PH (1)	PH25741A (fr)
PL (3)	PL160044B1 (fr)
PT (1)	PT88260B (fr)
RU (3)	RU1769759C (fr)
YU (3)	YU47200B (fr)
ZA (1)	ZA885996B (fr)

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GB8719368D0 (en) *	1987-08-15	1987-09-23	Wellcome Found	Heterocyclic compounds
PH27291A (en) *	1989-01-31	1993-05-04	Takeda Chemical Industries Ltd	Imidazolpyrimidazines their production and use
EP0440119A1 (fr) *	1990-01-31	1991-08-07	Takeda Chemical Industries, Ltd.	Composés de imidazopyridazine, leur préparation et utilisation
EP0444549B1 (fr) *	1990-03-01	1995-01-25	Takeda Chemical Industries, Ltd.	Imidazopyridazines, leur préparation et leur application
WO2000023450A1 (fr) *	1998-10-21	2000-04-27	Takeda Chemical Industries, Ltd.	Derives fusionnes de pyridazine, procede de preparation correspondant et utilisation de ces derives
CA2413802A1 (fr) *	2000-06-30	2002-01-10	Mark R. Schmitt	Triazolopyrimidines substitues comme agents anticancereux
JP3767352B2 (ja)	2000-09-18	2006-04-19	トヨタ自動車株式会社	内燃機関の制御装置
US6960584B2 (en) *	2001-04-10	2005-11-01	Merck & Co., Inc.	Inhibitors of Akt activity
JP5238697B2 (ja) *	2006-08-04	2013-07-17	武田薬品工業株式会社	縮合複素環誘導体およびその用途
WO2008058126A2 (fr) *	2006-11-06	2008-05-15	Supergen, Inc.	Dérivés d'imidazo[1,2-b]pyridazine et de pyrazolo[1,5-a]pyrimidine et utilisation de ceux-ci comme inhibiteurs de protéines kinases
BRPI0815503A2 (pt) *	2007-08-17	2014-09-30	Icagen Inc	Composto, composição farmacêutica, e, métodos para modular a atividade de um canal de íon potássio em um indivíduo, para aumentar o fluxo de íon por meio de canais de potássio dependentes da voltagem em uma célula e para tratar, prevenir, inibir ou aliviar um distúrbio ou condição do sistema nervoso central ou periférico
US8431608B2 (en)	2007-08-17	2013-04-30	Icagen Inc.	Heterocycles as potassium channel modulators
UY31676A1 (es) *	2008-02-28	2009-09-30		"derivados de 3-metil-imidiazo-[1,2-b]-piridazina"
EP2444403A1 (fr) *	2008-04-18	2012-04-25	Shionogi Co., Ltd.	Composé hétérocyclique doté d'une activité inhibitrice sur PI3K
UY32049A (es) *	2008-08-14	2010-03-26	Takeda Pharmaceutical	Inhibidores de cmet
TW201437211A (zh) *	2013-03-01	2014-10-01	Bayer Pharma AG	經取代咪唑并嗒□

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DE3131365A1 (de) *	1981-08-07	1983-02-24	Henkel KGaA, 4000 Düsseldorf	Neue diglycidyl-substituierte heterocyclische verbindungen, verfahren zu ihrer herstellung und ihre verwendung in arzneimittelzubereitungen mit cytostatischer wirksamkeit
DE3237243A1 (de) *	1982-02-05	1983-08-18	Lion Corp., Tokyo	1-phenyl-1h-pyrazolo (3,4-b) pyrazinderivate und verfahren zu ihrer herstellung
EP0075881B1 (fr) *	1981-09-26	1985-02-13	Takeda Chemical Industries, Ltd.	Dérivés du 7-déazapurine
DE3423092A1 (de) *	1984-06-22	1986-01-02	Dr. Karl Thomae Gmbh, 7950 Biberach	Neue 8-alkylthio-2-piperazino-pyrimido(5,4-d) pyrimidine, ihre herstellung und diese verbindungen enthaltende arzneimittel

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GB305093A (en) *	1928-01-30	1929-07-25	British Continental Motors Ltd	Improvements relating to induction passages of sleeve-valve internal combustion engines
US3615639A (en) *	1967-10-23	1971-10-26	Eastman Kodak Co	Direct positive silver halide emulsions containing dyes as electron acceptors and spectral sensitizers
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US3725407A (en) *	1971-04-08	1973-04-03	American Cyanamid Co	6-substituted amino-3-nitroimidazo(1,2-b)pyridazines and methods of preparing the same
FR2315507A1 (fr) *	1975-06-26	1977-01-21	Roussel Uclaf	Imidazo /1,2-b/ pyridazines substituees, procede de preparation et compositions pesticides les renfermant
US4105767A (en) *	1977-03-28	1978-08-08	Merck & Co., Inc.	Imidazo [1,2-a] pyridines substituted with a thienyl, thiazolyl, or thiadiazolyl group
US4166851A (en) *	1977-05-16	1979-09-04	Merck & Co., Inc.	Certain imidazo(1,2a)pyridine derivatives
US4154835A (en) *	1977-10-12	1979-05-15	Merck & Co., Inc.	Anthelmintic imidazo [1,2-a] pyridines
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US4464372A (en) *	1982-08-16	1984-08-07	Schering Corporation	Imidazo[1,2-b]pyridazines
IL69417A (en) *	1982-08-27	1987-12-20	Roussel Uclaf	2-acyl imidazo(1,2-a)pyrimidines,their preparation and pharmaceutical compositions containing them
US4654347A (en) *	1983-06-23	1987-03-31	American Cyanamid Company	Aryl and heteroaryl[[7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]methanones
DE3401911A1 (de) *	1984-01-20	1985-08-01	A. Nattermann & Cie GmbH, 5000 Köln	Substituierte 4,5-dihydro-6-vinyl-3(2h)-pyridazinone und 6-vinyl-3(2h)-pyridazinone sowie verfahren zu ihrer herstellung
US4569934A (en) *	1984-10-09	1986-02-11	American Cyanamid Company	Imidazo[1,2-b]pyridazines
DE3446812A1 (de) *	1984-12-21	1986-06-26	Dr. Karl Thomae Gmbh, 7950 Biberach	Neue imidazoderivate, ihre herstellung und diese verbindungen enthaltende arzneimittel
DE3446778A1 (de) *	1984-12-21	1986-07-03	Dr. Karl Thomae Gmbh, 7950 Biberach	Neue imidazoderivate, ihre herstellung und diese verbindungen enthaltende arzneimittel
DE3527036A1 (de) *	1985-07-27	1987-02-05	Merck Patent Gmbh	6-arylalkenylpyridazinone
DE3542661A1 (de) *	1985-12-03	1987-06-04	Bayer Ag	Imidazopyridazinalkensaeureamide, verfahren zu ihrer herstellung, zwischenprodukte zu ihrer herstellung
WO1989001333A1 (fr) *	1987-08-07	1989-02-23	The Australian National University	IMIDAZO[1,2-b]PYRIDAZINES
WO1989001478A1 (fr) *	1987-08-07	1989-02-23	The Australian National University	IMIDAZO[1,2-b]PYRIDAZINES AVEC SUBSTITUANTS ARYLOXY ET ARALKYLTHIO
GB8719368D0 (en) *	1987-08-15	1987-09-23	Wellcome Found	Heterocyclic compounds

1987
- 1987-08-15 GB GB878719368A patent/GB8719368D0/en active Pending
1988
- 1988-08-10 AP APAP/P/1988/000098A patent/AP89A/en active
- 1988-08-11 MC MC882000A patent/MC1969A1/fr unknown
- 1988-08-12 IL IL87435A patent/IL87435A/xx not_active IP Right Cessation
- 1988-08-12 MX MX1265588A patent/MX12655A/es unknown
- 1988-08-12 KR KR1019880010374A patent/KR890003764A/ko not_active Ceased
- 1988-08-12 NZ NZ225808A patent/NZ225808A/en unknown
- 1988-08-12 PH PH37401A patent/PH25741A/en unknown
- 1988-08-12 RU SU884356488A patent/RU1769759C/ru active
- 1988-08-12 DE DE3888897T patent/DE3888897T2/de not_active Expired - Fee Related
- 1988-08-12 ZA ZA885996A patent/ZA885996B/xx unknown
- 1988-08-12 AT AT88307513T patent/ATE103919T1/de not_active IP Right Cessation
- 1988-08-12 ES ES88307513T patent/ES2063039T3/es not_active Expired - Lifetime
- 1988-08-12 HU HU884333A patent/HU204052B/hu not_active IP Right Cessation
- 1988-08-12 DK DK451588A patent/DK168954B1/da not_active IP Right Cessation
- 1988-08-12 AU AU20979/88A patent/AU613392B2/en not_active Ceased
- 1988-08-12 DD DD88318868A patent/DD289529A5/de not_active IP Right Cessation
- 1988-08-12 PT PT88260A patent/PT88260B/pt not_active IP Right Cessation
- 1988-08-12 CA CA000574614A patent/CA1336432C/fr not_active Expired - Fee Related
- 1988-08-12 CN CN88106693A patent/CN1031532A/zh active Pending
- 1988-08-12 NO NO883613A patent/NO168305C/no unknown
- 1988-08-12 JP JP63200321A patent/JPS6468375A/ja active Pending
- 1988-08-12 MY MYPI88000935A patent/MY103602A/en unknown
- 1988-08-12 YU YU156988A patent/YU47200B/sh unknown
- 1988-08-12 PL PL1988290245A patent/PL160044B1/pl unknown
- 1988-08-12 PL PL1988274216A patent/PL159008B1/pl unknown
- 1988-08-12 FI FI883758A patent/FI89600C/fi not_active IP Right Cessation
- 1988-08-12 US US07/231,894 patent/US5091531A/en not_active Expired - Fee Related
- 1988-08-12 PL PL1988290246A patent/PL160045B1/pl unknown
- 1988-08-12 EP EP88307513A patent/EP0305093B1/fr not_active Expired - Lifetime
1989
- 1989-06-19 RU SU894614566A patent/RU2017741C1/ru active
- 1989-07-25 RU SU894614684A patent/RU1836372C/ru active
- 1989-10-18 YU YU202889A patent/YU47212B/sh unknown
- 1989-10-18 YU YU202789A patent/YU47130B/sh unknown
1993
- 1993-03-31 CN CN93103896A patent/CN1085901A/zh active Pending
- 1993-09-17 US US08/122,699 patent/US5371219A/en not_active Expired - Fee Related
- 1993-09-17 US US08/123,529 patent/US5380759A/en not_active Expired - Fee Related
1994
- 1994-07-08 US US08/272,009 patent/US5447956A/en not_active Expired - Fee Related
1995
- 1995-06-02 US US08/458,225 patent/US5538970A/en not_active Expired - Fee Related

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Also Published As

Publication number	Publication date
US5380759A (en)	1995-01-10
MC1969A1 (fr)	1989-09-29
CN1085901A (zh)	1994-04-27
HUT50473A (en)	1990-02-28
FI883758A0 (fi)	1988-08-12
YU202789A (en)	1990-04-30
PH25741A (en)	1991-10-18
PL274216A1 (en)	1989-05-02
YU47212B (sh)	1995-01-31
NO168305B (no)	1991-10-28
FI89600B (fi)	1993-07-15
CN1031532A (zh)	1989-03-08
YU202889A (en)	1990-04-30
MX12655A (es)	1993-10-01
YU47130B (sh)	1994-12-28
NO168305C (no)	1992-02-05
DK168954B1 (da)	1994-07-18
FI89600C (fi)	1993-10-25
JPS6468375A (en)	1989-03-14
ATE103919T1 (de)	1994-04-15
US5447956A (en)	1995-09-05
RU1769759C (ru)	1992-10-15
IL87435A0 (en)	1989-01-31
AU2097988A (en)	1989-02-16
AU613392B2 (en)	1991-08-01
US5538970A (en)	1996-07-23
DD289529A5 (de)	1991-05-02
PT88260A (pt)	1989-09-14
AP8800098A0 (en)	1988-08-01
ES2063039T3 (es)	1995-01-01
FI883758A7 (fi)	1989-02-16
NO883613D0 (no)	1988-08-12
DK451588D0 (da)	1988-08-12
PL159008B1 (pl)	1992-11-30
IL87435A (en)	1993-01-31
KR890003764A (ko)	1989-04-17
EP0305093B1 (fr)	1994-04-06
US5091531A (en)	1992-02-25
HU204052B (en)	1991-11-28
YU156988A (en)	1990-04-30
US5371219A (en)	1994-12-06
EP0305093A1 (fr)	1989-03-01
MY103602A (en)	1993-08-28
PL160044B1 (pl)	1993-02-26
NO883613L (no)	1989-02-16
PL160045B1 (en)	1993-02-26
YU47200B (sh)	1995-01-31
NZ225808A (en)	1991-07-26
PT88260B (pt)	1995-03-01
RU2017741C1 (ru)	1994-08-15
ZA885996B (en)	1990-04-25
DE3888897T2 (de)	1994-10-20
RU1836372C (ru)	1993-08-23
GB8719368D0 (en)	1987-09-23
DK451588A (da)	1989-02-16
CA1336432C (fr)	1995-07-25
DE3888897D1 (de)	1994-05-11

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AP89A (en)	1990-06-14	Heterocyclic compounds.
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