NO176760B - Intermediates for the preparation of imidazopyridazines - Google Patents
Intermediates for the preparation of imidazopyridazines Download PDFInfo
- Publication number
- NO176760B NO176760B NO904825A NO904825A NO176760B NO 176760 B NO176760 B NO 176760B NO 904825 A NO904825 A NO 904825A NO 904825 A NO904825 A NO 904825A NO 176760 B NO176760 B NO 176760B
- Authority
- NO
- Norway
- Prior art keywords
- group
- jab
- formula
- solid
- alkoxy
- Prior art date
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- 239000000543 intermediate Substances 0.000 title description 9
- 150000005233 imidazopyridazines Chemical class 0.000 title description 3
- 238000002360 preparation method Methods 0.000 title description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 31
- 239000007787 solid Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- -1 pyridyl1 Chemical group 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- PVLVHFKKQRYMOR-UHFFFAOYSA-N 1h-pyridazin-2-ylcarbamic acid Chemical compound OC(=O)NN1NC=CC=C1 PVLVHFKKQRYMOR-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- QPHLRCUCFDXGLY-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)methanol Chemical compound COC1=CC(CO)=CC(OC)=C1OC QPHLRCUCFDXGLY-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- OGPIBXIQNMQSPY-FDDCHVKYSA-N (S,S)-tubulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@H]1O[C@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 OGPIBXIQNMQSPY-FDDCHVKYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- SZAOTLVHWBSQPF-UHFFFAOYSA-N 1h-pyridazin-2-yl carbamate Chemical compound NC(=O)ON1NC=CC=C1 SZAOTLVHWBSQPF-UHFFFAOYSA-N 0.000 description 1
- MSBJCEKFIIGEOW-UHFFFAOYSA-N 1h-pyridazine-2-carboxylic acid Chemical compound OC(=O)N1NC=CC=C1 MSBJCEKFIIGEOW-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 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
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- DTXVKPOKPFWSFF-UHFFFAOYSA-N 3(S)-hydroxy-13-cis-eicosenoyl-CoA Chemical compound NC1=CC=C(Cl)N=N1 DTXVKPOKPFWSFF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DKAAMZZLUZUGHC-UHFFFAOYSA-N 6-[(3,4,5-trimethoxyphenyl)methoxy]pyridazin-3-amine Chemical compound COC1=C(OC)C(OC)=CC(COC=2N=NC(N)=CC=2)=C1 DKAAMZZLUZUGHC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 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 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 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
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
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- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 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
- 229960004528 vincristine Drugs 0.000 description 1
- 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 1
- 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 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører nye mellomprodukter for fremstilling av nye imidazopyridaziner The present invention relates to new intermediates for the production of new imidazopyridazines
Forskning innen kreftkjemoterapiområdet har medført produk-sjon av en mengde antisvulstmidler, som har forskjellig virksomhetsgrad. Vanlige klinisk anvendte midler innbefatter adriamycin, aktinomycin D, metotrexat, 5-fluoruracil, cis-platinum, vinkritisin og vinblastin. De til nå tilgjengelige antisvulstmidlene er kjent for å ha forskjellige ulemper, såsom toksisitet imot friske celler og resistens mot visse svulsttyper. Research in the area of cancer chemotherapy has led to the production of a number of anti-tumour agents, which have different degrees of activity. Common clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cis-platinum, vincritisine and vinblastine. The antitumor agents currently available are known to have various disadvantages, such as toxicity to healthy cells and resistance to certain tumor types.
I tillegg til å ha antisvulstaktivitet, er vinkristin en hemmer av mikrorørfunksjon. Andre forbindelser som har mikrorørhemmende aktivitet og som er "blitt rapportert å være potensielle antisvulstmidler er nocodazol, tubulazol og NSC-181928; In addition to having antitumor activity, vincristine is an inhibitor of microtubule function. Other compounds that have microtubule inhibitory activity and have been reported to be potential antitumor agents are nocodazole, tubulazole, and NSC-181928;
Ingen av disse forbindelsene er derimot enda blitt prøvet klinisk. However, none of these compounds have yet been tested clinically.
Det er fortsatt nødvendig med nye og forbedrede antisvulstmidler . There is still a need for new and improved antitumour agents.
Det er oppdaget en ny klasse imidazopyridazinderivater som utviser potent anti-svulstaktivitet. A new class of imidazopyridazine derivatives exhibiting potent anti-tumor activity has been discovered.
Foreliggende oppfinnelse vedrører følgelig mellomprodukter som er kjennetegnet ved at de har formel The present invention therefore relates to intermediate products which are characterized by their formula
R<*> står for en fenylgruppe, eventuelt med 1-4 substituenter valgt fra C^-^alkyl, C^_^alkoksy, C^_4alkoksy substituert med C^.galkoksy eller med <C>1_2alkoksy <C>1_2alkoksy, fenyl, halogen, mono-C1_4alkylamino og di-C-j^alkylamino, naftyl ;eventuelt substituert med Ci_4alkoksy, pyridy1, furyl, ;tienyl eller en C3_£alkylgruppe, ;X står for et oksygen- eller svovelatom eller en gruppe -CH2-; ;Y står for en gruppe CH2 eller -CH2-CH2; ;eller ;X og Y står sammen for gruppen -CH=CH-. ;Foreliggende mellomprodukter anvendes for fremstilling av forbindelser med den generelle formel (I) ;;hvori ;R<1> står for en eventuelt substituert ~~karbocyklisk eller heterocyklisk arylgruppe, eller en eventuelt substituert alkyl, alkenyl, cykloalkyl eller cykloalkenylgruppe; ;R 2 står for en eventuelt substituert alkyl, alkenyl, alkynyl, cykloalkyl eller cykloalkenylgruppe eller en eventuelt substituert karbocyklisk eller heterocyklisk aryl eller aralkylgruppe; ;r<3> står for et hydrogenatom eller en alkylgruppe; ;Med referanse til gruppe R<1> omfatter eksempler på egnede heterocykliske ringer tienyl, furyl og pyridylringer. ;Hvis ikke noe annet er indikert, kan alkylgruppene R<1> og R<2 >som er tilstede i den generelle formelen (I) være rett eller forgrenede kjedealkylgrupper. ;Visse forbindelser med formel (I) kan danne salter. Forbindelsene (I) som inneholder en basisk aminogruppe kan danne salter med syrer, og forbindelser som inneholder en sur gruppe kan danne salter med baser. ;En spesielt foretrukket gruppe av forbindelser med formel VI og VII er de hvor R<1> betyr en fenylgruppe eventuelt substituert med 1-4 substituenter valgt fra C^^-alkoksy (f.eks. metoksy eller etoksy), C1_4-alkyl (f.eks. metyl, etyl, n-propyl, i-propyl, n-butyl eller t-butyl), og halogen (f.eks. brom eller klor); ;og Y-X står for -C^O-gruppen. ;I tillegg til de ovenfor beskrevne egenskapene, har flere av forbindelsene vist at de utviser aktivitet mot en mengde humane svulstcellelinjer in vitro (DLD-1 human tykktarmkarsinoma, WiDr human tykktarmadenokarsinoma, HCT-116 human tykktarmkarsinoma og A549 human lungekarsinoma) og dette indikerer at forbindelsene har en vidspektret anti-svulstaktivitet. ;Uten å være bundet til noen teori, er det antatt at visse forbindelser virker som pro-medikamenter. Forbindelsene med formel (I) hvori R<3> er en alkylgruppe har dermed høyere aktivitet in vivo enn det som ville være ventet på basis av deres in vitro-aktivitet, og det er antatt at de blir omdannet in vivo til en forbindelse med formel (I) hvori R<1 >er hydrogen. ;Forbindelsen med den generelle formel (I) fremstilles ved ;(A) omsetning av foreliggende mellomprodukter med formel ;(VI) ;;som oppvarmes til en temperatur i området 80 til 150°C, eventuelt i nærvær av et oppløsningsmiddel og omsetning med en hensiktsmessig R<2>0H-alkohol; eller ved ;(B) omsetning av foreliggende mellomprodukt med formel ;(VII): ;;med et reagens som innfører -COgR^-gruppen. ;Det er antatt at fremgangsmåte (A) forløper via et isocyanat-derivatmellomprodukt med formel (XII): ;Acyl-azidderivater med formel (VI) kan bli fremstilt fra de korresponderende karboksyl syrene ved dannelse av et aktivert syrederivat, (f.eks. et syrehalogenid såsom syreklorid som er dannet ved omsetning med et halogenerende middel såsom oksalylklorid, tionylklorid eller fosforpentaklorid) etterfulgt av omsetning med et azid, f.eks. et alkalimetall-azid, fortrinnsvis i en vannholdig eteroppløsning f.eks. vannholdig dioksan. Karboksylsyrederivater som korresponderer med forbindelsene (VI) kan i seg bli fremstilt ved omsetning av en forbindelse med formel (II) med etylbrompyruvat i et aprotisk løsningsmiddel, så som dimetylformamid, 1,3-dimetylimidazolidinon eller heksametyl-fosforamid, og ved en ikke-ekstrem temperatur, f.eks. mellom 50-120°C for å tilveiebringe en ester, etterfulgt av hydrolyse for å tilveiebringe den ønskede syren. ;I fremgangsmåte (B) kan et reagens som introduserer -COgR<2->gruppen være det korresponderende halogenformat, f.eks. et alkylhalogenformat såsom metyl- eller etylklorformat. Forbindelser med formel (VII) kan i seg selv bli fremstilt fra en forbindelse med formel (I) ved fjerning av en -COgR<2->gruppe, (fortrinnsvis en labil gruppe såsom t-butoksy-karbonyl) under sure betingelser (ved f.eks. anvendelse av en eventuelt halogenert karboksylsyre såsom maursyre, klorform-syre eller trifluoreddiksyre), eventuelt i et oppløsnings-middel, f.eks. et halogenert hydrokarbon slik som diklormetan. Dermed kan en forbindelse med formel (I) bli omdannet i en spesiell fremstilling av fremgangsmåte (B) til en annen forbindelse med formel (I) ved fjerning av en -COgR^gruppe og en reaksjon for å innføre en annen -COgR^gruppe som beskrevet ovenfor. ;Forbindelsene som fremstilles av foreliggende mellomprodukter er nyttige for behandling av svulster. De kan bli anvendt til behandling av forskjellige kreftformer innbefattende leukemi, lymfomer, sarkomer og faste svulster. ;Oppfinnelsen vil nå bli illustrert ved følgende eksempler. Alle temperaturer er i °C. ;Proton-kjernemagnetisk resonansspektra ble tilveiebragt i en "Bruker AH200 FT NMR"- eller "Bruker HFX90 FT NMR"-maskin. ;Følgende forkortelser blir anvendt til fremstillingene og eksemplene. ;DME - dimetoksyetan ;FREMSTILLING AV MELLOMPRODUKT ;Mellomprodukt 1 ;3- amino- 6- ( 3 , 4 . 5- tr imetoksybenzyloksy ) pyridazin 3 ,4,5-trimetoksybenzylalkohol (Aldrich, 19,82 g, 0,1 mol), løst opp 1 DME (20 ml), ble tilsatt i løpet av 15 min. til en suspensjon bestående av kalium-t-butoksyd (11,22 g, 0,1 mol) i DME (80 ml) med omrøring under Ng og avkjøling i et is-bad. Etter 0,5 t. ble blandingen behandlet med 3-amino-6-klorpyri-dazin ("Heiv. Chim. Acta." 1954, 37, 121, J. Druey, Kd. Meier og K. Eichenberger) (12,95 g, 0,1 mol) og etter 1,5 t. ble den oppvarmet under tilbakestrømning i 3 t. Blandingen ble avkjølt og filtrert og det filtrerte faste stoffet ble vasket med eter. Filtratet ble fordampet under vakuum for å tilveiebringe en olje som var fordelt mellom etylacetat og vann. Den organiske fasen ble vasket med vann, tørket (NagSO^ og fordampet for å tilveiebringe en olje (A) som ble kromatografert på silisiumoksydgel eluerende med 5% metanol-kloroform. Eluerte fraksjoner ble slått sammen for å tilveiebringe en olje (B) som ble triturert med kloroform og diisopropyleter for å tilveiebringe tittelforbindelsen som et off-white faststoff (9,44 g), sm.p. = 142-144"; ;NMR SE (CDC13): 6,87 (1H, JAB<8,>8 Hz, 5-H), 6,78 (1H, JAB 8,8 Hz, 4-H), 6,72 (2H, s, PhH), 5,38 (2H, s, CHg), 4,45 (2H, br s, NHg), 3,87 (6H, s, OMe) og 3,84 (3H, s, OMe). ;Eksempel 1 ;2, 2. 2- 1r i fluoretyl- N- T6-( 3, 4. 5- trimetoksybenzyloksy ) imidazo-fl, 2- blpyridazin- 2- yllkarbamat ;a ) Etyl f 6 - ( 3. 4 . 5- trimetoksybenzyloksy) imidazori , 2- bl-pyridazin- 2- yllkarboksylat ;Etylbrompyruvat (117 g, 0,6 mol) ble satt til 3-amino-6-(3 , 4,5-trimetoksybenzyloksy)pyridazin (174,6 g, 0,6 mol og 2,6-lutidin (62,4 g, 0,6 mol) i tørr DMF (600 ml) med omrøring under Ng. Blandingen ble oppvarmet ved 100° i 3 t., avkjølt og konsentrert under vakuum og deretter behandlet med vann og filtrert for å tilveiebringe et brunt faststoff som ble vasket med vann og eter. Det faste stoffet ble krystallisert fra DMF og vann for å tilveiebringe tittelforbindelsen som et krystallinsk faststoff (88 g), smp. 159-163°. ;NMR SH (CDCI3): 8,31 (1H, s, 3H) , 7,84 (1H, JAB<8,>8 Hz, 8H), 6,82 (1H, JAB 8,8 Hz, 7H), 6,70 (2H, s, ArH), 5,30 (2H, s, CH2Ar), 4,45 (2H, q, J 7 Hz, 0CH2<C>H3), 3,88 (6H, s, OCH3), 3,86 (3H, s, OCH3) og 1,44 (3H, t, J 7 Hz, CH3). ;b ) 6( 3. 4, 5 - tr imetoksybenzyloksy ) imidazo[" l , 2- bl pyridazin- 2-karboksylsyre ;Produktet fra trinn (a) (1,94 g, 5 mmol ) ble oppvarmet under tilbakestrømming med omrøring med natriumhydroksyd-oppløsning (1 ml, 10 M, 10 mmol), vann (9 ml) og metanol (5 ml) i 20 min. Blandingen ble avkjølt og surgjort med fortynnet saltsyre og filtrert for å tilveiebringe et faststoff som ble tørket ved 60° under vakuum for å tilveiebringe tittelforbindelsen som et pulver (1,5 g), smp. 224-226°C (dekomp.). ;NMR SH (d6-DMS0): 8,56 (1H, s, 3H), 8,07 (1H, JAB 8,8 Hz, 8H), 7,05 (1H, JAB 8,8 Hz, 7H), 6,88 (2H, s, ArH), 5,29 (2H, s, CH2Ar), 3,82 (6H, s, OCH3) , 3,68 (3H, s, 0CH3) og 3,32 (1H, br.s, C02H). ;c ) 6- ( 3 , 4 . 5- tr imetoksybenzyloksy ) imidazo fl, 2- bl pyr idazin- 2-karboksylsyreazid ;Oksalkylklorid (0,13 ml, 1,5 mmol) ble satt til produktet fra trinn (b) (0,36 g, 1 mmol) og pyridin (0,079 g, 1 mmol) i tørr benzen (5 ml) med omrøring under N2. Blandingen ble oppvarmet under tilbakestrømming i 3 t., avkjølt, og fordampet under vakuum for å tilveiebringe et grått faststoff: Dette faststoffet ble behandlet med dioksan (10 ml), vann (10 ml) og natriumazid (overskudd) og kraftig omrørt over natt ved romtemperatur. Blandingen ble filtrert og det faste stoffet tørket under vakuum for å tilveiebringe tittelforbindelsen som et pulver (0,29 g), smp. > 139° ;(dekomp.), ;NMR SH (CDCI3): 8,35 (1H, s, 3H) , 7,85 (1H, JAB 8,8 Hz, 8H), 6,85 (1H, JAB 8,8 Hz, 7H), 6,70 (2H, s, ArH), 5,31 (2H, s, CH2Ar), 3,90 (6H, s, 0CH3) og 3,88 (3H, s, 0CH3) . ;d ) 2 . 2 , 2- trifluoretyl- N- r6-( 3, 4, 5 - 1r imetoksybenzy1 oksv)-imidazofl. 2— bl pyridazin- 2- yllkarbamat ;Produktet fra trinn (c) (2,3 g, 6 mmol), 2,2,2-trifluor-etanol (ca. 3 ml) og toluen (60 ml) ble oppvarmet med omrøring under N2 ved tilbakstrømming helt til TLC viste fullstendig reaksjon (ca. 2 t.). ;Blandingen ble avkjølt over natt og filtrert for å tilveiebringe et faststoff som ble vasket med eter og tørket for å tilveiebringe tittelforbindelsen som et pulver (0,43 g), sm.p. 205-210°C (dekomp.). ;NMR SH (d6-DMS0): 10,81 (1H, br.s, NH), 7,88 (1H, JAB 8,8 Hz, 8H), 7,85 (1H, s, 3H) , 6,90 (1H, JAB 8 Hz, 7H) , 6,85 (2H, s, ArH), 5,25 (2H, s, CH2Ar), 4,83 (2H, q, J 9 Hz, CH2CF3), 3,76 (6H, s, 0CH3) og 3,65 (3H, s, 0CH3). ;Eksempel 2 ;2- hydroksyetyl- N- r6-( 3. 4. 5 - tr imetoksybenzyloksy) imi dazo-[" 1, 2— bl pyridazin- 2- yllkarbamat ;En lignende fremgangsmåte som den som er beskrevet i eksempel l(d) ble fulgt med unntagelse av at råproduktet ble kromatografert på Si02 eluerende med 5$ metanol-kloroform med påfølgende omkrystallisering fra DMF-vann for å tilveiebringe tittelforbindelsen som et pulver, sm.p. 193-195°, ;NMR SH (d6-DMS0): 10,35 (1H, br.s, NH) , 7,85 (1H, JAB 8,8 Hz, 8H), 7,83 (1H, s, 3H), 6,86 (1H, JAB 8,8 Hz, 3H) , 6,84 ;(2H, s, ArH), 5,25 (2H, s, CH2Ar) , 4,82 (1H, t, J 4 Hz, OH), 4,15 (2H, m), 3,80 (6H, s, OCH3) og 3,66 (5H, m, 0CH2 og OCH3). ;Eksempel 3 ;2-( l- morfolino ) etyl- Nr6-( 3. 4, 5- trimetoksybenzyloksy Hmidazo-[~ 1. 2— blpyridazin- 2- yl~ l karbamat ;En lignende fremgangsmåte som den som er beskrevet i eksempel l(d) ble fulgt med unntagelse av at råproduktet ble kromatografert på Si02 eluerende med 5$ metanol-kloroform og kokt med litt etanol for å tilveiebringe tittelforbindelsen som et pulver, sm.p. 161-162°, ;NMR SH (d6-DMS0): 10,30 (1H, br. s , NH), 7,88 (1H, s, 3H) , 7,85 (1H, JAB 8,8 Hz, 8H) , 6,87 (1H, JAB 8,8 Hz, 7H) , 6,85 (2H, s, ArH), 5,26 (2H, s, CH2Ar) , 4,22 (2H, t, J 5 Hz, C0-0CH2), 3,80 (6H, s, 0CH3), 3,68 (3H, s, 0CH3), 3,58 (4H, m, CH20CH2), 2,59 (2H, t, J 5 Hz, C0-0CH2CH2N) og 2,45 (4H, m, CH2NCH2). ;Eksempel 4 ;2 , 3- dihydroksypropyl- N- r6-( 3. 4 , 5- tr imetoksybenzyloksy ) - imidazofl, 2- bl pyridazin- 2- yllkarbamat ;Produktet i eksempel l(c) ble omsatt med solketal ved anvendelse av en lignende fremgangsmåte som den som er beskrevet i eksempel l(d) med unntagelse av at den rå blandingen ble fordampet under vakuum og når reaksjonen mellom acylazid og solketal var fullført og deretter oppvarmet ved 60-70°C i 0,5 timer med fortynnet saltsyre og etanol. Reaksjonsblandingen ble nøytralisert med natrium-bikarbonatoppløsning, fordampet under vakuum og kromatografert på Si02 eluerende med 1% metanol-kloroform for å tilveiebringe tittelforbindelsen som et hvitt faststoff, sm.p. 175-176°C ;NMR SH (d6-DMSO): 10,28 (1H, brs, NH) , 7,88 (1H, JAB 8,8 Hz, 8H), 7,86 (1H, s, 3H), 6,87 (1H, JAB 8,8 Hz, 7H), 6,85 (2H, s, ArH), 5,28 (2H, s, ArCH2), 4,90 (1H, d, J 4 Hz, 2<*->0H), 4,65 (1H, t, J 4 Hz, l'-OH), 4,20-4,0 (2H, m, C0-0CH2), 3,80 (6H, s, 0CH3), 3,80-3,70 (1H, m, HO-CH), 3,69 (3H, s, 0CH3) og 3,40 (2H, t, J 4 Hz, H0CH2 ). R<*> stands for a phenyl group, optionally with 1-4 substituents selected from C^-^alkyl, C^_^ alkoxy, C^_4 alkoxy substituted with C^.galkoxy or with <C>1_2 alkoxy <C>1_2 alkoxy, phenyl , halogen, mono-C1_4alkylamino and di-C-j^alkylamino, naphthyl ; optionally substituted by C1_4 alkoxy, pyridyl1, furyl, ;thienyl or a C3_£alkyl group, ;X stands for an oxygen or sulfur atom or a group -CH2-; ;Y represents a group CH 2 or -CH 2 -CH 2 ; ;or ;X and Y together stand for the group -CH=CH-. The present intermediates are used for the preparation of compounds of the general formula (I) in which R<1> stands for an optionally substituted ~~carbocyclic or heterocyclic aryl group, or an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group; ;R 2 stands for an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group or an optionally substituted carbocyclic or heterocyclic aryl or aralkyl group; ;r<3> stands for a hydrogen atom or an alkyl group; ;With reference to group R<1>, examples of suitable heterocyclic rings include thienyl, furyl and pyridyl rings. Unless otherwise indicated, the alkyl groups R<1> and R<2> present in the general formula (I) may be straight or branched chain alkyl groups. Certain compounds of formula (I) can form salts. The compounds (I) containing a basic amino group can form salts with acids, and compounds containing an acidic group can form salts with bases. A particularly preferred group of compounds of formula VI and VII are those where R<1> means a phenyl group optionally substituted with 1-4 substituents selected from C^^- alkoxy (e.g. methoxy or ethoxy), C1-4-alkyl ( eg methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl), and halogen (eg bromine or chlorine); ;and Y-X stands for the -C^O group. In addition to the properties described above, several of the compounds have been shown to exhibit activity against a number of human tumor cell lines in vitro (DLD-1 human colon carcinoma, WiDr human colon adenocarcinoma, HCT-116 human colon carcinoma and A549 human lung carcinoma) and this indicates that the compounds have a broad-spectrum anti-tumor activity. Without being bound by any theory, certain compounds are believed to act as pro-drugs. The compounds of formula (I) in which R<3> is an alkyl group thus have higher activity in vivo than would be expected on the basis of their in vitro activity, and it is believed that they are converted in vivo to a compound of formula (I) wherein R<1 >is hydrogen. ;The compound with the general formula (I) is prepared by ;(A) reaction of present intermediates with formula ;(VI) ;;which is heated to a temperature in the range of 80 to 150°C, possibly in the presence of a solvent and reaction with a appropriate R<2>OH alcohol; or by ;(B) reacting the present intermediate with formula ;(VII): ;;with a reagent which introduces the -COgR^ group. ;It is assumed that method (A) proceeds via an isocyanate derivative intermediate with formula (XII): ;Acyl-azide derivatives with formula (VI) can be prepared from the corresponding carboxylic acids by forming an activated acid derivative, (e.g. an acid halide such as acid chloride formed by reaction with a halogenating agent such as oxalyl chloride, thionyl chloride or phosphorus pentachloride) followed by reaction with an azide, e.g. an alkali metal azide, preferably in an aqueous ether solution, e.g. aqueous dioxane. Carboxylic acid derivatives corresponding to compounds (VI) can themselves be prepared by reacting a compound of formula (II) with ethyl bromopyruvate in an aprotic solvent, such as dimethylformamide, 1,3-dimethylimidazolidinone or hexamethylphosphoramide, and by a non-extreme temperature, e.g. between 50-120°C to provide an ester, followed by hydrolysis to provide the desired acid. In method (B), a reagent which introduces the -COgR<2-> group can be the corresponding halogen formate, e.g. an alkyl halide formate such as methyl or ethyl chloroformate. Compounds of formula (VII) can themselves be prepared from a compound of formula (I) by removal of a -COgR<2-> group, (preferably a labile group such as t-butoxycarbonyl) under acidic conditions (at f .eg use of an optionally halogenated carboxylic acid such as formic acid, chloroform acid or trifluoroacetic acid), optionally in a solvent, e.g. a halogenated hydrocarbon such as dichloromethane. Thus, a compound of formula (I) can be converted in a particular preparation of method (B) into another compound of formula (I) by removal of a -COgR^ group and a reaction to introduce another -COgR^ group which described above. The compounds produced from the present intermediates are useful for the treatment of tumors. They can be used to treat various forms of cancer including leukaemia, lymphomas, sarcomas and solid tumours. The invention will now be illustrated by the following examples. All temperatures are in °C. ;Proton nuclear magnetic resonance spectra were obtained in a "Bruker AH200 FT NMR" or "Bruker HFX90 FT NMR" machine. ;The following abbreviations are used for the representations and examples. ;DME - dimethoxyethane ;PRODUCTION OF INTERMEDIATE ;Intermediate 1 ;3- amino- 6- ( 3 , 4 . 5- tri methoxybenzyloxy ) pyridazine 3 ,4,5-trimethoxybenzyl alcohol (Aldrich, 19.82 g, 0.1 mol), dissolved 1 DME (20 ml), was added during 15 min. to a suspension of potassium t-butoxide (11.22 g, 0.1 mol) in DME (80 mL) with stirring under Ng and cooling in an ice bath. After 0.5 h the mixture was treated with 3-amino-6-chloropyridazine ("Heiv. Chim. Acta." 1954, 37, 121, J. Druey, Kd. Meier and K. Eichenberger) (12.95 g, 0.1 mol) and after 1.5 h it was heated under reflux for 3 h. The mixture was cooled and filtered and the filtered solid was washed with ether. The filtrate was evaporated under vacuum to provide an oil which was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (NagSO4) and evaporated to give an oil (A) which was chromatographed on silica gel eluting with 5% methanol-chloroform. Eluted fractions were combined to give an oil (B) which was triturated with chloroform and diisopropyl ether to afford the title compound as an off-white solid (9.44 g), m.p. = 142-144"; ;NMR SE (CDC13): 6.87 (1H, JAB<8,> 8 Hz, 5-H), 6.78 (1H, JAB 8.8 Hz, 4-H), 6.72 (2H, s, PhH), 5.38 (2H, s, CHg), 4.45 (2H, br s, NHg), 3.87 (6H, s, OMe) and 3.84 (3H, s, OMe). ;Example 1 ;2, 2. 2- 1r in fluoroethyl- N- T6-( 3, 4. 5- trimethoxybenzyloxy ) imidazo-fl, 2- blpyridazin-2- ylcarbamate ; a ) Ethyl f 6 - ( 3. 4 . 5- trimethoxybenzyloxy ) imidazo , 2- bl- pyridazin- 2- ylcarboxylate ; Ethyl bromopyruvate (117 g, 0.6 mol) was added to 3-amino-6-(3,4,5-trimethoxybenzyloxy)pyridazine (174.6 g, 0.6 mol) and 2,6-lutidine (62.4 g, 0, 6 mol) in dry DMF (600 mL) with stirring under RT The mixture was heated at 100° for 3 hrs., cooled and concentrated under vacuum and then treated with water and filtered to provide a brown solid which was washed with water and ether. The solid was crystallized from DMF and water to provide the title compound as a crystalline solid (88 g), m.p. 159-163°. ;NMR SH (CDCl 3 ): 8.31 (1H, s, 3H), 7.84 (1H, JAB<8,>8 Hz, 8H), 6.82 (1H, JAB 8.8 Hz, 7H), 6.70 (2H, s, ArH), 5.30 (2H, s, CH2Ar), 4.45 (2H, q, J 7 Hz, 0CH2<C>H3), 3.88 (6H, s, OCH3 ), 3.86 (3H, s, OCH 3 ) and 1.44 (3H, t, J 7 Hz, CH 3 ). ;b ) 6( 3.4, 5 - tri methoxybenzyloxy ) imidazo[" l , 2-bl pyridazine-2-carboxylic acid ; The product from step (a) (1.94 g, 5 mmol ) was heated under reflux with stirring with sodium hydroxide solution (1 mL, 10 M, 10 mmol), water (9 mL) and methanol (5 mL) for 20 min. The mixture was cooled and acidified with dilute hydrochloric acid and filtered to give a solid which was dried at 60° under vacuum to provide the title compound as a powder (1.5 g), mp 224-226°C (decomp.) ;NMR SH (d 6 -DMSO): 8.56 (1H, s, 3H), 8, 07 (1H, JAB 8.8 Hz, 8H), 7.05 (1H, JAB 8.8 Hz, 7H), 6.88 (2H, s, ArH), 5.29 (2H, s, CH2Ar), 3.82 (6H, s, OCH3) , 3.68 (3H, s, 0CH3) and 3.32 (1H, br.s, CO2H). ;c ) 6-(3,4,5-trimethoxybenzyloxy) imidazo fl, 2- bl pyr idazine- 2-carboxylic acid azide;Oxalkyl chloride (0.13 mL, 1.5 mmol) was added to the product from step (b) (0.36 g, 1 mmol) and pyridine (0.079 g, 1 mmol) in dry benzene (5 mL) with stirring under N 2. The mixture was heated under reflux stirring for 3 h, cooled, and evaporated in vacuo to give a gray solid: This solid was treated with dioxane (10 mL), water (10 mL), and sodium azide (excess) and stirred vigorously overnight at room temperature. The mixture was filtered and the solid dried under vacuum to provide the title compound as a powder (0.29 g), m.p. > 139° ;(decomp.), ;NMR SH (CDCl3): 8.35 (1H, s, 3H) , 7.85 (1H, JAB 8.8 Hz, 8H), 6.85 (1H, JAB 8 .8 Hz, 7H), 6.70 (2H, s, ArH), 5.31 (2H, s, CH2Ar), 3.90 (6H, s, 0CH3) and 3.88 (3H, s, 0CH3) . d) 2. 2, 2-trifluoroethyl-N-r6-(3,4,5-1r-imethoxybenzy1oxv)-imidazofl. 2—bl pyridazin-2-yl carbamate; The product from step (c) (2.3 g, 6 mmol), 2,2,2-trifluoroethanol (ca. 3 mL) and toluene (60 mL) were heated with stirring under N2 at reflux until TLC showed complete reaction (approx. 2 h.). The mixture was cooled overnight and filtered to give a solid which was washed with ether and dried to give the title compound as a powder (0.43 g), m.p. 205-210°C (decomp.). ;NMR SH (d6-DMS0): 10.81 (1H, br.s, NH), 7.88 (1H, JAB 8.8 Hz, 8H), 7.85 (1H, s, 3H) , 6, 90 (1H, JAB 8 Hz, 7H) , 6.85 (2H, s, ArH), 5.25 (2H, s, CH2Ar), 4.83 (2H, q, J 9 Hz, CH2CF3), 3, 76 (6H, s, 0CH3) and 3.65 (3H, s, 0CH3). ;Example 2 ;2-Hydroxyethyl-N- r6-(3.4.5-trimethoxybenzyloxy)imidazo-[" 1,2-bl pyridazin-2-ylcarbamate;A similar procedure to that described in Example 1( d) was followed except that the crude product was chromatographed on SiO2 eluting with 5% methanol-chloroform followed by recrystallization from DMF-water to provide the title compound as a powder, mp 193-195°, ;NMR SH (d6- DMS0): 10.35 (1H, br.s, NH), 7.85 (1H, JAB 8.8 Hz, 8H), 7.83 (1H, s, 3H), 6.86 (1H, JAB 8 .8 Hz, 3H) , 6.84 ;(2H, s, ArH), 5.25 (2H, s, CH2Ar) , 4.82 (1H, t, J 4 Hz, OH), 4.15 (2H , m), 3.80 (6H, s, OCH3) and 3.66 (5H, m, 0CH2 and OCH3). ;Example 3 ;2-( l- morpholino ) ethyl- Nr6-( 3. 4, 5- Trimethoxybenzyloxy Hmidazo-[~ 1. 2- blpyridazin-2-yl~ l carbamate; A similar procedure to that described in Example 1(d) was followed with the exception that the crude product was chromatographed on SiO 2 eluting with 5% methanol-chloroform and boiled with a little ethanol to provide the title elf the original compound as a powder, m.p. 161-162°, ;NMR SH (d6-DMS0): 10.30 (1H, br. s , NH), 7.88 (1H, s, 3H) , 7.85 (1H, JAB 8.8 Hz, 8H) , 6.87 (1H, JAB 8.8 Hz, 7H) , 6.85 (2H, s, ArH), 5.26 (2H, s, CH2Ar) , 4.22 (2H, t, J 5 Hz, C0-0CH2), 3.80 (6H, s, 0CH3), 3.68 (3H, s, 0CH3), 3.58 (4H, m, CH20CH2), 2.59 (2H, t, J 5 Hz, C0-0CH2CH2N) and 2.45 (4H, m, CH2NCH2). ;Example 4 ;2,3-dihydroxypropyl-N-r6-(3,4,5-trimethoxybenzyloxy)-imidazofl,2-bl pyridazin-2-ylcarbamate;The product in example 1(c) was reacted with solketal using a similar procedure to that described in Example 1(d) except that the crude mixture was evaporated under vacuum and when the reaction between the acyl azide and the solketal was complete and then heated at 60-70°C for 0.5 hours with dilute hydrochloric acid and ethanol. The reaction mixture was neutralized with sodium bicarbonate solution, evaporated in vacuo and chromatographed on SiO 2 eluting with 1% methanol-chloroform to provide the title compound as a white solid, m.p. 175-176°C; NMR SH (d6-DMSO): 10.28 (1H, brs, NH), 7.88 (1H, JAB 8.8 Hz, 8H), 7.86 (1H, s, 3H) , 6.87 (1H, JAB 8.8 Hz, 7H), 6.85 (2H, s, ArH), 5.28 (2H, s, ArCH2), 4.90 (1H, d, J 4 Hz, 2<*->0H), 4.65 (1H, t, J 4 Hz, 1'-OH), 4.20-4.0 (2H, m, C0-0CH2), 3.80 (6H, s , 0CH3 ), 3.80-3.70 (1H, m, HO-CH), 3.69 (3H, s, 0CH3 ) and 3.40 (2H, t, J 4 Hz, H0CH2 ).
Eksempel 5 Example 5
2- dimetvlamlnoetyl- N - f 6 - ( 3 , 4 , 5- trimetoksybenzyIoksy)-imidazori, 2- b] pyridazin- 2- yllkarbamat 2- Dimethylaminoethyl- N - f 6 - ( 3 , 4 , 5- trimethoxybenzyloxy)-imidazori, 2- b] pyridazin- 2- ylcarbamate
Produktet ifølge eksempel l(c) ble omsatt med (2-dimetyl-amino)etanol ved anvendelse av en lignende fremgangsmåte som den som er beskrevet i eksempel l(d) med unntagelse av at råproduktet ble kromatografert på Si02 eluerende med 5$ metanol-kloroform for å tilveiebringe et faststoff som ble vasket med etanol og tørket for å tilveiebringe tittelforbindelsen som et hvitt pulver, sm.p. 185-186°C. The product according to Example 1(c) was reacted with (2-dimethylamino)ethanol using a similar procedure to that described in Example 1(d) with the exception that the crude product was chromatographed on SiO 2 eluting with 5% methanol chloroform to provide a solid which was washed with ethanol and dried to provide the title compound as a white powder, m.p. 185-186°C.
NMR SH (d6-DMS0): 10,32 (1H, brs, NH), 7,88 (1H, JAB 8,8 Hz, 8H), 7,85 (1H, s, 3H), 6,89 (1H, JAB 8,8 Hz, 7H), 6,85 (2H, s, ArH), 5,77 (2H, s, ArCH2 ) , 4,60 (2H, t, J 4 Hz, C0-0CH2), 3,80 (6H, s, 0CH3) , 3,69 (3H, s, OCH3) , 2,50 (2H, t, CH2N) og 2,21 (6H, s, NMe2) . NMR SH (d6-DMS0): 10.32 (1H, brs, NH), 7.88 (1H, JAB 8.8 Hz, 8H), 7.85 (1H, s, 3H), 6.89 (1H , JAB 8.8 Hz, 7H), 6.85 (2H, s, ArH), 5.77 (2H, s, ArCH2 ) , 4.60 (2H, t, J 4 Hz, C0-0CH2 ), 3 .80 (6H, s, 0CH3) , 3.69 (3H, s, OCH3) , 2.50 (2H, t, CH2N) and 2.21 (6H, s, NMe2) .
Eksempel 6 Example 6
Fenyl - N- r6-( 3, 4. 5- trimetoksybenzyloksy) imidazo fl. 2- bl pyr i - dazin- 2- yllkarbamat Phenyl - N- r6-(3, 4. 5- trimethoxybenzyloxy) imidazo fl. 2- bl pyr i - dazin- 2- yl carbamate
Produktet ifølge eksempel l(c) ble omsatt med fenol ved anvendelse av en lignende fremgangsmåte som den som er beskrevet i eksempel l(d) med unntagelse av at råproduktet ble kromatografert på Si02 eluerende med 5$ metanol-kloroform for å tilveiebringe et faststoff som ble vasket med aceto-nitril og tørket for å tilveiebringe tittelforbindelsen som et hvitt pulver, sm.p. 210-213°C. The product of Example 1(c) was reacted with phenol using a similar procedure to that described in Example 1(d) except that the crude product was chromatographed on SiO 2 eluting with 5% methanol-chloroform to provide a solid which was washed with acetonitrile and dried to provide the title compound as a white powder, m.p. 210-213°C.
NMR SH (CDCI3): 10,12 (1H, brs, NH), 8,05 (1H, s, 3H), 7,80 (1H, JAB 8,8 Hz, 8H), 7,55-7,15 (5H, m, Ph), 6,69 (2H, s, ArH), 6,67 (1H, JAB 8,8 Hz, 7H) , 5,28 (2H, s, ArCH2 ) og 3,90 (9H, s, 0CH3). NMR SH (CDCl 3 ): 10.12 (1H, brs, NH), 8.05 (1H, s, 3H), 7.80 (1H, JAB 8.8 Hz, 8H), 7.55-7.15 (5H, m, Ph), 6.69 (2H, s, ArH), 6.67 (1H, JAB 8.8 Hz, 7H) , 5.28 (2H, s, ArCH2 ) and 3.90 (9H , p, 0CH3).
Eksempel 7 Example 7
Metyl- N- r6-( 3. 4, 5 - 1 r Ime toks ybenz yl ok sy) imldazo fl . 2- blpyri-dazin- 2- yll karbamat Methyl- N- r6-( 3. 4, 5 - 1 r Ime toks ybenz yl ok sy) imldazo fl . 2- blpyri-dazin- 2- yl carbamate
a) 2- amino- 6-( 3. 4. 5- trimetoksybenzyloksy) lmidazori, 2-blpyridazin- trifluoracetat a) 2-amino- 6-(3.4.5-trimethoxybenzyloxy)lmidazoli, 2-blpyridazine-trifluoroacetate
t-butyl-N-[6-(3,4,5 -1r imetoksybenzy1oksy)imidazo[l,2-b]pyridazin-2-yl]karbamat (eksempel 13 norsk patent no. 168305, 0,43 g, 1 mmol) ble oppløst i diklormetan (2 ml) og behandlet med trifluoreddiksyre (1 ml). Etter 2 t ved romtemperatur ble blandingen fordampet under vakuum for å tilveiebringe en brun olje som ble triturert med dietyl-eter for å tilveiebringe tittelforbindelsen (0,25 g) som kremfaststoff, smp. 150-157°C, t-butyl-N-[6-(3,4,5-1r-imethoxybenzyloxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (example 13 Norwegian patent no. 168305, 0.43 g, 1 mmol ) was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (1 mL). After 2 h at room temperature, the mixture was evaporated under vacuum to provide a brown oil which was triturated with diethyl ether to provide the title compound (0.25 g) as a cream solid, m.p. 150-157°C,
NMR SH (d6-DMS0): 8,0 (1H, JAB 8,8 Hz, 8H), 7,48 (1H, s, 3H), 7,16 (1H, JAB 8,8 Hz, 7H), 6,44 (2H, s, CH2) , 4,5 (brs, NH3), 3,89 (6H s, OMe) og 3,75 (3H, s, OMe). NMR SH (d 6 -DMSO): 8.0 (1H, JAB 8.8 Hz, 8H), 7.48 (1H, s, 3H), 7.16 (1H, JAB 8.8 Hz, 7H), 6 .44 (2H, s, CH2), 4.5 (brs, NH3), 3.89 (6H s, OMe) and 3.75 (3H, s, OMe).
b ) Metyl- Nr6-( 3. 4. 5- trimetoksybenzyloksy) imidazori. 2- bl-pyridazin- 2- yllkarbamat b ) Methyl-Nr6-(3.4.5-trimethoxybenzyloxy)imidazoli. 2- bl-pyridazine- 2- yl carbamate
Produktet fra trinn (a) (1,0 g, 3,03 mmol) ble suspendert i diklormetan og rystet med fortynnet natrium-hydroksydoppløsning. Den organiske fasen ble tørket (Na2S04) og fordampet for å tilveiebringe en brun olje som ble løst opp i diklormetan og behandlet, ved omrøring, med trietylamin (0,42 ml, 3,03 mmol), metylklorformat (0,23 ml, 3,03 mmol) og 4-dimetylaminopyridin (18 mg, 0,3 mmol). Blandingen ble omrørt ved romtemperatur i 17 t, deretter varmet under tilbakestrømming i 2 t og fordampet under vakuum. Det resulterende faste stoffet ble fordelt mellom kloroform og vann, den organiske fasen ble separert, tørket (Na2S04) og fordampet for å tilveiebringe et fast stoff som ble kromatograf ert på Si02 og eluering med 2$ metanol-kloroform. Produktet ble omkrystallisert fra DMF-HgO for å tilveiebringe tittelforbindelsen (0,27 g), smp. 210-212°C, NMR var identisk med produktet i eksempel 1.. The product from step (a) (1.0 g, 3.03 mmol) was suspended in dichloromethane and shaken with dilute sodium hydroxide solution. The organic phase was dried (Na 2 SO 4 ) and evaporated to provide a brown oil which was dissolved in dichloromethane and treated, with stirring, with triethylamine (0.42 mL, 3.03 mmol), methyl chloroformate (0.23 mL, 3 .03 mmol) and 4-dimethylaminopyridine (18 mg, 0.3 mmol). The mixture was stirred at room temperature for 17 h, then heated under reflux for 2 h and evaporated under vacuum. The resulting solid was partitioned between chloroform and water, the organic phase was separated, dried (Na 2 SO 4 ) and evaporated to give a solid which was chromatographed on SiO 2 eluting with 2% methanol-chloroform. The product was recrystallized from DMF-HgO to provide the title compound (0.27 g), m.p. 210-212°C, NMR was identical to the product in example 1..
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO904825A NO176760C (en) | 1987-08-15 | 1990-11-06 | Intermediates for the preparation of imidazopyridazines |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878719368A GB8719368D0 (en) | 1987-08-15 | 1987-08-15 | Heterocyclic compounds |
| NO883613A NO168305C (en) | 1987-08-15 | 1988-08-12 | Heterocyclic Compounds |
| NO904825A NO176760C (en) | 1987-08-15 | 1990-11-06 | Intermediates for the preparation of imidazopyridazines |
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| Publication Number | Publication Date |
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| NO904825L NO904825L (en) | 1989-02-16 |
| NO904825D0 NO904825D0 (en) | 1990-11-06 |
| NO176760B true NO176760B (en) | 1995-02-13 |
| NO176760C NO176760C (en) | 1995-05-24 |
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| NO904825A NO176760C (en) | 1987-08-15 | 1990-11-06 | Intermediates for the preparation of imidazopyridazines |
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| NO176760C (en) | 1995-05-24 |
| NO904825L (en) | 1989-02-16 |
| NO904825D0 (en) | 1990-11-06 |
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