NO874954L - Phosphine. - Google Patents
Phosphine.Info
- Publication number
- NO874954L NO874954L NO874954A NO874954A NO874954L NO 874954 L NO874954 L NO 874954L NO 874954 A NO874954 A NO 874954A NO 874954 A NO874954 A NO 874954A NO 874954 L NO874954 L NO 874954L
- Authority
- NO
- Norway
- Prior art keywords
- bis
- formula
- pyridylphosphino
- ethane
- compounds
- Prior art date
Links
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 90
- 239000000460 chlorine Substances 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 150000002344 gold compounds Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 31
- 229910052737 gold Inorganic materials 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000010931 gold Substances 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 241001465754 Metazoa Species 0.000 description 19
- -1 phosphine compound Chemical class 0.000 description 19
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 15
- 229910052794 bromium Inorganic materials 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 14
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 13
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 208000032839 leukemia Diseases 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 230000004565 tumor cell growth Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 7
- 229950006389 thiodiglycol Drugs 0.000 description 7
- GBLNXAZZONXIQE-UHFFFAOYSA-N 2-dipyridin-2-ylphosphanylethyl(dipyridin-2-yl)phosphane Chemical compound C=1C=CC=NC=1P(C=1N=CC=CC=1)CCP(C=1N=CC=CC=1)C1=CC=CC=N1 GBLNXAZZONXIQE-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- NGDNCZPCIZNCQS-UHFFFAOYSA-N ctk3j8699 Chemical compound Cl=S NGDNCZPCIZNCQS-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 description 6
- PMCMJPXEJUKOAO-UHFFFAOYSA-M gold(1+);bromide Chemical compound [Au]Br PMCMJPXEJUKOAO-UHFFFAOYSA-M 0.000 description 6
- 239000008389 polyethoxylated castor oil Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000001294 propane Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 241000191368 Chlorobi Species 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000001273 butane Substances 0.000 description 5
- SBWAJHLQMFBNIN-UHFFFAOYSA-N dichloro(2-dichlorophosphanylethyl)phosphane Chemical compound ClP(Cl)CCP(Cl)Cl SBWAJHLQMFBNIN-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 5
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 4
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 4
- BSDGZUDFPKIYQG-UHFFFAOYSA-N 4-bromopyridine Chemical compound BrC1=CC=NC=C1 BSDGZUDFPKIYQG-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000001382 Experimental Melanoma Diseases 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 231100000682 maximum tolerated dose Toxicity 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KHMYIIPFUJCUEK-UHFFFAOYSA-N 1-diethylphosphanylethyl(diethyl)phosphane Chemical compound CCP(CC)C(C)P(CC)CC KHMYIIPFUJCUEK-UHFFFAOYSA-N 0.000 description 2
- MIOCUERTSIJEDP-UHFFFAOYSA-N 2-diethylphosphanylethyl(diethyl)phosphane Chemical compound CCP(CC)CCP(CC)CC MIOCUERTSIJEDP-UHFFFAOYSA-N 0.000 description 2
- OHXAKBURQXRNQJ-UHFFFAOYSA-N 2-dipyridin-4-ylphosphanylethyl(dipyridin-4-yl)phosphane Chemical compound C=1C=NC=CC=1P(C=1C=CN=CC=1)CCP(C=1C=CN=CC=1)C1=CC=NC=C1 OHXAKBURQXRNQJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- VZZJVOCVAZHETD-UHFFFAOYSA-N diethylphosphane Chemical compound CCPCC VZZJVOCVAZHETD-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002343 gold Chemical class 0.000 description 2
- ATGIETUGWDAYPU-UHFFFAOYSA-M gold monoiodide Chemical compound [Au]I ATGIETUGWDAYPU-UHFFFAOYSA-M 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- KDKMTIRSYIHSTB-MROZADKFSA-N (2r,3r,4r)-2,3,4,5-tetrahydroxypentanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=S KDKMTIRSYIHSTB-MROZADKFSA-N 0.000 description 1
- ABXYOVCSAGTJAC-JGWLITMVSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=S ABXYOVCSAGTJAC-JGWLITMVSA-N 0.000 description 1
- ZDXOURSGHNOFHL-VFQQELCFSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanethial;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=S ZDXOURSGHNOFHL-VFQQELCFSA-N 0.000 description 1
- ABXYOVCSAGTJAC-DPYQTVNSSA-N (2r,3s,4s,5r)-2,3,4,5,6-pentahydroxyhexanethial Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=S ABXYOVCSAGTJAC-DPYQTVNSSA-N 0.000 description 1
- WWPRMQSMBRFAPZ-KCDKBNATSA-N (2s,3r,4r,5s)-2,3,4,5-tetrahydroxyhexanethial Chemical compound C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=S WWPRMQSMBRFAPZ-KCDKBNATSA-N 0.000 description 1
- ABXYOVCSAGTJAC-KVTDHHQDSA-N (2s,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=S ABXYOVCSAGTJAC-KVTDHHQDSA-N 0.000 description 1
- FAHAFPWNBVQHLR-UHFFFAOYSA-N 1-[bis(furan-2-yl)phosphanyl]butan-2-yl-bis(furan-2-yl)phosphane Chemical compound C=1C=COC=1P(C=1OC=CC=1)C(CC)CP(C=1OC=CC=1)C1=CC=CO1 FAHAFPWNBVQHLR-UHFFFAOYSA-N 0.000 description 1
- DXHVPISORHAEMD-UHFFFAOYSA-N 1-[bis(furan-2-yl)phosphanyl]hexan-2-yl-bis(furan-2-yl)phosphane Chemical compound C=1C=COC=1P(C=1OC=CC=1)C(CCCC)CP(C=1OC=CC=1)C1=CC=CO1 DXHVPISORHAEMD-UHFFFAOYSA-N 0.000 description 1
- JETSBSXZJNEONQ-UHFFFAOYSA-N 1-[bis(furan-2-yl)phosphanyl]pentan-2-yl-bis(furan-2-yl)phosphane Chemical compound C=1C=COC=1P(C=1OC=CC=1)C(CCC)CP(C=1OC=CC=1)C1=CC=CO1 JETSBSXZJNEONQ-UHFFFAOYSA-N 0.000 description 1
- PKDVEWYYZQMQAZ-UHFFFAOYSA-N 1-[bis(furan-2-yl)phosphanyl]propan-2-yl-bis(furan-2-yl)phosphane Chemical compound C=1C=COC=1P(C=1OC=CC=1)C(C)CP(C=1OC=CC=1)C1=CC=CO1 PKDVEWYYZQMQAZ-UHFFFAOYSA-N 0.000 description 1
- ZWAJONDTYCQXGB-UHFFFAOYSA-N 1-diphenylphosphanylhexan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(CCCC)CP(C=1C=CC=CC=1)C1=CC=CC=C1 ZWAJONDTYCQXGB-UHFFFAOYSA-N 0.000 description 1
- WGOBPPNNYVSJTE-UHFFFAOYSA-N 1-diphenylphosphanylpropan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)CP(C=1C=CC=CC=1)C1=CC=CC=C1 WGOBPPNNYVSJTE-UHFFFAOYSA-N 0.000 description 1
- AIFHNSYXLIQRPY-UHFFFAOYSA-N 1-dipyridin-2-ylphosphanylbutan-2-yl(dipyridin-2-yl)phosphane Chemical compound C=1C=CC=NC=1P(C=1N=CC=CC=1)C(CC)CP(C=1N=CC=CC=1)C1=CC=CC=N1 AIFHNSYXLIQRPY-UHFFFAOYSA-N 0.000 description 1
- MNBISBPVXBVMHY-UHFFFAOYSA-N 1-dipyridin-2-ylphosphanylhexan-2-yl(dipyridin-2-yl)phosphane Chemical compound C=1C=CC=NC=1P(C=1N=CC=CC=1)C(CCCC)CP(C=1N=CC=CC=1)C1=CC=CC=N1 MNBISBPVXBVMHY-UHFFFAOYSA-N 0.000 description 1
- PVRIDWJPKKASSA-UHFFFAOYSA-N 1-dipyridin-2-ylphosphanylpentan-2-yl(dipyridin-2-yl)phosphane Chemical compound C=1C=CC=NC=1P(C=1N=CC=CC=1)C(CCC)CP(C=1N=CC=CC=1)C1=CC=CC=N1 PVRIDWJPKKASSA-UHFFFAOYSA-N 0.000 description 1
- VWJZXCXPLIOBJA-UHFFFAOYSA-N 1-dipyridin-2-ylphosphanylpropan-2-yl(dipyridin-2-yl)phosphane Chemical compound C=1C=CC=NC=1P(C=1N=CC=CC=1)C(C)CP(C=1N=CC=CC=1)C1=CC=CC=N1 VWJZXCXPLIOBJA-UHFFFAOYSA-N 0.000 description 1
- KUAVHCBLXVYTAB-UHFFFAOYSA-N 1-dipyridin-4-ylphosphanylbutan-2-yl(dipyridin-4-yl)phosphane Chemical compound C=1C=NC=CC=1P(C=1C=CN=CC=1)C(CC)CP(C=1C=CN=CC=1)C1=CC=NC=C1 KUAVHCBLXVYTAB-UHFFFAOYSA-N 0.000 description 1
- BGFJZPMGISHGJP-UHFFFAOYSA-N 1-dipyridin-4-ylphosphanylhexan-2-yl(dipyridin-4-yl)phosphane Chemical compound C=1C=NC=CC=1P(C=1C=CN=CC=1)C(CCCC)CP(C=1C=CN=CC=1)C1=CC=NC=C1 BGFJZPMGISHGJP-UHFFFAOYSA-N 0.000 description 1
- UVQKEUCUSPPQFB-UHFFFAOYSA-N 1-dipyridin-4-ylphosphanylpentan-2-yl(dipyridin-4-yl)phosphane Chemical compound C=1C=NC=CC=1P(C=1C=CN=CC=1)C(CCC)CP(C=1C=CN=CC=1)C1=CC=NC=C1 UVQKEUCUSPPQFB-UHFFFAOYSA-N 0.000 description 1
- DFFFLHZSKGWZOE-UHFFFAOYSA-N 1-dithiophen-2-ylphosphanylbutan-2-yl(dithiophen-2-yl)phosphane Chemical compound C=1C=CSC=1P(C=1SC=CC=1)C(CC)CP(C=1SC=CC=1)C1=CC=CS1 DFFFLHZSKGWZOE-UHFFFAOYSA-N 0.000 description 1
- WLOIESKQSGIRMR-UHFFFAOYSA-N 1-dithiophen-2-ylphosphanylhexan-2-yl(dithiophen-2-yl)phosphane Chemical compound C=1C=CSC=1P(C=1SC=CC=1)C(CCCC)CP(C=1SC=CC=1)C1=CC=CS1 WLOIESKQSGIRMR-UHFFFAOYSA-N 0.000 description 1
- HQIFCQINNOMTII-UHFFFAOYSA-N 1-dithiophen-2-ylphosphanylpentan-2-yl(dithiophen-2-yl)phosphane Chemical compound C=1C=CSC=1P(C=1SC=CC=1)C(CCC)CP(C=1SC=CC=1)C1=CC=CS1 HQIFCQINNOMTII-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- XOBXDKKTLAHVKM-UHFFFAOYSA-N 2-dithiophen-2-ylphosphanylethyl(dithiophen-2-yl)phosphane Chemical compound C=1C=CSC=1P(C=1SC=CC=1)CCP(C=1SC=CC=1)C1=CC=CS1 XOBXDKKTLAHVKM-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- KAVIXEFDMXCWGJ-UHFFFAOYSA-N 3-dipyridin-2-ylphosphanylpropyl(dipyridin-2-yl)phosphane Chemical compound C=1C=CC=NC=1P(C=1N=CC=CC=1)CCCP(C=1N=CC=CC=1)C1=CC=CC=N1 KAVIXEFDMXCWGJ-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 229910003771 Gold(I) chloride Inorganic materials 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JYULNMQVMVQBEZ-OUAUKWLOSA-N [(2r,3r,4r)-3,4-diacetyloxy-1-hydroxy-5-sulfanylidenepentan-2-yl] acetate Chemical compound CC(=O)O[C@H](CO)[C@@H](OC(C)=O)[C@@H](OC(C)=O)C=S JYULNMQVMVQBEZ-OUAUKWLOSA-N 0.000 description 1
- FPEMWQZJYZMECA-KNFQTBNASA-N [(2s,3r,4r,5s)-3,4-diacetyloxy-5-hydroxy-1-sulfanylidenehexan-2-yl] acetate Chemical compound CC(=O)O[C@H]([C@@H](O)C)[C@@H](OC(C)=O)[C@H](OC(C)=O)C=S FPEMWQZJYZMECA-KNFQTBNASA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- ILJKKPLHRPIQLD-UHFFFAOYSA-N sulfurochloridic acid;hydrate Chemical compound O.OS(Cl)(=O)=O ILJKKPLHRPIQLD-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører nye fosfinforbindelser som har tumorcelle-vekstinhiberende aktivitet, farmasøytiske blandinger som inneholder en effektiv, tumorcelle-vekstinhiberende mengde av en slik fosfinforbindelse, og en fremgangsmåte ved behandling av tumorceller som er ømfindtlige overfor en slik forbindelse ved å gi tumorcelle-vekstinhiberende mengder av en fosfinforbindelse til et vertsdyr som er påvirket av slike tumorceller. The present invention relates to new phosphine compounds that have tumor cell growth-inhibiting activity, pharmaceutical compositions containing an effective, tumor cell growth-inhibiting amount of such a phosphine compound, and a method for treating tumor cells that are sensitive to such a compound by providing tumor cell growth-inhibiting amounts of a phosphine compound to a host animal affected by such tumor cells.
De heterocykliske fosfinforbindelser i denne oppfinnelse er ikke kjente. Cariati et al., Inorg. Chim. Acta, 1 (2), 315 - 318 (1967); Bates et al., Inorg Chim. Acta, 81 (2), 151 - 156 The heterocyclic phosphine compounds of this invention are not known. Cariati et al., Inorg. Chim. Acta, 1 (2), 315-318 (1967); Bates et al., Inorg Chim. Acta, 81 (2), 151 - 156
(1984) og McAuliffe et al., J.C.S. Dalton, 1730 (1979), beskriver bis^1,2-bis(difenyifosfin)etanJgull(I)klorid. (1984) and McAuliffe et al., J.C.S. Dalton, 1730 (1979), describes bis^1,2-bis(diphenyphosphine)ethane/gold(I) chloride.
Digullforbindelsene i noen av de farmasøytiske blandinger ved denne forbindelse er kjente. Sadler et al., J. Chem. Soc, Dalton Trans, 969 - 974 (1984), foreslår syntesen av diklorbis[1,2-bis(difenylfosfin)etan]digull(I), men er ikke i stand til å isolere forbindelsen. Schmidbaur et al., Chem. The digold compounds in some of the pharmaceutical mixtures of this compound are known. Sadler et al., J. Chem. Soc, Dalton Trans, 969 - 974 (1984), proposes the synthesis of dichlorobis[1,2-bis(diphenylphosphine)ethane]digold(I), but is unable to isolate the compound. Schmidbaur et al., Chem.
Ber, 110, 2751 - 2557 (1977), beskriver diklorbis[i,2-bis(dife-nylfosfin ) me tan]] digull (I) . Stringer et al., sammendrag fra 15th Middle Atlantic Regional Meeting of the American Chemical Society, 7. - 9. januar 1981, Washington, D.C., beskriver syntesen av diklorbisf1,2-bis(dietylfosfin)etanj digull(I), og diper-kloratobis [i ,2-bis(dietylfosfin)etan]digull(I), og fastslår at disse tre forbindelser ble undersøkt etter aktivitet i adju-vans -indusert arthritis i Charles River wistar-rotten. Imid-lertid er det ingen omtale i Stringer et al. publikasjonen om at slike forbindelser faktisk har anti-arthritis eller noen annen terapeutisk anvendelig biologisk aktivitet. Ber, 110, 2751-2557 (1977), describes dichlorobis[i,2-bis(diphenylphosphine) methane]] digold (I). Stringer et al., abstracts of the 15th Middle Atlantic Regional Meeting of the American Chemical Society, January 7-9, 1981, Washington, D.C., describe the synthesis of dichlorobisf1,2-bis(diethylphosphine)ethanedigold(I), and diper- chloratobis[i,2-bis(diethylphosphine)ethane]digold(I), and states that these three compounds were examined for activity in adjuvant-induced arthritis in the Charles River wistar rat. However, there is no mention in Stringer et al. the publication that such compounds actually have anti-arthritis or some other therapeutically useful biological activity.
Struck et al., J. Med. Chem., 9, 414 - 416 (1966), beskriver cytotoksisk aktivitet for 1,2-bis(difenylfosfin)etan som brukes som utgangsmateriale for fremstilling av noen av de farmasøytiske blandinger og fremgangsmåter ved behandling i denne oppfinnelse. Struck et al., J. Med. Chem., 9, 414-416 (1966), describes cytotoxic activity for 1,2-bis(diphenylphosphine)ethane which is used as a starting material for the preparation of some of the pharmaceutical compositions and methods of treatment in this invention.
Ingen av de forannevnte publikasjoner beskriver eller foreslår forbindelsene, farmasøytiske blandinger eller fremgangsmåter ved behandling i foreliggende oppfinnelse. None of the aforementioned publications describe or suggest the compounds, pharmaceutical mixtures or methods of treatment in the present invention.
Denne oppfinnelse vedrører forbindelser med formelen This invention relates to compounds of the formula
hvori: in which:
R er den samme og er 2-pyridyl, 4-pyridyl, 2-tienyl eller 2-furyl; R is the same and is 2-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl;
X er den samme og er halogen eller tiosukker; X is the same and is halogen or thiosugar;
M er 0 eller 1, forutsatt at når M er 1 , er R 2-pyridyl eller 4-pyridyl; og M is 0 or 1, provided that when M is 1, R is 2-pyridyl or 4-pyridyl; and
A er en rett eller forgrenet alkandiylkjede med fra ett til seks karbonatomer. A is a straight or branched alkanediyl chain with from one to six carbon atoms.
Når X er tiosukker, går bindingen av X til gullatomet gjen-nom svovelatomet til tiosukkeret. When X is thiosugar, the bond of X to the gold atom goes through the sulfur atom of the thiosugar.
Denne oppfinnelse vedrører også en forbindelse med formelen This invention also relates to a compound of the formula
hvori: in which:
R^ er den samme og er 2-pyridyl; R 1 is the same and is 2-pyridyl;
A er den samme og er en rett eller forgrenet alkandiylkjede med fra ett til seks karbonatomer; og A is the same and is a straight or branched alkanediyl chain of from one to six carbon atoms; and
X^ er den samme og er halogen.X^ is the same and is halogen.
Denne oppfinnelse vedrører altså en farmasøytisk blanding som omfatter en effektiv, tumorcelle-vekstinhiberende mengde av en aktiv bestanddel og en inert, farmasøytisk akseptabel bærer eller fortynningsmiddel, hvori blandingen er anvendelig for å inhibere veksten av dyretumorceller som er ømfindtlige for den aktive bestanddel, og hvor den aktive bestanddel er en forbindelse med formel (I) eller en forbindelse med formelen: This invention therefore relates to a pharmaceutical mixture comprising an effective, tumor cell growth-inhibiting amount of an active ingredient and an inert, pharmaceutically acceptable carrier or diluent, in which the mixture is useful for inhibiting the growth of animal tumor cells which are sensitive to the active ingredient, and where the active ingredient is a compound of formula (I) or a compound of the formula:
hvori: in which:
R 2 er den samme og er fenyl, etyl eller 2-pyridyl; A er en rett eller forgrenet alkandiylkjede med fra ett til seks karbonatomer; Y er en kjede mellom de fire P-atomer med strukturen R 2 is the same and is phenyl, ethyl or 2-pyridyl; A is a straight or branched alkanediyl chain of from one to six carbon atoms; Y is a chain between the four P atoms with the structure
og and
X^ er halogen; X 1 is halogen;
forutsatt at når Y er provided that when Y is
2 2
er R 2-pyridyl; is R 2 -pyridyl;
og en farmasøytisk akseptabel bærer.and a pharmaceutically acceptable carrier.
Et annet aspekt av denne oppfinnelse vedrører en fremgangsmåte for å inhibere veksten av dyretumorceller som er ømfindtlige overfor forbindelser med formel (I) eller formel (III), hvori man gir et dyr som er påvirket av tumorcellene en virksom, tumorcelle-vekstinhiberende mengde av en forbindelse med formel (I ) eller formel (III ) . Another aspect of this invention relates to a method of inhibiting the growth of animal tumor cells sensitive to compounds of formula (I) or formula (III), wherein an animal affected by the tumor cells is given an effective tumor cell growth inhibitory amount of a compound of formula (I) or formula (III).
En fagmann vil se at alle forbindelsene med formel (II)One skilled in the art will see that all the compounds of formula (II)
er omfattet av rammen av formel (III).is covered by the framework of formula (III).
Med uttrykket "tiosukker" menes enhver 1-tioaldose. Eksempler på slike tiosukkere er 1-tioglukose, 1-tiogalaktose, 1-tiomanose, 1-tioribose, 1-tiomaltose, 1-tiofucose, tetra-O-acetyl-1-tioglukose, tetra-O-acetyl-1-tiomanose, tetra-O-acetyl-1-tiogalaktose, tri-O-acetyl-1-tioribose, hepta-O-acetyl-1-tiomaltose og tri-O-acetyl-1-tiofucose. By the term "thiosugar" is meant any 1-thioaldose. Examples of such thiosugars are 1-thioglucose, 1-thiogalactose, 1-thiomannose, 1-thioribose, 1-thiomaltose, 1-thiofucose, tetra-O-acetyl-1-thioglucose, tetra-O-acetyl-1-thiomannose, tetra -O-acetyl-1-thiogalactose, tri-O-acetyl-1-thioribose, hepta-O-acetyl-1-thiomaltose and tri-O-acetyl-1-thiofucose.
Alle forbindelsene med formlene (I), (II) og (III) kan fremstilles ved tilgjengelige metoder for en fagmann. All the compounds of formulas (I), (II) and (III) can be prepared by methods available to a person skilled in the art.
Generelt kan forbindelser med formel (I) hvori M er 0 fremstilles ved å omsette den tilsvarende heterocyklus i en vannfri etyleter med et organilitiumreagens såsom n-butyllitium i et ikke-reaktivt organisk løsningsmiddel med den tilsvarende forbindelse med formelen: In general, compounds of formula (I) in which M is 0 can be prepared by reacting the corresponding heterocycle in an anhydrous ethyl ether with an organolithium reagent such as n-butyllithium in a non-reactive organic solvent with the corresponding compound of the formula:
hvor A er som ovenfor definert. where A is defined as above.
Alle de nødvendige heterocykler, organolitiumreagenserAll the necessary heterocycles, organolithium reagents
og formel A-forbindelser kan kjøpes, f.eks. fra Strem Chemicals, Inc., Newburyport, Massachusetts. and formula A compounds can be purchased, e.g. from Strem Chemicals, Inc., Newburyport, Massachusetts.
Generelt er utgangsmaterialene for formel (I)-forbindelsene hvori M er 1 og X er klor, de tilsvarende difosfinohydro-karboner med formel (I) hvori M er 0. For å oppnå digullproduk-tene med formel (I) omsettes et tilsvarende difosfinohydrokar-bon med formel (I) enten direkte med klorgullsyretetrahydrat eller en redusert form av syrehydratet fremstilt ved behandling med tiodiglykol i et tilsvarende ikke-reaktivt organisk løsnings-middel . In general, the starting materials for the compounds of formula (I) in which M is 1 and X is chlorine are the corresponding diphosphinohydrocarbons of formula (I) in which M is 0. To obtain the digold products of formula (I) a corresponding diphosphinohydrocarbon is reacted bon with formula (I) either directly with chlorosulfuric acid tetrahydrate or a reduced form of the acid hydrate produced by treatment with thiodiglycol in a corresponding non-reactive organic solvent.
For å oppnå formel (I)-forbindelsene, hvori X er tiosukker, omsettes den tilsvarende formel (I)-forbindelsen hvori X er klor med det tilsvarende natriumtiosukker. De nødvendige natri-umtiosukkere kan kjøpes, f.eks. fra Sigma Chemical Co., St. Louis, Missouri, eller fremstilles ved vanlige teknikker. To obtain the compounds of formula (I), in which X is thiosugar, the corresponding compound of formula (I) in which X is chlorine is reacted with the corresponding sodium thiosugar. The necessary sodium-umthiosugars can be purchased, e.g. from Sigma Chemical Co., St. Louis, Missouri, or prepared by conventional techniques.
Formel (I)- forbindelser hvori X er brom fremstilles vedFormula (I) compounds in which X is bromine are prepared by
å omsette den tilsvarende ligande med formel (I) hvori M er 0 med bromgullsyrehydrat (som f.eks. kan kjøpes fra Strem Chemicals, Inc., Newburyport, Massachusetts), som er blitt redusert ved behandling med tiodiglykol; eller ved å omsette den tilsvarende ligande med formel (I) hvori M er 0 med bromgullsyrehydrat direkte i et tilsvarende ikke-reaktivt organisk løs-ningsmiddel. Alternativt fremstilles formel (I)-forbindelser hvori X er brom ved å omsette den tilsvarende forbindelse med formel (I) hvori X er klor, med natriumbromid i et hensiktsmessig organisk løsningsmiddel såsom vandig etanol eller DMF. reacting the corresponding ligand of formula (I) wherein M is 0 with bromogold acid hydrate (available for example from Strem Chemicals, Inc., Newburyport, Massachusetts), which has been reduced by treatment with thiodiglycol; or by reacting the corresponding ligand of formula (I) in which M is 0 with bromogold acid hydrate directly in a corresponding non-reactive organic solvent. Alternatively, compounds of formula (I) in which X is bromine are prepared by reacting the corresponding compound of formula (I) in which X is chlorine, with sodium bromide in a suitable organic solvent such as aqueous ethanol or DMF.
Formel (I)-forbindelser X er jod fremstilles ved å behandle den tilsvarende forbindelse med formel (I) hvori X er klor eller brom med natriumjodid i et tilsvarende organisk løsningsmiddel åsom aceton. Formula (I) compounds X is iodine are prepared by treating the corresponding compound of formula (I) in which X is chlorine or bromine with sodium iodide in a corresponding organic solvent such as acetone.
Generelt kan formel (II)-forbindelser erholdes ved å omsette den tilsvarende formel (I)-forbindelse hvori M er 0 eller 1 med den tilsvarende formel (I)-forbindelse hvori M er 0 i et tilsvarende ikke-reaktivt organisk løsningsmiddel. In general, compounds of formula (II) can be obtained by reacting the corresponding compound of formula (I) in which M is 0 or 1 with the corresponding compound of formula (I) in which M is 0 in a corresponding non-reactive organic solvent.
Generelt kan forbindelsene med formel (III) hvori Y er In general, the compounds of formula (III) in which Y is
fremstilles ved å omsette ett mol av den tilsvarende ligande med formel: med ett mol av det tilsvarende gullkompleks med formelen: is prepared by reacting one mole of the corresponding ligand of formula: with one mole of the corresponding gold complex of formula:
hvori R 3 er den samme og er fenyl eller etyl; X 1er halogen og A er som ovenfor definert, i et ikke-reaktivt organisk løs-ningsmiddel . wherein R 3 is the same and is phenyl or ethyl; X 1 is halogen and A is, as defined above, in a non-reactive organic solvent.
Alle de nødvendige formel B-ligander kan kjøpes, f.eks. fra Stren Chemicals, Inc., Newburyport, Massachusetts. All the necessary formula B ligands can be purchased, e.g. from Stren Chemicals, Inc., Newburyport, Massachusetts.
Formel C-gullkompleksene, hvori X^ er klor fremstilles lett ved å omsette den tilsvarende ligande av formel B med klorgullsyre-tetrahydrat som er blitt redusert ved behandling med tiodiglykol. Formel C-gullkomplekser hvori X1 er klor, kan også lett fremstilles ved å omsette den tilsvarerne ligande med formler B direkte med klorgullsyrehydrat i et tilsvarende ikke-reaktivt organisk løsningsmiddel. The formula C gold complexes in which X^ is chlorine are readily prepared by reacting the corresponding ligand of formula B with chlorosulfuric acid tetrahydrate which has been reduced by treatment with thiodiglycol. Formula C gold complexes in which X1 is chlorine can also be readily prepared by reacting the corresponding ligand of formulas B directly with chlorosulfuric acid hydrate in a corresponding non-reactive organic solvent.
Formel C-komplekser hvori X^ er brom fremstilles ved å omsette den tilsvarende ligande med formel B med bromgullsyrehydrat (som f.eks. kan kjøpes fra Strme Chemicals, Inc., Newburyport, Massachusetts) som er blitt redusert for behandling med tiodiglykol, eller ved å omsette den tilsvarende ligande med formel B direkte med bromgullsyrehydrat i et tilsvarende ikke-reaktivt organisk løsningsmiddel. Alternativt fremstilles formel C-komplekser hvori X^ er brom ved å omsette den tilsvarende forbindelse med formel C hvori X^ er klor med natriumbro mid i hensiktsmessig organisk løsningsmiddel såsom vandig etanol eller DMF- Complexes of formula C in which X^ is bromine are prepared by reacting the corresponding ligand of formula B with bromogold acid hydrate (available, for example, from Strme Chemicals, Inc., Newburyport, Mass.) which has been reduced for treatment with thiodiglycol, or by reacting the corresponding ligand of formula B directly with bromogold acid hydrate in a corresponding non-reactive organic solvent. Alternatively, complexes of formula C in which X^ is bromine are prepared by reacting the corresponding compound of formula C in which X^ is chlorine with sodium bromide in a suitable organic solvent such as aqueous ethanol or DMF-
Formel (III)-forbindelser, hvori X er brom, fremstilles ved å omsette ett mol av den tilsvarende forbindelse med formel C,hvori X^ er brom, med ett mol av den tilsvarende forbindelse med formel B. Alternativt fremstilles formel (III)-forbindelser hvori X^ er brom ved å omsette den tilsvarende formel (III)-forbindelse hvori X^ er klor med natriumbromid i et hensiktsmessig organisk løsningsmiddel såsom vandig etanol eller DMF. Formula (III) compounds, in which X is bromine, are prepared by reacting one mole of the corresponding compound of formula C, in which X^ is bromine, with one mole of the corresponding compound of formula B. Alternatively, formula (III)- compounds wherein X^ is bromine by reacting the corresponding formula (III) compound wherein X^ is chlorine with sodium bromide in a suitable organic solvent such as aqueous ethanol or DMF.
Formel (III)-forbindelser hvori X^ er jod fremstillesCompounds of formula (III) in which X^ is iodine are prepared
ved å omsette den tilsvarende formel (III)-forbindelse hvori X er klor eller brom, med natriumjodid i et hensiktsmessig organisk løsningsmiddel, såsom aceton. by reacting the corresponding compound of formula (III) wherein X is chlorine or bromine, with sodium iodide in a suitable organic solvent, such as acetone.
Forbindelser med formel (I) og (III) har tumorcelle-vekstinhiberende aktivitet som er blitt påvist i minst én dyretumor-modell. Compounds of formula (I) and (III) have tumor cell growth inhibitory activity which has been demonstrated in at least one animal tumor model.
P388 lymfocytt-leukemi er for tiden den mest utbredte dyretumor-modell for å undersøke antitumormidler og for detal-jert vurdering av aktiv forbindelse. Dette tumorsystem er ål-ment akseptert som et antitumormiddel-undersøkelsesredskap fordi det er følsomt overfor praktisk talt alle de klinisk aktive antineoplastiske midler, kvantitativt og reproduserbart, egnet for undersøkelse i stor skala, og forutsigbar for aktivitet i andre dyretumor-modeller. Legemidler som er meget aktive i intraperitoneal (ip) P388 leukemi er generelt aktive i andre tumormodeller også. Antitumoraktiviteten til forbindelser med formel (I) og (III) demonstreres i P388 leukemi-musemodellen ved anvendelse av den følgende forskrift: 10^ P388-leukemiceller inokuleres ip i B 6D2F^-mus. Tjue-fire timer senere, hvis tumorinokulumet viser seg å være fritt for bakteriekontaminasjon (bestemt ved 24 timers inkubering i tioglykollat-medium) fordeles dyr statistisk i grupper på 6 og holdes i skoeskebur. Forbindelsen som skal undersøkes oppløses i saltvann hvis den er løselig deri eller i et minimalt volum av enten N,N-dimetylacetamid (DMA) eller 95% etanol (avhengig av løselighet). Et likt volum saltvann settes til disse forbindelser oppløst i en organisk bærer, og hvis legemiddelet faller ut av løsningen tilsettes et likt volum polyetoksylert lakserolje og deretter saltvann opptil en slik konsentrasjon at den ønskede dose avgis i 0,5 ml. Sluttkonsentrasjonen av DMA, etanol og/eller polyetoksylert lakserolje er -10%. Fortynninger for lavere doser lages med saltvann, slik P388 lymphocyte leukemia is currently the most widely used animal tumor model for investigating antitumor agents and for detailed assessment of active compounds. This tumor system is widely accepted as an antitumor agent investigation tool because it is sensitive to practically all clinically active antineoplastic agents, quantitative and reproducible, suitable for large-scale investigation, and predictable for activity in other animal tumor models. Drugs that are highly active in intraperitoneal (ip) P388 leukemia are generally active in other tumor models as well. The antitumor activity of compounds of formula (I) and (III) is demonstrated in the P388 leukemia mouse model using the following regimen: 10 3 P388 leukemia cells are inoculated ip into B 6D2F 3 mice. Twenty-four hours later, if the tumor inoculum is found to be free of bacterial contamination (as determined by 24 hours of incubation in thioglycollate medium), animals are statistically divided into groups of 6 and housed in shoebox cages. The compound to be examined is dissolved in saline if it is soluble therein or in a minimal volume of either N,N-dimethylacetamide (DMA) or 95% ethanol (depending on solubility). An equal volume of salt water is added to these compounds dissolved in an organic carrier, and if the drug falls out of the solution, an equal volume of polyethoxylated castor oil is added and then salt water up to such a concentration that the desired dose is delivered in 0.5 ml. The final concentration of DMA, ethanol and/or polyethoxylated castor oil is -10%. Dilutions for lower doses are made with saline, like this
at det er en økning av andelen organiske løsningsmidler i bæreren med avtagende dose. Disse bærere gir løselige formuleringer (eller suspensjoner). Formuleringene fremstilles umiddelbart før injeksjon. Forbindelsen gis ip på dagene 1 til og med 5 (dvs. behandling begynnes 24 timer etter tumorinokulering). Hvert eksperiment inneholder tre grupper på 6 dyr som ubehandlede kontroller og dyr behandlet med en positiv kontroll, cisplatin, ved to dosenivåer. Dyrene veies som én gruppe på dagene 1, that there is an increase in the proportion of organic solvents in the carrier with decreasing dose. These carriers provide soluble formulations (or suspensions). The formulations are prepared immediately before injection. The compound is given ip on days 1 through 5 (ie, treatment begins 24 hours after tumor inoculation). Each experiment contains three groups of 6 animals as untreated controls and animals treated with a positive control, cisplatin, at two dose levels. The animals are weighed as one group on days 1,
5 og 9, og gjennomsnittsvektforandringen (A vekt) brukes 5 and 9, and the average weight change (A weight) is used
som et mål for toksisitet. Hvert eksperiment inneholder også en inokulumtitrering - - grupper på åtte mus inokulert ip med 10"* til 10^ P388 leukemiceller. Titreringen brukes til å beregne celledreping oppnådd ved behandling med legemidler. Dyrene kontrolleres daglig for dødelighet og eksperimentene avsluttes etter 45 dager. Sluttpunktet er midlere overlevelsestid (MST) og økning i levetid (ILS) som er prosentdelen av økning i MST i forhold til ubehandlede kontroller. Ubehandlede kontroller inokulert ip med 10 P388 leukemiceller overlever generelt gjennomsnitt-lig 9 til 11 dager. Et legemiddel anses aktivt hvis det gir - 25% ILS. as a measure of toxicity. Each experiment also contains an inoculum titration - - groups of eight mice inoculated ip with 10"* to 10^ P388 leukemia cells. The titration is used to calculate cell killing achieved by drug treatment. Animals are checked daily for mortality and experiments are terminated after 45 days. The end point is median survival time (MST) and increase in lifespan (ILS) which is the percentage increase in MST relative to untreated controls. Untreated controls inoculated ip with 10 P388 leukemia cells generally survive an average of 9 to 11 days. A drug is considered active if it - 25% ILS.
En sammenfatning av undersøkelsen av flere forbindelser med formel (I) i in vivo ip P388-modellen er vist i den følgende tabell A. A summary of the investigation of several compounds of formula (I) in the in vivo ip P388 model is shown in the following Table A.
BAsert på data fremsatt i tabell A, viste forbindelser med formel (I) betydelig anti-tumoraktivitet i in vivo P388 leukemi-tumormålingen. Based on the data presented in Table A, compounds of formula (I) showed significant anti-tumor activity in the in vivo P388 leukemia tumor assay.
En sammenfatning av resultatene av flere forbindelser med formel (III) i in vivo ip P388 modellen er vist i den føl-gende tabell B. A summary of the results of several compounds of formula (III) in the in vivo ip P388 model is shown in the following table B.
Basert på data gitt i tabell B, viste forbindelser med formel (III) signifikant anti-tumoraktivitet i iri vivo ip P388 leukemi tumor-målingen. Det bør bemerkes at den 4-pyridylana-loge av forbindelsen nr. 10 i tabell B også ble undersøkt to ganger i ip P388 leukemi-målingen, men viste utilstrekkelig anti-tumoraktivitet ( dvs. < 25%) i begge forsøk. Based on data given in Table B, compounds of formula (III) showed significant anti-tumor activity in the iri vivo ip P388 leukemia tumor assay. It should be noted that the 4-pyridylana log of compound #10 in Table B was also tested twice in the ip P388 leukemia assay, but showed insufficient anti-tumor activity (ie, < 25%) in both experiments.
Den cytotoksiske aktiviteten til to formel (III)-forbindelser ble undersøkt in<_>vivo ved bruk av B16 melanoma-celler. The cytotoxic activity of two compounds of formula (III) was investigated in<_>vivo using B16 melanoma cells.
I dette system inokuleres grupper pp B6D2F^-mus ip med 0,5 mlIn this system, groups pp B6D2F^ mice are inoculated ip with 0.5 ml
av et 10% medium av B16-melanomet fremstilt fra samlede sc-tumo-rer utskåret ved 14-21 dager fra C57B1/6-donatormus. Daglig behandling begynnes 24 timer etter tumorimplantasjon, og fortset-tes daglig i ti (10) dager. Administreringsveien for legemiddelet er ip. Musene kontrolleres daglig med hensyn til overle-velse i seksty (60) dager. Anti-tumoraktivitet bestemmes ved forlengelse av midlere overlevelsestid. En ILS på 25% viser aktivitet i denne tumormodellen. of a 10% medium of the B16 melanoma prepared from pooled sc tumors excised at 14-21 days from C57B1/6 donor mice. Daily treatment begins 24 hours after tumor implantation, and continues daily for ten (10) days. The route of administration for the drug is ip. The mice are checked daily for survival for sixty (60) days. Anti-tumour activity is determined by prolongation of mean survival time. An ILS of 25% shows activity in this tumor model.
En sammenfatning av målingene av to forbindelser med formel (III) i iri vivo ip B 16 melanoma-måling er vist i tabell C. A summary of the measurements of two compounds of formula (III) in the iri vivo ip B 16 melanoma assay is shown in Table C.
Den farmasøytiske blanding i denne oppfinnelse omfatter The pharmaceutical composition in this invention comprises
en effektiv, tumorcelle-vekstinhiberende mengde av en forbindelse med formel (I) eller formel (III) og en inert farmasøytisk akseptabel bærer eller fortynningsmiddel. Disse blandinger fremstilles i enhetsdoseringsform egnet for parenteral administrering. an effective tumor cell growth inhibitory amount of a compound of formula (I) or formula (III) and an inert pharmaceutically acceptable carrier or diluent. These mixtures are prepared in unit dosage form suitable for parenteral administration.
Blandinger for parenteral administrering inneholder sterile vandige eller ikke-vandige løsninger, suspensjoner eller emulsjo- ner. Blandingen kan foreligge i form av en løsning av den aktive bestanddel i et minimumsvolum dimetylacetamid eller etanol, f.eks. 5 volumprosent bragt opp til volum med peanøttolje eller normal saltløsning. Polyetoksylert lakserolje, f.eks. 2 til 5 volumprosent, kan også brukes for å løseliggjøre den aktive bestanddel. I tillegg kan blandingen foreligge i form av et slam med f.eks. hydroksypropylcellulose eller annet egnet opp-slemmingsmiddel. Som emulgeringsmiddel kan f.eks. lecitin brukes. Blandingen kan også foreligge i form av et sterilt faststoff som kan oppløses i et sterilt injiserbart medium ummidel-bart før bruk. Mixtures for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. The mixture may be in the form of a solution of the active ingredient in a minimum volume of dimethylacetamide or ethanol, e.g. 5 volume percent brought up to volume with peanut oil or normal saline solution. Polyethoxylated castor oil, e.g. 2 to 5 percent by volume can also be used to solubilize the active ingredient. In addition, the mixture can be in the form of a slurry with e.g. hydroxypropyl cellulose or other suitable suspending agent. As an emulsifier, e.g. lecithin is used. The mixture can also be in the form of a sterile solid which can be dissolved in a sterile injectable medium immediately before use.
Freireich et al., Cancer Chemo. Rept., 50, 219 - 244 (1966) sammenlignet den kvantitative giftigheten av 18 antikraft-legemidler i 6 arter etter å korrigere dataene til et jevnt behand-lingsskjema for fem påfølgende dager. Denne analysen viste at mus, rotte, hund, menneske, ape hadde hovedsakelig samme maksimale tolererte dose (MTD) sammenlignet på grunnlag av mg/m<2>legemsoverflate. Denne undersøkelsen tydet på at fase I-kliniske forsøk trygt kunne igangsettes ved en tredjedes dose av animalsk MTD. Musen var like anvendelig som noen annen art i denne hen-seende som grunnlag for beregning. Den riktige terapeutisk virksomme dose for en forbindelse fremstilt ifølge oppfinnelsen kan derfor lett bestemmes av en fagmann ut fra enkel eksperimen-tering med laboratoriedyr, fortrinnsvis mus. Freireich et al., Cancer Chemo. Rept., 50, 219-244 (1966) compared the quantitative toxicity of 18 antikraft drugs in 6 species after correcting the data to a uniform treatment schedule for five consecutive days. This analysis showed that mouse, rat, dog, human, monkey had essentially the same maximum tolerated dose (MTD) compared on a mg/m<2>body surface basis. This investigation indicated that phase I clinical trials could safely be initiated at a third-party dose of the animal MTD. The mouse was as applicable as any other species in this respect as a basis for calculation. The correct therapeutically effective dose for a compound produced according to the invention can therefore be easily determined by a person skilled in the art from simple experimentation with laboratory animals, preferably mice.
Det vil være klart at de faktiske foretrukne doseringerIt will be clear that the actual preferred dosages
av forbindelser med formel (I) eller formel (III) som brukes i blandingene i denne oppfinnelse vil variere avhengig av den spesielle forbindelse som brukes, den spesielle formulerte blanding, administreringsformen, og det spesielle sted, vert og sykdom som behandles. Den innvendige administreringsvei bør velges for å sikre at en effektiv tumorcelle-vekstinhiberende mengde av forbindelsen med formel (i) eller formel (III) kommer i kontakt med tumoren. Optimale doser for et gitt sett betingel-ser kan bestemmes av fagmannen ved bruk av vanlige doserings-bestemmelsesforsøk ut fra ovennevnte eksperimentelle data. For parenteral administrering av en forbindelse med formel (III) eller en gullholdig forbindelse med formel (I) er den generelt anvendte dose fra ca. 5 til ca. 100 mg/m<2>kroppsflate pr. dag i én til fem dager, gjentatt omtrent hver fjerde uke for fire of compounds of formula (I) or formula (III) used in the compositions of this invention will vary depending on the particular compound used, the particular formulated composition, the form of administration, and the particular site, host and disease being treated. The internal route of administration should be chosen to ensure that an effective tumor cell growth inhibitory amount of the compound of formula (i) or formula (III) contacts the tumor. Optimum dosages for a given set of conditions can be determined by the person skilled in the art using usual dosage determination experiments based on the above-mentioned experimental data. For parenteral administration of a compound of formula (III) or a gold-containing compound of formula (I), the generally used dose is from approx. 5 to approx. 100 mg/m<2>body surface per day for one to five days, repeated approximately every four weeks for four
behandlingskurer. For parenteral administrering av en ikke-gullholdig forbindelse med formel (I) er den anvendte dose fortrinnsvis fra ca. 15 til ca. 600 mg/m<2>kroppsflate pr. dag i 5 dager, gjentatt hver fjerde uke for fire behandlingskurer. treatment courses. For parenteral administration of a non-gold-containing compound of formula (I), the dose used is preferably from approx. 15 to approx. 600 mg/m<2>body surface per day for 5 days, repeated every four weeks for four courses of treatment.
Fremgangsmåten for å inhibere veksten i dyretumorceller som er ømfindtlige overfor en forbindelse med formel (I) eller formel (III) ifølge denne oppfinnelse består i å gi et vertsdyr påvirket av tumorcellene en effektiv tumorcelle-vekstinhiberende mengde av en forbindelse med formel (I) eller formel (III). The method of inhibiting the growth of animal tumor cells which are sensitive to a compound of formula (I) or formula (III) according to this invention consists in giving a host animal affected by the tumor cells an effective tumor cell growth-inhibiting amount of a compound of formula (I) or formula (III).
EKSEMPLEREXAMPLES
De følgende eksempler illustrerer den kjemiske fremstilling av flere forbindelser med formel (I) og formel (III) som kan brukes i blandingene og fremgangsmåten i denne oppf .i nnelse og som sådan ikke må anses som begrensende for omfanget derav. Alle temperaturer er i °C. The following examples illustrate the chemical preparation of several compounds of formula (I) and formula (III) which can be used in the mixtures and the method of this invention and as such must not be regarded as limiting the scope thereof. All temperatures are in °C.
EKSEMPEL 1 EXAMPLE 1
1, 2- bis( di- 2- pyridylfosfino) etan1, 2-bis(di-2- pyridylphosphino) ethane
Under en argonatmosfære ble 2-brompyridin (30,9 g, 0,19 mol) i vandig etyleter (50 ml) satt til n-butyllitium (0,19 mol) Under an argon atmosphere, 2-bromopyridine (30.9 g, 0.19 mol) in aqueous ethyl ether (50 mL) was added to n-butyllithium (0.19 mol)
i heksan (73 ml) mens temperaturen ble holdt under -50°C. Etter røring i 1 time ble ytterligere 7,5 g 2-brompyridin tilsatt, in hexane (73 mL) while maintaining the temperature below -50°C. After stirring for 1 hour, a further 7.5 g of 2-bromopyridine was added,
og blandingen ble rørt i 30 minutter. En eterløsning (100 ml)and the mixture was stirred for 30 minutes. An ether solution (100 ml)
av 1,2-bis(diklorfosfino)etan (10 g, 43 mmol), fra Strem Chemicals, Inc., Newburyport, Massachusetts, ble tilsatt, og blandingen ble rørt i 1 time ved -50°C, og fikk så oppvarmes til romtemperatur natten over. Mettet vandig ammoniumklorid ble isolert og oppløst i kloroform, tørket (Na2SO^), filtrert og løsningsmid-delet ble fjernet og ga en mørk rest. Resten ble behandlet med aceton, og så ble acetonet avkjølt og ga et lyst gult faststoff (4,5 g). Omkrystallisering fra aceton ga 2,64 g tittel-forbindelse, smeltepunkt 134 - 135°C: EKSEMPEL 2 of 1,2-bis(dichlorophosphino)ethane (10 g, 43 mmol), from Strem Chemicals, Inc., Newburyport, Mass., was added and the mixture was stirred for 1 hour at -50°C, then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride was isolated and dissolved in chloroform, dried (Na 2 SO 4 ), filtered and the solvent removed to give a dark residue. The residue was treated with acetone and then the acetone was cooled to give a light yellow solid (4.5 g). Recrystallization from acetone gave 2.64 g of the title compound, mp 134 - 135°C: EXAMPLE 2
1, 2- bis( di- 4- pyridylfosfino) etan1, 2-bis(di-4-pyridylphosphino)ethane
Under en argonatmosfære satte man 4-brompyridin (30,9 g, 0,19 mol) i vannfri etyleter (50 ml) til n-butyllitium (0,19 mol) i heksan (73 ml) mens temperaturen ble holdt under -50°C. Etter røring i 1 time ble ytterligere 7,5 g 4-brompyridin tilsatt, og blandingen ble rørt i 30 minutter. En eterløsning (100 ml)av 1,2-bis(diklorfosfino)etan (10 g, 43 mmol), fra Strem Chemicals, Inc., Newburyport, Massachusetts ble tilsatt Under an argon atmosphere, 4-bromopyridine (30.9 g, 0.19 mol) in anhydrous ethyl ether (50 mL) was added to n-butyllithium (0.19 mol) in hexane (73 mL) while maintaining the temperature below -50° C. After stirring for 1 hour, an additional 7.5 g of 4-bromopyridine was added, and the mixture was stirred for 30 minutes. An ethereal solution (100 mL) of 1,2-bis(dichlorophosphino)ethane (10 g, 43 mmol), from Strem Chemicals, Inc., Newburyport, Massachusetts was added
og blandingen ble oppvarmet til romtemperatur natten over. Etter 18 timer ved romtemperatur ble vandig mettet ammoniumklorid tilsatt og det faste stoff ble fjernet. Det resterende faste stoff i kolben ble samlet, oppløst i kloroform, behandlet med aktivt karbon, filtrert og løsningsmiddelet fjernet. Hurtig kromatografi (SiC^, 7% metanol/metylenklorid) av resten ga en liten mengde av det ønskede produkt, sm.p. 183 - 185°C. and the mixture was warmed to room temperature overnight. After 18 hours at room temperature, aqueous saturated ammonium chloride was added and the solid was removed. The remaining solid in the flask was collected, dissolved in chloroform, treated with activated carbon, filtered and the solvent removed. Flash chromatography (SiCl 2 , 7% methanol/methylene chloride) of the residue gave a small amount of the desired product, m.p. 183 - 185°C.
EKSEMPEL 3 EXAMPLE 3
1, 2- bis( di- 2- tienylfosfino) etan1, 2-bis(di-2-thienylphosphino) ethane
Under argon ved romtemperatur satte man tiofen (16 g,Under argon at room temperature, thiophene (16 g,
0,19 mol) i vannfri etyleter (50 ml) til en heksan (73 ml) løs-ning av n-butyllitium (0,19 mol) som var blitt fortynnet med eter (50 ml). Etter røring i 1 time ble blandingen avkjølt til 0°C. Så ble 1,2-bis(diklorfosfino)etan (10 g, 0,043 mol) 0.19 mol) in anhydrous ethyl ether (50 ml) to a hexane (73 ml) solution of n-butyllithium (0.19 mol) which had been diluted with ether (50 ml). After stirring for 1 hour, the mixture was cooled to 0°C. Then 1,2-bis(dichlorophosphino)ethane (10 g, 0.043 mol)
fra Strem Chemicals, inc, Newburyport, Massachusetts, i 50 ml eter tilsatt, og blandingen fikk oppvarmes til romtemperatur og ble rørt i 2 timer. Mettet, vandig ammoniumkloridløsning ble tilsatt og det faste materiale samlet. Dette ble oppløst i kloroform, vasket med vann, tørket (MgSO^), filtrert og løs-ningsmiddelet konsentrert, hvilket ga et faststoff som ble samlet og tørket og ga 4,2 g, sm.p. 108 - 110°C. Kromatografi (Si02, 2:1 CC14/CH2C12) ga tittelproduktet i analytisk renhet etter krystal1isering fra etanol, sm.p. 114 - 115°C. from Strem Chemicals, inc., Newburyport, Mass., in 50 mL of ether added, and the mixture was allowed to warm to room temperature and stirred for 2 hours. Saturated aqueous ammonium chloride solution was added and the solids collected. This was dissolved in chloroform, washed with water, dried (MgSO 4 ), filtered and the solvent concentrated to give a solid which was collected and dried to give 4.2 g, m.p. 108 - 110°C. Chromatography (SiO 2 , 2:1 CC 14 /CH 2 Cl 2 ) gave the title product in analytical purity after crystallization from ethanol, m.p. 114 - 115°C.
EKSEMPEL 4 EXAMPLE 4
1. 2- bis( di- 2- furylfosfino) etan1. 2-bis(di-2-furylphosphino)ethane
Furan (12,9 g, 0,19 mol) ivannfrietyleter (50 ml) ble satt til en heksan (73 ml) løsning av n-butyllitium (0,19 mol) fortynnet med eter (50 ml) og holdt ved romtemperatur. Blandingen ble rørt i 2 timer, avkjølt til 0°C, og 1,2-bis-diklorfos-fino)etan (10 g, 0,043 mol) fra Strem Chemicals, Inc., Newburyport, Massachusetts i 50 ml eter tilsatt. Blandingen ble rørt i 18 timer og oppvarmet til romtemperatur. Mettet vandig ammoniumklorid ble tilsatt og blandingen ble rørt i 1 time. Det faste stoff ble fjernet. Blandingen ble ekstrahert med eter, Furan (12.9 g, 0.19 mol) in anhydrous ethyl ether (50 mL) was added to a hexane (73 mL) solution of n-butyllithium (0.19 mol) diluted with ether (50 mL) and kept at room temperature. The mixture was stirred for 2 hours, cooled to 0°C, and 1,2-bis-dichlorophos-fino)ethane (10 g, 0.043 mol) from Strem Chemicals, Inc., Newburyport, Massachusetts in 50 mL of ether added. The mixture was stirred for 18 hours and warmed to room temperature. Saturated aqueous ammonium chloride was added and the mixture was stirred for 1 hour. The solid was removed. The mixture was extracted with ether,
og så ble kloroform og ekstraktene kombinert. Det faste stoff fra de kombinerte organiske ekstrakter ble fjernet og løsnings-middelet fjernet i vakuum. Resten ble behandlet med varm heksan, avkjølt og det faste stoff samlet (4,7 g). Omkrystallisering fra etanol ga 1,5 g av tittelproduktet som nåler, sm.p. 94 - 96°C. and then chloroform and the extracts were combined. The solid from the combined organic extracts was removed and the solvent removed in vacuo. The residue was treated with hot hexane, cooled and the solid collected (4.7 g). Recrystallization from ethanol gave 1.5 g of the title product as needles, m.p. 94 - 96°C.
EKSEMPEL 5EXAMPLE 5
Ved bruk av fremgangsmåten i eksempel 1 for å omsetteWhen using the procedure in example 1 to convert
den tilsvarende heterocyklus med den tilsvarende formel (A)-forbindelse, fremstilles de følgende forbindelser med formel the corresponding heterocycle with the corresponding formula (A) compound, the following compounds of formula are prepared
(I) : (I) :
a. 1,2-bis(di-2pyridylfosfino)metana. 1,2-bis(di-2-pyridylphosphino)methane
b. 1,2-bis(di-2-pyridylfosfino)propanb. 1,2-bis(di-2-pyridylphosphino)propane
c. 1,2-bis(di-2-pyridylfosfino)butanc. 1,2-bis(di-2-pyridylphosphino)butane
d. 1,2-bis(di-2-pyridylfosfino)pentand. 1,2-bis(di-2-pyridylphosphino)pentane
e. 1,2-bis(di-2-pyridylfosfino)heksane. 1,2-bis(di-2-pyridylphosphino)hexane
f. 1,2-bis(di-4-pyridylfosfino)metanf. 1,2-bis(di-4-pyridylphosphino)methane
g. 1,2-bis8di-4-pyridylfosfino)propang. 1,2-bis8di-4-pyridylphosphino)propane
h. 1,2-bis(di-4-pyridylfosfino)butanh. 1,2-bis(di-4-pyridylphosphino)butane
i. 1,2-bis(di-4-pyridylfosfino)pentani. 1,2-bis(di-4-pyridylphosphino)pentane
j. 1,2-bis(di-4-pyridylfosfino)heksanj. 1,2-bis(di-4-pyridylphosphino)hexane
k. 1,2-bis(di-2-tienylfosfino)metank. 1,2-bis(di-2-thienylphosphino)methane
1. 1,2-bis8di-2-tienylfosfino)propan1. 1,2-bis8di-2-thienylphosphino)propane
m. 1,2-bis(di-2-tienylfosfino)butanm. 1,2-bis(di-2-thienylphosphino)butane
n. 1,2-bis(di-2-tienylfosfino)pentann. 1,2-bis(di-2-thienylphosphino)pentane
o. 1,2-bis(di-2-tienylfosfino)heksano. 1,2-bis(di-2-thienylphosphino)hexane
p. 1,2-bis(di-2-furylfosfino)metanp. 1,2-bis(di-2-furylphosphino)methane
q. 1,2-bis(di-2-furylfosfino)propanq. 1,2-bis(di-2-furylphosphino)propane
r. 1,2-bis(di-2-furylfosfino)butanr. 1,2-bis(di-2-furylphosphino)butane
s. 1,2-bis(di-2-furylfosfino)pentanpp. 1,2-bis(di-2-furylphosphino)pentane
t. 1,2-bis(di-2-furylfosfino)heksant. 1,2-bis(di-2-furylphosphino)hexane
EKSEMPEL 6EXAMPLE 6
En spesifikk utførelsesform av en blanding fremstilt ifølge oppfinnelsen, en aktiv bestanddel, såsom én del av forbindelsen fra eksempel 1, oppløses i fem deler dimetylacetamid og fem deler polyetoksylert lakserolje, og deretter normal saltløsning qs og gis parenteralt i en dose på 30 mg/m<2>til et vertsdyr påvirket av tumorceller sorn er ømfindtlige for denne forbindelsen . A specific embodiment of a mixture prepared according to the invention, an active ingredient, such as one part of the compound from example 1, is dissolved in five parts of dimethylacetamide and five parts of polyethoxylated castor oil, and then normal saline qs and given parenterally at a dose of 30 mg/m <2> to a host animal affected by tumor cells sorn are sensitive to this compound.
EKSEMPEL 7 EXAMPLE 7
DiklorbisCl, 2- bis( difenylfosfino) etanj digullDichlorbisCl, 2-bis(diphenylphosphino) ethane digold
a) p - jj,2-bis(difenylfosfino)etan]bis [kl or gull (I )J a) p - jj,2-bis(diphenylphosphino)ethane]bis [cl or gold (I )J
Klorgullsyrehydrat (1,6 g, 3,8 mmol) i etanol (20 ml)Hydrochloric acid hydrate (1.6 g, 3.8 mmol) in ethanol (20 mL)
ble satt til bis(1,2-difenylfosfino)etan (1,83 g, 4,5 mmol)was added to bis(1,2-diphenylphosphino)ethane (1.83 g, 4.5 mmol)
fra Strem Chemicals, Inc., Newburyport, Massachusetts, i 1:1 kloroform/etanol (40 ml) holdt ved romtemperatur. Etter én time ble den hvite felling samlet, oppløst i metylenklorid, filtrert og etanol tilsatt for å igangsette utfelling. Etter from Strem Chemicals, Inc., Newburyport, Mass., in 1:1 chloroform/ethanol (40 mL) maintained at room temperature. After one hour the white precipitate was collected, dissolved in methylene chloride, filtered and ethanol added to initiate precipitation. After
henstand ble produktet samlet og tørket og ga 0,97 g (50%) av tittelgullkomplekset som hadde et smeltepunkt på 291 - 293°C. standing, the product was collected and dried to give 0.97 g (50%) of the title gold complex which had a melting point of 291 - 293°C.
(b) Diklorbis [i ,2-bis(difenylfosfino)etan]digull(b) Dichlorobis[i,2-bis(diphenylphosphino)ethane]digold
En løsning av 1,2-bis(difenylfosfino)etan (2,31 g, 5,8 mmol) fra Strem Chemicals, Inc., Newburyport, Massachusetts, i kloroform (100 ml) ble satt til et slam av y-(j ,2-bis(difenylfosfino)etan]bisklorgull) (5,0 g, 5,8 mmol) fremstilt som ovenfor beskrevet i kloroform (500 ml) holdt ved romtemperatur. Etter 45 minutter ble reaksjonsblandingen homogen (klar) og løsnings-middel ble fjernet i vakuum. Resten ble oppløst i en minimums-mengde kloroform og eter ble tilsatt. Etter avkjøling ble fellingen samlet og tørket og ga 3,0 g (41%) av tittelproduktet, sm.p. 298 - 302°C. A solution of 1,2-bis(diphenylphosphino)ethane (2.31 g, 5.8 mmol) from Strem Chemicals, Inc., Newburyport, Mass., in chloroform (100 mL) was added to a slurry of y-(j ,2-bis(diphenylphosphino)ethane]bischlorogold) (5.0 g, 5.8 mmol) prepared as described above in chloroform (500 mL) kept at room temperature. After 45 minutes, the reaction mixture became homogeneous (clear) and the solvent was removed in vacuo. The residue was dissolved in a minimum amount of chloroform and ether was added. After cooling, the precipitate was collected and dried to give 3.0 g (41%) of the title product, m.p. 298 - 302°C.
EKSEMPEL 8EXAMPLE 8
Diklorbis 1, 2- bis( dietylfosfino) etan digullDichlorbis 1, 2-bis(diethylphosphino) ethane digold
a) y - [i ,2-bis(dietylfosfino)etan] bis£klorgull(lf] a) y - [i,2-bis(diethylphosphino)ethane] bis£chlorogold(lf)
Klorgullsyretetrahydrat (7,88 g) i vann (35 ml) ble redusert med tiodiglykol (5,5 g) i etanol (12 ml) ved 0°C på vanlig måte. En løsning av 1,2-bis(dietylfosfino)etan (2,06 g) fra Strem Chemicals, Inc., Newburyport, Massachusetts, i etanol Chlorosulfuric acid tetrahydrate (7.88 g) in water (35 ml) was reduced with thiodiglycol (5.5 g) in ethanol (12 ml) at 0°C in the usual manner. A solution of 1,2-bis(diethylphosphino)ethane (2.06 g) from Strem Chemicals, Inc., Newburyport, Mass., in ethanol
(15 ml) ble tilsatt. Etter røring i 1 time ble reaksjonsblandingen helt i 400 ml isvann og ekstrahert med metylenklorid. (15 ml) was added. After stirring for 1 hour, the reaction mixture was poured into 400 ml of ice water and extracted with methylene chloride.
De kombinerte ekstrakter ble tørket (MgSO^), filtrert og avkjølt natten over. Det resulterende faste stoff ble samlet og luft-tørket og ga 3,0 g av tittelproduktet, sm.p. 168 - 170°C. The combined extracts were dried (MgSO 4 ), filtered and cooled overnight. The resulting solid was collected and air-dried to give 3.0 g of the title product, m.p. 168 - 170°C.
b) Diklorbis 1,2-bis(dietylfosfino)etan digullb) Dichlorobis 1,2-bis(diethylphosphino)ethane digold
Tilsetning av 1,2-bis(dietylfosfino)etan (0,31 g, 1,49 Addition of 1,2-bis(diethylphosphino)ethane (0.31 g, 1.49
mmol) fra Strem Chemicals, Inc., Newburyport, Massachusetts,mmol) from Strem Chemicals, Inc., Newburyport, Massachusetts,
i én eneste porsjon til en løsning av y- [i ,2-bis(dietylfosfino)-etan"]bisf klorgull ) (1,0 g, 1,49 mmol) som beskrevet ovenfor i kloroform (200 ml) ble utført, og den resulterende klare løsning i 30 minutter. Løsningsmiddelet ble fjernet i vakuum, resten krystalliserte fra kloroform/eter og ga 1,0 g (77%) av tittelproduktet, sm.p. 211 - 214°C. in a single portion to a solution of γ-[i,2-bis(diethylphosphino)ethane"]bisf chlorogold ) (1.0 g, 1.49 mmol) as described above in chloroform (200 mL) was carried out, and the resulting clear solution for 30 min.The solvent was removed in vacuo, the residue crystallized from chloroform/ether to give 1.0 g (77%) of the title product, mp 211-214°C.
EKSEMPEL 9EXAMPLE 9
Ved å bruke fremgangsmåten fra eksempel 7 (b) eller eksempel 8 (b) for å omsette det tilsvarende gullkompleks med formel Using the procedure of Example 7 (b) or Example 8 (b) to react the corresponding gold complex of formula
(C) (fremstilt ifølge fremgangsmåten fra eksempel 7 (a) eller 7 (a) ved å anvende tilsvarende halogengullsyrehydrat) med den (C) (prepared according to the method of example 7 (a) or 7 (a) by using the corresponding haloauric acid hydrate) with the
tilsvarende ligande med formel (B) fremstilles de følgende forbindelser med formel (III), hvori X<1>er klor eller brom; og/eller ved å omsette den tilsvarende formel (III)-forbindelse, hvori X 1er klor, med natriumbromid i et tilsvarende organisk løsnings-middel såsom vandig etanol eller DMF, de følgende formel (III)-forbindelser hvori X^ er brom fremstilles; og ved å omsette den tilsvarende formel (III)-forbindelse hvori X^ er klor eller brom med natriumjodid i et tilsvarende organisk løsningsmiddel, såsom aceton, fremstilles de følgende forbindelser med formel (III) hvori X er jod: corresponding ligands of formula (B) the following compounds of formula (III) are prepared, in which X<1> is chlorine or bromine; and/or by reacting the corresponding compound of formula (III), wherein X 1 is chlorine, with sodium bromide in a corresponding organic solvent such as aqueous ethanol or DMF, the following compounds of formula (III) wherein X 1 is bromine are prepared; and by reacting the corresponding compound of formula (III) in which X is chlorine or bromine with sodium iodide in a corresponding organic solvent, such as acetone, the following compounds of formula (III) in which X is iodine are prepared:
a) diklorbisfl,2-bis(difenylfosfino)metan] digulla) dichlorobisfl,2-bis(diphenylphosphino)methane]digold
b) diklorbis[l,2-bis(difenylfosfino)propan] digullb) dichlorobis[1,2-bis(diphenylphosphino)propane]digold
c) diklorbisTl,2-bis(difenylfosfino)butan]digullc) dichlorobisT1,2-bis(diphenylphosphino)butane]digold
d) diklorbis £l ,2-bis(difenylfosfino)pentan]digulld) dichlorobis £1,2-bis(diphenylphosphino)pentane]digold
e) diklorbis£l,2-bis(difenylfosfino)heksan}digulle) dichlorobis£1,2-bis(diphenylphosphino)hexane}digold
f) diklorbis[i,2-bis(dietylfosfino)metan}digullf) dichlorobis[i,2-bis(diethylphosphino)methane}digold
g) diklorbisfl , 2-bis ( dietylf osf ino ) propan] digullg) dichlorobisfl , 2-bis ( diethylph osphino ) propane] digul
h) diklorbis[1,2-bis(diety1fosfino)butan}digul1h) dichlorobis[1,2-bis(diethylphosphino)butane}digul1
i) diklorbis \_1 , 2-bis ( dietylf osf ino ) pentan} digulli) dichlorobis \_1 , 2-bis ( diethylph osphino ) pentane} digold
j ) diklorbis £l ,2-bis(dietylfosfino)heksan}digull k) dijodbis (j ,2-bis(difenylfosfino)etan3 digull 1) dibrombis (j ,2-bis(difenylfosfino)etanj digull j ) dichlorobis £l ,2-bis(diethylphosphino)hexane}digold k) diiodobis(j ,2-bis(diphenylphosphino)ethane3 digold 1) dibrombis (j ,2-bis(diphenylphosphino)ethanej digold
EKSEMPEL 10EXAMPLE 10
Som en spesifikk utførelsesform av en blanding fremstiltAs a specific embodiment of a mixture prepared
i denne oppfinnelse oppløses en aktiv bestanddel såsom én del av forbindelsen fra eksempel 7 i 5 deler dimetylacetamid og 5 deler polyetoksylert lakserolje og deretter normal saltløs-ning qs, og gis parenteralt i en dose på 5 mg/m<2>til et vertsdyr påvirket av tumorceller som er ømfindtlige for denne forbindelse. in this invention, an active ingredient such as one part of the compound from example 7 is dissolved in 5 parts dimethylacetamide and 5 parts polyethoxylated castor oil and then normal saline solution qs, and given parenterally in a dose of 5 mg/m<2> to an affected host animal of tumor cells that are sensitive to this compound.
EKSEMPEL 11 EXAMPLE 11
V- [ 1 , 2- bis (d i- 2- pyridylfosfino) etanlbis( klorgull)V- [ 1 , 2- bis (d i- 2- pyridylphosphino) ethane bis(chlorosulfur)
Under en argonatmosfære ble 2-brompyridin (30,95 g, 0,19 mol) i vannfri etyleter (50 ml) satt til n-butyllitium (0,19 mol) i heksan (73 ml) mens temperaturen ble holdt under -50°C. Etter røring i 1 time, ble ytterligere 7,5 g 2-brompyridin tilsatt, og blandingen ble rørt i 30 minutter. En eterløsning (100 ml) av 1,2-bis(diklorfosfino)etan (10 g, 43 mmol) fra Strem Chemicals, Inc., Newburyport, Massachusetts, ble tilsatt, og blandingen ble rørt i 1 time ved -50°C, og fikk så oppvarmes til romtemperatur natten over. Mettet vandig ammoniumklorid ble tilsatt, og blandingen ble rørt i 1 time. Det faste stoff ble samlet og oppløst i kloroform, tørket (Na2SC>4), filtrert og løsningsmiddelet ble fjernet og ga en mørk rest. Resten ble behandlet med aceton og acetonet ble avkjølt og ga et lyse-gult faststoff (4,5 g). Omkrystallisering fra aceton ga 2,64 g 1,2-bis(di-2-pyridylfosfino)-etan, sm.p. 134 - 135°C. Under an argon atmosphere, 2-bromopyridine (30.95 g, 0.19 mol) in anhydrous ethyl ether (50 mL) was added to n-butyllithium (0.19 mol) in hexane (73 mL) while maintaining the temperature below -50° C. After stirring for 1 hour, an additional 7.5 g of 2-bromopyridine was added and the mixture was stirred for 30 minutes. An ethereal solution (100 mL) of 1,2-bis(dichlorophosphino)ethane (10 g, 43 mmol) from Strem Chemicals, Inc., Newburyport, Mass., was added and the mixture was stirred for 1 hour at -50°C, and then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride was added and the mixture was stirred for 1 hour. The solid was collected and dissolved in chloroform, dried (Na2SO4), filtered and the solvent removed to give a dark residue. The residue was treated with acetone and the acetone was cooled to give a pale yellow solid (4.5 g). Recrystallization from acetone gave 2.64 g of 1,2-bis(di-2-pyridylphosphino)ethane, m.p. 134 - 135°C.
Tiodiglykol (1 g, 8,18 mmol) i vann (10 ml)/metanol (30 ml) ble satt til klorgullsyretetrahydrat (0,88 g, 2,14 mmol) i vann (10 ml) holdt ved 0°C. Etter røring i 15 minutter, ble 1,2-bis(di-2-pyridylfosfino)etan, (0,43 g, 1,07 mmol) fremstilt som beskrevet ovenfor i aceton (50 ml)/kloroform' (10 ml) tilsatt, og blandingen ble rørt i 2 timer. Metanol ble tilsatt, og produktet ble samlet og slemmet med CI-^C^/CHCl^, fortynnet med metanol og avkjølt. Det resulterende faste stoff ble samlet og tørket og ga 0,38 g (41%) av tittelproduktet, sm.p. 292 - 293°C. Thiodiglycol (1 g, 8.18 mmol) in water (10 mL)/methanol (30 mL) was added to chlorosulfuric acid tetrahydrate (0.88 g, 2.14 mmol) in water (10 mL) kept at 0 °C. After stirring for 15 min, 1,2-bis(di-2-pyridylphosphino)ethane, (0.43 g, 1.07 mmol) prepared as described above in acetone (50 mL)/chloroform' (10 mL) was added , and the mixture was stirred for 2 hours. Methanol was added, and the product was collected and slurried with Cl - 2 C 2 /CHCl 2 , diluted with methanol and cooled. The resulting solid was collected and dried to give 0.38 g (41%) of the title product, m.p. 292 - 293°C.
EKSEMPEL 12 EXAMPLE 12
y -\ j , 2- bis ( di- 2- pyridylfosfino) eta n} bis t( 1 - tioif- D- glukopyrano-sato- S) gull y -\ j , 2- bis ( di- 2- pyridylphosphino) eta n} bis t( 1 - thioif- D- glucopyrano-sato- S) gold
En blanding av natriumtioglukose (0,33 g, 1,5 mmol) fra Sigma Chemical Company, St. Louis, Missouri, og fl-[i , 2-bis (di-2-pyridylfosfino)etan]bis(klorgull) (0,6 g, 0,69 mol), fremstilt som beskrevet i eksempel 1, i kloroform (75 ml)/metanol (75 ml)/ vann (10 ml) ble rørt ved romtemperatur i 2 timer og løsnings-middelet fordampet. Resten ble oppløst i kloroform og fellingen ble samlet. Det faste stoff ble oppløst i metanol, filtrert og løsningsmiddelet fordampet. Resten ble oppløst i aceton, avkjølt og fellingen ble samlet og tørket og ga 0,49 g (60%) A mixture of sodium thioglucose (0.33 g, 1.5 mmol) from Sigma Chemical Company, St. Louis, Missouri, and fl-[i , 2-bis(di-2-pyridylphosphino)ethane]bis(chlorosulfur) (0 .6 g, 0.69 mol), prepared as described in Example 1, in chloroform (75 ml)/methanol (75 ml)/water (10 ml) was stirred at room temperature for 2 hours and the solvent evaporated. The residue was dissolved in chloroform and the precipitate was collected. The solid was dissolved in methanol, filtered and the solvent evaporated. The residue was dissolved in acetone, cooled and the precipitate was collected and dried to give 0.49 g (60%)
av tittelforbindelsen som et hvitt, amorft faststoff.of the title compound as a white, amorphous solid.
EKSEMPEL 13 EXAMPLE 13
u- [ i , 2- bis( di- 4- pyridylfosfino) etan] bis( klorgull)u- [ i , 2- bis( di- 4- pyridylphosphino) ethane] bis( chlorosulfur)
Under en argonatmosfære ble 4-brompyridin (30,95 g, 0,19 mol) i vannfri etyleter (50 ml) satt til n-butyllitium (0,19 mol) i heksan (73 ml) mens temperaturen ble holdt under -50°C. Etter røring i 1 time ble ytterligere 7,5 g 4-brompyridin tilsatt og blandingen ble rørt i 30 minutter. En eterløsning (100 ml) Under an argon atmosphere, 4-bromopyridine (30.95 g, 0.19 mol) in anhydrous ethyl ether (50 mL) was added to n-butyllithium (0.19 mol) in hexane (73 mL) while maintaining the temperature below -50° C. After stirring for 1 hour, an additional 7.5 g of 4-bromopyridine was added and the mixture was stirred for 30 minutes. An ether solution (100 ml)
av 1,2-bis(diklorfosfino)etan (10 g, 43 mmol) fra Strem Cehmi-cals, Inc., Newburyport, Massachusetts ble tilsatt og blandingen ble rørt i 1 time ved -50°C, og fikk så oppvarmes til romtemperatur natten over. Etter 18 timer ved romtemperatur ble vandig mettet ammoniumklorid tilsatt og det faste stoff fjernet. Det resterende faste stoff i kolben ble samlet, oppløst i kloroform, behandlet med aktivert karbon, filtrert og så ble løsningsmidde-let fjernet. Hurtig kromatografi (SiO^, 7% metanol/metylenklorid) av resten ga en liten mengde 1-2-bis(di-4-pyridylfosfino)-etan, sm.p. 183 - 185°C. of 1,2-bis(dichlorophosphino)ethane (10 g, 43 mmol) from Strem Chemicals, Inc., Newburyport, Massachusetts was added and the mixture was stirred for 1 hour at -50°C, then allowed to warm to room temperature overnight. After 18 hours at room temperature, aqueous saturated ammonium chloride was added and the solid was removed. The remaining solid in the flask was collected, dissolved in chloroform, treated with activated carbon, filtered and then the solvent was removed. Flash chromatography (SiO 2 , 7% methanol/methylene chloride) of the residue gave a small amount of 1-2-bis(di-4-pyridylphosphino)ethane, m.p. 183 - 185°C.
Tiodiglykol (2 g, 16,4 mmol) i vann (10 ml)/metanol (30 ml) ble satt til klorgullsyretetrahydrat (1,58 g, 3,83 mmol) Thiodiglycol (2 g, 16.4 mmol) in water (10 mL)/methanol (30 mL) was added to chlorosulfuric acid tetrahydrate (1.58 g, 3.83 mmol)
i vann (10 ml) holdt på 0°C. Etter røring i 15 minutter ble 1-2-bis(di-4-pyridylfosfino)etan (0,77 g, 1,9 mmol) fremstilt som beskrevet ovenfor i C^C^ (10 ml)/metanol (30 ml) tilsatt og blandingen ble rørt i 1 time. Metanol ble tilsatt og fellingen samlet og rørt i acetonitril, filtrert og tørket, hvilket ga 0,75 g (45%) av tittelproduktet, sm.p. 241 - 242°C. in water (10 ml) kept at 0°C. After stirring for 15 min, 1-2-bis(di-4-pyridylphosphino)ethane (0.77 g, 1.9 mmol) prepared as described above in C₂C₂ (10 mL)/methanol (30 mL) was added and the mixture was stirred for 1 hour. Methanol was added and the precipitate collected and stirred in acetonitrile, filtered and dried to give 0.75 g (45%) of the title product, m.p. 241 - 242°C.
EKSEMPEL 14 EXAMPLE 14
Klorbis[ 1, 2- bis( di- 2- pyridylfosfino) etan] gullChlorbis[ 1, 2- bis(di- 2- pyridylphosphino) ethane] gold
En løsning av 1,2-bis(di-2-pyridylfosfino)etan (0,17 g, 0,42 mmol), fremstilt som beskrevet i eksempel 1 i CH2CI2(25 ml) ble satt til en suspensjon av \ i- \ j , 2-bis (di-2-pyridylf osf ino ) - etan]bis-(klorgull) (0,12 g, 0,14 mmol) i CH2C12(25 ml) og blandingen ble rørt ved romtemperatur i 18 timer og ga en klar løsning. Løsningsmiddelet ble fordampet og resten ble oppløst i metanol og fortynnet med etyleter. Etter kjøling ble fellingen samlet og tørket og ga 0,28 g (98%) av tittelproduktet, sm.p. A solution of 1,2-bis(di-2-pyridylphosphino)ethane (0.17 g, 0.42 mmol), prepared as described in Example 1 in CH 2 Cl 2 (25 mL) was added to a suspension of j , 2-bis(di-2-pyridylphosphino)-ethane]bis-(chlorosulfur) (0.12 g, 0.14 mmol) in CH 2 Cl 2 (25 mL) and the mixture was stirred at room temperature for 18 h to give a clear solution. The solvent was evaporated and the residue was dissolved in methanol and diluted with ethyl ether. After cooling, the precipitate was collected and dried to give 0.28 g (98%) of the title product, m.p.
257 - 258°C. 257 - 258°C.
EKSEMPEL 15EXAMPLE 15
a) Ved å bruke fremgangsmåten som er beskrevet i eksempel 11 eller 13 ved direkte å oppvarme det tilsvarende halogengullsyrehydrat med den tilsvarende difosfinohydrokarbonforbin-delse med formel (I) hvori M er 0 i et tilsvarende ikke-reaktivt organisk løsningsmiddel eller ved å omsette det tilsvarende halogengullsyrehydrat som er blitt redusert ved behandling med tidiglykol med den tilsvarende forbindelse med formel (I) hvori M er 0, fremstilles de følgende formel (I)-forbindelser hvori a) By using the method described in example 11 or 13 by directly heating the corresponding halogold acid hydrate with the corresponding diphosphinohydrocarbon compound of formula (I) in which M is 0 in a corresponding non-reactive organic solvent or by reacting the corresponding halogold acid hydrate which has been reduced by treatment with tidiglycol with the corresponding compound of formula (I) in which M is 0, the following compounds of formula (I) are prepared in which
M er 1 og X er klor eller brom; eller ved å omsette den tilsvarende formel (I)-forbindelse hvori M er 1 og X er klor med natriumbromid i et hensiktsmessig organisk løsningsmiddel, såsom vandig etanol eller DMF, fremstilles de følgende formel (I)-forbindelser hvori M er 1 og X er brom; eller ved å omsette den tilsvarende formel (I)-forbindelse hvori M er 1 og X er klor eller brom med natriumjodid i et hensiktsmessig organisk løsningsmiddel såsom aceton, fremstilles de følgende formel (I)-forbindelser hvori M er 1 og X er jod: M is 1 and X is chlorine or bromine; or by reacting the corresponding compound of formula (I) in which M is 1 and X is chlorine with sodium bromide in a suitable organic solvent, such as aqueous ethanol or DMF, the following compounds of formula (I) are prepared in which M is 1 and X is bromine; or by reacting the corresponding compound of formula (I) in which M is 1 and X is chlorine or bromine with sodium iodide in a suitable organic solvent such as acetone, the following compounds of formula (I) are prepared in which M is 1 and X is iodine:
i) y - [i,1-bis(di-2-pyridylfosfino)metan]bis-(klorgull)i) y - [i,1-bis(di-2-pyridylphosphino)methane]bis-(chlorogold)
ii) p - jj,3-bis(di-2-pyridylfosfino)propan]bis-(klorgull)ii) p - jj,3-bis(di-2-pyridylphosphino)propane]bis-(chlorosulfur)
iii) f-l - D ,4-bis(di-2-pyridylfosfino)butanjbis(klorgull)iii) f-1 - D ,4-bis(di-2-pyridylphosphino)butane bis(chlorosulfur)
iv) (J - [i ,5-bis(di-2-pyridylfosfino)pentanjbisfklorgull)iv) (J - [i,5-bis(di-2-pyridylphosphino)pentanylbischlorogold)
v) H~ D,6-bis(di-2-pyridylfosfino)heksan] bis(klorgull)v) H~ D,6-bis(di-2-pyridylphosphino)hexane] bis(chlorogold)
vi ) p!-[l ,2-bis(di-2 -pyridylfosfino)etanjbis(bromgull)vi ) p1-[1,2-bis(di-2-pyridylphosphino)ethane bis(bromogold)
vii) ^ - (j ,2-bis(di-2-pyridylfosfino)etanJbis( jodgull )vii) ^ - (j ,2-bis(di-2-pyridylphosphino)ethaneJbis( iodogold )
viii) \ i- \_ 1 , 2-bis (di-4-pyridylf osf ino )metanj bis ( klorgull)viii) \i- \_ 1 , 2-bis (di-4-pyridylphosphino)methane bis (chlorosulphur)
ix) ^-[l,2-bis(di-4-pyridylfosfino)propan]bis(klorgull)ix) ^-[1,2-bis(di-4-pyridylphosphino)propane]bis(chlorogold)
x) H~£l ,2-bis(di-4-pyridylfosfino)butan]bis(klorgull)x) H~£l ,2-bis(di-4-pyridylphosphino)butane]bis(chlorosulfur)
xi) H~C^ f2-bis(di-4-py ridylfosfino) pentan] bis(klorgull)xi) H~C^ f2-bis(di-4-pyridylphosphino) pentane] bis(chlorosulfur)
xii) ,2-bis(di-4-pyridylfosfino)heksanjbis(klorgull)xii) ,2-bis(di-4-pyridylphosphino)hexanejbis(chlorogold)
xiii) JJ-[1 ,2-bis(di-4-py ridylfosfino) etan] bis ( bromgull)xiii) JJ-[1,2-bis(di-4-pyridylphosphino) ethane] bis (bromo gold)
xiv) ,2-bis(di-4-pyridylfosfino)etanJbis( jodgull)xiv) ,2-bis(di-4-pyridylphosphino)ethaneJbis(iodogold)
b) Ved å bruke fremgangsmåten som er beskrevet i eksempel 14 ved å omsette den tilsvarende formel (I)-forbindelse hvori R er 2-pyridyl, fremstilt som beskrevet ovenfor med tilsvarende formel (I)-forbindelse, hvori M er 0 fremstilt som beskrevet ovenfor, fremstilles de følgende formel (I)-forbindelser, hvori M er 1: i) klorbis [i ,1-bis(di-2-pyridylfosfino)metan]gull ii) klorbis[1,3-bis(di-2-pyridylfosfino)propan]gull iii) klorbis [i,4-bis(di-2-pyridylfosfino)butan]gu11 b) Using the method described in example 14 by reacting the corresponding compound of formula (I) in which R is 2-pyridyl, prepared as described above with the corresponding compound of formula (I) in which M is 0 prepared as described above, the following compounds of formula (I) are prepared, wherein M is 1: i) chlorobis[i,1-bis(di-2-pyridylphosphino)methane]gold ii) chlorobis[1,3-bis(di-2- pyridylphosphino)propane]gold iii) chlorobis[i,4-bis(di-2-pyridylphosphino)butane]gu11
iv) klorbis(J ,5-bis(di-2-pyridylfosfino)pentan]gull v) klorbis[j ,6-bis(di-2-pyridylfosfino)heksanjgull vi) jodbis [i ,2-bis(di-2-pyridylfosf ino)etanj gull vii) brombis [i,2-bis(di-2-pyridylfosfino)etanjgull iv) chlorobis(J ,5-bis(di-2-pyridylphosphino)pentane]gold v) chlorobis[j ,6-bis(di-2-pyridylphosphino)hexanejgold vi) iodobis[i ,2-bis(di-2- pyridylphosphino)ethane gold vii) bromobis[i,2-bis(di-2-pyridylphosphino)ethane gold
EKSEMPEL 16EXAMPLE 16
Ved å bruke fremgangsmåten fra eksempel 12 og omsetteBy using the procedure from example 12 and converting
den tilsvarenden formel (I)-forbindelse hvori X er klor, fremstilt ifølge fremgangsmåten i eksempel 11, 13 eller 15, med det tilsvarende tiosukker, fremstilles de følgende formel (I)-forbindelser, hvori X er tiosukker: the corresponding formula (I) compound in which X is chlorine, prepared according to the method in example 11, 13 or 15, with the corresponding thiosugar, the following formula (I) compounds are prepared, in which X is thiosugar:
a) yi - [i , 1-bis(di-2-pyridylfosfino)metan]bis( 1 -tio-(i-D-gluko-pyranosato-S)gull b) jj- [j ,3-bis(di-2-py ridylfosfino) propanjbis ( 1 -1 io-fi^D-gluko-pyranosato-S)gull c) yl-jj , 4-bis ( di-2-pyridylf osf ino ) butanjbis ( 1 -tio-fi>-D-gluko-pyranosato-S)gull d) ^-[j i5-bis(di-2-pyridylfosfino)petnanjbis( 1-tio-^-D-gluko-pyranosator-S)gull e) ]\~ [i ,6-bis(di-2- py ridylfosfino) heksan]] bis ( 1 -tio-(?-D-gluko-pyranosato-S)gull f) ^ - [j ,2-bis(di-2-pyridylfosfino)etanJbis( 1-tio-|&-D-galakto-pyranosator-S)gull g) (4-Ll»2-bis( di-2-pyridyl f osf inO ) etanj bis ( 1 -tio-Ø-D-mannopy-ranosato-S)gull h) ^-[j ,2-bis(di-2-pyridylfosfino)etanj bis(1-tio-ft-D-ribofu-ranosato-S)gull a) yi - [i , 1-bis(di-2-pyridylphosphino)methane]bis( 1 -thio-(i-D-gluco-pyranosato-S)gold b) jj- [j ,3-bis(di-2- pyridylphosphino) propanjbis ( 1 -1 io-fi^D-gluco-pyranosato-S)gold c) yl-jj , 4-bis ( di-2-pyridylph osf ino ) butanjbis ( 1 -thio-fi>-D- gluco-pyranosate-S)gold d) ^-[j i5-bis(di-2-pyridylphosphino)petnanjbis( 1-thio-^-D-gluco-pyranosate-S)gold e) ]\~ [i ,6- bis(di-2-pyridylphosphino)hexane]] bis ( 1 -thio-(?-D-gluco-pyranosato-S)gold f) ^ - [j ,2-bis(di-2-pyridylphosphino)ethaneJbis( 1 -thio-|&-D-galacto-pyranosator-S)gold g) (4-Ll»2-bis( di-2-pyridyl f osph inO ) ethanej bis ( 1 -thio-Ø-D-mannopy-ranosato- S)gold h) ^-[j ,2-bis(di-2-pyridylphosphino)ethane and bis(1-thio-ft-D-ribofuranosato-S)gold
i) - [] , 1-bis(di-4-py ridylfosfino) me tanjbis( 1 -tio-(J-D-gluko-pyranosato-S)gull i) - [] , 1-bis(di-4-pyridylphosphino)methanjbis(1-thio-(J-D-gluco-pyranosato-S)gold
j ) |J- [i , 2-bis (di-4-pyridyl f osf ino ) etanj bis ( 1 -tio-(3-D-gluko-pyranosato-S)gull j ) |J- [i , 2-bis (di-4-pyridyl phosphino ) ethane bis ( 1 -thio-(3-D-gluco-pyranosato-S) gold
k ) p - jj , 3-bis (di-4-pyridyl f osf ino ) propan]bis ( 1 -tio-(£-D-gluko-pyranosato-S)gull k ) p - jj , 3-bis (di-4-pyridyl f osphino ) propane] bis ( 1 -thio-(£-D-gluco-pyranosato-S)gold
1) |4- [i , 4-bis (di-4-pyridyl f osf ino ) butan^bis ( 1 -tio-fr-D-gluko-pyranosato-S)gull 1) |4- [i , 4-bis (di-4-pyridyl f osphino ) butane^bis ( 1 -thio-fr-D-gluco-pyranosato-S) gold
m) ^- [i,5-bis(di-4-pyridylfosfino)pentan]bis(1-tio-fi-D-gluko-pyranosato-S)gull m) ^- [i,5-bis(di-4-pyridylphosphino)pentane]bis(1-thio-fi-D-gluco-pyranosato-S)gold
n ) ^ - [i , 6-bis (di-4-pyridyl f osf ino ) heksan] bis ( 1 -tio-(l-D-gluko-pyranosato-S)gull n ) ^ - [i , 6-bis (di-4-pyridyl f osphino ) hexane] bis ( 1 -thio-(1-D-gluco-pyranosato-S)gold
o) }l-[l,2-bis( di-4-pyridyl f osf ino ) etan] bis ( 1 -tio-$-D-galakto-pyranosato-S)gull o) }l-[l,2-bis(di-4-pyridylphosphino)ethane]bis(1-thio-$-D-galacto-pyranosato-S)gold
p) ,2-bis(di-4-pyridylfosfino)etanJbis(1 - tio-$-D-manno-pyranosato-S )gull p) ,2-bis(di-4-pyridylphosphino)ethaneJbis(1-thio-$-D-manno-pyranosato-S )gold
q) j^-D / 2-bis(di-4-pyridylfosfino) etan]Jbis ( 1-tio-D-ribofurano-sato-S)gull q) j^-D / 2-bis(di-4-pyridylphosphino)ethane]Jbis ( 1-thio-D-ribofurano-sato-S)gold
EKSEMPEL 17EXAMPLE 17
En spesifikk utførelses form av en blanding inneholdendeA specific embodiment of a mixture containing
en aktiv bestanddel såsom en del av forbindelsen fra eksempel 11, oppløses i 5 deler dimetylacetamid og 5 deler polyetoksylert lakserolje og deretter noraml saltløsning qs, og gis parenteralt i én dose på 5 mg/m<2>til et vertsdyr påvirket av tumorceller som er ømfindtlige overfor denne forbindelse. an active ingredient such as a portion of the compound from Example 11, is dissolved in 5 parts dimethylacetamide and 5 parts polyethoxylated castor oil and then normal saline qs, and given parenterally in a single dose of 5 mg/m<2> to a host animal affected by tumor cells that are sensitive to this connection.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO874954A NO874954D0 (en) | 1985-04-16 | 1987-11-27 | Phosphine. |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US72377885A | 1985-04-16 | 1985-04-16 | |
US73452485A | 1985-05-16 | 1985-05-16 | |
US73601885A | 1985-05-20 | 1985-05-20 | |
US82935986A | 1986-02-14 | 1986-02-14 | |
NO861461A NO861461L (en) | 1985-04-16 | 1986-04-15 | Phosphine. |
NO874954A NO874954D0 (en) | 1985-04-16 | 1987-11-27 | Phosphine. |
Publications (2)
Publication Number | Publication Date |
---|---|
NO874954L true NO874954L (en) | 1986-10-17 |
NO874954D0 NO874954D0 (en) | 1987-11-27 |
Family
ID=27555240
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO874954A NO874954D0 (en) | 1985-04-16 | 1987-11-27 | Phosphine. |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO874954D0 (en) |
-
1987
- 1987-11-27 NO NO874954A patent/NO874954D0/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO874954D0 (en) | 1987-11-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wada et al. | A highly basic triphenylphosphine,[2, 4, 6-(MeO) 3 C 6 H 2] 3 P | |
EP0164970B1 (en) | Tumor cell growth-inhibiting pharmaceutical compositions containing phosphino-hydrocarbon-gold, silver or copper complexes | |
CA1238854A (en) | ANTITUMOR PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATING TUMORS EMPLOYING ¬.alpha.,W- BIS(DISUBSTITUTEDPHOSPHINO)HYDROCARBON| DIGOLD (I) DIGOLD (III), DISILVER (I) AND DICOPPER (I) DERIVATIVES | |
US20070249837A1 (en) | Process for the Preparation of Pyridine Derivatives | |
Kulcsar et al. | Organoselenium (II) and selenium (IV) compounds containing 2-(Me2NCH2) C6H4 moieties: solution behavior and solid state structure | |
Featherman et al. | Carbon-13 magnetic resonance spectral study of some phosphorinanes and their 1-sulfides | |
Miller | A Pyrolytic Synthesis of Ylides. Isolation of Trimethylphosphinetrimethylsilylmethylene | |
NO861461L (en) | Phosphine. | |
Nakamoto et al. | Stereomutation and apicophilicity of diastereomeric spirophosphoranes (10-P-5) | |
NO874954L (en) | Phosphine. | |
Ghavale et al. | Synthesis, structure and reactivity of a selenoxide derived from a bulky selenide: Bis (2, 4, 6-trimethylphenyl) selenoxide | |
NO882368L (en) | Phosphine. | |
US4902675A (en) | "2-pyridyl and 4-pyridyl phosphine gold (I) anti tumor complexes" | |
Irgolic | Tellurium: Literature survey covering the year 1978 | |
Burakevich et al. | Phenylfurazan oxide. Chemistry | |
Glidewell | Ambident nucleophiles: II. Reactions of phosphoramidates and phosphorimidates with some halides of group IV | |
Huynh et al. | ortho-Lithiation of Benzene-1, 2-dithiol: A Methodology for ortho-Functionalization of Benzene-1, 2-dithiol | |
Weir et al. | Stereochemistry and metal-centered rearrangements of eight-coordinate niobium (V) and tantalum (V) dithiocarbamates and monothiocarbamates | |
US4716230A (en) | Certain bis(di-2 or 4-pyridyl-phosphino) alkanes #10 having anti-tumor properties | |
US4755611A (en) | Certain bio-(bi-2-thienyl or 2-furyl phosphino) lower alkanes having anti-tumor properties | |
US4764509A (en) | Pharmaceutical compositions containing di-gold phosphine | |
Reinhard et al. | 5-Aminocyclopentadienes by intramolecular addition of enolether to aminoallene functionalities | |
US3853912A (en) | N-(alkylthiophenyl) maleimides | |
US3379732A (en) | Phosphate esters of 2, 6-diiodo-4-nitrophenol | |
US3394166A (en) | Triphenylphosphine (dithiocarboxy) cyanomethylene and derivatives |