WO1993019076A1 - θ6 METAL COMPLEXES OF 4-ARYL-1,4-DIHYDROPYRIDINES - Google Patents
θ6 METAL COMPLEXES OF 4-ARYL-1,4-DIHYDROPYRIDINES Download PDFInfo
- Publication number
- WO1993019076A1 WO1993019076A1 PCT/US1993/002682 US9302682W WO9319076A1 WO 1993019076 A1 WO1993019076 A1 WO 1993019076A1 US 9302682 W US9302682 W US 9302682W WO 9319076 A1 WO9319076 A1 WO 9319076A1
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- Prior art keywords
- metal
- compound
- electrons
- dihydropyridine
- group
- Prior art date
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- 229910052751 metal Inorganic materials 0.000 title claims abstract description 85
- 239000002184 metal Substances 0.000 title claims abstract description 85
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims abstract description 38
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002253 acid Substances 0.000 claims abstract description 36
- 102000003922 Calcium Channels Human genes 0.000 claims abstract description 21
- 108090000312 Calcium Channels Proteins 0.000 claims abstract description 21
- 229940127291 Calcium channel antagonist Drugs 0.000 claims abstract description 20
- 239000003446 ligand Substances 0.000 claims description 85
- 102000005962 receptors Human genes 0.000 claims description 33
- 108020003175 receptors Proteins 0.000 claims description 33
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 29
- 230000027455 binding Effects 0.000 claims description 26
- 239000011651 chromium Substances 0.000 claims description 21
- -1 dihydropyridine compound Chemical class 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000011261 inert gas Substances 0.000 claims description 14
- 239000000480 calcium channel blocker Substances 0.000 claims description 13
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052804 chromium Inorganic materials 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 230000003993 interaction Effects 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 8
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 102000013138 Drug Receptors Human genes 0.000 claims description 7
- 108010065556 Drug Receptors Proteins 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 238000006263 metalation reaction Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 230000000737 periodic effect Effects 0.000 claims description 5
- 230000010799 Receptor Interactions Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 229910052750 molybdenum Inorganic materials 0.000 claims description 4
- 238000012587 nuclear overhauser effect experiment Methods 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 238000002329 infrared spectrum Methods 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- 238000004296 chiral HPLC Methods 0.000 claims description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims 2
- 239000011733 molybdenum Substances 0.000 claims 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims 2
- 239000010937 tungsten Substances 0.000 claims 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 claims 1
- 230000004071 biological effect Effects 0.000 abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 230000003595 spectral effect Effects 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 230000009102 absorption Effects 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 150000002148 esters Chemical group 0.000 description 9
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- LOFJKBAHPJENQS-UHFFFAOYSA-N tris(oxomethylidene)chromium Chemical compound O=C=[Cr](=C=O)=C=O LOFJKBAHPJENQS-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical group O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 5
- 150000003934 aromatic aldehydes Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000004466 2D NOESY spectrum Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000002739 metals Chemical class 0.000 description 4
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000012565 NMR experiment Methods 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 150000003624 transition metals Chemical group 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- JJWKPURADFRFRB-UHFFFAOYSA-N carbonyl sulfide Chemical compound O=C=S JJWKPURADFRFRB-UHFFFAOYSA-N 0.000 description 2
- 230000009137 competitive binding Effects 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 230000004118 muscle contraction Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000004791 1D NOESY Methods 0.000 description 1
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical group COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 1
- 150000008091 4-phenyl-1,4-dihydropyridines Chemical class 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 229910019813 Cr(CO)6 Inorganic materials 0.000 description 1
- 238000004957 LCAO calculation Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 238000009838 combustion analysis Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- YMWUJEATGCHHMB-DICFDUPASA-N deuterated dichloromethane Substances [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 1
- VQZSDRXKLXBRHJ-UHFFFAOYSA-N diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1 VQZSDRXKLXBRHJ-UHFFFAOYSA-N 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001308 heart ventricle Anatomy 0.000 description 1
- CLUPOLFGIGLMIQ-UHFFFAOYSA-N heptane;propan-2-ol Chemical compound CC(C)O.CCCCCCC CLUPOLFGIGLMIQ-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
Definitions
- This invention is directed to ⁇ 6 metal complexes of 4-aryl-1,4-dihydropyridines. These compounds are calcium channel antagonists and are useful for
- Muscle contraction and neuronal discharge are regulated by the passage of calcium ions into cells through voltage-dependent channels in the cell membrane.
- a number of drugs are known that act as agonists or antagonists for the flow of calcium ions through the calcium channel.
- the 4-aryl-1,4-dihydropyridines are an important class of calcium channel antagonist drugs that inhibit flow of calcium ions through the channels into cells to diminish muscle contraction and neuronal discharge.
- 4-aryl-1,4-dihydropyridines wherein the arene group is substituted with substituents selected from the group consisting of halogeno, cyano, nitro, alkyl, and trifluoralkyl.
- heteroalkenyl, and alkenyl metal complexes are heteroalkenyl, and alkenyl metal complexes.
- 4-aryl-1,4-dihydropyridines described in previous patents or the scientific literature include ⁇ 6 metal-ligand complexes of the 4-aryl group.
- dihydropyridine analogs may also correlate with the absolute configuration of sterogenic centers, i.e., one enantiomer may be an antagonist while the other is an agonist. Reuter et al., Ann. N.Y. Acad. Sci., 522:162 (1987). Although the absolute configuration of the dihydropyridine analogs may be important to the activity of these drugs, it has been difficult to study the relationship of stereochemistry to biological activity in the past because the enantiomers are either difficult to separate or to synthesize.
- the present invention is directed to ⁇ 6 metal arene complexes of 4-aryl-1,4-dihydropyridine compounds wherein the metal has an inert gas configuration and a plurality of ⁇ acid ligands bound thereto.
- the ⁇ acid ligands are selected from the group consisting of carbonyl (CO), nitrosyl (NO), trialkyl phosphines (R 3 P) or triphenyl phosphine (Ph 3 P), phosphites (RO) 3 P, and carbonyl sulfide, or independently selected from the group consisting of CO and Ph 3 P.
- the metal arene complex is more preferably a tricarbonyl metal complex, and most preferably a tricarbonyl chromium complex.
- tricarbonyl chromium complexes have been found to have calcium channel antagonist activity, and are also useful in spectroscopic methods for studying binding of the complex to calcium channel receptors.
- ⁇ 6 arene-metal complexes of 4-aryl-1,4-dihydropyridines comprising formula (I) below, or biologically active salts thereof.
- An ⁇ 6 arene-metal complex is a complex wherein all carbon atoms of the arene ring are bonded to the metal atom.
- R 1 , R 2 , R 3 , and R 4 are lower alkyl chains, either straight chain or branched, wherein lower alkyl is defined as a carbon chain having three carbon atoms or less;
- R 5 is a metal- ⁇ acid ligand substituent wherein the metal has an inert gas configuration or wherein the outer-shell electrons of the metal, the electrons that are used by the ligand to form bond with the metal, and the 6 ⁇ electrons of the arene group are a total of eighteen electrons.
- the preferred metals for the present invention are those in Group Via of the periodic chart, namely Cr, Mo, and W.
- An especially preferred metal is chromium, although any metal-ligand-arene ring combination wherein the metal has an inert gas configuration or that satisfies the eighteen
- R 6 is selected from the group consisting of hydrogen, electron withdrawing groups and electron donating groups. More specifically, but without
- R 6 may be selected from the group consisting of hydrogen, halogen, lower alkyls, lower alkyl halides, lower alkoxys, and lower alkoxy halides.
- the metal complexes of the present invention are made from the corresponding 4-aryl-1,4-dihydropyridines.
- 4-aryl-1,4-dihydropyridines are then reacted with a metal- ⁇ acid ligand reagent in a regiospecific reaction that attaches the metal-ligand substituent to
- MC-DHPs 4-aryl-1,4-dihydropyridines
- the MC-DHPs of the present invention are the first example of using the
- FIG. 1 is a three-dimensional drawing of the crystal structure of 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-m-methoxy-phenyl]pyridine.
- FIG. 2A is a three-dimensional drawing of the boat conformation of the 4-aryl-1,4-dihydropyridines illustrating the nomenclature of the compound.
- FIG. 2B is a planar representation of the compound of FIG. 2A showing a plane of symmetry
- FIG. 3 is a 2-D NOESY NMR spectra of 3,5- dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-m-methoxy-phenyl]pyridine showing interactions between the protons of the compound.
- FIG. 4 is a graph of the log of K I for nifedipine analogs vs. the log of K I for several MC-DHPs showing the biological activity of several metallated compounds of the present invention compared to the nonmetallated compound.
- the present invention provides compounds of the general formula (I) as well as biologically active salts of such compounds.
- a biologically active salt is defined as any salt that does not interfere with the compound's calcium channel antagonist capability.
- examples of such salts include salts having chlorine or organic compounds, such as acetate or carbonate, as the counter ion.
- the compounds represented by formula (I) exist in more than one isomeric form because R 6 can be attached to either the ortho, meta, or para position of the arene group.
- R 6 can be attached to either the ortho, meta, or para position of the arene group.
- the 4-aryl ring is substituted with both R 5 and R 6 , and R 6 is in the ortho or meta position, the compounds exist as two enantiomers.
- the MC-DHP has a plane of symmetry (FIG. 2B) that bisects the molecule into two identical halves. Hence, these molecules are achiral.
- R 6 in the ortho or meta position the molecules do not have a plane of symmetry and they are chiral.
- the present invention includes all isomeric and enantiomeric forms of the MC-DHPs, including racemic mixtures and enantiomerically enriched mixtures.
- "Enantiomerically enriched” is defined to mean a mixture of stereoisomers having a greater percentage of one enantiomer so that the mixture rotates plane polarized light.
- R 1 , R 2 , R 3 , and R 4 are lower alkyl chains wherein the carbon chain has three or less carbon atoms.
- the carbon chains can be straight chains or branched chains. Examples include methyl, ethyl, propyl, and isopropyl groups.
- R 1 through R 4 can be selected independently from one another such that each substituent is different.
- the R 5 metal ligand of formula (I) is an ⁇ 6 metal complex of the arene group of the 4-aryl-1,4-dihydropyridines wherein the metal has a plurality of ⁇ acid ligands bound thereto.
- a ligand is a molecule or ion that has at least one electron pair that can be donated to an electron acceptor such as a metal.
- a ⁇ acid ligand forms compounds with transition metal atoms because the metal has d orbitals that can be used in bonding, and the ligand has both donor and acceptor orbitals. Bonding of CO to a transition metal
- the ⁇ acid ligand stabilizes low oxidation states in metals (i.e., low positive, zero or negative formal oxidation states) because these ligands have vacant orbitals of ⁇ symmetry that can accept electron density from filled metal orbitals to form a type of ⁇ bonding.
- This ⁇ back-bonding is synergistic with the donation of lone-pair electrons from the ligand in forming ⁇ bonds with the metal.
- This ability of a ligand to accept electron density into low-lying empty ⁇ orbitals is referred to as ⁇ acidity wherein acidity is used in the Lewis acid sense.
- ⁇ acidity wherein acidity is used in the Lewis acid sense.
- a preferred ⁇ acid ligand for the present invention is CO, and a preferred R 5 substituent is a metal-tricarbonyl substituent.
- the compounds of the present invention are preferably if metal arene complexes of a 4-aryl-1,4-dihydropyridine wherein the metal has a plurality of ⁇ acid ligands bound thereto and has an inert gas
- An inert gas configuration is one in which the bonding and nonbonding orbitals resulting from the linear combination of atomic orbitals are filled.
- Cr has nine bonding and nonbonding orbitals when it bonds with a ⁇ acid ligand.
- each bonding and nonbonding orbital is filled with two electrons from the ligands bound to the metal (for a total of 18 electrons), the Cr assumes an inert gas configuration.
- a particular inert gas configuration is achieved in a ⁇ 6 metal arene complex of a 4-aryl-1,4-dihydropyridine wherein the metal has a plurality of ⁇ acid ligands bound thereto, and the outer shell
- the electrons used by the ⁇ acid ligands to bind to the metal, and the 6 ⁇ electrons of the arene group are a total of eighteen electrons.
- the eighteen electrons necessary to provide an inert gas configuration are satisfied by: (1) the 6 ⁇ electrons of the arene ring; (2) the number of outer-shell electrons supplied by the particular metal, which depends upon the oxidation state of the metal; and (3) the number of electrons used by the ⁇ acid ligands to bind to the metal.
- Two electrons are used by the ⁇ acid ligands for each carbonyl and Ph 3 P, whereas three
- CO and Ph 3 P can be selected independently from each other so that the metal may have three carbonyl or three triphenylphosphine ligands, or an appropriate
- a specific example of a metal-ligand-arene combination satisfying the eighteen electron count is: (1) Cr (0), having five 3d electrons and one 4s electron for a total of 6 outer-shell electrons; three carbonyl ligands donating two electrons each for a total of six electrons; and the six ⁇ electrons of the arene ring. These eighteen electrons provide an inert gas
- a second example of a metal-ligand-arene combination satisfying the eighteen electron count is: (1) Cr (0), having five 3d electrons and one 4s electron for a total of six outer-shell electrons; two NO ligands donating three electrons each for a total of six
- a third example of a metal-ligand- ⁇ 6 arene combination satisfying the eighteen electron count is an Fe(0)-ligand-arene combination: Fe(0) has six 3d electrons and two 4s electrons for a total of eight electrons; two carbonyl or triphenylphosphine ligands donating two electrons each for a total of four
- These eighteen electrons provide an inert gas configuration for Fe(CO) 2 -arene, Fe[(Ph 3 )P] 2 -arene, or Fe(diene) 2 -arene complexes.
- any metal-ligand- ⁇ 6 arene combination that provides an inert gas configuration for the metal is within the scope of the present invention. More particularly, for the transition metals, an inert gas configuration may be satisfied by providing a metal-ligand- ⁇ 6 arene
- the metals may be those that have six electrons in their outer shell. Therefore, a preferred group of metals are those in Group VIa of the periodic chart, namely Cr(3d 5 ,4s 1 ), Mo(4d 5 ,5s 1 ), and W(5d 4 , 6s 2 ). More particularly, a preferred embodiment of the present invention employs tricarbonyl chromium as the R 5 group.
- R 6 may be hydrogen, an electron withdrawing group (EWG), or an electron donating group (EDG).
- EWG electron withdrawing group
- EDG electron donating group
- “Electron withdrawing” is defined as any compound or substituent that withdraws electron density to a greater extent than does a hydrogen atom.
- Examples of electron withdrawing groups that are suitable for R 6 include halogens and lower alkyl halides.
- “Electron donating” is defined as any compound or substituent that releases electron density greater than does a hydrogen atom.
- Examples of electron donating groups that are suitable for R 6 include methyl, ethyl, and alkoxy. More particularly, R 6 may be selected from the group consisting of hydrogen, halogen, lower alkyls, lower alkyl halides, lower alkoxys, and lower alkoxy halides.
- R 6 may be at any isomeric position on the arene ring, i.e., in the ortho, meta, or para position.
- FIG. 1 shows the crystal structure of 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-m-methoxy-phenyl]pyridine having the Cr(CO) 3 group attached to one face of the arene group and situated over the C-3 or C-5 ester as the compounds are numbered in FIG. 2.
- the crystal structure indicates that the compounds may adopt a favorable minimum-energy conformation wherein the dihydropyridine is relatively planar and the metal-ligand substituent is in a position that also allows the compounds to bind to the calcium channel protein receptor.
- FIG. 2 shows the boat conformation of the dihydropyridine molecule.
- FIG. 2 also illustrates the endo-exo and ap-sp terminology that it is used to describe the conformations of the 4-aryl-1,4-dihydropyridines.
- Endo refers to a conformation wherein the arene group has rotated about the C-4-arene bond so that the R 6 derivative is opposite the bowsprit hydrogen.
- the esters can be found in an sp
- the compounds of the present invention are synthesized by first forming the 4-aryl-1,4-dihydropyridines according to the Hantzsch pyridine synthesis.
- an aromatic aldehyde such as benzaldehyde
- the 4-aryl-1,4-dihydropyridines are formed in a typical yield of about 42-80%.
- the Hantzsch pyridine reaction is followed by thin layer chromatography (TLC), and the disappearance of the aromatic aldehyde is monitored using ultraviolet irradiation.
- TLC thin layer chromatography
- the TLC is typically run in an solvent system comprising a 1:1:1 mixture of hexane/ethyl acetate/methylene chloride.
- the product has a typical Rf of about .15-.35 in this solvent system.
- R 1 -R 2 can also be changed. For instance, by adding one carbon atom to the starting material, the methyl groups at C-2 and C-6 are changed to ethyl groups, as in Scheme 2 below.
- R 6 includes a variety of substituents.
- R 6 is determined by selecting an aromatic aldehyde as the starting material that has the
- triflouroalkylbenzaldehydes were used as the aromatic aldehyde starting materials. Tolualdehydes or other alkylbenzaldehydes can also be used as the starting material. These materials, including the anisaldehydes, can be obtained from chemical companies such as Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wisconsin.
- the product was typically purified by filtering it through celite and then
- the product can also be purified using silica-gel
- 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4 [ ⁇ 6 -tricarbonylchromiumphenyl] pyridine was obtained from 3 ,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine by reacting chromium hexacarbonyl in refluxing N-butylether-tetrahydrofuran solution (9:1). The product was obtained in 76% yield as a bright yellow crystalline solid by recrystallization from
- carbonyl ligands can be removed and replaced by a Ph 3 P ligand.
- the carbonyl ligands can be removed by means known in the art such as photolysis. In this manner, the tricarbonyl complex can be converted into a
- carbonyl-bis(triphenylphosphine) metal complex carbonyl-bis(triphenylphosphine) metal complex.
- carbonyl or triphenylphosphine ligands can be replaced with an appropriate stoichiometric number of other ⁇ acid ligands.
- the 4-aryl-1,4-dihydropyridines have two six electron systems: the six electrons of the
- the metal- ⁇ acid ligand reagent has a choice of six electron systems with which to react. It has been found, however, that regiospecific metallation occurs in the present
- the preferred compounds of the present invention are: 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-o-fluorophenyl] pyridine;
- a particularly preferred embodiment of the compounds of the present invention are 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-o-fluorophenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-o-trifluoromethylphenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[ ⁇ 6 -tricarbonylchromium-o-chlorophenyl] pyridine, and
- Chiral MC-DHP compounds result from the synthesis described above when R 6 is other than hydrogen and is in the ortho or meta position.
- the stereoisomers can be separated by HPLC chiral stationary phase
- the particular chiral stationary phase column used for separating the MC-DHP enantiomers was either a Chiralcel-OJ column or a Chiracel-OD column, both manufactured by Daicel Chemical Industries, Inc., Exton, Pennsylvania.
- the stationary phase is silica impregnated with a modified cellulose derivative, the Chiralcel-OD column being a carbonate derivative, and the Chiralcel-OJ column being an ester derivative.
- the compound was dissolved in 10% isopropanol-heptane and injected into the HPLC Chiralcel-OJ or Chiralcel-OD column.
- the compounds separated according to this method are
- a is the chromatographic separation factor, where an a value of 1.05 represents a baseline separation.
- the enantiomers can be separated in either analytical quantities (equal to or less than a mg) or, if a semi-preparative 20 ⁇ 250 mm OJ column is used, then preparative amounts (5-10 mg) can be separated on each HPLC injection.
- the arene metal group is an electron withdrawing moiety. Electron withdrawing groups on dihydropyridine rings often correlate with greater calcium channel antagonist biological activity. However, the steric bulk of the tricarbonyl metal substituent must be presented in a favorable orientation in the receptor "cavity" in order for the compounds to bind with the protein receptor. Prior to making and isolating the compounds of the present invention, it was not known what effect the relatively bulky metal-ligand
- FIG. 1 structure of the 2-methoxy derivative (FIG. 1) shows that the tricarbonyl chromium substituent is positioned over one of the ester groups at either the C-3 or C-5 positions. This structure apparently and unexpectedly allows the compound to assume a favorable topographic configuration that allows it to bond to the calcium channel. While the solid state crystal structure may not correlate well with the solution dynamics of the compounds, it at least indicates that a favorable, minimum-energy conformation may exist that allows the 4-aryl-1,4-dihydropyridine-metal complexes to bind to the protein receptor.
- Nonspecific binding is binding of the antagonist to a location on a protein other than the calcium channel receptor site. Specificity of binding refers to the predominance of specific over nonspecific binding.
- membrane protein (40-120 micrograms) was incubated in 5 ml of 50 mM tris buffer at pH 7.2 for 90 minutes at 25° with 5 ⁇ 10 -11 (+) [ 3 H]PN 200 110
- [ 3 H]PN 200 110 is a standard
- radiolabeled calcium antagonist used to test the binding efficacy of potential calcium channel blockers.
- MC-DHPs Competitive binding of the MC-DHPs was performed by binding the [ 3 H]PN 200 110 to a calcium channel receptor and measuring the degree to which it was displaced from the receptor by varying concentrations of the MC-DHPs.
- the competing MC-DHPs were prepared in 100% ethanol as 10 -3 M stock solutions. Subsequent dilutions were made using 50% ethanol (10 -4 M) or distilled water (10 -5 and greater). All dilutions were prepared on the day of the experiment. Concentrations of ethanol up to 0.2% (v:v) did not affect specific binding. Binding data were analyzed by iterative curve fitting programs (BDATA, CDATA, EMF software, Knoxville, Tennessee). Iterative curve fitting is a mathematical procedure for matching an observed series of data to a function, and estimating the level of confidence in the correlation.
- FT-IR, 13 C-NMR, 2D-NMR and NOE can be performed on the receptor and bound antagonist.
- the shift of the carbonyl absorption would be monitored between 2200-1800 cm -1 .
- the spectral shifts of the carbonyls on the metal atom will change sufficiently on binding to the protein receptor to provide information about how the protein binds to the MC-DHPs. For example, if the carbonyl substituents hydrogen bond to the amino acids of the protein receptor, the bond order of the carbonyl is effectively reduced. As a result, the FT-IR bands corresponding to the carbonyl substituents shift to lower frequencies.
- FIG. 3 shows a 2-D NOESY spectra of 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl- 4[n 6 -tricarbonylchromium-m-methoxyphenyl] pyridine.
- the 2-D NOESY spectra provides information concerning the conformation of the MC-DHPs.
- the e-f correlation arises from interactions between the m-OCH 3 group and the C-2/6 methyl groups of the DHP, and therefore provides evidence that the MC-DHPs exist in the endo conformation (see FIG. 2A).
- the f-g correlation is between ethyl esters and arises from an ap ester conformation.
- the g-e correlation probably arises from the m-OCH 3 group in the endo conformation and an ap ester.
- NOE experiments were also used to determine the conformation of the MC-DHPs. NOE experiments determine the proximity of nuclei, and are more generally used to determine the proximity of protons on the same molecule. When protons absorb energy in an NMR experiment, they are excited to a higher energy state. The excited nuclei must thereafter relax and release the excited state energy to the surrounding chemical environment. If an excited proton is within about 4 A of another proton, then the excited proton may release its energy to the proton proximate to it. Thus, the NOE
- the conformation information obtained from the 2-D NOESY NMR spectra and the NOE experiments can be compared with the spectral absorptions of the MC-DHPs upon binding to the model peptides or the calcium channel receptor. This information can be used to investigate the conformational changes that occur when the MC-DHPs bind to model peptides or the calcium channel receptor.
- Ligands other than carbonyl may be used to form the MC-DHPs. These ligands can have nuclei suitable for NMR experiments such as ( 15 NO). Therefore, a heteronuclear NMR (an NMR that excites heteroatoms as opposed to exciting hydrogen) can focus on a particular heteroatom such as N. The heteronuclear NMR spectra of the ligand will provide information concerning the chemical environment of each heteroatom examined
- nuclei such as 15 N and 31 P
- the coupling of protons from the calcium channel receptor to the ligands would result in spectral shifts in the NMR, both for the heteroatom in heteroatom NMR spectra and for protons coupled to the heteroatom in the proton spectra.
- [ 3 H]PN 200 110 is shown below in Table 5.
- the K I values of the MC-DHPs compare favorably with the K I value for the 4-phenyl-1,4-dihydropyridines that are not
- K I is the concentration at which 50% of the
- radiolabeled calcium antagonist is displaced from a membrane preparation that contains the protein receptor. Therefore, a lower K I value correlates with greater MC-DHP-receptor binding activity.
- nH is the Hill
- the O-Cl derivative has a lower K I value than does the m-methoxy derivative.
- Table 5 indicates that a lower concentration of the electron withdrawing derivatives is required to effectively compete with [ 3 H]PN 200 110 than the electron donating derivatives.
- FIG. 4 is a substantially straight line graph of the log of the K I for nifedipine versus the log K I of the MC-DHPs shown on the graph.
- FIG. 4 shows that the electron withdrawing groups are much more active than the electron releasing groups.
- the CF 3 -chromium derivative [CF 3 is a strong electron withdrawing substituent] has a - log [K I ] value of about 10
- the 2-methoxy derivative an electron donating
- FIG. 4 shows that the 2-CF 3 .
- chromium derivative has a greater activity than the 2-methoxy-chromium derivative.
- the least reactive is the 4-methoxy derivative, presumably because the 4-substituted compounds interfere with binding at the protein receptor.
- a robust calcium channel antagonist is one having a K I ⁇ 10 -6 , and the results shown in FIG. 4 and Table 5 indicate that the MC-DHPs of the present invention are robust calcium channel antagonists. Moreover, these results suggest that the MC-DHPs readily bind to the protein receptor. Thus, the MC-DHPs of the present invention are efficient calcium channel antagonists, and moreover, because of their unique spectroscopic
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Abstract
The present invention is directed to θ6 metal complexes of the arene group of 4-aryl-1,4-dihydropyridines. The 4-aryl-1,4-dihydropyridines are made according to the Hantzsch pyridine synthesis, and are then reacted with a π acid ligand-metal reagent to attach the metal in an θ6 fashion to the 6π electrons of the arene ring. The 4-aryl-1,4-dihydropyridine metal complexes are designed to provide useful spectroscopic information concerning the conformation of the 4-aryl-1,4-dihydropyridines and how such compounds interact with the calcium channel protein. Moreover, the 4-aryl-1,4-dihydropyridine metal complexes are robust calcium antagonists and compare to or exceed the biological activity of previously known calcium channel antagonists.
Description
η6 METAL COMPLEXES OF 4-ARYL- 1, 4-DIHYDROPYRIDINES
Field of the Invention
This invention is directed to η6 metal complexes of 4-aryl-1,4-dihydropyridines. These compounds are calcium channel antagonists and are useful for
investigating drug-protein receptor interactions.
Acknowledgement
This invention was developed with funding from the National Institutes of Health, Contract No. 1-R15-GM42029-01, and the National Science Foundation,
Contract No. R11-8902065. The United States government may have rights in the invention.
Background of the Invention
Muscle contraction and neuronal discharge are regulated by the passage of calcium ions into cells through voltage-dependent channels in the cell membrane. A number of drugs are known that act as agonists or antagonists for the flow of calcium ions through the calcium channel. The 4-aryl-1,4-dihydropyridines are an important class of calcium channel antagonist drugs that inhibit flow of calcium ions through the channels into cells to diminish muscle contraction and neuronal discharge.
The 4-aryl-1,4-dihydropyridines have been described previously in the scientific literature, and a number of patents have disclosed these compounds. For instance, Semararo et al.'s U.S. Patent Nos. 4,935,548 and 5,011,848 describe 4-aryl-1,4-dihydropyridines substituted with an aerylate derivative ortho to the dihydropyridine. Stoltefuss et al.'s U.S. Patent No. 5,017,590 and Wehinger et al.'s U.S. Patent No.
4,988,717 describe 4-aryl-1,4-dihydropyridines having chiral C-3 ester side chains. Hargreaves et al.'s U.S. Patent No. 4,873,254 describes
4-aryl-1,4-dihydropyridines wherein the arene group is substituted with substituents selected from the group consisting of halogeno, cyano, nitro, alkyl, and
trifluoralkyl. The arene group may also include =N-O-N=attached to the 5- and 6- positions.
Metal complexes have been described for some chemical systems other than the 4-aryl-1,4-dihydropyridines. It is known, for instance, that
Cr(CO)6 reacts efficiently with dienamines. Kutney et al., J. Am. Chem. Soc., 95:3058-3060 (1973); Kutney et al., J. Am. Chem. Soc., 96:7364-7365 (1974). Hegedus et al., "Principles and Applications of Organotransition Chemistry," University Science Books, Mill Valley, Ca. (1980) describes a number of aryl, alkenyl,
heteroalkenyl, and alkenyl metal complexes.
Furthermore, tricarbonyl metal complexes of biologically important hydrocarbons such as the steroids have been made. Steroids such as progesterone [Jaouen, et al., Inorσ. Chem., 27:1850-1852 (1988)] and estrogen [Jaouen et al., Pure & Appl. Chem., 57:1865-1874
(1985)], however, do not include highly reactive
functional groups, nor do they include more than one six electron region that may react with a metal reagent.
Hence, there is no competition between sites at which metallation may occur. Furthermore, this prior work does not disclose how metal reagents will react with highly functionalized molecules that have more than one six electron region capable of reacting with a metal reagent. Moreover, none of the
4-aryl-1,4-dihydropyridines described in previous patents or the scientific literature include η6 metal-ligand complexes of the 4-aryl group.
It has also been observed that structural changes in biologically active compounds, especially changes that introduce sterically bulky groups, may perturb drug-receptor interactions or abolish biological activity. For example, a quantitative structure
activity relationship directed to the pharmacology of 46 dihydropyridines concluded that steric interactions are important in determining the biological activity of 4- aryl-1,4-dihydropyridine calcium antagonists such as
nifedipine [1,4-dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-3,5-pyridinedicarboxylic acid dimethyl ester] analogs. Triggle et al., J. Med. Chem., 31:2103-2107 (1988).
Hence, one would expect that introducing bulky groups into dihydropyridines could diminish calcium channel blocking activity.
Increased biological activity for
dihydropyridine analogs may also correlate with the absolute configuration of sterogenic centers, i.e., one enantiomer may be an antagonist while the other is an agonist. Reuter et al., Ann. N.Y. Acad. Sci., 522:162 (1987). Although the absolute configuration of the dihydropyridine analogs may be important to the activity of these drugs, it has been difficult to study the relationship of stereochemistry to biological activity in the past because the enantiomers are either difficult to separate or to synthesize.
Although many 4-aryl-1,4-dihydropyridine compounds have been described in the literature, the search continues for novel 4-aryl-1,4-dihydropyridines that are useful calcium channel blockers. Efforts must also be made to find new methods for investigating the structure activity relationship, including the drug-receptor binding interactions, of such compounds. The study of this relationship will help assess which structural molecular changes result in maximal
biological activity. Previously described 4-aryl-1,4-dihydropyridines, although they may have biological activity, do not provide information concerning the structure activity relationships involved in binding to calcium channel proteins unless the biological
activities of a series of 4-aryl-1,4-dihydropyridines are compared. It would be more efficient to design one molecule or a small class of molecules to provide information concerning the structure activity
relationship involved in binding calcium antagonists to calcium channel proteins.
SUMMARY OF THE INVENTION
The present invention is directed to η6 metal arene complexes of 4-aryl-1,4-dihydropyridine compounds wherein the metal has an inert gas configuration and a plurality of π acid ligands bound thereto. The π acid ligands are selected from the group consisting of carbonyl (CO), nitrosyl (NO), trialkyl phosphines (R3P) or triphenyl phosphine (Ph3P), phosphites (RO)3P, and carbonyl sulfide, or independently selected from the group consisting of CO and Ph3P. The metal arene complex is more preferably a tricarbonyl metal complex, and most preferably a tricarbonyl chromium complex. The
tricarbonyl chromium complexes have been found to have calcium channel antagonist activity, and are also useful in spectroscopic methods for studying binding of the complex to calcium channel receptors. The
dihydropyridines of the present invention are
particularly useful for spectroscopic studies of the carbon monoxide ligand because the metal shifts the spectral bands of the ligands bound to the metal to a region where there is minimal interference from other spectral absorptions. Hence, the molecular interactions of the ligand and receptor can be observed
spectroscopically in a region that is relatively free of interference from other spectral absorptions.
More particularly, the present invention is directed to η6 arene-metal complexes of 4-aryl-1,4-dihydropyridines comprising formula (I) below, or biologically active salts thereof. An η6 arene-metal complex is a complex wherein all carbon atoms of the arene ring are bonded to the metal atom. With reference to compound (I), R1, R2, R3, and R4 are lower alkyl chains, either straight chain or branched, wherein lower alkyl is defined as a carbon chain having three carbon atoms or less; R5 is a metal-π acid ligand substituent wherein the metal has an inert gas configuration or wherein the outer-shell electrons of the metal, the electrons that are used by the ligand to form bond with
the metal, and the 6 π electrons of the arene group are a total of eighteen electrons. The preferred metals for the present invention are those in Group Via of the periodic chart, namely Cr, Mo, and W. An especially preferred metal is chromium, although any metal-ligand-arene ring combination wherein the metal has an inert gas configuration or that satisfies the eighteen
electron count is within the scope of the present invention; and R6 is selected from the group consisting of hydrogen, electron withdrawing groups and electron donating groups. More specifically, but without
limitation, R6 may be selected from the group consisting of hydrogen, halogen, lower alkyls, lower alkyl halides, lower alkoxys, and lower alkoxy halides.
Formula 1
The metal complexes of the present invention are made from the corresponding 4-aryl-1,4-dihydropyridines. The 4-aryl-1,4-dihydropyridines are synthesized in refluxing ammonia from a mixture of an aromatic aldehyde and 2 equivalents of a β-ketoester. The resulting
4-aryl-1,4-dihydropyridines are then reacted with a metal-π acid ligand reagent in a regiospecific reaction that attaches the metal-ligand substituent to
predominantly the 6 π electrons of the arene system, as opposed to the six electrons of the dienamine.
Regiospecific metallation is achieved by reacting the 4-aryl-1,4-dihydropyridines with metal-carbonyl reagents in refluxing
N-butylether/tetrahydrofuran (9:1).
Steric hindrance is an important factor in determining the biological activity of the 4-aryl-1,4-dihydropyridines. Dihydropyridines having bulky
substitutents, especially in the para position, have been found to be less likely to bind to the calcium channel receptor. The metal-ligand complexes of the 4-aryl-1,4-dihydropyridines (MC-DHPs) have an
intermediate size, hence it was uncertain whether steric hindrance would prevent the MC-DHPs from binding to channel receptors or other proteins. These steric considerations made it unclear that the MC-DHPs of the present invention would have calcium channel blocking activity or be useful in determining spectroscopic changes that occur when the 4-aryl-1,4-dihydropyridines interact with protein receptors.
However, it has been found that the 4-aryl-1,4-dihydropyridine metal complexes are robust calcium antagonists and compare to or exceed the biological activity of previously known calcium channel
antagonists. Furthermore, the MC-DHPs of the present invention are the first example of using the
spectroscopic characteristics of η6 metal-ligand
complexes to study the drug receptor interactions of the 4-aryl-1,4-dihydropyridines. The spectroscopic shifts in the ligands that accompany the binding of the metal-ligand substituent to the 4-aryl-1,4-dihydropyridines and the MC-DHPs to calcium channel receptor, such as the carbonyl shifts in the IR and 13C spectra, and the proton shifts in the proton NMR spectra, are helpful in
studying the conformation of the MC-DHPs and the
interactions that occur when the MC-DHPs bind to the calcium protein receptor. Furthermore, it has been possible to separate enantiomers of the MC-DHP using either analytical or semi-preparative chiral stationary
phase HPLC techniques. Thus, it is possible to study what effect the different enantiomers have on biological activity.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a three-dimensional drawing of the crystal structure of 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-m-methoxy-phenyl]pyridine.
FIG. 2A is a three-dimensional drawing of the boat conformation of the 4-aryl-1,4-dihydropyridines illustrating the nomenclature of the compound.
FIG. 2B is a planar representation of the compound of FIG. 2A showing a plane of symmetry
bisecting the molecule.
FIG. 3 is a 2-D NOESY NMR spectra of 3,5- dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-m-methoxy-phenyl]pyridine showing interactions between the protons of the compound.
FIG. 4 is a graph of the log of KI for nifedipine analogs vs. the log of KI for several MC-DHPs showing the biological activity of several metallated compounds of the present invention compared to the nonmetallated compound.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of the general formula (I) as well as biologically active salts of such compounds.
Formula 1
A biologically active salt is defined as any salt that does not interfere with the compound's calcium channel antagonist capability. Without limitation, examples of such salts include salts having chlorine or organic compounds, such as acetate or carbonate, as the counter ion.
The compounds represented by formula (I) exist in more than one isomeric form because R6 can be attached to either the ortho, meta, or para position of the arene group. When the 4-aryl ring is substituted with both R5 and R6, and R6 is in the ortho or meta position, the compounds exist as two enantiomers. If the metal is attached to one face and R6 is in the para position, the MC-DHP has a plane of symmetry (FIG. 2B) that bisects the molecule into two identical halves. Hence, these molecules are achiral. However, with R6 in the ortho or meta position, the molecules do not have a plane of symmetry and they are chiral. The present invention includes all isomeric and enantiomeric forms of the MC-DHPs, including racemic mixtures and enantiomerically enriched mixtures. "Enantiomerically enriched" is defined to mean a mixture of stereoisomers having a greater percentage of one enantiomer so that the mixture rotates plane polarized light.
In compound (I), R1, R2, R3, and R4, are lower alkyl chains wherein the carbon chain has three or less carbon atoms. The carbon chains can be straight chains or branched chains. Examples include methyl, ethyl, propyl, and isopropyl groups. Furthermore, R1 through R4 can be selected independently from one another such that each substituent is different.
The R5 metal ligand of formula (I) is an η6 metal complex of the arene group of the 4-aryl-1,4-dihydropyridines wherein the metal has a plurality of π acid ligands bound thereto. A ligand is a molecule or ion that has at least one electron pair that can be donated to an electron acceptor such as a metal. A π acid ligand forms compounds with transition metal atoms because the metal has d orbitals that can be used in bonding, and the ligand has both donor and acceptor orbitals. Bonding of CO to a transition metal
illustrates the mechanism of π bonding ligands. A filled carbon σ orbital of the CO overlays with a σ orbital on the metal ion. Electron flow from the carbon to the metal in this overlap would lead to an
unacceptable concentrar.ion of electron density on a metal ion that does not have at least a +2 charge. The metal reduces the electron density by pushing electrons back to the π orbitals of the ligand, which is possible because the ligand's orbitals can accept electron density.
The π acid ligand stabilizes low oxidation states in metals (i.e., low positive, zero or negative formal oxidation states) because these ligands have vacant orbitals of π symmetry that can accept electron density from filled metal orbitals to form a type of π bonding. This π back-bonding is synergistic with the donation of lone-pair electrons from the ligand in forming σ bonds with the metal. This ability of a ligand to accept electron density into low-lying empty π orbitals is referred to as π acidity wherein acidity is used in the Lewis acid sense. The concept of π acid
ligands is well understood in the art, and is described in greater detail in Cotton and Wilkinson, Advanced
Inorganic Chemistry, 4th Edition (1980) at pages 62, 82-95, and 1049-1079, which are incorporated by reference. Examples of such π acid ligands include, without
limitation, CO, NO, and Ph3P. A preferred π acid ligand for the present invention is CO, and a preferred R5 substituent is a metal-tricarbonyl substituent.
The compounds of the present invention are preferably if metal arene complexes of a 4-aryl-1,4-dihydropyridine wherein the metal has a plurality of π acid ligands bound thereto and has an inert gas
configuration. An inert gas configuration is one in which the bonding and nonbonding orbitals resulting from the linear combination of atomic orbitals are filled.
For example, Cr has nine bonding and nonbonding orbitals when it bonds with a π acid ligand. When each bonding and nonbonding orbital is filled with two electrons from the ligands bound to the metal (for a total of 18 electrons), the Cr assumes an inert gas configuration.
A particular inert gas configuration is achieved in a η6 metal arene complex of a 4-aryl-1,4-dihydropyridine wherein the metal has a plurality of π acid ligands bound thereto, and the outer shell
electrons of the metal, the electrons used by the π acid ligands to bind to the metal, and the 6 π electrons of the arene group are a total of eighteen electrons.
Therefore, the eighteen electrons necessary to provide an inert gas configuration are satisfied by: (1) the 6 π electrons of the arene ring; (2) the number of outer-shell electrons supplied by the particular metal, which depends upon the oxidation state of the metal; and (3) the number of electrons used by the π acid ligands to bind to the metal. Two electrons are used by the π acid ligands for each carbonyl and Ph3P, whereas three
electrons are required for each NO ligand. Hence, CO and Ph3P can be selected independently from each other so that the metal may have three carbonyl or three
triphenylphosphine ligands, or an appropriate
stochiometric combination of CO and Ph3P ligands, such as M(CO)2Ph3P or M(CO) (Ph3P)2.
A specific example of a metal-ligand-arene combination satisfying the eighteen electron count is: (1) Cr (0), having five 3d electrons and one 4s electron for a total of 6 outer-shell electrons; three carbonyl ligands donating two electrons each for a total of six electrons; and the six π electrons of the arene ring. These eighteen electrons provide an inert gas
configuration for chromium in the Cr(CO)3-η6 arene complex. The outer-shell electron count for the other atoms in Group VIa (W and Mo) are the same as Cr, and the W(CO)3-η6 arene and Mo(CO)3-η6 arene complexes would satisfy the eighteen electron requirement in the same way.
A second example of a metal-ligand-arene combination satisfying the eighteen electron count is: (1) Cr (0), having five 3d electrons and one 4s electron for a total of six outer-shell electrons; two NO ligands donating three electrons each for a total of six
electrons; and the six π electrons of the arene ring. These eighteen electrons provide an inert gas
configuration for chromium in the Cr(NO)2-η6 arene complex.
A third example of a metal-ligand-η6 arene combination satisfying the eighteen electron count is an Fe(0)-ligand-arene combination: Fe(0) has six 3d electrons and two 4s electrons for a total of eight electrons; two carbonyl or triphenylphosphine ligands donating two electrons each for a total of four
electrons, or the four π electrons of a diene; and the six n electrons of the arene ring. These eighteen electrons provide an inert gas configuration for Fe(CO)2-arene, Fe[(Ph3)P]2-arene, or Fe(diene)2-arene complexes.
One skilled in the art will realize that any metal-ligand-η6 arene combination that provides an inert gas configuration for the metal is within the scope of
the present invention. More particularly, for the transition metals, an inert gas configuration may be satisfied by providing a metal-ligand-η6 arene
combination having a total of eighteen electrons.
Alternatively, the metals may be those that have six electrons in their outer shell. Therefore, a preferred group of metals are those in Group VIa of the periodic chart, namely Cr(3d5,4s1), Mo(4d5,5s1), and W(5d4, 6s2). More particularly, a preferred embodiment of the present invention employs tricarbonyl chromium as the R5 group.
R6 may be hydrogen, an electron withdrawing group (EWG), or an electron donating group (EDG). "Electron withdrawing" is defined as any compound or substituent that withdraws electron density to a greater extent than does a hydrogen atom. Examples of electron withdrawing groups that are suitable for R6 include halogens and lower alkyl halides. "Electron donating" is defined as any compound or substituent that releases electron density greater than does a hydrogen atom. Examples of electron donating groups that are suitable for R6 include methyl, ethyl, and alkoxy. More particularly, R6 may be selected from the group consisting of hydrogen, halogen, lower alkyls, lower alkyl halides, lower alkoxys, and lower alkoxy halides. Furthermore, R6 may be at any isomeric position on the arene ring, i.e., in the ortho, meta, or para position.
The compounds of the present invention have the metal-carbonyl substituent attached to one face of the arene ring. FIG. 1 shows the crystal structure of 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-m-methoxy-phenyl]pyridine having the Cr(CO)3 group attached to one face of the arene group and situated over the C-3 or C-5 ester as the compounds are numbered in FIG. 2. The crystal structure indicates that the compounds may adopt a favorable minimum-energy conformation wherein the dihydropyridine is relatively planar and the metal-ligand substituent is in a position
that also allows the compounds to bind to the calcium channel protein receptor.
FIG. 2 shows the boat conformation of the dihydropyridine molecule. FIG. 2 also illustrates the endo-exo and ap-sp terminology that it is used to describe the conformations of the 4-aryl-1,4-dihydropyridines. Endo refers to a conformation wherein the arene group has rotated about the C-4-arene bond so that the R6 derivative is opposite the bowsprit hydrogen. Furthermore, the esters can be found in an sp
(synperiplanar, i.e., the esters are on the same (syn) side of the molecule and in the same plane)
conformation, or in an ap (antiperiplanar, i.e., on opposite sides (anti) of the molecule but in the same plane) conformation.
The compounds of the present invention are synthesized by first forming the 4-aryl-1,4-dihydropyridines according to the Hantzsch pyridine synthesis. As a typical example of this reaction, an aromatic aldehyde, such as benzaldehyde, is reacted with 2 equivalents of ethyl acetoacetate in refluxing
ammonia. Without limiting the invention to one
mechanistic theory, this reaction is believed to proceed as shown in Scheme 1.
Scheme 1
In this manner, the 4-aryl-1,4-dihydropyridines are formed in a typical yield of about 42-80%.
The Hantzsch pyridine reaction is followed by thin layer chromatography (TLC), and the disappearance of the aromatic aldehyde is monitored using ultraviolet irradiation. The TLC is typically run in an solvent system comprising a 1:1:1 mixture of hexane/ethyl acetate/methylene chloride. The product has a typical Rf of about .15-.35 in this solvent system.
One skilled in the art will realize that, by varying the alkyl chains on the esters of the β-keto ester starting material, the alkyl chains of the C-3 and C-5 esters may also be varied. Moreover, by lengthening the carbon chain of the β-ketoester starting material, R1-R2 can also be changed. For instance, by adding one carbon atom to the starting material, the methyl groups at C-2 and C-6 are changed to ethyl groups, as in Scheme 2 below.
Scheme 2
As stated above, R6 includes a variety of substituents. R6 is determined by selecting an aromatic aldehyde as the starting material that has the
appropriate substituent attached to the aromatic ring at a desired position relative to the aldehyde functional group. For instance, if the starting aldehyde is ortho, meta, or para anisaldehyde (o-,m-, or p-methoxy
benzaldehyde) the
4-aryl-1,4-dihydropyridines are substituted with a methoxy group at the ortho, meta, or para position of the arene group. This strategy is shown in Scheme 3.
Scheme 3
Similarly, halobenzaldehydes and
triflouroalkylbenzaldehydes were used as the aromatic aldehyde starting materials. Tolualdehydes or other alkylbenzaldehydes can also be used as the starting
material. These materials, including the anisaldehydes, can be obtained from chemical companies such as Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wisconsin.
Once the desired 4-aryl-1,4-dihydropyridine was obtained, the MC-DHPs were formed by dissolving the
4-aryl-1,4-dihydropyridine in n-butlether/tetrahydrofuran (9:1) to form a solution having a concentration of about 0.05-0.20 M. This solution was maintained under an inert atmosphere such as nitrogen or argon. A carbonyl-metal reagent,
typically a hexacarbonyl metal, was then added to the solvent and the resulting mixture heated to reflux.
Example 1. This reaction is generally allowed to
continue for about 72 hours. The product was typically purified by filtering it through celite and then
recrystallizing it using hexanes/ethyl acetate. The product can also be purified using silica-gel
chromatography.
Example 1
3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4 [η6-tricarbonylchromiumphenyl] pyridine was obtained from 3 ,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine by reacting chromium hexacarbonyl in refluxing N-butylether-tetrahydrofuran solution (9:1). The product was obtained in 76% yield as a bright yellow crystalline solid by recrystallization from
benzene/hexanes. The spectroscopic properties and combustion analysis of this compound were: IR: 1964, 1884, 1695. 1H NMR: 55.87 (br. s 1H); 5.6 (d, 2H); 5.43 (t, 1H); 4.98 (t, 2H); 4.82 (S, 1H); 4.22 (q, 4H); 2.41 (s, 6H); 1.29 (t, 6H). 13C NMR: 233.3 (CrCO), 167.1, 145.3, 118.9, 102.9, 97.4, 96.0, 87.7, 60.3, 36.7,
19.55, 14.3. Mass spectrum: M/Z 465 (1.1% rel.
intensity, M+), 437 (3), 409 (8.4), 381 (91); 392 (3.2), 336 (2.2), 252 (100). Analysis. (C22H23NO7Cr)
calculated: c, 56.77; h, 4.98; N, 3.01. Found: c 56.53; h 4.83; n, 3.8.
Once the metal-arene complex is formed, it is possible to substitute a different π acid ligand for those bound to the metal. For instance, if the metal has 3 carbonyl ligands bound thereto, one of the
carbonyl ligands can be removed and replaced by a Ph3P ligand. The carbonyl ligands can be removed by means known in the art such as photolysis. In this manner, the tricarbonyl complex can be converted into a
dicarbonyl-triphenylphosphine metal complex or a
carbonyl-bis(triphenylphosphine) metal complex. In a similar fashion, carbonyl or triphenylphosphine ligands can be replaced with an appropriate stoichiometric number of other π acid ligands.
The 4-aryl-1,4-dihydropyridines have two six electron systems: the six electrons of the
dihydropyridine's dienamine system; and the 6 π
electrons of the phenyl ring. Thus, the metal-π acid ligand reagent has a choice of six electron systems with which to react. It has been found, however, that regiospecific metallation occurs in the present
invention. Regiospecific metallation, defined as attachment of the metal to predominantly the 6 π
electrons of the arene group, is unambiguously
established as η6 to the 4-aryl substituent by the 1H and 13C NMR chemical shifts. Assignments also have been made unambiguously by 2D 1H-13C correlation, and off resonance decoupling. As an example of how the spectral
assignments confirm that metallation is η6, the
following assignments were made for 3 , 5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4-[η6-tricarbonyl chromium phenyl] pyridine. The proton chemical shifts of the 4-phenyl substituent for the starting material (57.0-7.2 ppm) shifted dramatically upfield (54.9 to 5.6) upon substitution with chromium tricarbonyl. Similarly, the carbon signals for the aromatic ring were prominently shifted upfield, from 147.7, 127.8, 127.7, and 126 to 118.9, 97.4, 96.0, and 87.HP LaserJet Series
IItional)HPLASEII.PRS and 103.8 (C=C-NH-) for the
starting material to 167.1, 145.3 and 102.9 for the corresponding tricarbonyl chromium complex.
The compounds made according to the synthetic schemes discussed above are listed in Table 1, along with the corresponding IR spectral data, MS molecular ion peak, yield, and melting point. Additional NMR spectroscopic data for the compounds is presented in Tables 2 and 3. The data presented in Tables 1-3 establishes that the compounds as listed were actually made. Moreover, the data provides reference values for comparing the spectral shifts of the compounds upon binding to either model receptors or calcium channel receptors. Table 2 also shows that the 13C absorption for the carbonyl ligands is between about 200 ppm and 235 ppm, well above the absorption for the ester side chain carbonyl from about 165 ppm to about 175 ppm. Hence, the absorption in the carbonyl ligand is not obscured by other spectral absorptions.
TABLE 1 Physical Characterization Data for Tricarbonyl Chromium Complexes of Hantzsch Esters
Entry R G Yield(%)a m.p. IRb MSc
(ºC) (υCO) (X RI)
1 CH3 o-F 49 188(d) 1973 424
(ethanol) 1899 (2.8)e
1700
2 CH2CH3 0-CF3 42 125-6 1980 533 (0.2)
(Ether1910 488 (0.3)f
hexane) 1695
3 CH2CH3 o-Cl 74 161-2 1972 499 (0.2)
(THF- 1901 456 (3.2)f
heptane) 1694 454 (6.2)f
4 CH3 o-Cl 63 190Cd) 1972 442 (1.2)e
(EtQAc- 1902 440 (2.7)e
heptane) 1699
5 CH2CH3 H 76 157-8 1963 465
(hexane) 1884 (1.1)
1695
6 CH3 H 80 193-4 1964 437
(benzene) 1886 (1.6)
1702
7 CH2CH3 o-OCH3 59 175(d) 1961 495
(THF- 1882 (0.6)
heptane) 1694
8 CH3 o-OCH3 71 220(d) 1960d 467 (0.7)
(EtOAc- 1882 436 (4.3)e
heptane) 1703
9 CH2CH3 m-OCH3 66 143-4 1960 495
(hexane) 1879 (1.0)
1695
10 CH2CH3 p-OCH3 56 170-2 1961 495
(ethanol) 1880 (0.4)
1692 aYield of product after isolation and purification, all compounds gave analytical (C,H,N) and/or accurate mass results within acceptable limits, results of which have been provided to the editor.
bDichloromethane solvent, unless otherwise noted.
cHolecular ion unless otherwise noted.
dTetrahydrofuran solvent.
e[M-OCH3].
f[M-OCH2CH3]]
TABLE 2
13 C NMR Chemical Shifts, CDCl3 unless otherwise noted. (Coupling constants are in Hz)
Entry 1 ,4-Dihydropyridine C-2, 6 CH3's 4-Aryl G CCORCr(CO)3
C-2,6 C-3,5 C-4
1a 146.8 101. 31.2 18.0 125.9 (d,JCF=273) ... 166.6, 203.2 146.4 100. 7 17.7 110.4 (d,JCF=15) 166.4
97.4 (d,JCF=5) 50.8
96.4 (d,JCF=8)
86.8
78.3 (d,JCF =23)
2 144.4 105.6 43.3 19.3 117.2 123.9 167.2 231.1 143.9 103.7 100.1 (JCF=34) (JCF=276) 166.9
94.7, 93.8 60.5, 60.2
88.3, 84.5 13.9
3 144.8 105.1 34.8 19.6 119.1. 116.2 ... 166.9 232.1 143.7 104.9 19.4 96.2, 95.0 60.6, 60.1
87.7, 85.3 14.4, 14.3
4 145.0 104.9 34.8 19.6 118.6, 116.2 ... 167.2 232.1 144.3 104.4 19.2 96.1, 95.0 167.1
87.8, 85.3 51.5, 51.2
5 145.3 102.9 36.7 19.6 118.9 ... 167.1 233.3
97.4 60.3
96.0 14.3
87.7
6a 155.1 101.9 35.9 16.3 125.6 ... 176.5 214.9
104.9 51.7
102.2
94.0
7 144.5 104.0 32.3 19.3 142.4, 110.3 55.4 167.2 233.5 143.9 103.8 19.2 98.8, 95.1 60.1 , 59.9
82.7, 71.6
8a 146. 101. 31.7 17.8 143.0. 110.1 55.8 167.2 202.2 145. 100. 17.7 99.0, 97.0 166.7
84.6, 74.4 40.7, 50.6
9 145, 102.6 36.9 19.6 139.2, 121.4 55.9 167.1 233.7 145, 102.4 90.0, 89.9 167.0
84.0, 80.2 60.3
14.3
10 145.3 102.8 35.6 19.6 143.7, 113.6 55.4 167.2 233.6
19.5 96.7, 76.6 60.3
14.3 a DMSO-d6
TABLE 3
1 H NMR Chemical Shifts, CDCl3 solvent unless otherwise noted.
Entry 1,4-Dihydropyridine 4-Aryl G COORN-H
C-4 C-2,6 CH3's
1a 5.00 (s,1H) 2.42 (s,3H) 5.52-8 (m,2H) -132.5c 3.73 (s,3H) 6.02 (br.s.,1H)
2.35 (s,3H) 5.18 (d,1H) 3.66 (s,3H)
4.67 (t,1H)
2 5.18 (s,1H) 2.30 (s,6H) 5.47-5.5 -40.6d 4.09-4.29 (m,4H) 6.04 (br.s.,1H)
(m, 2H) 1.31 (t,3H)
5.17 (d,1H) 1.25 (t,3H)
5.02 (t,1H)
3 5.14 (S,1H) 2.46 (s,3H) 5.57 (d,1H) ... 4.10-4.40 (m,4H) 5.8 (s,1H)
2.39 (s,3H) 5.46 (t,1H) 1.34 (s,3H)
5.19 (d,1H) 1.25 (s,3H)
4.71 (t,1H)
4 5.12 (sr1H) 2.47 (s,3H) 5.56 (d,1H) ... 3.80 (s,3H) 5.78 (br.s,1H)
2.41 (s,3H) 5.45 (t,1H) 3.66 (s,3H)
5.2 (d,1H)
4.71 (t,1H)
5 4.82 (s,1H) 2.40 (s,6H) 5.60 (d,2H) ... 4.21-4.23 (m,4H) 5.87 (s,1H)
5.43 (t,1H) 1.29 (t,6H)
4.98 (t,2H)
6b 4.62 (s,1H) 2.29 (s,6H) 5.75 (t,1H) ... 3.62 (s,6H) 9.22 (s,1H)
5.63 (d,2H)
5.33 (t,2H)
7 5.18 (s,1H) 2.41 (s,3H) 5.62 (d,1H) 3.74 (s,3H) 4.20 (q,2H) 5.9 (br.s,1H)
2.35 (s,3H) 5.51 (t,1H) 4.12 (q,2H)
4.86 (d,1H) 1.30 (t,3H)
4.62 (t,1H) 1.23 (t,3H)
8 5.16 (s,1H) 2.43 (s,3H) 5.56 (d,1H) 3.7 (s,3H) 3.76 (s,6H) 5.79 (br.s,1H)
2.34 (S,3H) 5.51 (t,1H)
4.87 (d,1H)
4.62 (t,1H)
9 4.96 (s,1H) 2.39 (s,6H) 5.48 (m,1H) 3.63 (s,3H) 4.1-4.3 (m,4H) 6.04 (br.s,1H)
5.1-5.2 (m,3H) 1.31 (t,3H)
1.29 (t,3H)
10 4.76 (s,1H) 2.38 (s,6H) 5.63 (d,2H) 3.66 (s,3H) 4.2 (q,4H) 6.11 (br.s.,1H)
4.90 (d,2H) 1.28 (t,6H) aCD2Cl2
bDMSO-d6
cDecoupled 19F NMR, compared to -118.3 for the corresponding "free ligand."
decoupled 19F NMR, compared to -55.2 for the corresponding "free ligand." The preferred compounds of the present invention are: 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-fluorophenyl] pyridine;
3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-trifluoromethylphenyl]
pyridine; 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl]
pyridine; 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl]
pyridine; 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromiumphenyl] pyridine;
3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromiumphenyl] pyridine;
3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-methoxyphenyl] pyridine;
3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-methoxyphenyl] pyridine;
3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-m-methoxyphenyl] pyridine;
and 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-p-methoxyphenyl]
pyridine.
A particularly preferred embodiment of the compounds of the present invention are 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-fluorophenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-trifluoromethylphenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl] pyridine, and
3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl] pyridine.
Chiral MC-DHP compounds result from the synthesis described above when R6 is other than hydrogen and is in the ortho or meta position. The stereoisomers can be separated by HPLC chiral stationary phase
techniques. The particular chiral stationary phase column used for separating the MC-DHP enantiomers was either a Chiralcel-OJ column or a Chiracel-OD column, both manufactured by Daicel Chemical Industries, Inc., Exton, Pennsylvania. The stationary phase is silica impregnated with a modified cellulose derivative, the
Chiralcel-OD column being a carbonate derivative, and the Chiralcel-OJ column being an ester derivative.
To separate the enantiomers, the compound was dissolved in 10% isopropanol-heptane and injected into the HPLC Chiralcel-OJ or Chiralcel-OD column. The compounds separated according to this method are
presented below in Table 4. The tR entry is the
retention time of the compounds in minutes on the chiral HPLC column, and a is the chromatographic separation factor, where an a value of 1.05 represents a baseline separation. The enantiomers can be separated in either analytical quantities (equal to or less than a mg) or, if a semi-preparative 20 × 250 mm OJ column is used, then preparative amounts (5-10 mg) can be separated on each HPLC injection.
TABLE 4
HPLC-CSP separation of Tricarbonyl Chromium complexes of Hantzsch esters, Entry numbers correspond to compounds in Table 1.
Compound R G tR 'a αb
(min.) 1 CH3 o-F tR1'=92.2 1.08
tR2'=100.0
2 CH2CH3 O-CF3 tR1'=5.4 1.89
tR2'=10.2
3 CH2CH3 o-Cl tR1'=76.0 1.26
tR2'=95.5
4 CH3 o-Cl tR1'=97.0 1.15
tR2'=111.4
7 CH2CH3 o-OCH3 tR1'=121.9 1.05
tR2'=127.9
tR1'=32.2 3.03c
tR2'=97.6
8 CH3 o-OCH3 tR1'=172.0 1.09
tR2'=183.2
9 CH2CH3 m-OCH3 tR1'=70.6 1.10
tR2'=77.8
tR1'=151.9 1.25c
tR2'=190.3 aAdjusted retention times.
bSeparation of enantiomers was performed on a Chiralcel-OD column.
cChiralcel-OJ, at 50°C. The arene metal group is an electron withdrawing moiety. Electron withdrawing groups on dihydropyridine rings often correlate with greater calcium channel antagonist biological activity. However, the steric bulk of the tricarbonyl metal substituent must be presented in a favorable orientation in the receptor "cavity" in order for the compounds to bind with the protein receptor. Prior to making and isolating the compounds of the present invention, it was not known what effect the relatively bulky metal-ligand
substituent would have on the compound's binding to the protein receptor. It was possible that the metal would be excessively bulky and therefore diminish or eliminate
calcium channel blocking activity. The crystal
structure of the 2-methoxy derivative (FIG. 1) shows that the tricarbonyl chromium substituent is positioned over one of the ester groups at either the C-3 or C-5 positions. This structure apparently and unexpectedly allows the compound to assume a favorable topographic configuration that allows it to bond to the calcium channel. While the solid state crystal structure may not correlate well with the solution dynamics of the compounds, it at least indicates that a favorable, minimum-energy conformation may exist that allows the 4-aryl-1,4-dihydropyridine-metal complexes to bind to the protein receptor.
Protein Receptor Binding
Studies were performed to assess the specificity of binding and expected biological activity of the
compounds of the present invention. Specific binding occurs when the calcium channel antagonist binds to the calcium channel region of the protein receptor.
Nonspecific binding is binding of the antagonist to a location on a protein other than the calcium channel receptor site. Specificity of binding refers to the predominance of specific over nonspecific binding.
To investigate the specificity of the MC-DHP compounds and their use as probes for drug receptor interaction, fresh membrane preparations were treated with a [(hydroxymethyl)amino] methane (tris) buffer solution of the compounds. Microsomal membranes from guinea pig heart ventricles were prepared as described in J. Pharmacological Experimental Therapy. 225:291 (1983), and J. Pharmacological Experimental Therapy.
231:291 (1984), incorporated herein by reference.
Briefly, membrane protein (40-120 micrograms) was incubated in 5 ml of 50 mM tris buffer at pH 7.2 for 90 minutes at 25° with 5 × 10-11 (+) [3H]PN 200 110
(isopropyl-4-(2,1,3-benzoxydizol-4-yl)1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate) and varying concentrations of the competing MC-DHPs of the
present invention. [3H]PN 200 110 is a standard
radiolabeled calcium antagonist used to test the binding efficacy of potential calcium channel blockers. (+)
[3H]PN 200 110 with a specific activity of 70 Ci/Mol [Ci = curies = 3.7 × 1010 Bq; becquerel (Bq) = 1 nuclear transformation/second] was purchased from DuPont-New England Nuclear of Boston, Massachusetts. Duplicate tubes containing 10-7 M (+) [3H]PN 200 110 were used to define nonspecific binding. All tubes, including the duplicate tubes, were filtered and washed rapidly with 2-5 ml portions of ice-cold tris buffer in a Brandell cell harvester [Model M-24R, Brandell Instruments Ltd., Gaithesburg, Maryland]. The trapped radioactivity was then counted by liquid scintillation spectrometry at an efficiency of 40-45% to determine whether or to what extent binding occurred.
Competitive binding of the MC-DHPs was performed by binding the [3H]PN 200 110 to a calcium channel receptor and measuring the degree to which it was displaced from the receptor by varying concentrations of the MC-DHPs. The competing MC-DHPs were prepared in 100% ethanol as 10-3 M stock solutions. Subsequent dilutions were made using 50% ethanol (10-4 M) or distilled water (10-5 and greater). All dilutions were prepared on the day of the experiment. Concentrations of ethanol up to 0.2% (v:v) did not affect specific binding. Binding data were analyzed by iterative curve fitting programs (BDATA, CDATA, EMF software, Knoxville, Tennessee). Iterative curve fitting is a mathematical procedure for matching an observed series of data to a function, and estimating the level of confidence in the correlation.
After allowing for specific binding to the membrane preparation containing the calcium channel protein receptor, FT-IR, 13C-NMR, 2D-NMR and NOE can be performed on the receptor and bound antagonist. The shift of the carbonyl absorption would be monitored between 2200-1800 cm-1. The spectral shifts of the carbonyls on the metal atom will change sufficiently on binding to the protein
receptor to provide information about how the protein binds to the MC-DHPs. For example, if the carbonyl substituents hydrogen bond to the amino acids of the protein receptor, the bond order of the carbonyl is effectively reduced. As a result, the FT-IR bands corresponding to the carbonyl substituents shift to lower frequencies.
Experiments using characteristic 13C NMR carbonyl absorptions of the metal carbonyl groups were conducted with the isolated compound not bound to the calcium channel protein. See Table 2. Due to both the low natural abundance of 13C and limitations due to the concentrations of MC-DHP, the MC-DHPs can be enriched in a stable isotope at the metal-carbonyl functional group. The metal-carbonyl substituent can be enriched in 13C by performing a 13C photochemical exchange with CO. See, for instance, Bitterwolf et al., Polyhedron. 7:1377-82 (1988), incorporated herein by reference. 13CO can be purchased from chemical companies such as Aldrich
Chemical Company of Milwaukee, Wisconsin. As with the IR spectra, the shifts of the carbon atom of the
carbonyl group correlate with the chemical environment of the MC-DHPs. If the carbonyl is hydrogen bonded, the conjugation of the C-O is reduced. Therefore, the corresponding peak in the 13C NMR shifts from about 250 ppm to about 200 ppm. Initial binding and spectral studies involved model - (ARG-X-X)n - ARG peptides, which were also prepared enriched in 13C.
In addition to the FT-IR and 13C NMR studies described above, both NOE and 2-D NOESY NMR experiments can be used to study the conformation of the MC-DHPs and their interaction with both the model peptides and putative receptor protein. FIG. 3 shows a 2-D NOESY spectra of 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl- 4[n6-tricarbonylchromium-m-methoxyphenyl] pyridine. The 2-D NOESY spectra provides information concerning the conformation of the MC-DHPs. In FIG. 3, the
correlations of the protons labelled a-e and b-e
correspond to the
m-OCH3. The e-f correlation arises from interactions between the m-OCH3 group and the C-2/6 methyl groups of the DHP, and therefore provides evidence that the MC-DHPs exist in the endo conformation (see FIG. 2A). The f-g correlation is between ethyl esters and arises from an ap ester conformation. The g-e correlation probably arises from the m-OCH3 group in the endo conformation and an ap ester.
NOE experiments were also used to determine the conformation of the MC-DHPs. NOE experiments determine the proximity of nuclei, and are more generally used to determine the proximity of protons on the same molecule. When protons absorb energy in an NMR experiment, they are excited to a higher energy state. The excited nuclei must thereafter relax and release the excited state energy to the surrounding chemical environment. If an excited proton is within about 4 A of another proton, then the excited proton may release its energy to the proton proximate to it. Thus, the NOE
experiments provided further information concerning the conformation of the
MC-DHPs. The conformation information obtained from the 2-D NOESY NMR spectra and the NOE experiments can be compared with the spectral absorptions of the MC-DHPs upon binding to the model peptides or the calcium channel receptor. This information can be used to investigate the conformational changes that occur when the MC-DHPs bind to model peptides or the calcium channel receptor.
Ligands other than carbonyl may be used to form the MC-DHPs. These ligands can have nuclei suitable for NMR experiments such as (15NO). Therefore, a heteronuclear NMR (an NMR that excites heteroatoms as opposed to exciting hydrogen) can focus on a particular heteroatom such as N. The heteronuclear NMR spectra of the ligand will provide information concerning the chemical
environment of each heteroatom examined
spectroscopically. Furthermore, proton coupling to nuclei such as 15N and 31P can be determined
spectroscopically. Therefore, if the carbonyl ligand is replaced with a nitrosyl ligand (15NO) or a Ph3 31P ligand, then additional NMR experiments can be conducted which would provide information regarding the chemical
environment of the ligands. For example, the coupling of protons from the calcium channel receptor to the ligands would result in spectral shifts in the NMR, both for the heteroatom in heteroatom NMR spectra and for protons coupled to the heteroatom in the proton spectra.
The effect of MC-DHPs on the binding of
[3H]PN 200 110 is shown below in Table 5. The KI values of the MC-DHPs compare favorably with the KI value for the 4-phenyl-1,4-dihydropyridines that are not
substituted with the R5 metal-ligand complex (see Fig. 4). KI is the concentration at which 50% of the
radiolabeled calcium antagonist is displaced from a membrane preparation that contains the protein receptor. Therefore, a lower KI value correlates with greater MC-DHP-receptor binding activity. nH is the Hill
coefficient and is a measure of whether the drug-receptor interaction is unimolecular, biomolecular etc. The Hill coefficients shown below indicate that the interaction between the MC-DHPs and the protein receptor is unimolecular.
TABLE 5
Effect of MC-DHPs on [ 3H]PN 200110 binding to guinea pig heart membranes.28 Entry numbers correspond to compounds in Table 1.
Compound G R Kl,M nH N
3 o-Cl CH2CH3 1.91 ± 0.59 × 10-9 0.96 t 0.07 6
5 H CH2CH3 9.2 ± 2.0 × 10-9 0.72 ± 0.05 6
6 H CH3 1.56 ± 0.41 × 10-7 0.87 ± 0.05 4
9 m-OCH3 CH2CH3 7.41 ± 1.6 × 10-8 0.97 ± 0.13 4 N = number of individual experiments each performed in duplicate.
Within the limitations of this series, it appears that binding follows the order EWG greater than H
greater than EDG. For instance, the O-Cl derivative has a lower KI value than does the m-methoxy derivative.
Hence, Table 5 indicates that a lower concentration of the electron withdrawing derivatives is required to effectively compete with [3H]PN 200 110 than the electron donating derivatives.
FIG. 4 is a substantially straight line graph of the log of the KI for nifedipine versus the log KI of the MC-DHPs shown on the graph. FIG. 4 shows that the electron withdrawing groups are much more active than the electron releasing groups. For example, the CF3-chromium derivative [CF3 is a strong electron withdrawing substituent] has a - log [KI] value of about 10, whereas the 2-methoxy derivative (an electron donating
substituent) has a -log [KI] value of about 8. The smaller the value of KI, the more active a compound is in competitive binding studies. The -log of a small KI value is a larger positive number than the -log of a large KI value. Therefore, FIG. 4 shows that the 2-CF3. chromium derivative has a greater activity than the 2-methoxy-chromium derivative. Moreover, the least reactive is the 4-methoxy derivative, presumably because
the 4-substituted compounds interfere with binding at the protein receptor.
A robust calcium channel antagonist is one having a KI < 10-6, and the results shown in FIG. 4 and Table 5 indicate that the MC-DHPs of the present invention are robust calcium channel antagonists. Moreover, these results suggest that the MC-DHPs readily bind to the protein receptor. Thus, the MC-DHPs of the present invention are efficient calcium channel antagonists, and moreover, because of their unique spectroscopic
properties, provide detailed spectroscopic information concerning the solution and solid state conformation of the MC-DHPs and how they may bind to the protein
receptor.
Having illustrated and described the principles of the invention in several preferred embodiments, it should be apparent to those skilled in the art that the invention can be modified in arrangement and detail without departing from such principles. We claim all modifications coming within the spirit and scope of the following claims.
Claims
1. A calcium channel antagonist compound
comprising an η6 metal arene complex of a 4-aryl-1,4-dihydropyridine wherein the metal has a plurality of π acid ligands bound thereto and has an inert gas
configuration.
2. The compound according to claim 1 wherein the π acid ligands are selected from the group consisting of CO, NO, and Ph3P.
3. The compound according to claim 1 wherein the π acid ligands are independently selected from the group consisting of CO and Ph3P.
4. The compound according to claim 1 wherein the metal is chromium (0) and the plurality of π acid ligands are three carbonyl ligands.
5. The compound according to claim 1 wherein the outer shell electrons of the metal, the 6 π electrons of the arene ring, and the electrons used by the π acid ligands to form a bond with the metal are a total of eighteen electrons.
6. A calcium channel antagonist compound
comprising an η6 metal arene complex of a 4-aryl-1,4-dihydropyridine wherein the metal has a plurality of π acid ligands bound thereto, and the outer shell
electrons of the metal, the electrons used by the π acid ligands to form a bond with the metal, and the 6 π electrons of the arene group are a total of eighteen electrons.
7. A compound according to claim 6 wherein the metal is selected from Group Via of the periodic chart.
8. A compound according to claim 6 wherein the metal is selected from the group consisting of chromium, molybdenum, and tungsten.
9. A compound according to claim 1 wherein R5 is chromium (O), and the plurality of π acid ligands are three carbonyl ligands.
10. A calcium channel antagonist compound
according to formula (I), or a biologically active salt thereof:
wherein R1, R2, R3, and R4 are independently selected from the group consisting of lower alkyls, R5 is a metal substituent having a plurality of π acid ligands bound thereto wherein the outer shell electrons of the metal, the electrons used by the π acid ligands to form a bond with the metal, and the 6 π electrons of the arene group are a total of eighteen electrons, and R6 is selected from the group consisting of hydrogen, electron
withdrawing groups and electron donating groups.
11. The dihydropyridine compound of claim 10 wherein R6 is selected from the group consisting of hydrogen, halogen, lower alkyls, lower alkyl halides, lower alkoxys, and lower alkoxy halides.
12. The dihydropyridine compound of claim 10 wherein the metal is selected from Column Via of the periodic chart.
13. The dihydropyridine compound of claim 10 wherein the metal is selected from the group consisting of chromium, tungsten, and molybdenum.
14. The dihydropyridine compound of claim 10 wherein the metal is chromium and the plurality of π acid ligands are three carbonyl ligands.
15. The dihydropyridine compound of claim 10 wherein R6 is in the ortho or meta position.
16. The compound according to claim 10 wherein R1, R2, R3, and R4 are selected independently from the group consisting of methyl and ethyl.
17. The dihydropyridine compound of claim 10 wherein the compound is chiral.
18. The dihydropyridine compound of claim 10 wherein the dihydropyridine compound is enantiomerically enriched.
19. The dihydropyridine compound of claim 10 wherein the compound is selected from the group
consisting of 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-fluorophenyl]
pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-trifluoromethylphenyl]
pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl] pyridine, 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromiumphenyl] pyridine, 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromiumphenyl]pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-methoxyphenyl] pyridine, 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-methoxyphenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-m-methoxyphenyl] pyridine, and 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-p-methoxyphenyl] pyridine.
20. The compound according to claim 19 wherein said compound displaces [3H]PN 200 110 binding at calcium channels in cardiac membrane preparations.
21. The compound according to claim 20 wherein said compound is selected from the group consisting of 3,5-dicarbomethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-fluorophenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-trifluoromethylphenyl] pyridine, 3,5-dicarboethoxy-1,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl] pyridine, and
3,5-dicarbomethoxy-l,4-dihydro-2,6-dimethyl-4[η6-tricarbonylchromium-o-chlorophenyl] pyridine.
22. A method for regiospecifically metallating a 4-aryl group of a 4-aryl-1,4-dihydropyridine comprising reacting the 4-aryl-1,4-dihydropyridine compound with a metal-π acid ligand compound in refluxing n-butylether/tetrahydrofuran.
23. The method according to claim 22 wherein the metal-π acid ligand compound is chromium hexacarbonyl.
24. A method for analyzing drug receptor
interactions, comprising the steps of:
treating fresh membrane preparations with a solution of a 4-arene-1,4-dihydropyridine compound which is regiospecifically metallated with a metal-π acid ligand compound wherein the outer shell electrons of the metal, the electrons used by the π acid ligands to form a bond with the metal, and the 6 π electrons of the arene group are a total of eighteen electrons; and
determining the spectroscopic changes that occur when the compound resulting from regiospecific
metallation of the 4-arene-1,4-dihydropyridine interacts with a drug receptor.
25. The method according to claim 24 wherein the metal is selected from column Via of the periodic chart.
26. The method according to claim 24 wherein the metal is chromium (O) and the π acid ligands bound thereto are three carbonyl ligands.
27. The method according to claim 26 wherein the method is used to analyze the spectroscopic changes that occur upon interaction of 4-arenetricarbonylchromium-1,4-dihydropyridines with a calcium channel protein.
28. The method according to claim 24 wherein the step of determining the spectroscopic changes includes determining the shift of the carbonyl groups in an IR spectra, the shift of carbonyl carbon atoms in a 13C NMR spectra, and the shift of proton atoms in a proton NMR spectra.
29. The method according to claim 24 wherein the carbonyl groups are monitored from about 1800 cm-1 to about 2200 cm-1 in the IR spectra and from about 200 ppm to about 250 ppm in the 13C spectra.
30. The method according to claim 24 wherein the conformation of the drug upon binding to the protein receptor is determined by Nuclear Overhauser Effect experiments.
31. The method according to claim 24 wherein the compound resulting from regiospecific metallation of the 4-arene-1,4-dihydropyridine is chiral and including the step of separating enantiomers using a chiral HPLC column.
32. The method according to claim 31 wherein the membrane preparations are allowed to
interact with each enantiomer.
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WO2011149757A1 (en) * | 2010-05-26 | 2011-12-01 | Synthonics, Inc. | Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients |
CN110483563A (en) * | 2019-09-06 | 2019-11-22 | 山西医科大学 | A kind of preparation method and application of novel ionic betanaphthol aldehyde schiff bases zirconium complex |
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Non-Patent Citations (4)
Title |
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HEGEDUS, "Principles and Applications of Organotransition Chemistry", Chapter 14, 651-672, (1980). * |
J. MED. CHEM., 35, 1165-1168, (1992), HUBLER et al., "Tricarbonyl Chromium...". * |
JAOUEN et al., "Transition Metal Carbonyl Oestrogen Receptor Assay", PURE & APP. CHEM., 57:1865-1874, (1985). * |
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Cited By (5)
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US8779175B2 (en) | 2004-10-25 | 2014-07-15 | Synthonics, Inc. | Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients |
US9624256B2 (en) | 2004-10-25 | 2017-04-18 | Synthonics, Inc. | Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients |
WO2011149757A1 (en) * | 2010-05-26 | 2011-12-01 | Synthonics, Inc. | Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients |
CN110483563A (en) * | 2019-09-06 | 2019-11-22 | 山西医科大学 | A kind of preparation method and application of novel ionic betanaphthol aldehyde schiff bases zirconium complex |
CN110483563B (en) * | 2019-09-06 | 2021-12-28 | 山西医科大学 | Preparation method and application of novel ionic beta-naphthoic aldehyde Schiff base zirconium complex |
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