WO2011137739A1 - Platinum (ii) complexes having n-alkyl substituted trans-1,2-diaminocyclohexanes as ligands and preparation method thereof - Google Patents
Platinum (ii) complexes having n-alkyl substituted trans-1,2-diaminocyclohexanes as ligands and preparation method thereof Download PDFInfo
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- WO2011137739A1 WO2011137739A1 PCT/CN2011/073630 CN2011073630W WO2011137739A1 WO 2011137739 A1 WO2011137739 A1 WO 2011137739A1 CN 2011073630 W CN2011073630 W CN 2011073630W WO 2011137739 A1 WO2011137739 A1 WO 2011137739A1
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- formula
- platinum
- substituted
- alkyl
- complex
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- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical class N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 title claims abstract description 36
- 239000003446 ligand Substances 0.000 title claims abstract description 33
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 239000007858 starting material Substances 0.000 claims abstract description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 7
- 239000011591 potassium Substances 0.000 claims abstract description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 39
- -1 carboxylic acid anion Chemical class 0.000 claims description 38
- CFQCIHVMOFOCGH-UHFFFAOYSA-N platinum ruthenium Chemical compound [Ru].[Pt] CFQCIHVMOFOCGH-UHFFFAOYSA-N 0.000 claims description 22
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 229910052697 platinum Inorganic materials 0.000 claims description 11
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000002192 fatty aldehydes Chemical class 0.000 claims description 4
- 150000003057 platinum Chemical class 0.000 claims description 4
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 3
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052709 silver Inorganic materials 0.000 claims description 3
- 239000004332 silver Substances 0.000 claims description 3
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 3
- HQLILHPGWSURBT-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxy]acetic acid Chemical compound CC(C)(C)OCC(O)=O HQLILHPGWSURBT-UHFFFAOYSA-N 0.000 claims description 2
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
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- 208000020816 lung neoplasm Diseases 0.000 abstract description 3
- 201000007270 liver cancer Diseases 0.000 abstract description 2
- 208000014018 liver neoplasm Diseases 0.000 abstract description 2
- 150000001450 anions Chemical class 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 50
- 102100028735 Dachshund homolog 1 Human genes 0.000 description 49
- 101000915055 Homo sapiens Dachshund homolog 1 Proteins 0.000 description 49
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 239000000843 powder Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000011734 sodium Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 8
- 101150065749 Churc1 gene Proteins 0.000 description 8
- 102100038239 Protein Churchill Human genes 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229960003975 potassium Drugs 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)*(C)CC(*C1CCCCC1)=C Chemical compound CC(C)*(C)CC(*C1CCCCC1)=C 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- GETUVALQSXUKQD-UHFFFAOYSA-N azetidine-3,3-dicarboxylic acid Chemical class OC(=O)C1(C(O)=O)CNC1 GETUVALQSXUKQD-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
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- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
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- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
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- CDVMXMZPDJHSCC-UHFFFAOYSA-N chembl1684662 Chemical compound C=1C=C2C=C(C=3C4=NC=CC=C4NN=3)NC2=CC=1CC(=O)C1=CC=CC=C1 CDVMXMZPDJHSCC-UHFFFAOYSA-N 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000005406 washing Methods 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a fluorene-alkyl substituted trans 1,2-cyclohexanediamine as a ruthenium Platinum ( ⁇ ) complex of ligand and preparation method thereof.
- a fluorene-alkyl substituted trans 1,2-cyclohexanediamine as a ruthenium Platinum ( ⁇ ) complex of ligand and preparation method thereof.
- a primary object of the present invention is to provide a platinum complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand.
- Y in the formula (la) is an organic carboxylic acid anion
- Z in the formula (lb) is an organic dicarboxylic acid dianion
- 1 is a 3 ⁇ 4 - 3 ⁇ 4 alkyl group
- an asterisk * represents a chiral carbon atom
- the compound of the formula (la) and the formula (lb) is a chiral isomer having a 1R, 2R-configuration and/or a 2 configuration.
- the above C 3 -C 8 alkyl group may be a chain alkyl group or a cyclic alkyl group.
- Y in formula (la) is -C 16 alkoxyacetate or C 2 -C 18 alkylcarboxylate
- Z in formula (lb) is an organic dicarboxylic acid dianion, including oxalic acid Root, malonate, 1,1-cyclosuccinate, 3-hydroxy-1,1-cyclosuccinate, 3-alkoxy-1,1-cyclosuccinate, 3-aza-1, 1-cyclosuccinate, N-substituted 3-aza-1, 1-cyclosuccinate or camphordionate; N-substituted 3-aza-1, 1-cyclobutanedioate, substituent Benzyl substituted with benzyl, C r C 4 alkyl a benzyl group substituted with a dC 4 alkoxy group or a halogen group, wherein the substituent on the benzyl group may be at any position of the aromatic ring.
- the structure of a platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand is represented by the formula ( lb ), wherein R is a butyl group and a cyclopentane group.
- Base, Z is oxalate, malonate, 1,1-cyclosuccinate; more preferred structure is: R is sec-butyl, cyclopentyl, Z is oxalate, malonate, 1,1-ring Succinate.
- the structure of the platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand is as shown in formula (la) or formula (lb), wherein R Is propyl, Y is C 2 -C 4 alkoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1, 1
- the substituent is a benzyl group, a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group;
- a more preferred structure is: R is an isopropyl group, and Y is a different Propyloxyacetate or tert-butoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1
- Hal represents Cl—, Br— or ⁇
- asterisk* represents a chiral carbon atom
- the compound of formula (2) is a chiral isoform having a 1R, 2R-configuration and/or a 2 configuration. Structure.
- the preparation method of the platinum (ruthenium) complex in which the ⁇ -alkyl substituted trans 1,2-cyclohexanediamine is a ligand comprises the following steps: trans 1,2-cyclohexanediamine protected by a single Boc
- the compound represented by the formula (3) is obtained by the following Scheme I, and then the formula (3)
- the compound shown is reacted with potassium tetrahalide (potassium) hydride to give the compound of formula (2);
- R is a C 3 -C 8 alkyl group according to any one of claims 1 to 6, the fatty aldehyde is a C 3 - C 8 chain alkyl aldehyde, and the aliphatic ketone is - 3 ⁇ 4 of a chain or cyclic alkyl ketone, when R is a chain alkyl group, a chain alkyl aldehyde or a chain alkyl ketone is used; when a chain alkyl aldehyde is used, R1 is.
- R 2 is a hydrogen atom; when a chain alkyl ketone is used, R 1 and R 2 are respectively a linear alkyl group of dC 6 , the sum of the carbon atoms of the two should be less than 7 or equal to 7; In the case of a cyclic alkyl group, a cyclic alkyl ketone is used, wherein X is a C 2 - C 7 alkylene group.
- the preparation of the compound of the above formula (3) has been disclosed in the prior application (CN200910027237.8).
- the Boc-protected trans 1,2-cyclohexanediamine When the Boc-protected trans 1,2-cyclohexanediamine is reacted with an aldehyde or a ketone, it is first dehydrated to form a Schiff base, which is generally isolated and purified for use in the next reaction.
- the reactants are low-grade fatty aldehydes or aliphatic ketones, because these reactants have a low boiling point, and no suitable organic solvent can be used for dehydration without aldehyde or ketone evaporation with steam;
- the base is generally liquid and difficult to purify. Therefore, for the reaction of Boc-protected trans 1,2-cyclohexanediamine with a fatty aldehyde or a fatty ketone, the Schiff base obtained in the first step of Scheme I can usually be directly separated into the next reaction without isolation.
- the N-alkyl substituted trans 1,2-cyclohexanediamine prepared according to the route I method is mainly obtained in the form of its hydrochloride salt, and the hydrochloride salt and a quantitative base such as sodium hydroxide or potassium hydroxide in water.
- the corresponding N-monosubstituted trans 1,2-cyclohexanediamine can be obtained.
- a specific method for obtaining a compound of the formula (2) by reacting a compound represented by the formula (3) with potassium tetrahalide (potassium)ate may be: a tetrahaloplatinum (potassium citrate) (6.00 mmol) and N - alkyl substituted trans 1,2-cyclohexanediamine (6.00 mmol) mixed in 50 In a solution of water, stir at room temperature overnight, with a large amount of yellow precipitate formed, filtered, washed repeatedly with water, absolute ethanol and diethyl ether, and dried to give a yellow powder.
- the compound of the formula (2) can be produced according to a known reaction to produce a compound of the formula (la) or the formula (lb), as in any one of the following methods, method 1: in the absence of light, in an aqueous solution, by silver ion removal The halide ion in formula (2) is then reacted with an alkali metal salt or ammonium salt of Y as defined by formula (la) to form a platinum (ruthenium) complex represented by formula (la), or as defined by formula (lb) Reaction of an alkali metal salt or an ammonium salt of Z to form a platinum (ruthenium) complex represented by formula (lb); Method 2: a silver salt of Y defined by formula (la) in an aqueous solution under protection from light Reaction with a platinum (II) complex represented by the formula (2) to form a platinum (ruthenium) complex represented by the formula (la), or a silver salt of Z defined by the formula (lb) and a formula (2) The platinum (ruthenium) complex reacts
- the dihalo [N-alkyl substituted trans 1,2-cyclohexanediamine] platinum (II) (2.90 mmol) represented by the formula (2) was suspended in 100 mL of water, and silver nitrate (5.80 mmol) was added thereto. After 24 to 36 hours in the dark at 60 ° C, the diatomaceous earth was assisted by filtration. A 30 mL aqueous solution of sodium carboxylate (5.80 mmol) or sodium dicarboxylate (2.90 mmol) was added to the filtrate, and then reacted at 80 ° C for 24 to 48 hours in the dark, and the solution was concentrated to precipitate a large amount of solid. Filtration, repeated washing with water, ethanol and diethyl ether, and drying in vacuo to give the desired product.
- the compounds prepared by the process of the present invention have determined the molecular structure of the compounds by infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry.
- the platinum ( ⁇ ) complex represented by the formula (la) and the formula (lb) of the present invention has a significant inhibitory effect on human liver cancer cell HepG_2, human breast cancer cell MCF-7, human lung cancer cell A549 and human colon cancer cell HCT-116.
- the inhibitory effects of related compounds and controls on different cancer cells are shown in Table 1. Specific embodiment
- the reaction was stopped, 250 mL of methanol was removed under reduced pressure, 300 mL of water was added, and extracted with diethyl ether three times (250 mIJ).
- the aqueous phase was adjusted to pH 10 with 5M aqueous sodium hydroxide solution, extracted 4 times with dichloromethane (250 mIJ times), the organic phase was combined, washed twice with saturated sodium chloride solution (100 ml J times), and the organic phase was treated with anhydrous sulfuric acid.
- the sodium was dried overnight and filtered.
- the filtrate was concentrated under reduced pressure to about 200 mL, and recrystallized from 400 mL of petroleum ether (60-90 ° C) to give white white solid (83.0 g, 77.0%).
- ⁇ platinum complexes represented by formula (la) and formula (lb) were tested for in vitro antitumor activity.
- the cancer cells used were human hepatoma cells HepG-2, human breast cancer cells MCF-7, human body.
- the positive control used for lung cancer cell A549 and human colon cancer cell HCT-116 is the existing drug cisplatin, oxaliplatin or carboplatin.
- the specific experimental methods are as follows: The cell viability is detected by MTT assay, and the cells growing in the logarithmic growth phase are counted by 0.01% trypsin, counted, and inoculated in a 96-well plate at a cell density of 2.0 ⁇ 10 3 /well, Cultured in a 5% C0 2 incubator at 37 °C Night. Six concentration gradients were set for each compound, three wells were set for each concentration, and each concentration was added to the corresponding wells, cultured in a 5% C0 2 37 °C incubator for 72 hours, and 20 mL of 5 mg/mL MTT was added. .
- the supernatant was aspirated, dissolved in 100 mL of DMSO, and the absorbance at 550 nm (Ll) was measured using a SpectraMAX 340.
- the reference wavelength was 690 nm (L2), and the (LI-L2) value was compared to the inhibitor. Drawing at different concentrations, the IC 5 o value was fitted by the formula.
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Abstract
Platinum (II) complexes having N-alkyl substituted trans-1,2-diaminocyclohexanes as ligands and the preparation method thereof are provided. The structures of the platinum (II) complexes having N-alkyl substituted trans-1,2-diaminocyclohexanes as ligands are as shown by formula (1a) and formula (1b), in which Y is an anion of organic carboxylic acid, Z is a dianion of organic dicarboxylic acid, and R is C3-8 alkyl. The said preparation method is as follows: using trans-1,2-diaminocyclohexane protected by mon-Boc as a starting material to obtain the compound represented by formula (3), then reacting it with potassium platinate tetrahalide to obtain the said compound of formula (2), reacting the compound of formula (2) to obtain the said compound of formula (1a) or formula (1b). The platinum (II) complexes shown by formula (1a) and formula (1b) in the present invention have obvious inhibition on human liver cancer cells HepG-2, human breast cancer cells MCF-7, human lung cancer cells A549, and human colon cancer cells HCT-116.
Description
N-烧基取代反式 1, 2-环己二胺为配体的铂 ( Π )配合物及其制备方法 技术领域 本发明涉及 Ν-烷基取代反式 1, 2-环己二胺为配体的铂(Π )配合物及其制备方法。 技术背景 最近十几年, 基于对铂配合物耐药机理的深入了解, 有关铂药物的研究已不再局限于顺 铂的经典构效关系, 人们开始探索新的途径研发新型铂类药物。 迄今已设计出多种不同于原 有构效关系的非经典铂类药物, 其中之一就是具有空间位阻的铂配合物。 该类代表性的化合 物就是目前已进入临床试验的 ZD0473 , 即顺 -二氯 *氨 * ( 2-甲基吡啶)合铂(11 )。 反式 1, 2- 环己二胺, 特别是其手性异构体 [ lR,2R-(-)-l,2-环己二胺, 作为载体配基, 经常被用于制备抗 肿瘤铂类配合物, 典型的化合物如已上市的药物奥沙利铂(Oxaplat in)和米铂 (Miroplat in)。 研究人员希望在反式 1, 2-环己二胺的基本结构上进行修饰, 从而以此作为配体制备新型结构 的铂配合物, 进一步筛选出高效、 低毒、 水溶性或脂溶性好、 选择性高的候选药物。 发明内容 本发明的主要目的是提供 N-烷基取代反式 1, 2-环己二胺为配体的铂配合物。 TECHNICAL FIELD The present invention relates to a fluorene-alkyl substituted trans 1,2-cyclohexanediamine as a ruthenium Platinum (Π) complex of ligand and preparation method thereof. BACKGROUND OF THE INVENTION In the past decade or so, based on an in-depth understanding of the mechanism of resistance to platinum complexes, research on platinum drugs has been no longer limited to the classical structure-activity relationship of cisplatin, and people have begun to explore new ways to develop new platinum drugs. To date, a number of non-classical platinum drugs have been designed that differ from the original structure-activity relationship, one of which is a sterically hindered platinum complex. Representative compounds of this type are ZD0473, which is currently in clinical trials, namely cis-dichloro*amino*(2-methylpyridine)platinum (11). Trans 1,2-cyclohexanediamine, especially its chiral isomer [ lR,2R-(-)-l,2-cyclohexanediamine, as a carrier ligand, is often used to prepare anti-tumor platinum Complexes, typical compounds such as the marketed drugs Oxaplatin and Miroplat in. The researchers hope to modify the basic structure of trans 1,2-cyclohexanediamine to prepare a new structure of platinum complexes as ligands, and further screen for high efficiency, low toxicity, water solubility or good fat solubility. A highly selective drug candidate. SUMMARY OF THE INVENTION A primary object of the present invention is to provide a platinum complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand.
本发明的目的还在于提供上述 N-烷基取代反式 1, 2-环己二胺为配体的铂配合物的制备 方法。 It is also an object of the present invention to provide a process for the preparation of a platinum complex in which the above N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand.
种 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 结构如式(la)和式(lb)所 a platinum (ruthenium) complex in which N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, the structure is as shown in formula (la) and formula (lb)
式 (la)中的 Y是有机羧酸阴离子, 式 (lb)中的 Z为有机二羧酸双阴离子; 式 (la)和式 (lb) 中, 1 是¾-¾的烷基, 星号 *代表手性碳原子, 式 (la)和式 (lb)所示化合物是具有 1R, 2R-构 型和 /或 2 构型的手性异构体。 上述 C3-C8的烷基可以是链状烷基或环状烷基。 Y in the formula (la) is an organic carboxylic acid anion, Z in the formula (lb) is an organic dicarboxylic acid dianion; in the formula (la) and the formula (lb), 1 is a 3⁄4 - 3⁄4 alkyl group, an asterisk * represents a chiral carbon atom, and the compound of the formula (la) and the formula (lb) is a chiral isomer having a 1R, 2R-configuration and/or a 2 configuration. The above C 3 -C 8 alkyl group may be a chain alkyl group or a cyclic alkyl group.
作为优选方案, 式 (la)中的 Y为 -C16的烷氧基乙酸根或 C2-C18的烷基羧酸根; 式 (lb) 中的 Z是有机二羧酸双阴离子, 包括草酸根、 丙二酸根、 1,1-环丁二酸根、 3-羟基 -1,1-环丁二 酸根、 3-烷氧基 -1,1-环丁二酸根、 3-氮杂 -1, 1-环丁二酸根、 N-取代的 3-氮杂 -1, 1-环丁二酸 根或樟脑二酸根; N-取代的 3-氮杂 -1, 1-环丁二酸根中, 取代基为苄基、 CrC4烷基取代的苄
基、 d-C4烷氧基取代的苄基或卤原子取代的苄基, 其中苄基上的取代基可以在芳环的任一位 置。 Preferably, Y in formula (la) is -C 16 alkoxyacetate or C 2 -C 18 alkylcarboxylate; Z in formula (lb) is an organic dicarboxylic acid dianion, including oxalic acid Root, malonate, 1,1-cyclosuccinate, 3-hydroxy-1,1-cyclosuccinate, 3-alkoxy-1,1-cyclosuccinate, 3-aza-1, 1-cyclosuccinate, N-substituted 3-aza-1, 1-cyclosuccinate or camphordionate; N-substituted 3-aza-1, 1-cyclobutanedioate, substituent Benzyl substituted with benzyl, C r C 4 alkyl a benzyl group substituted with a dC 4 alkoxy group or a halogen group, wherein the substituent on the benzyl group may be at any position of the aromatic ring.
作为优选方案, 一种 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物的结构如式 ( lb )所示, 其中 R为丁基、 环戊基, Z为草酸根、 丙二酸根、 1,1-环丁二酸根; 更优选的结 构为: R为仲丁基、 环戊基, Z为草酸根、 丙二酸根、 1,1-环丁二酸根。 Preferably, the structure of a platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand is represented by the formula ( lb ), wherein R is a butyl group and a cyclopentane group. Base, Z is oxalate, malonate, 1,1-cyclosuccinate; more preferred structure is: R is sec-butyl, cyclopentyl, Z is oxalate, malonate, 1,1-ring Succinate.
作为另一种优选方案, N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物的结构如 式(la)或式 (lb ) 所示, 其中 R为丙基, Y为 C2-C4的烷氧基乙酸根, Z为 N-取代的 3-氮杂 -1, 1-环丁二酸根, N-取代的 3-氮杂 -1, 1-环丁二酸根中, 取代基为苄基、 甲基取代的苄基、 甲氧基取代的苄基或卤原子取代的苄基; 更优选的结构为: R为异丙基, Y为异丙氧基乙酸 根或叔丁氧基乙酸根, Z为 N-取代的 3-氮杂 -1, 1-环丁二酸根, N-取代的 3-氮杂 -1, 1-环丁 二酸根中, 取代基为甲基取代的苄基、 甲氧基取代的苄基或卤原子取代的苄基。 As another preferred embodiment, the structure of the platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand is as shown in formula (la) or formula (lb), wherein R Is propyl, Y is C 2 -C 4 alkoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1, 1 In the cyclosuccinate, the substituent is a benzyl group, a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group; a more preferred structure is: R is an isopropyl group, and Y is a different Propyloxyacetate or tert-butoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1,1-cyclobutanedioate In the above, the substituent is a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group.
一种 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 作为制备前述式 (la)和式 (lb)所述 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物的中间体,结构如式 (2)所示: A platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, as a reverse of the N-alkyl substitution described in the above formula (la) and formula (lb) Formula 1, 2-cyclohexanediamine is an intermediate of a platinum (ruthenium) complex of a ligand, and the structure is as shown in the formula (2):
式 (2) 其中, Hal代表 Cl—、 Br—或 Γ, 星号 *代表手性碳原子, 式(2)所述化合物是具有 1R, 2R- 构型和 /或 2 构型的手性异构体。 Wherein, Hal represents Cl—, Br— or Γ, asterisk* represents a chiral carbon atom, and the compound of formula (2) is a chiral isoform having a 1R, 2R-configuration and/or a 2 configuration. Structure.
所述 Ν-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物的制备方法包括以下步骤: 以单 Boc保护的反式 1, 2-环己二胺为起始物(D. W. Lee, H. -J. Ha, W. K. Lee, Synthetic Communications, 2007, 37, 737-742)通过下述合成路线 I得到式(3)代表的化合物,然后以式( 3 ) 所示化合物与四卤合铂(Π )酸钾反应, 得到式 (2) 所述化合物; The preparation method of the platinum (ruthenium) complex in which the Ν-alkyl substituted trans 1,2-cyclohexanediamine is a ligand comprises the following steps: trans 1,2-cyclohexanediamine protected by a single Boc For the starting material (DW Lee, H.-J. Ha, WK Lee, Synthetic Communications, 2007, 37, 737-742), the compound represented by the formula (3) is obtained by the following Scheme I, and then the formula (3) The compound shown is reacted with potassium tetrahalide (potassium) hydride to give the compound of formula (2);
^ ( 3 ) 所述单 Boc保护的反式 1, 2-环己二胺由式 (4)表示
式 (4 ) ^ ( 3 ) The mono Boc protected trans 1,2-cyclohexanediamine is represented by the formula (4) Formula (4)
其中 Boc代表叔丁氧羰基; 路线 I如下所示: Wherein Boc represents t-butoxycarbonyl; Route I is as follows:
路线 I中, R是如权利要求 1-6任一项所述的 C3-C8的烷基, 所述脂肪醛为 C3-C8的链状 烷基醛, 所述脂肪酮为 -¾的链状或环状烷基酮, 当 R为链状烷基时, 使用链状烷基醛或 链状烷基酮; 当使用链状烷基醛时, R1为。2 7的烷基, R2为氢原子; 当使用链状烷基酮时, R1和 R2分别为 d-C6的链状烷基, 两者的碳原子数之和应小于 7或等于 7; 当 R为环状烷 基时, 使用环状烷基酮, 其中 X为 C2-C7的亚烷基。 上述式 (3)所述化合物的制备方法在在先 申请 (CN200910027237.8) 中已经公开。 Boc保护的反式 1,2-环己二胺与醛或酮反应时, 先 脱水形成席夫碱, 一般可经分离纯化后, 用于下一步反应。 但对于反应物为低级的脂肪醛或 脂肪酮时却不适合, 因为这些反应物的沸点较低, 没有合适的有机溶剂既能脱水, 又不使醛 或酮随蒸汽蒸出;另外相应的席夫碱一般为液体,也不易纯化。因此对于 Boc保护的反式 1,2- 环己二胺与脂肪醛或脂肪酮的反应, 路线 I中第一步所得的席夫碱通常可以不用分离, 直接 进入下一步反应。 In the route I, R is a C 3 -C 8 alkyl group according to any one of claims 1 to 6, the fatty aldehyde is a C 3 - C 8 chain alkyl aldehyde, and the aliphatic ketone is - 3⁄4 of a chain or cyclic alkyl ketone, when R is a chain alkyl group, a chain alkyl aldehyde or a chain alkyl ketone is used; when a chain alkyl aldehyde is used, R1 is. 2 7 alkyl, R 2 is a hydrogen atom; when a chain alkyl ketone is used, R 1 and R 2 are respectively a linear alkyl group of dC 6 , the sum of the carbon atoms of the two should be less than 7 or equal to 7; In the case of a cyclic alkyl group, a cyclic alkyl ketone is used, wherein X is a C 2 - C 7 alkylene group. The preparation of the compound of the above formula (3) has been disclosed in the prior application (CN200910027237.8). When the Boc-protected trans 1,2-cyclohexanediamine is reacted with an aldehyde or a ketone, it is first dehydrated to form a Schiff base, which is generally isolated and purified for use in the next reaction. However, it is not suitable for the case where the reactants are low-grade fatty aldehydes or aliphatic ketones, because these reactants have a low boiling point, and no suitable organic solvent can be used for dehydration without aldehyde or ketone evaporation with steam; The base is generally liquid and difficult to purify. Therefore, for the reaction of Boc-protected trans 1,2-cyclohexanediamine with a fatty aldehyde or a fatty ketone, the Schiff base obtained in the first step of Scheme I can usually be directly separated into the next reaction without isolation.
按照路线 I方法制备的 N-烷基取代的反式 1, 2-环己二胺主要以其盐酸盐的形式获得, 将 盐酸盐与定量的碱如氢氧化钠或氢氧化钾在水中作用,即可得到相应的 N-单取代的反式 1, 2- 环己二胺。 The N-alkyl substituted trans 1,2-cyclohexanediamine prepared according to the route I method is mainly obtained in the form of its hydrochloride salt, and the hydrochloride salt and a quantitative base such as sodium hydroxide or potassium hydroxide in water. The corresponding N-monosubstituted trans 1,2-cyclohexanediamine can be obtained.
以式 (3 ) 所示化合物与四卤合铂(Π )酸钾反应, 得到式 (2) 所述化合物的具体方法可 以是: 将四卤合铂(Π )酸钾 (6.00mmol)和 N-烷基取代反式 1,2-环己二胺 (6.00mmol)混合于 50
mL水中, 室温避光搅拌过夜, 有大量黄色沉淀生成, 过滤, 分别用水、 无水乙醇、 乙醚反复 洗涤, 干燥得黄色粉末。 A specific method for obtaining a compound of the formula (2) by reacting a compound represented by the formula (3) with potassium tetrahalide (potassium)ate may be: a tetrahaloplatinum (potassium citrate) (6.00 mmol) and N - alkyl substituted trans 1,2-cyclohexanediamine (6.00 mmol) mixed in 50 In a solution of water, stir at room temperature overnight, with a large amount of yellow precipitate formed, filtered, washed repeatedly with water, absolute ethanol and diethyl ether, and dried to give a yellow powder.
式 (2)所述化合物可根据公知反应生成式 (la) 或式 (lb ) 中所述化合物, 如下述任一 种方法, 方法 1 : 在避光条件下, 于水溶液中, 通过银离子除去式 (2)中的卤离子, 然后与式 ( la)所定义的 Y的碱金属盐或铵盐反应生成式(la)所示的铂(Π )配合物, 或与式(lb)所定义 的 Z的碱金属盐或铵盐反应生成式(lb)所示的铂(Π )配合物; 方法 2: 在避光条件下, 于水 溶液中,通过式(la)所定义的 Y的银盐与式 (2)所示的铂( II )配合物反应生成式(la)所示的铂 ( Π )配合物, 或通过式(lb)所定义的 Z 的银盐与式 (2)所示的铂(Π )配合物反应生成式(lb) 所示的铂(Π )配合物。 The compound of the formula (2) can be produced according to a known reaction to produce a compound of the formula (la) or the formula (lb), as in any one of the following methods, method 1: in the absence of light, in an aqueous solution, by silver ion removal The halide ion in formula (2) is then reacted with an alkali metal salt or ammonium salt of Y as defined by formula (la) to form a platinum (ruthenium) complex represented by formula (la), or as defined by formula (lb) Reaction of an alkali metal salt or an ammonium salt of Z to form a platinum (ruthenium) complex represented by formula (lb); Method 2: a silver salt of Y defined by formula (la) in an aqueous solution under protection from light Reaction with a platinum (II) complex represented by the formula (2) to form a platinum (ruthenium) complex represented by the formula (la), or a silver salt of Z defined by the formula (lb) and a formula (2) The platinum (ruthenium) complex reacts to form a platinum (ruthenium) complex of formula (lb).
具体步骤如下: Specific steps are as follows:
方法 1 : method 1 :
将式 (2)所示的二卤 [N-烷基取代反式 1,2-环己二胺]合铂(II ) (2.90mmol) 悬浮于 lOOmL 水中, 加入硝酸银(5.80mmol), 于 60 °C下避光反应 24-36小时后, 硅藻土辅助过滤。 滤液中 加入羧酸钠 (5.80mmol)或二羧酸钠 (2.90mmol)的 30 mL水溶液,然后于 80°C下避光反应 24-48 小时, 将溶液浓縮, 析出大量固体。 过滤, 用水、 乙醇、 乙醚反复洗涤, 真空干燥, 得目标 产物。 The dihalo [N-alkyl substituted trans 1,2-cyclohexanediamine] platinum (II) (2.90 mmol) represented by the formula (2) was suspended in 100 mL of water, and silver nitrate (5.80 mmol) was added thereto. After 24 to 36 hours in the dark at 60 ° C, the diatomaceous earth was assisted by filtration. A 30 mL aqueous solution of sodium carboxylate (5.80 mmol) or sodium dicarboxylate (2.90 mmol) was added to the filtrate, and then reacted at 80 ° C for 24 to 48 hours in the dark, and the solution was concentrated to precipitate a large amount of solid. Filtration, repeated washing with water, ethanol and diethyl ether, and drying in vacuo to give the desired product.
方法 2: Method 2:
将式 (2) 所示的二卤 [N-烷基取代反式 1, 2-环己二胺]合铂(n) (2.90mmol)与新制的羧酸 银 (2.90 mmol)或羧酸二银 (1.45mmol)悬浮于 lOOmL水中, 于 70°C避光反应 24-48小时, 然后 用硅藻土辅助过滤, 将滤液浓縮, 析出大量固体, 过滤, 真空干燥, 得目标产物。 Dihalo[N-alkyl substituted trans 1,2-cyclohexanediamine]platinum (n) (2.90 mmol) represented by formula (2) and freshly prepared silver carboxylate (2.90 mmol) or carboxylic acid Silver (1.45 mmol) was suspended in 100 mL of water, and reacted at 70 ° C for 24 to 48 hours in the dark, and then filtered with celite, and the filtrate was concentrated to precipitate a large amount of solid, which was filtered and dried in vacuo to give the desired product.
按本发明方法制备的化合物已经红外光谱、 核磁氢谱和质谱确定了化合物的分子结构。 本发明式(la)和式(lb)所示铂(Π )配合物对人体肝癌细胞 HepG_2、 人体乳腺癌细胞 MCF-7、 人体肺癌细胞 A549和人体结肠癌细胞 HCT-116具有明显抑制作用, 相关化合物与对 照物对不同癌细胞的抑制作用见表 1。 具体实施例 The compounds prepared by the process of the present invention have determined the molecular structure of the compounds by infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry. The platinum (Π) complex represented by the formula (la) and the formula (lb) of the present invention has a significant inhibitory effect on human liver cancer cell HepG_2, human breast cancer cell MCF-7, human lung cancer cell A549 and human colon cancer cell HCT-116. The inhibitory effects of related compounds and controls on different cancer cells are shown in Table 1. Specific embodiment
本发明由下述实施例得到进一步的说明, 但这些说明并不是限制本发明。除特别指出外, 实施例中所述 N-烷基取代反式 1, 2-环己二胺配体的两个手性碳原子的构型分别为 1R和 2R; 核磁氢谱数据中, DACH代表反式 1, 2-环己二胺的骨架。 The invention is further illustrated by the following examples, which are not intended to limit the invention. Unless otherwise indicated, the configuration of the two chiral carbon atoms of the N-alkyl substituted trans 1,2-cyclohexanediamine ligand in the examples is 1R and 2R, respectively; in the magnetic resonance data, DACH Represents the backbone of trans 1,2-cyclohexanediamine.
按方法 1制备,浅黄色粉末,产率: 51 o IR (KBr, cm"1): 3113 (br), 2935, 2871, 1616, 1450, 1385, 1198, 1116, 988, 942, 713, 595; 1H-NMR (J6-DMSO/TMS, ppm) : δ 0.90(t, 3H, CH2C¾), δ 2.06-1.02(m, 12H, CH2 of DACH and CU3CH2CH2), δ 2.14(m, 2H, NHCH2), δ 2.50- 2.34(m, 2Η, NHCH), δ 3.23(s, 6Η, OCH3), δ 3.81(s, 4Η, COCH20), δ 5.11 (m, 1Η, CH2NH), 56.10-5.99 (dd, 2Η CHNH2); ESI-MS : m/z [M+Na]+ = 566 (100%) o 实施例 2. 化合物 2a (C22H44N206Pt)的制备
Prepared according to Method 1, pale yellow powder, yield: 51 o IR (KBr, cm" 1 ): 3113 (br), 2935, 2871, 1616, 1450, 1385, 1198, 1116, 988, 942, 713, 595; 1H-NMR (J 6 -DMSO/TMS, ppm) : δ 0.90 (t, 3H, CH 2 C3⁄4), δ 2.06-1.02 (m, 12H, CH 2 of DACH and CU 3 CH 2 CH 2 ), δ 2.14 (m, 2H, NHCH 2 ), δ 2.50- 2.34(m, 2Η, NHCH), δ 3.23(s, 6Η, OCH 3 ), δ 3.81(s, 4Η, COCH 2 0), δ 5.11 (m, 1Η , CH 2 NH), 56.10-5.99 (dd, 2Η CHNH2); ESI-MS: m/z [M+Na] + = 566 (100%) o Example 2. Compound 2a (C 22 H 44 N 2 0 Preparation of 6 Pt)
按方法 1制备, 浅黄色粉末, 55%。 IR (KBr, cm- 3461 (br), 3124, 2971, 2935, 2870, 1624, 1456, 1385, 1310, 1192, 1108, 892, 837, 712; 1H-NMR (J6-DMSO/TMS, ppm) : δ 0.90(t, 3H, CH2C¾), δ 1.11(S, 18H, 2C (CH3)3), δ 1.95-0.98 (m, 12H, CH2 of DACH and CH3CH2CH2), δ 2.15 (m, 2H, NHCH2), δ 2.62-2.42 (m, 2Η, NHCH), δ 3.85(s, 4Η, COCH20), δ 5.95 (m, 1Η, CH2局, 56.69-6.17 (dd, 2H, CHNH2) ; ESI-MS m/z: [M+Na]+ = 650 (100%) o 实施例 3. 化合物 3a (C23H35N305Pt)的制备
Prepared according to Method 1, pale yellow powder, 55%. IR (KBr, cm-3461 (br), 3124, 2971, 2935, 2870, 1624, 1456, 1385, 1310, 1192, 1108, 892, 837, 712; 1H-NMR (J 6 -DMSO/TMS, ppm) : δ 0.90(t, 3H, CH 2 C3⁄4), δ 1.11(S, 18H, 2C (CH 3 ) 3 ), δ 1.95-0.98 (m, 12H, CH 2 of DACH and CH 3 CH 2 CH 2 ), δ 2.15 (m, 2H, NHCH 2 ), δ 2.62-2.42 (m, 2Η, NHCH), δ 3.85(s, 4Η, COCH 2 0), δ 5.95 (m, 1Η, CH 2 , 56.69-6.17 ( Dd, 2H, CHNH 2 ); ESI-MS m/z: [M+Na] + = 650 (100%) o Example 3. Preparation of Compound 3a (C 23 H 35 N 3 0 5 Pt)
按方法 2制备,浅黄色粉末,产率: 65%。 IR (KBr, cm"1): 3417(br), 3078, 2936, 2865, 1627, 1495, 1458, 1380, 1250, 1048, 1025, 758; 1H NMR (J6-DMSO/TMS, ppm): δ 0.90(t, 3H CH2C¾), δ 0.98-1.96(m, 12H, CH2 of DACH and CU3CH2CH2), δ 2.27(m, 2H, NHCH2), δ 2.44-2.62(m, 2Η, NHCH), δ 3.43(m, 2Η, CH2Ph), δ 3.59(s, 3Η, PhOC¾), δ 3.85-4.08(m, 4Η H2)2), δ 5.74(m, 1Η, CH2NH), δ 6.21-6.26(dd, 2Η, CHNH2), δ 6.88-7.21(m, 4Η, Ar-H); ESI-MS: m/z [M+H]+ = 629(100%)。 Prepared according to Method 2, light yellow powder, yield: 65%. IR (KBr, cm" 1 ): 3417(br), 3078, 2936, 2865, 1627, 1495, 1458, 1380, 1250, 1048, 1025, 758; 1H NMR (J 6 -DMSO/TMS, ppm): δ 0.90(t, 3H CH 2 C3⁄4), δ 0.98-1.96 (m, 12H, CH 2 of DACH and CU 3 CH 2 CH 2 ), δ 2.27 (m, 2H, NHCH 2 ), δ 2.44-2.62 (m, 2Η, NHCH), δ 3.43(m, 2Η, CH 2 Ph), δ 3.59(s, 3Η, PhOC3⁄4), δ 3.85-4.08(m, 4Η H 2 ) 2 ), δ 5.74(m, 1Η, CH 2 NH), δ 6.21-6.26 (dd, 2 Η, CHNH 2 ), δ 6.88-7.21 (m, 4 Η, Ar-H); ESI-MS: m/z [M+H] + = 629 (100%).
按方法 2制备, 浅黄色粉末,产率: 55%。 IR (KBr, cm"1): 3403 (br), 3189, 2936, 2861, 1591, 1471, 1443, 1358, 1210, 1183, 1049, 910, 871, 753, 698, 591; 1H-NMR (J6-DMSO/ TMS, ppm): S0.92(t, 3H, CH2C¾), 51.97-0.95(m, 12H, CH2 of DACH and CH3CH2CH2), δ 2.32(m, 2H, NHCH2), δ 2.75-2.50(m, 2Η, NHCH), 53.63(s, 2Η, CH2Ph), 53.94-3.78(m, 4Η, N(CH2j2), S5.20(m, 1Η, CH2NH), 56.29-5.93(dd, 2Η, CHNH2), 57.44-7.26(m, 4Η, Ar-Η); ESI-MS m/z: [M+H]+ = 634 (100%) 实施例 5. 化合物 5a(C22H32ClN304Pt)的制备 Prepared according to Method 2, light yellow powder, yield: 55%. IR (KBr, cm" 1 ): 3403 (br), 3189, 2936, 2861, 1591, 1471, 1443, 1358, 1210, 1183, 1049, 910, 871, 753, 698, 591; 1H-NMR (J 6 -DMSO/ TMS, ppm): S0.92 (t, 3H, CH 2 C3⁄4), 51.97-0.95 (m, 12H, CH 2 of DACH and CH 3 CH 2 CH 2 ), δ 2.32 (m, 2H, NHCH 2 ), δ 2.75-2.50(m, 2Η, NHCH), 53.63(s, 2Η, CH 2 Ph), 53.94-3.78(m, 4Η, N(CH 2 j 2 ), S5.20(m, 1Η, CH 2 NH), 56.29-5.93 (dd, 2Η, CHNH 2 ), 57.44-7.26 (m, 4Η, Ar-Η); ESI-MS m/z: [M+H] + = 634 (100%) Example 5. Preparation of Compound 5a (C 22 H 32 ClN 3 0 4 Pt)
按方法 2制备,浅黄色粉末,产率: 54%。 IR (KBr, cm"1): 3403 (br), 3092, 2937, 2862, 1596, 1473, 1455, 1379, 1210, 1181, 1130, 1078, 866, 785, 733, 682, 525; 1H-NMR (J6-DMSO/TMS, ppm): δ 0.90(t, 3H, CH2C¾), δ 2.06-1.02(m, 12H, CH2 of DACH and CU3CH2CH2), δ 2.27 (m, 2H, NHCH2), δ 2.75-2.50(m, 2Η, NHCH), δ 3.60(s, 2Η, CH2Ph), δ 3.86-3.77(m, 4Η, N(CH2j2), δ 5.19(m, 1Η, CH2NH), 56.28-5.91(dd, 2Η, CHNH2), 57.52-7.26(m, 4Η, Ar-Η); ESI-MS m/z: [M+H]+ = 634 (100%) 实施例 6. 化合物 6a (C22H32ClN304Pt)的制备 Prepared according to Method 2, light yellow powder, yield: 54%. IR (KBr, cm" 1 ): 3403 (br), 3092, 2937, 2862, 1596, 1473, 1455, 1379, 1210, 1181, 1130, 1078, 866, 785, 733, 682, 525; 1H-NMR ( J 6 -DMSO/TMS, ppm): δ 0.90 (t, 3H, CH 2 C3⁄4), δ 2.06-1.02 (m, 12H, CH 2 of DACH and CU 3 CH 2 CH 2 ), δ 2.27 (m, 2H , NHCH 2 ), δ 2.75-2.50 (m, 2Η, NHCH), δ 3.60(s, 2Η, CH 2 Ph), δ 3.86-3.77(m, 4Η, N(CH 2 j 2 ), δ 5.19(m , 1Η, CH 2 NH), 56.28-5.91(dd, 2Η, CHNH 2 ), 57.52-7.26(m, 4Η, Ar-Η); ESI-MS m/z: [M+H] + = 634 (100 %) Example 6. Preparation of Compound 6a (C 22 H 32 ClN 3 0 4 Pt)
按方法 2制备,浅黄色粉末,产率: 59% IR (KBr, cm"1): 3403 (br), 3094, 2936, 2864, 1615 1491, 1451, 1382, 1282, 1210, 1177, 1091, 1015, 910, 855, 811, 773, 728, 699, 591;
Ή-NMR (J6-DMSO/TMS, ppm): δ 0.90(t, 3H, CH2C¾), δ 2.08-1.03(m, 12H, CH2 of DACH and CH3CH2CH2), δ 2.27(m, 2Η, NHCH2), δ 2.84-2.50(m, 2Η, NHCH), S3.45(S, 2Η, CH2Ph), δ 4.20-3.71(m, 4Η, N(CH2j2), δ 5.75(m, 1Η, C¾局, 56.64-6.32(dd, 2Η, CHNH2), 57.51-7.25(m, 4Η, Ar-Η); ESI-MS m/z: [M+H]+ = 634 (100%) 实施例 7. 化合物 lb(C19H38N206Pt)的制备 Prepared according to Method 2, light yellow powder, Yield: 59% IR (KBr, cm" 1 ): 3403 (br), 3094, 2936, 2864, 1615 1491, 1451, 1382, 1282, 1210, 1177, 1091, 1015 , 910, 855, 811, 773, 728, 699, 591; Ή-NMR (J 6 -DMSO/TMS, ppm): δ 0.90 (t, 3H, CH 2 C 3⁄4), δ 2.08-1.03 (m, 12H, CH 2 of DACH and CH3CH2CH2), δ 2.27 (m, 2 Η, NHCH 2 ), δ 2.84-2.50(m, 2Η, NHCH), S3.45(S, 2Η, CH 2 Ph), δ 4.20-3.71(m, 4Η, N(CH 2 j 2 ), δ 5.75(m , 1Η, C3⁄4, 56.64-6.32(dd, 2Η, CHNH 2 ), 57.51-7.25(m, 4Η, Ar-Η); ESI-MS m/z: [M+H] + = 634 (100%) Example 7. Preparation of Compound lb (C 19 H 38 N 2 6 Pt)
按方法 1制备,浅黄色粉末,产率: 56%。 IR(KBr, cm"1): 3448 (br), 3134, 2972, 2936, 2867, 1648, 1384, 1177, 1126, 1021, 934, 828, 715, 607; 1H-NMR (J6-DMSO/TMS, ppm): δ 1.41-1.06(m. 18H, CH(CH3)2 and 2CH(C¾)2), δ 2.25-1.06 (m, 9H, CH2 of DACH and CH(CH3)2 ), δ 2.94-2.49 (m, 2H, NHCH), S3.65(m, 2Η, 20CH(CH3)2), 53.97(m, 4H, (C02)2CH20 ), δ 5.42 (m, 1Η, CH2NH . 55.65 (br, 2Η, CH2NH2); ESI-MS m/z: [M+Na]+ = 608 (100%)。 Prepared according to Method 1, pale yellow powder, yield: 56%. IR (KBr, cm" 1 ): 3448 (br), 3134, 2972, 2936, 2867, 1648, 1384, 1177, 1126, 1021, 934, 828, 715, 607; 1H-NMR (J 6 -DMSO/TMS , ppm): δ 1.41-1.06 (m. 18H, CH(CH 3 ) 2 and 2CH(C3⁄4) 2 ), δ 2.25-1.06 (m, 9H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 2.94-2.49 (m, 2H, NHCH), S3.65 (m, 2Η, 20CH(CH 3 ) 2 ), 53.97(m, 4H, (C0 2 ) 2 CH 2 0 ), δ 5.42 (m, 1Η, CH 2 NH . 55.65 (br, 2 Η, CH 2 NH 2 ); ESI-MS m/z: [M+Na] + = 608 (100%).
实施例 8. 化合物 2b (C21H42N206Pt)的制备 Example 8. Preparation of Compound 2b (C 21 H 42 N 2 6 Pt)
按方法 1制备,浅黄色粉末,产率: 59%。 IR(KBr, cm"1): 3438 (br), 3150, 2973, 2937, 2869, 1616, 1385, 1252, 1192, 1099, 916, 892, 828, 713, 613, 529; 1H-NMR (J6-DMSO/TMS, ppm): δ 1.40-1.07 (m, 24H, CH(C¾)2 and 2C (CH3)3), δ 2.24-0.93 (m, 9H, CH2 of DACH and CH(CH3)2), δ 2.93-2.49 (m, 2H, NHCH), 53.89-3.58(m, 4Η, (C02)2CH20), δ 5.38 (m, 1Η, CH2NH), 55.59 (br, 2Η CH2NH2); ESI-MS m/z: [M+Na]+ = 636 (100%) 实施例 9. 化合物 3b (C22H33N305Pt)的制备 Prepared according to Method 1, pale yellow powder, yield: 59%. IR (KBr, cm" 1 ): 3438 (br), 3150, 2973, 2937, 2869, 1616, 1385, 1252, 1192, 1099, 916, 892, 828, 713, 613, 529; 1H-NMR (J 6 -DMSO/TMS, ppm): δ 1.40-1.07 (m, 24H, CH(C3⁄4) 2 and 2C (CH 3 ) 3 ), δ 2.24-0.93 (m, 9H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 2.93-2.49 (m, 2H, NHCH), 53.89-3.58 (m, 4Η, (C0 2 ) 2 CH 2 0), δ 5.38 (m, 1Η, CH 2 NH), 55.59 (br, 2Η) CH2NH2); ESI-MS m/z: [M+Na] + = 636 (100%) Example 9. Preparation of Compound 3b (C 22 H 33 N 3 5 5 Pt)
按方法 2制备,白色粉末,产率:54%。IR (KBr, cm"1): 3417(br), 3122, 2937, 2863, 1622, 1494, 1457, 1376, 1250, 1176, 1024; 1H NMR (J6-DMSO/TMS, ppm): δ 1.04-2.10(m, 15H, CH2 of DACH and CH(CH3)2), δ 1.83-2.50(m, 4H, NHCH and NHCH2), δ 3.45(m, 2Η, CH2Ph), δ 3.78(s, 3Η, PhOO¾), δ 3.43-3.92(m, 4Η, NfCH2j2), δ 5.45(m, 1Η, CH2NH), δ 5.87-6.20(m, 2Η, CHNH2), δ 6.86-7.45(m, 4Η, Ar-Η); ESI-MS: m/z [M+H] + = 615(100%) 实施例 10. 化合物 4b (C22H33N305Pt)的制备 Prepared according to Method 2, white powder, yield: 54%. IR (KBr, cm" 1 ): 3417(br), 3122, 2937, 2863, 1622, 1494, 1457, 1376, 1250, 1176, 1024; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.04- 2.10(m, 15H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 1.83-2.50(m, 4H, NHCH and NHCH 2 ), δ 3.45(m, 2Η, CH 2 Ph), δ 3.78(s , 3Η, PhOO3⁄4), δ 3.43-3.92(m, 4Η, NfCH 2 j 2 ), δ 5.45(m, 1Η, CH 2 NH), δ 5.87-6.20(m, 2Η, CHNH 2 ), δ 6.86-7.45 (m, 4Η, Ar-Η); ESI-MS: m/z [M+H] + = 615 (100%) Example 10. Preparation of Compound 4b (C 22 H 33 N 3 5 5 Pt)
按方法 2制备,白色粉末,产率:51%。IR (KBr, cm"1): 3416(br), 3122, 2938, 2864, 1602, 1491, 1455, 1390, 1266, 1178, 1045; 1H NMR (J6-DMSO/TMS, ppm): δ 1.03-2.12 (m, 15H, CH2 of DACH and CH(CH3)2), δ 1.92-2.5 l(m, 4H, NHCH and NHCH2), δ 3.45 (m, 2Η, CH2Ph), δ 3.79(s, 3Η, PhOC¾), δ 3.45-4.14(m, 4Η, NfCH2j2), δ 5.50(m, 1Η, CH2NH), δ 5.89-6.18(m, 2Η, CHNH2), δ 6.76-7.41(m, 4Η, Ar-Η); ESI-MS: m/z [M+Na]+ = 637(50%) 实施例 11. 化合物 5b (C22H33N304Pt)的制备 Prepared according to Method 2, white powder, yield: 51%. IR (KBr, cm" 1 ): 3416(br), 3122, 2938, 2864, 1602, 1491, 1455, 1390, 1266, 1178, 1045; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.03- 2.12 (m, 15H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 1.92-2.5 l(m, 4H, NHCH and NHCH 2 ), δ 3.45 (m, 2Η, CH 2 Ph), δ 3.79 ( s, 3Η, PhOC3⁄4), δ 3.45-4.14(m, 4Η, NfCH 2 j 2 ), δ 5.50(m, 1Η, CH 2 NH), δ 5.89-6.18(m, 2Η, CHNH2), δ 6.76-7.41 (m, 4Η, Ar-Η); ESI-MS: m/z [M+Na] + = 637 (50%) Example 11. Preparation of Compound 5b (C 22 H 33 N 3 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 60%。 IR (KBr, cm"1): 3417(br), 2939, 2863, 1616, 1455, 1389, 1176, 1079, 957; 1H NMR (J6-DMSO/TMS, ppm): δ 1.03-2.10(m, 15H, CH2 of DACH and CH(CH3)2), δ 1.82-2.30(m, 4H, NHCH and NHCH2), δ 2.27(s, 3Η, PhC¾), δ 3.43(m, 2Η, CH2Ph), δ 3.61-4.08(m, 4Η, NfCH2j2), δ 5.30(m, 1Η, CH2NH), δ 5.89-6.35(m, 2Η, CHNH2), δ 7.10-7.32(m, 4Η, Ar-Η); ESI-MS: m/z [M+H]+ = 599(100%) 实施例 12. 化合物 6b (C22H33N304Pt)的制备
Prepared according to Method 2, light yellow powder, Yield: 60%. IR (KBr, cm" 1 ): 3417(br), 2939, 2863, 1616, 1455, 1389, 1176, 1079, 957; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.03-2.10 (m, 15H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 1.82-2.30(m, 4H, NHCH and NHCH 2 ), δ 2.27(s, 3Η, PhC3⁄4), δ 3.43(m, 2Η, CH 2 Ph ), δ 3.61-4.08(m, 4Η, NfCH 2 j 2 ), δ 5.30(m, 1Η, CH 2 NH), δ 5.89-6.35(m, 2Η, CHNH 2 ), δ 7.10-7.32(m, 4Η , Ar-Η); ESI-MS: m/z [M+H] + = 599 (100%) Example 12. Preparation of Compound 6b (C 22 H 33 N 3 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 59%。 IR (KBr, cm"1): 3417(br), 3121, 2938, 2864, 1609, 1449, 1390, 1180, 1071, 916; 1H NMR (J6-DMSO/TMS, ppm): δ 1.03-1.93(m, 15H, CH2 of DACH and CH(CH3)2), δ 1.93-2.52(m, 4H, NHCH and NHCH2), δ 2.27(s, 3Η, PhC¾), δ 3.42(m, 2Η, CH2Ph), δ 3.42-4.14(m, 4Η, NfCH2j2), δ 5.30(m, 1Η, CH2NH), δ 5.89-6.19(m, 2Η, CHNH2), δ 7.00-7.34(m, 4Η, Ar-Η); ESI-MS: m/z [M+Na]+ = 621(100%) 实施例 13. 化合物 lc (C12H22N204Pt)的制备 Prepared according to Method 2, light yellow powder, yield: 59%. IR (KBr, cm" 1 ): 3417(br), 3121, 2938, 2864, 1609, 1449, 1390, 1180, 1071, 916; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.03-1.93 ( m, 15H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 1.93-2.52 (m, 4H, NHCH and NHCH 2 ), δ 2.27(s, 3Η, PhC3⁄4), δ 3.42(m, 2Η, CH 2 Ph), δ 3.42-4.14(m, 4Η, NfCH 2 j 2 ), δ 5.30(m, 1Η, CH 2 NH), δ 5.89-6.19(m, 2Η, CHNH 2 ), δ 7.00-7.34(m , 4Η, Ar-Η); ESI-MS: m/z [M+Na] + = 621 (100%) Example 13. Preparation of Compound lc (C 12 H 22 N 2 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 58%。 IR (KBr, cm-1): 3446(br), 3199, 3103, 2938, 2864. 1703, 1672, 1452, 1385, 1249, 1173, 1068, 1032; 1H NMR (J6-DMSO TMS, ppm): δ 0.84-1.17(m. 6H, CH3CHCH2CH3), δ 1.18-2.25(m, 10H, CH2 of DACH and CHCH2CH3), δ 2.70-3.45(m, 3H. NHCH and NH2CH), δ 5.31(d, 1Η, CHNH), δ 5.85-6.13 (m, 2Η, CHNH2); ESI-MS: m/z [M+Na]4 = 476(100%)。 Prepared according to Method 2, light yellow powder, yield: 58%. IR (KBr, cm- 1 ): 3446(br), 3199, 3103, 2938, 2864. 1703, 1672, 1452, 1385, 1249, 1173, 1068, 1032; 1H NMR (J 6 -DMSO TMS, ppm): δ 0.84-1.17 (m. 6H, CH 3 CHCH 2 CH 3 ), δ 1.18-2.25 (m, 10H, CH 2 of DACH and CHCH 2 CH 3 ), δ 2.70-3.45 (m, 3H. NHCH and NH 2 CH), δ 5.31 (d, 1 Η, CHNH), δ 5.85-6.13 (m, 2 Η, CHNH 2 ); ESI-MS: m/z [M+Na] 4 = 476 (100%).
实施例 14. 化合物 2c (C13H24N204Pt)的制备 Example 14. Preparation of Compound 2c (C 13 H 24 N 2 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 63%。 IR (KBr, cm-1): 3434(br), 3167, 3103, 2938, 2865, 1647, 1451, 1385, 1255, 1212, 1070, 1017; 1H NMR (J6-DMSO/TMS, ppm): δ 0.85-1.08(m, 6H CH3CHCH2CH3), δ 1.23-2.14(m, 10H, CH2 of DACH and CHCH2CH3), δ 2.29-3.48(m, 3H NHCH and NH2CH), δ 3.22(m, 2Η, CH2(CO)2), δ 5.21-5.94(m, 3Η, C¥L2NH and CHNH2) ; ESI-MS: m/z [M+Na]+ = 490(100%) 实施例 15. 化合物 3c (C16H28N204Pt)的制备
Prepared according to Method 2, light yellow powder, yield: 63%. IR (KBr, cm- 1 ): 3434(br), 3167, 3103, 2938, 2865, 1647, 1451, 1385, 1255, 1212, 1070, 1017; 1H NMR (J 6 -DMSO/TMS, ppm): δ 0.85-1.08 (m, 6H CH 3 CHCH 2 CH 3 ), δ 1.23-2.14 (m, 10H, CH 2 of DACH and CHCH 2 CH 3 ), δ 2.29-3.48 (m, 3H NHCH and NH 2 CH), δ 3.22(m, 2Η, CH 2 (CO) 2 ), δ 5.21-5.94 (m, 3Η, C¥L 2 NH and CHNH 2 ) ; ESI-MS: m/z [M+Na] + = 490 ( 100%) Example 15. Preparation of Compound 3c (C 16 H 28 N 2 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 59%。 IR (KBr, cm-1): 3444(br), 3173, 3108, 2940, 2864, 1646, 1455, 1364, 1117, 1069, 1030; 1H NMR (J6-DMSO/TMS, ppm): δ 0.83-1.21 (m, 6H CH3CHCH2CH3), δ 1.23-2.68(m, 16H, CH2 of DACH and CHCH2CH3 and cyclobutyl), δ 2.63-2.68(m, 2H, NHCH), δ 3.43(m, 1Η, NH2CH), δ 4.31-5.86(m, 3Η, C¥L2NH and CHNH2); ESI-MS: m/z [M+Na]+ = 530(100%)。 实施例 16. 化合物 ld (C13H24N204Pt)的制备 Prepared according to Method 2, light yellow powder, yield: 59%. IR (KBr, cm- 1 ): 3444(br), 3173, 3108, 2940, 2864, 1646, 1455, 1364, 1117, 1069, 1030; 1H NMR (J 6 -DMSO/TMS, ppm): δ 0.83- 1.21 (m, 6H CH 3 CHCH 2 CH 3 ), δ 1.23-2.68 (m, 16H, CH 2 of DACH and CHCH 2 CH 3 and cyclobutyl), δ 2.63-2.68 (m, 2H, NHCH), δ 3.43 ( m, 1 Η, NH 2 CH), δ 4.31-5.86 (m, 3 Η, C?L 2 NH and CHNH 2 ); ESI-MS: m/z [M+Na] + = 530 (100%). Example 16. Preparation of Compound ld (C 13 H 24 N 2 0 4 Pt)
按方法 2制备, 浅黄色粉末,产率: 65%。 IR (KBr, cm"1): 3434(br), 3122, 2941, 2863, 1647, 1453, 1363, 1251, 1119, 1071, 1023, 906, 777; 1H NMR (J6-DMSO/TMS, ppm): δ 0.89-1.09(m, 6H, CH2CH(CH3)2), δ 1.12-2.15(m, 9H, CH(CH3)2 and CH2 of DACH), δ 2.12-2.44(m, 4H, NHCH2 and NHCH and NH2CH), δ 3.12-3.23(m, 2Η, CH2(CO)2), δ 5.31-6.12(m, 3Η, CH2NH and CHNH2); ESI-MS: m/z [M+Na]+ = 490(100%) 实施例 17. 化合物 2d(C18H36N206Pt)的制备 Prepared according to Method 2, light yellow powder, yield: 65%. IR (KBr, cm" 1 ): 3434(br), 3122, 2941, 2863, 1647, 1453, 1363, 1251, 1119, 1071, 1023, 906, 777; 1H NMR (J 6 -DMSO/TMS, ppm) : δ 0.89-1.09(m, 6H, CH 2 CH(CH 3 ) 2 ), δ 1.12-2.15(m, 9H, CH(CH 3 ) 2 and CH 2 of DACH), δ 2.12-2.44(m, 4H , NHCH2 and NHCH and NH 2 CH), δ 3.12-3.23 (m, 2Η, CH 2 (CO) 2 ), δ 5.31-6.12 (m, 3Η, CH 2 NH and CHNH2); ESI-MS: m/z [M+Na] + = 490 (100%) Example 17. Preparation of Compound 2d (C 18 H 36 N 2 6 6 Pt)
按方法 1制备, 浅黄色粉末,产率: 52%。 IR(KBr, cm"1): 3425 (br), 3159, 3097, 2942, 2867, 1644, 1452, 1385, 1169, 1092, 959, 932, 741, 592; 1H-NMR (D20/TMS, ppm): 51.10-0.87(m, 12H, CH(CH3)2 and 2CH2C¾), 52.27-1.10(m, 9H, CH2 of DACH and (CH3)2CH), S2.49(m, 2Η NHCH2), 53.90-3.42(m, 12Η, NHCH and NHCH2 and C02CH2OCH2CH3) ; ESI-MS m/z: [M+H] =570 (100%) Prepared according to Method 1, pale yellow powder, yield: 52%. IR (KBr, cm" 1 ): 3425 (br), 3159, 3097, 2942, 2867, 1644, 1452, 1385, 1169, 1092, 959, 932, 741, 592; 1H-NMR (D 2 0/TMS, Ppm): 51.10-0.87 (m, 12H, CH(CH 3 ) 2 and 2CH 2 C3⁄4), 52.27-1.10 (m, 9H, CH 2 of DACH and (CH 3 ) 2 CH), S2.49 (m, 2ΗNHCH 2 ), 53.90-3.42 (m, 12Η, NHCH and NHCH 2 and C0 2 CH 2 OCH 2 CH 3 ) ; ESI-MS m/z: [M+H] = 570 (100%)
注: N-取代反式 1, 2-环己二胺配体为外消旋体。 实施例 18. 化合物 3d(C22H44N206Pt)的制备
Note: The N-substituted trans 1,2-cyclohexanediamine ligand is a racemate. Example 18. Preparation of Compound 3d (C 22 H44N 2 6 Pt)
按方法 1制备, 浅黄色粉末, 产率 58%。 IR(KBr, cm— i): 3425 (br), 3159, 3097, 2942, 2867, 1644, 1452, 1385, 1169, 1092, 959, 932, 741, 592; 1H-NMR (D20/TMS, ppm) : S0.88(t, 6H, 2CH20¾, S1.28(dd, 6H, CU(CH3)2), 52.27-1.06 (m, 17H, CH2 of DACH and (CH3)2CH and 2CH3CH2CH2), 52.49(m, 2Η, NHCH2), 53.39(m, 6Η, 20CH2 and NHCH2) ; ESI-MS m/z: [M+H]+ = 626 (100%) Prepared according to Method 1, pale yellow powder, yield 58%. IR (KBr, cm-i): 3425 (br), 3159, 3097, 2942, 2867, 1644, 1452, 1385, 1169, 1092, 959, 932, 741, 592; 1H-NMR (D 2 0/TMS, Ppm) : S0.88(t, 6H, 2CH 2 03⁄4, S1.28(dd, 6H, CU(CH 3 ) 2 ), 52.27-1.06 (m, 17H, CH 2 of DACH and (CH 3 ) 2 CH And 2CH3CH2CH2), 52.49 (m, 2 Η, NHCH 2 ), 53.39 (m, 6 Η, 20CH 2 and NHCH 2 ); ESI-MS m/z: [M+H] + = 626 (100%)
注: N-取代反式 1, 2-环己二胺配体为外消旋体。 实施例 19. 化合物 le(C24H37N305Pt)的制备 Note: The N-substituted trans 1,2-cyclohexanediamine ligand is a racemate. Example 19. Preparation of Compound le (C 24 H 37 N 3 0 5 Pt)
按方法 2制备, 浅黄色粉末, 产率: 69%。 IR (KBr, cm-1): 3422(br), 3263, 3129, 2940, 2864, 1611, 1515, 1462, 1390, 1345, 1251, 1180, 1033, 823; 1H NMR (J6-DMSO TMS, ppm): δ 1.03-1.08(m, 9H, C(CH3)3), δ 1.27-1.55(m, 8H, CH2 of DACH), δ 1.95(m, 4H, NHCH2 and NHCH and NH2CH), δ 3.41-3.45(m, 4Η, CH2NCH2), δ 3.52(s, 3Η, PhOC¾), δ 3.71-3.77(m, 2Η, NCH2Ar), δ 6.83-7.17(m, 4Η, ArH) ; ESI-MS: [M+H]+ = 643(100%)。 Prepared according to Method 2, light yellow powder, yield: 69%. IR (KBr, cm- 1 ): 3422(br), 3263, 3129, 2940, 2864, 1611, 1515, 1462, 1390, 1345, 1251, 1180, 1033, 823; 1H NMR (J 6 -DMSO TMS, ppm ): δ 1.03-1.08 (m, 9H, C(CH 3 ) 3 ), δ 1.27-1.55 (m, 8H, CH 2 of DACH), δ 1.95 (m, 4H, NHCH 2 and NHCH and NH 2 CH) , δ 3.41-3.45(m, 4Η, CH 2 NCH 2 ), δ 3.52(s, 3Η, PhOC3⁄4), δ 3.71-3.77(m, 2Η, NCH 2 Ar), δ 6.83-7.17(m, 4Η, ArH ; ESI-MS: [M+H] + = 643 (100%).
注: N-取代反式 1, 2-环己二胺配体的两个手性碳原子的构型分别为 M和 2 。 实施例 20. 化合物 2e(C24H37N304Pt)的制备 Note: The configuration of the two chiral carbon atoms of the N-substituted trans 1,2-cyclohexanediamine ligand is M and 2, respectively. Example 20. Preparation of Compound 2e (C 24 H 37 N 3 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 60%。 IR (KBr, cm"1): 3420(br), 3121, 2940, 2863, 1615, 1518, 1455, 1387, 1339, 1209, 1168, 1036, 815; 1H NMR (J6-DMSO/TMS, ppm): δ 1.02-1. l l(m, 9H, C(CH3)3), δ 1.21-1.56(m, 8H, CH2 of DACH), δ 1.98-2.27 (m, 4H, NHCH2 and NHCH and
Prepared according to Method 2, light yellow powder, Yield: 60%. IR (KBr, cm" 1 ): 3420(br), 3121, 2940, 2863, 1615, 1518, 1455, 1387, 1339, 1209, 1168, 1036, 815; 1H NMR (J 6 -DMSO/TMS, ppm) : δ 1.02-1. ll(m, 9H, C(CH 3 ) 3 ), δ 1.21-1.56(m, 8H, CH 2 of DACH), δ 1.98-2.27 (m, 4H, NHCH 2 and NHCH and
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按方法 2制备,白色粉末,产率:61%。IR (KBr, cm"1): 3418(br), 3090, 2934, 2858, 1622, 1453, 1375, 1178, 1067, 1028; 1H NMR (J6-DMSO/TMS, ppm): δ 1.08-1.48(m, 14H, CH2 of DACH and cyclopentyl), δ 1.72-2.11(m, 4H, CH2 of DACH and cyclopentyl), δ 2.11(m, 3H, CH of DACH and cyclopentyl), δ 3.43-3.60(m, 4H, CH2NCH2), δ 3.74-3.91(m, 2Η, NCH2Ar), δ 7.22-7.45(m, 5Η, ArH); ESI-MS: m/z [M+H] + = 625(100%)。 Prepared according to Method 2, white powder, yield: 61%. IR (KBr, cm" 1 ): 3418(br), 3090, 2934, 2858, 1622, 1453, 1375, 1178, 1067, 1028; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.08-1.48 ( m, 14H, CH 2 of DACH and cyclopentyl), δ 1.72-2.11 (m, 4H, CH 2 of DACH and cyclopentyl), δ 2.11 (m, 3H, CH of DACH and cyclopentyl), δ 3.43-3.60 (m, 4H, CH 2 NCH 2 ), δ 3.74-3.91 (m, 2 Η, NCH 2 Ar), δ 7.22-7.45 (m, 5 Η, ArH); ESI-MS: m/z [M+H] + = 625 ( 100%).
实施例 27. 化合物 3g(C25H37N304Pt)的制备 Example 27. Preparation of Compound 3g (C 25 H 37 N 3 0 4 Pt)
按方法 2制备,白色粉末,产率:60%。IR (KBr, cm"1): 3403(br), 3104, 2935, 2858, 1609, 1450. 1383, 1176, 1069; 1H NMR (J6-DMSO/TMS, ppm): δ 1.06-1.50(m, 12H, CH2 of DACH and cyclopentyl), δ 1.72-1.91(m, 6H, CH2 of DACH and cyclopentyl), δ 2.16(m, 3H, CH of DACH and cyclopentyl), δ 2.29(s, 3H, PhC¾), δ 3.36-3.58(m, 4H, CH2NCH2), δ 3.76(m, 2Η, NCH2Ar), δ 7.10-7.31(m, 4Η, ArH); ESI-MS: m/z [M]+H+ = 639(100%) 实施例 28. 化合物 4g(C25H37N304Pt)的制备 Prepared according to Method 2, white powder, yield: 60%. IR (KBr, cm" 1 ): 3403 (br), 3104, 2935, 2858, 1609, 1450. 1383, 1176, 1069; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.06-1.50 (m, 12H, CH 2 of DACH and cyclopentyl), δ 1.72-1.91 (m, 6H, CH 2 of DACH and cyclopentyl), δ 2.16 (m, 3H, CH of DACH and cyclopentyl), δ 2.29(s, 3H, PhC3⁄4) , δ 3.36-3.58 (m, 4H, CH 2 NCH 2 ), δ 3.76 (m, 2 Η, NCH 2 Ar), δ 7.10-7.31 (m, 4 Η, ArH); ESI-MS: m/z [M] +H + = 639 (100%) Example 28. Preparation of Compound 4g (C 25 H 37 N 3 0 4 Pt)
按方法 2制备,白色粉末,产率:51%。IR (KBr, cm"1): 3421 (br), 3051, 2933, 2858, 1609, 1449, 1363, 1177, 1068, 1036; 1H NMR (J6-DMSO/TMS, ppm): δ 1.09-1.50(m, 12H, CH2 of DACH
and cyclopentyl), δ 1.72-2.16(m, 6H, CH2 of DACH and cyclopentyl), δ 2.25(m, 3H, CH of DACH and cyclopentyl), δ 2.32(s, 3H, PhC¾), δ 3.42-3.55(m, 4H, CH2NCH2), δ 3.75-3.79(m, 2Η, NCH2Ar), δ 7.07-7.25(m, 4Η, ArH); ESI-MS: m/z [M+H] + = 639(100%)。 实施例 29. 化合物 lh(C19H34N204Pt Prepared according to Method 2, white powder, yield: 51%. IR (KBr, cm" 1 ): 3421 (br), 3051, 2933, 2858, 1609, 1449, 1363, 1177, 1068, 1036; 1H NMR (J 6 -DMSO/TMS, ppm): δ 1.09-1.50 ( m, 12H, CH 2 of DACH And cyclopentyl), δ 1.72-2.16(m, 6H, CH 2 of DACH and cyclopentyl), δ 2.25(m, 3H, CH of DACH and cyclopentyl), δ 2.32(s, 3H, PhC3⁄4), δ 3.42-3.55( m, 4H, CH 2 NCH 2 ), δ 3.75-3.79 (m, 2 Η, NCH 2 Ar), δ 7.07-7.25 (m, 4 Η, ArH); ESI-MS: m/z [M+H] + = 639 (100%). Example 29. Compound lh (C 19 H 34 N 2 0 4 Pt
按方法 2制备, 浅黄色粉末, 产率: 50%。 IR (KBr, cm- i): 3420(br), 2939, 1596(br), 1457, 1384, 1350, 1173, 1126, 801; 1H NMR (J6-DMSO TMS, ppm): δ 0.74-0.86(m, 3H, CCH3 of camphorato), δ 0.97-1.37(m, 20H, CH2 of DACH and CHCH2CH2C, CH3 of camphorato and CH(CH3)2), δ 1.51(m, 4H, CH2 of DACH), δ 2.01(m, 3H, NHCH and CH of camphorato), δ 3.45(m, 1Η, CH(CH3)2), δ 5.80-6.80(m, 3H, CHNH and CHNH2); ESI-MS: m/z [M+H]+ = 550(80%), [M+Na]+ = 572(20%) Prepared according to Method 2, light yellow powder, yield: 50%. IR (KBr, cm-i): 3420(br), 2939, 1596(br), 1457, 1384, 1350, 1173, 1126, 801; 1H NMR (J 6 -DMSO TMS, ppm): δ 0.74-0.86 ( m, 3H, CCH 3 of camphorato), δ 0.97-1.37 (m, 20H, CH 2 of DACH and CHCH 2 CH 2 C, CH 3 of camphorato and CH(CH 3 ) 2 ), δ 1.51 (m, 4H, CH 2 of DACH), δ 2.01 (m, 3H, NHCH and CH of camphorato), δ 3.45 (m, 1 Η, CH(CH 3 ) 2 ), δ 5.80-6.80 (m, 3H, CHNH and CHNH 2 ); ESI-MS: m/z [M+H] + = 550 (80%), [M+Na] + = 572 (20%)
注: 樟脑酸根由天然樟脑酸转化得到。 实施例 30. 化合物 2h(C2QH36N204Pt)的制备 Note: Camphorate is converted from natural camphoric acid. Example 30. Preparation of Compound 2h (C 2Q H 36 N 2 0 4 Pt)
按方法 2制备, 浅黄色粉末, 产率: 50%。 IR (KBr, cm- i): 3429(br), 2957, 1603(br), 1457, 1382, 1348, 1169, 1125, 909, 801; 1H NMR (J6-DMSO/TMS, ppm): δ 0.75(m, 3H, CCH3 of camphorato), δ 0.89-1.39(m, 21H, CH2 of DACH and CHCH2CH2C, CH3 of camphorato and NHCH2CH2CH2C¾ of n-Bu), δ 1.49(m, 4Η, CH2 of DACH), δ 1.95(m, 3H, NHCH and CH of camphorato), δ 3.40(m, 2Η, NHCH2 of n-Bu), δ 4.80-6.80(m, 3Η, CHNHand CHNH2); ESI-MS: m/z [M+H]+ = 564(50%), [M+Na+CH3OH] +=619(20%)。 Prepared according to Method 2, light yellow powder, yield: 50%. IR (KBr, cm-i): 3429(br), 2957, 1603(br), 1457, 1382, 1348, 1169, 1125, 909, 801; 1H NMR (J 6 -DMSO/TMS, ppm): δ 0.75 (m, 3H, CCH 3 of camphorato), δ 0.89-1.39 (m, 21H, CH 2 of DACH and CHCH 2 CH 2 C, CH 3 of camphorato and NHCH 2 CH 2 CH 2 C3⁄4 of n-Bu), δ 1.49 (m, 4Η, CH 2 of DACH), δ 1.95 (m, 3H, NHCH and CH of camphorato), δ 3.40 (m, 2Η, NHCH 2 of n-Bu), δ 4.80-6.80 (m, 3Η, CHNHand CHNH 2 ); ESI-MS: m/z [M+H] + = 564 (50%), [M+Na+CH 3 OH] += 619 (20%).
注: 樟脑酸根由天然樟脑酸转化得到。 实施例 31. 化合物 lx(C1QH22Cl2N2Pt)的制备
Note: Camphorate is converted from natural camphoric acid. Example 31. Preparation of Compound 1x (C 1Q H 22 Cl 2 N 2 Pt)
按以下方法制备: 将四氯合铂(Π )酸钾 (6.00mmol)和 N-正丁基 -1R,2R-反式环己二胺 (6.00mmol)混合于 50 mL水中, 室温避光搅拌过夜, 有大量黄色沉淀生成, 过滤, 分别用水、 无水乙醇、 乙醚反复洗涤, 干燥得黄色粉末, 产率: 89%。 IR (KBr, cm—1): 3490(br), 3187, 3117, 2935, 2863, 1582, 1451, 1380, 1239, 1192, 1157, 1068, 1038, 1014, 908; 1H NMR (J6-DMSO/ TMS, ppm): δ 0.90(t, 3H, CH2CH3), δ 1.02-1.97 (m, 12H, CH2 of DACH and CH3CH2CH2), δ 2.12(m, 2H, NHCH2), δ 2.48-2.50(m, 2Η, NHCH), δ 5.37(m, 1Η, CH2NH), δ 6.10-6.45(dd, 2Η, CHNH2) ; ESI-MS: m/z [M+Na]+ = 459(100%) 实施例 32. 化合物 2x(C9H2QCl2N2Pt)的制备 Prepared as follows: Potassium tetrachloroplatinate (6.00 mmol) and N-n-butyl-1R, 2R-trans cyclohexanediamine (6.00 mmol) were mixed in 50 mL of water, and kept at room temperature in the dark. After overnight, a large amount of a yellow precipitate formed, which was filtered, washed repeatedly with water, anhydrous ethanol and diethyl ether, and dried to yield a yellow powder. Yield: 89%. IR (KBr, cm- 1 ): 3490(br), 3187, 3117, 2935, 2863, 1582, 1451, 1380, 1239, 1192, 1157, 1068, 1038, 1014, 908; 1H NMR (J 6 -DMSO/ TMS, ppm): δ 0.90 (t, 3H, CH 2 CH 3 ), δ 1.02-1.97 (m, 12H, CH 2 of DACH and CH 3 CH 2 CH 2 ), δ 2.12 (m, 2H, NHCH 2 ) , δ 2.48-2.50(m, 2Η, NHCH), δ 5.37(m, 1Η, CH 2 NH), δ 6.10-6.45(dd, 2Η, CHNH 2 ) ; ESI-MS: m/z [M+Na] + = 459 (100%) Example 32 compound 2x (C 9 H 2Q Cl 2 N 2 Pt) preparation of
制备方法同实施例 31, 黄色粉末, 产率: 90%。 IR (KBr, cm- 3475(br), 3258, 3194, 2924, 2867, 1594, 1451, 1423, 1390, 1267, 1190, 1157, 1124, 1068, 1006, 920, 797; 1H NMR (J6-DMSO/TMS, ppm): δ 1.07-1.35(m, 6H, CH(CH3)2), δ 1.04-2.17(m, 9H, CH2 of DACH and CH(CH3)2), δ 3.01-3.45(m, 2H, NHCH), δ 5.38(m, 1Η, CH2NH), δ 6.05-6.14(dd, 2Η, CHNH2) ; ESI-MS: m/z [M+Na]+ = 445(100%) 实施例 33. 化合物 3x(C1QH22Cl2N2Pt)的制备 The preparation method was the same as that in Example 31, yellow powder, yield: 90%. IR (KBr, cm-3474(br), 3258, 3194, 2924, 2867, 1594, 1451, 1423, 1390, 1267, 1190, 1157, 1124, 1068, 1006, 920, 797; 1H NMR (J6-DMSO/ TMS, ppm): δ 1.07-1.35 (m, 6H, CH(CH 3 ) 2 ), δ 1.04-2.17 (m, 9H, CH 2 of DACH and CH(CH 3 ) 2 ), δ 3.01-3.45 (m , 2H, NHCH), δ 5.38 (m, 1 Η, CH 2 NH), δ 6.05-6.14 (dd, 2Η, CHNH 2 ) ; ESI-MS: m/z [M+Na] + = 445 (100%) Example 33. Preparation of Compound 3x (C 1Q H 22 Cl 2 N 2 Pt)
制备方法同实施例 31, 黄色粉末, 产率: 88%。 n^KBr' cm-1): 3495(br), 3249, 3186, 3117, 2936, 2864, 1581, 1450, 1392, 1368, 1186, 1156, 1132, 1070, 1032, 997; 1H NMR (J6-DMSO/TMS ppm): δ 0.90-1.07(m, 6H, CH2CH(CH3)2), δ 1.10-2.15(m, 9H, CH(CH3)2 and CH2 of DACH), δ 2.12-2.44(m, 4H, NHCH2 and NHCH and NH2CH), δ 5.31-6.10(m, 3Η, CH2NH and CHNH2) ; ESI-MS: m/z [M+Na]+ = 459(100%) 实施例 34. 化合物 4x(CuH22Cl2N2Pt)的制备
The preparation was carried out in the same manner as in Example 31, yellow powder, yield: 88%. n^KBr' cm- 1 ): 3495(br), 3249, 3186, 3117, 2936, 2864, 1581, 1450, 1392, 1368, 1186, 1156, 1132, 1070, 1032, 997; 1H NMR (J 6 - DMSO/TMS ppm): δ 0.90-1.07 (m, 6H, CH 2 CH(CH 3 ) 2 ), δ 1.10-2.15 (m, 9H, CH(CH 3 ) 2 and CH 2 of DACH), δ 2.12- 2.44 (m, 4H, NHCH 2 and NHCH and NH 2 CH), δ 5.31-6.10 (m, 3 Η, CH 2 NH and CHNH 2 ); ESI-MS: m/z [M+Na] + = 459 (100 %) Example 34. Preparation of compound 4x (C u H 22 Cl 2 N 2 Pt)
制备方法同实施例 31,黄色粉末,产率: 88 o IR (KBr, cm"1): 3257, 3178, 3142, 2938, 2864, 1591, 1566, 1447, 1127, 1066; 1H NMR (J6-DMSO/TMS, ppm): δ 1.00-1.21(m, 4H, CH2 of DACH), δ 1.37-1.50(m, 4H, CH2 of cyclopentyl), δ 1.59- 1.60(m, 1H, CH2 of DACH), δ 1.65-1.70(m, 1H, CH2 of cyclopentyl), δ 1.79-2.18(m, 6H, CH2 of DACH and cyclopentyl), δ 2.20-2.25(m, 1H, CHNH of DACH), δ 2.30-2.37 (m, 1H, CHNH of DACH), δ 3.09-3.12 (m, 1H, CHNH of cyclopentyl); ESI-MS: m/z [M+Na]+ = 471(100%) o 实施例 35. 单 Boc保护的反式 1,2-环己二胺的制备 The preparation method was the same as that in Example 31, yellow powder, yield: 88 o IR (KBr, cm" 1 ): 3257, 3178, 3142, 2938, 2864, 1591, 1566, 1447, 1127, 1066; 1H NMR (J 6 - DMSO/TMS, ppm): δ 1.00-1.21 (m, 4H, CH 2 of DACH), δ 1.37-1.50 (m, 4H, CH 2 of cyclopentyl), δ 1.59- 1.60 (m, 1H, CH 2 of DACH ), δ 1.65-1.70 (m, 1H, CH 2 of cyclopentyl), δ 1.79-2.18 (m, 6H, CH 2 of DACH and cyclopentyl), δ 2.20-2.25 (m, 1H, CHNH of DACH), δ 2.30 -2.37 (m, 1H, CHNH of DACH), δ 3.09-3.12 (m, 1H, CHNH of cyclopentyl); ESI-MS: m/z [M+Na] + = 471 (100%) o Example 35. Preparation of single Boc protected trans 1,2-cyclohexanediamine
量取 500mL 甲醇, 放入 2 L烧瓶中, 加入 500mmol 1R,2R-反式环己二胺或 1 2 反式环 己二胺, 室温搅拌溶解, 搅拌下缓慢滴加 2.5mol/L 氯化氢 /甲醇溶液 200mL, 控制温度不超 过 5°C。加毕后恢复至室温,加入 200mL水,室温下搅拌 30min。用 250mL甲醇溶解 550mmol (Boc)20,室温下滴加至上述溶液,约 30min加完,再室温搅拌 lh 。停止反应,减压除去 250mL 甲醇, 加入 300mL水, 用乙醚萃取 3次 (250mIJ次) 。 水相用 5M氢氧化钠水溶液调节 pH 值 10左右, 用二氯甲烷萃取 4次 (250mIJ次) , 合并有机相, 用饱和氯化钠溶液洗涤 2次 ( lOOmlJ次) , 有机相用无水硫酸钠干燥过夜, 过滤。 滤液减压浓縮至约 200mL左右, 加入 400mL石油醚 (60— 90°C)重结晶, 得白色针状固体 83.0g(77.0%)。 IR(KBr, cm"1): 3350, 3291, 3183(br), 2978, 2931, 2857, 1695, 1592, 1554, 1445, 1183, 1041, 849, 761 ; 1H-NMR(CDC13/TMS): δ 1.45 (S, 9H, C(CH3)3), 52.01-1.02 (m, 8H, CH2 of DACH), 53.14-2.28 (m,2H, NH2CH), 54.49 (br,lH, CONH); ESI-MS m/z: [M+H]+ =215(100%)。 实施例 36. 配体 1-R.2HC1的合成 (路线 I) Measure 500 mL of methanol, put it into a 2 L flask, add 500 mmol of 1R, 2R-trans cyclohexanediamine or 12 2 trans-cyclohexanediamine, stir to dissolve at room temperature, and slowly add 2.5 mol/L hydrogen chloride/methanol under stirring. The solution was 200 mL and the control temperature did not exceed 5 °C. After the addition was completed, the temperature was returned to room temperature, 200 mL of water was added, and the mixture was stirred at room temperature for 30 min. The 550 mmol (Boc) 20 was dissolved in 250 mL of methanol, and added to the above solution at room temperature, and the addition was completed in about 30 minutes, and then stirred at room temperature for 1 hour. The reaction was stopped, 250 mL of methanol was removed under reduced pressure, 300 mL of water was added, and extracted with diethyl ether three times (250 mIJ). The aqueous phase was adjusted to pH 10 with 5M aqueous sodium hydroxide solution, extracted 4 times with dichloromethane (250 mIJ times), the organic phase was combined, washed twice with saturated sodium chloride solution (100 ml J times), and the organic phase was treated with anhydrous sulfuric acid. The sodium was dried overnight and filtered. The filtrate was concentrated under reduced pressure to about 200 mL, and recrystallized from 400 mL of petroleum ether (60-90 ° C) to give white white solid (83.0 g, 77.0%). IR (KBr, cm" 1 ): 3350, 3291, 3183 (br), 2978, 2931, 2857, 1695, 1592, 1554, 1445, 1183, 1041, 849, 761 ; 1H-NMR (CDC1 3 /TMS): δ 1.45 (S, 9H, C(CH 3 ) 3 ), 52.01-1.02 (m, 8H, CH 2 of DACH), 53.14-2.28 (m, 2H, NH 2 CH), 54.49 (br, lH, CONH) ESI-MS m/z: [M+H] + = 215 (100%). Example 36. Synthesis of Ligand 1-R.2HC1 (Line I)
称取 SM-R 17.12g ( 80mmol),置入 500mL三口烧瓶中,用 350mL甲醇溶解,加入 17.28g ( 240mmol) 正丁醛, 室温下搅拌约 20min, 分批加入硼氢化钠 9.00g ( 240mmol) 后, 再搅 拌 3h。 减压除去溶剂, 加入 300mL 乙酸乙酯溶解残留物, 有机相用 150mL饱和食盐水洗涤 两次, 150mL水洗涤一次。 用无水硫酸钠干燥有机相, 过滤, 减压除去溶剂。 用 200mL无 水乙醚溶解, 加入 150mL 4M 氯化氢 /乙酸乙酯, 搅拌约 lOmin后, 有气体冒出, 逐渐有白 色固体析出,室温搅拌约 6h 。过滤,滤饼用无水乙醚洗涤 3次,真空干燥,得白色固体 15.6g (80.1 IR(KBr, cm"1) : 3416 (br), 2942, 2870, 1607, 1458, 1027; 1H-NMR(D20/TMS) : δ 0.94 (t, 3H, CH2C¾), 51.41-1.39 (m, 4H, CH3CH2CH2), 52.32-1.52 (m, 8H, CH2 of DACH), 53.26-3.04 (m, 2H, NHCH2), 53.50-3.40 (m, 2Η, NHCH) ; ESI-MS m/z: [M-2HC1+H]+ =171(100%)。 实施例 37. 配体 2-R.2HC1的合成 (路线 I) Weighed 17.12g (80mmol) of SM-R, placed in a 500mL three-necked flask, dissolved in 350mL of methanol, added 17.28g (240mmol) of n-butyraldehyde, stirred at room temperature for about 20min, and added 9.00g (240mmol) of sodium borohydride in batches. After that, stir for another 3 hours. The solvent was removed under reduced pressure, and the residue was crystallised eluted with ethyl acetate (300 mL), and the organic phase was washed twice with 150 mL of brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. After dissolving in 200 mL of anhydrous diethyl ether, 150 mL of 4 M hydrogen chloride / ethyl acetate was added, and after stirring for about 10 min, a gas appeared, and a white solid gradually precipitated, and stirred at room temperature for about 6 h. Filtration, the filter cake was washed 3 times with dry diethyl ether and dried in vacuo to give a white solid 15.6 g (80.1 IR (KBr, cm" 1 ): 3416 (br), 2942, 2870, 1607, 1458, 1027; 1H-NMR ( D 2 0/TMS) : δ 0.94 (t, 3H, CH 2 C3⁄4), 51.41-1.39 (m, 4H, CH 3 CH 2 CH 2 ), 52.32-1.52 (m, 8H, CH 2 of DACH), 53.26 -3.04 (m, 2H, NHCH 2 ), 53.50-3.40 (m, 2 Η, NHCH); ESI-MS m/z: [M-2HC1+H] + = 171 (100%). Example 37. Ligand Synthesis of 2-R.2HC1 (Route I)
以 SM-R为起始物,异丁醛为反应物,按实施例 36方法得白色固体 15.0g (77.0 (KBr, cm"1) : 3430 (br), 2945, 2871, 1027, 1001; 1H-NMR(D2O rMS) : δ 1.02 (d, 6H, C¾CHC¾), 52.34-1.38 (m, 8H, CH2 of DACH), 52.09 (m, 1H, CH(CH3)2), 53.11-2.94 (d, 2H, NH CH2), 53.52-3.41 (m, 2H, CHNH) ; ESI-MS m/z: [M-2HC1+H]+ =171 (100%)。 实施例 38. 配体 3-R.2HC1的合成 (路线 I) Using SM-R as the starting material and isobutyraldehyde as the reactant, a white solid 15.0 g (77.0 (KBr, cm" 1 ) : 3430 (br), 2945, 2871, 1027, 1001; 1H was obtained as in Example 36. - NMR (D 2 O rMS) : δ 1.02 (d, 6H, C3⁄4CHC3⁄4), 52.34-1.38 (m, 8H, CH 2 of DACH), 52.09 (m, 1H, CH(CH 3 ) 2 ), 53.11-2.94 (d, 2H, NH CH 2 ), 53.52-3.41 (m, 2H, CHNH); ESI-MS m/z: [M-2HC1+H] + = 171 (100%). Example 38. Ligand 3 Synthesis of -R.2HC1 (Route I)
以 SM-R为起始物,丁酮为反应物,按实施例 36方法得白色固体 14.5g (74.5%) IR(KBr, cm"1) : 3428(br), 2942, 2986, 1096, 1024; 1H-NMR(D20/TMS) : δ 1.01-0.95 (m, 3H, C¾CH2), 52.32-1.37 (m, 8H, CH2 of DACH), 51.37-1.30 (m, 3H, CHC¾), 51.38-1.30 (m, 2H, CH3CH2), 53.39-3.38 (m, 1Η, NHCHCH3), 53.48-3.40 (m, 2H, CHNH) ; ESI-MS m/z: [M-2HC1+H]+ =171 (100%) 实施例 39. 配体 4-R.2HC1的合成 (路线 I)
Using SM-R as the starting material and methyl ethyl ketone as the reactant, 14.5 g (74.5%) of white solid was obtained by the method of Example 36. IR (KBr, cm" 1 ) : 3428 (br), 2942, 2986, 1096, 1024 1H-NMR(D 2 0/TMS) : δ 1.01-0.95 (m, 3H, C3⁄4CH 2 ), 52.32-1.37 (m, 8H, CH 2 of DACH), 51.37-1.30 (m, 3H, CHC3⁄4), 51.38-1.30 (m, 2H, CH 3 CH 2 ), 53.39-3.38 (m, 1Η, NHCHCH 3 ), 53.48-3.40 (m, 2H, CHNH) ; ESI-MS m/z: [M-2HC1+H ] + = 171 (100%) Example 39. Synthesis of Ligand 4-R.2HC1 (Route I)
以 SM-R为起始物,丙酮为反应物,按实施例 36方法得白色固体 13.0g (70.9%) IR(KBr, cm"1) : 3431 (br), 2975, 2946, 1098, 1032; 1H-NMR(D20/TMS) : δΙ .38-1.25 (m, 6H, CH(CH3)2), 52.26-1.38 (m, 8H, CH2 of DACH), 53.67-3.58 (m, 1H, NHCHCH3), 53.41-3.35 (m, 2H, NHCH) ; ESI-MS m/z: [M-2HC1+H]+ =157 (100%)。 实施例 40. 配体 5-R.2HC1的合成 (路线 I) Using SM-R as the starting material and acetone as the reactant, a white solid (13.0 g (70.9%) of IR (KBr, cm" 1 ): 3431 (br), 2975, 2946, 1098, 1032 was obtained as in Example 36; 1H-NMR (D 2 0/TMS) : δΙ .38-1.25 (m, 6H, CH(CH 3 ) 2 ), 52.26-1.38 (m, 8H, CH 2 of DACH), 53.67-3.58 (m, 1H , NHCHCH 3 ), 53.41-3.35 (m, 2H, NHCH); ESI-MS m/z: [M-2HC1+H] + = 157 (100%). Example 40. Ligand 5-R.2HC1 Synthesis (route I)
以 SM-R为起始物,环己酮为反应物,按实施例 36方法得白色固体 18.0g (84.0 ) dR(KBr, cm"1): 3429(br), 2939, 2860, 1030; 1H-NMR(D20/TMS) : 52.27-1.13 (m, 18H, CH2 of DACH and CHX), 53.45-3.32 (m, 3H, NHCH) ; ESI-MS m/z: [M-2HC1+H]+ =197(100%)。 Using SM-R as the starting material and cyclohexanone as the reactant, a white solid 18.0 g (84.0 ) dR (KBr, cm" 1 ) was obtained as in Example 36: 3429 (br), 2939, 2860, 1030; 1H -NMR (D 2 0/TMS): 52.27-1.13 (m, 18H, CH 2 of DACH and CHX), 53.45-3.32 (m, 3H, NHCH); ESI-MS m/z: [M-2HC1+H ] + = 197 (100%).
注: CHX代表环己基。 实施例 41. 配体 6-R.2HC1的合成 (路线 I)
Note: CHX stands for cyclohexyl. Example 41. Synthesis of Ligand 6-R.2HC1 (Route I)
以 SM-R为起始物,环戊酮为反应物,按实施例 36方法得白色固体 16.1g (79.1 ) dR(KBr, cm"1) : 3430(br), 2940, 2869, 2814, 1030; 1H-NMR(D2O rMS) : 52.36-1.37 (m, 16H, CH2 of DACH and CPX), 53.47-3.40 (m, 3H, NHCH) ; ESI-MS m/z: [M-2HC1+H]+ =183(100%)。 Using SM-R as the starting material and cyclopentanone as the reactant, a white solid 16.1 g (79.1) dR (KBr, cm" 1 ) was obtained as in Example 36: 3430 (br), 2940, 2869, 2814, 1030 1H-NMR(D 2 O rMS) : 52.36-1.37 (m, 16H, CH 2 of DACH and CPX), 53.47-3.40 (m, 3H, NHCH) ; ESI-MS m/z: [M-2HC1+ H] + = 183 (100%).
注: CPX代表环戊基。 实施例 42. 典型化合物的体外抗肿瘤活性测定 Note: CPX stands for cyclopentyl. Example 42. In vitro antitumor activity assay of typical compounds
对式(la)和式(lb)所示一些典型的铂(Π )配合物做了体外抗肿瘤活性测定, 所用的癌细 胞有人体肝癌细胞 HepG-2、 人体乳腺癌细胞 MCF-7、 人体肺癌细胞 A549和人体结肠癌细胞 HCT-116 , 所用的阳性对照物为现有药物顺铂、 奥沙利铂或卡铂。 具体的实验方法如下: 运用 MTT法检测细胞存活率, 即将生长在对数生长期的细胞, 经 0.01%的胰酶消化, 计 数, 以 2.0xl03/well的细胞密度接种在 96孔板中 lOOmL, 置于 5% C02培养箱内 37 °C培养过
夜。 每一化合物设六个浓度梯度, 每一浓度设三复孔, 每一浓度分别加入到对应孔中, 5% C0237°C培养箱内培养 72小时, 加入 20 mL 的 5 mg/mL MTT。 37°C孵育 3小时后, 吸弃上 清, 加入 100 mL的 DMSO溶解, 使用 SpectraMAX 340测 550 nm(Ll)光吸收值, 参考波长 690nm(L2), 将 (LI- L2)值对抑制剂不同浓度作图, 经公式拟合得 IC5o值。 Some typical platinum (Π) complexes represented by formula (la) and formula (lb) were tested for in vitro antitumor activity. The cancer cells used were human hepatoma cells HepG-2, human breast cancer cells MCF-7, human body. The positive control used for lung cancer cell A549 and human colon cancer cell HCT-116 is the existing drug cisplatin, oxaliplatin or carboplatin. The specific experimental methods are as follows: The cell viability is detected by MTT assay, and the cells growing in the logarithmic growth phase are counted by 0.01% trypsin, counted, and inoculated in a 96-well plate at a cell density of 2.0×10 3 /well, Cultured in a 5% C0 2 incubator at 37 °C Night. Six concentration gradients were set for each compound, three wells were set for each concentration, and each concentration was added to the corresponding wells, cultured in a 5% C0 2 37 °C incubator for 72 hours, and 20 mL of 5 mg/mL MTT was added. . After incubating for 3 hours at 37 ° C, the supernatant was aspirated, dissolved in 100 mL of DMSO, and the absorbance at 550 nm (Ll) was measured using a SpectraMAX 340. The reference wavelength was 690 nm (L2), and the (LI-L2) value was compared to the inhibitor. Drawing at different concentrations, the IC 5 o value was fitted by the formula.
表 1. 铂 ( II ) 配合物的 IC50值 Table 1. IC 50 values for platinum ( II ) complexes
Claims
1. 一种 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特征在于, 其结构 如式(la)或式(lb)所示: A platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, characterized in that the structure is as shown in formula (la) or formula (lb):
式 (la)中的 Y为有机羧酸阴离子, 式 (lb)中的 Z为有机二羧酸双阴离子, 式 (la)和式 (lb) 中, R是 C3-C8的烷基, 星号 *代表手性碳原子, 式 (la)和式 (lb)所述化合物是具有 1R, 2R-构 型和 /或 2 构型的手性异构体。 Y in the formula (la) is an organic carboxylic acid anion, Z in the formula (lb) is an organic dicarboxylic acid dianion, and in the formula (la) and the formula (lb), R is a C 3 - C 8 alkyl group. The asterisk * represents a chiral carbon atom, and the compound of the formula (la) and the formula (lb) is a chiral isomer having a 1R, 2R-configuration and/or a 2 configuration.
2. 如权利要求 1所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特 征在于, 式 (la)中的 Y为 -C16的烷氧基乙酸根或 C2-C18的烷基羧酸根; 式 (lb)中的 Z为草 酸根、 丙二酸根、 1,1-环丁二酸根、 3-羟基 -1,1-环丁二酸根、 3-烷氧基 -1,1-环丁二酸根、 3-氮 杂 -1, 1-环丁二酸根、 N-取代的 3-氮杂 -1, 1-环丁二酸根或樟脑二酸根, N-取代的 3-氮杂 -1, 1- 环丁二酸根中, 取代基为苄基、 -C4烷基取代的苄基、 -C4烷氧基取代的苄基或卤原子取 代的苄基。 2. The platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine according to claim 1 is a ligand, wherein Y in the formula (la) is -C Alkoxyacetate of 16 or C 2 -C 18 alkylcarboxylate; Z in formula (lb) is oxalate, malonate, 1,1-cyclosuccinate, 3-hydroxy-1,1 - cyclosuccinate, 3-alkoxy-1,1-cyclosuccinate, 3-aza-1, 1-cyclobutuccinate, N-substituted 3-aza-1, 1-cyclobutane Diacid or camphoric acid, N-substituted 3-aza-1, 1-cyclosuccinate, the substituent is benzyl, -C 4 alkyl substituted benzyl, -C 4 alkoxy substituted a benzyl group or a halogen atom substituted benzyl group.
3. 如权利要求 2所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特 征在于, 其结构如式 (lb )所示, 其中 R为丁基、 环戊基, Z为草酸根、 丙二酸根、 1,1-环丁 二酸根。 The platinum (ruthenium) complex in which the N-alkyl-substituted trans 1,2-cyclohexanediamine according to claim 2 is a ligand, wherein the structure is as shown in the formula (lb). Wherein R is butyl, cyclopentyl, and Z is oxalate, malonate, 1,1-cyclosuccinate.
4. 如权利要求 3所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特 征在于, R为仲丁基、 环戊基, Z为草酸根、 丙二酸根、 1,1-环丁二酸根。 The platinum (ruthenium) complex in which the N-alkyl substituted trans 1,2-cyclohexanediamine according to claim 3 is a ligand, wherein R is a sec-butyl group, a cyclopentyl group, Z is oxalate, malonate, 1,1-cyclosuccinate.
5. 如权利要求 2所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特 征在于, 其结构如式(la)或式 (lb ) 所示, 其中 R为丙基, Y为 C2-C4的烷氧基乙酸根, Z 为 N-取代的 3-氮杂 -1, 1-环丁二酸根, N-取代的 3-氮杂 -1, 1-环丁二酸根中, 取代基为苄基、 甲基取代的苄基、 甲氧基取代的苄基或卤原子取代的苄基。 The platinum (ruthenium) complex in which the N-alkyl-substituted trans 1,2-cyclohexanediamine according to claim 2 is a ligand, which has a structure of the formula (la) or formula ( Shown in lb), wherein R is propyl, Y is C 2 -C 4 alkoxyacetate, Z is N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3 In the aza-1,1-cyclosuccinate, the substituent is a benzyl group, a methyl-substituted benzyl group, a methoxy-substituted benzyl group or a halogen-substituted benzyl group.
6. 如权利要求 5所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特 征在于, R为异丙基, Y为异丙氧基乙酸根或叔丁氧基乙酸根, Z为 N-取代的 3-氮杂 -1, 1- 环丁二酸根, N-取代的 3-氮杂 -1, 1-环丁二酸根中, 取代基为甲基取代的苄基或甲氧基取代 的苄基。 6. The platinum (ruthenium) complex of the N-alkyl substituted trans 1,2-cyclohexanediamine according to claim 5, wherein R is an isopropyl group and Y is an isopropyl group. Oxyacetate or tert-butoxyacetate, Z is an N-substituted 3-aza-1,1-cyclosuccinate, N-substituted 3-aza-1,1-cyclosuccinate The substituent is a methyl substituted benzyl or a methoxy substituted benzyl.
7. 一种 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物, 其特征在于, 其结构 如式 (2)所示; 7. A platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand, characterized in that the structure is as shown in formula (2);
式 (2) 其中, Hal代表 Cl—、 Br—或 Γ, R是如权利要求 1-6任一项所述的 C3-C8的烷基, 星号 * 代表手性碳原子, 式 (2) 所述化合物是具有 1R,2R-构型和 /或 1^,2^-构型的手性异构体。 Wherein, Hal represents Cl—, Br— or Γ, R is a C 3 -C 8 alkyl group according to any one of claims 1 to 6, and the asterisk * represents a chiral carbon atom, 2) The compound is a chiral isomer having a 1R, 2R-configuration and/or a 1^, 2^-configuration.
8. 一种 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π)配合物的制备方法, 其特征在 于, 包括以下步骤: 以单 Boc保护的反式 1, 2-环己二胺为起始物通过下述合成路线 I得到式 (3)代表的化合物, 然后以式 (3) 所示化合物与四卤合铂 (Π)酸钾反应, 得到式 (2) 所述化 合物; A method for preparing a platinum (ruthenium) complex in which an N-alkyl-substituted trans 1,2-cyclohexanediamine is a ligand, comprising the steps of: trans-protected by a single Boc , 2-cyclohexanediamine as a starting material, the compound represented by the formula (3) is obtained by the following scheme I, and then the compound represented by the formula (3) is reacted with potassium tetrahalide (potassium)ate to obtain a formula ( 2) the compound;
^ (3) 所述单 Boc保护的反式 1, 2-环己二胺由式 (4)表示: ^ (3) The single Boc protected trans 1,2-cyclohexanediamine is represented by the formula (4):
一曰 (Xa trip (X
其中 Boc代表叔丁氧羰基; 路线 I如下所示: —曰 Wherein Boc represents a tert-butoxycarbonyl group; Route I is as follows: —曰
T)T)
路线 I中, R是如权利要求 1-6任一项所述的 C3-C8的烷基, 所述脂肪醛为 C3-C8的链状 烷基醛, 所述脂肪酮为 8的链状或环状烷基酮, 当 R为链状烷基时, 使用链状烷基醛或 链状烷基酮, 当使用链状烷基醛时, R1为。2 7的烷基, R2为氢原子; 当使用链状烷基酮时, R1和 R2分别为 d-C6的链状烷基, 两者的碳原子数之和应小于 7或等于 7; 当 R为环状烷 基时, 使用环状烷基酮, 其中 X为 C2-C7的亚烷基。 In the route I, R is a C 3 -C 8 alkyl group according to any one of claims 1 to 6, the fatty aldehyde is a C 3 - C 8 chain alkyl aldehyde, and the aliphatic ketone is 8 A chain or cyclic alkyl ketone, when R is a chain alkyl group, a chain alkyl aldehyde or a chain alkyl ketone is used, and when a chain alkyl aldehyde is used, R1 is. 2 7 alkyl, R 2 is a hydrogen atom; when a chain alkyl ketone is used, R 1 and R 2 are respectively a linear alkyl group of dC 6 , the sum of the carbon atoms of the two should be less than 7 or equal to 7; In the case of a cyclic alkyl group, a cyclic alkyl ketone is used, wherein X is a C 2 - C 7 alkylene group.
9. 如权利要求 7所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂( II )配合物的制备 方法, 其特征在于, 由式 (2) 所述化合物反应生成式 (la) 或式 (lb) 中所述化合物。 The method for producing a platinum (II) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand according to claim 7, wherein the method is represented by the formula (2) The compound is reacted to form a compound of formula (la) or formula (lb).
10. 如权利要求 8所述的 N-烷基取代的反式 1, 2-环己二胺为配体的铂(Π )配合物的制备 方法, 其特征在于, 由式 (2) 所述化合物反应生成式 (la) 或式 (lb) 中所述化合物的方法 为: The method for producing a platinum (ruthenium) complex in which an N-alkyl substituted trans 1,2-cyclohexanediamine is a ligand according to claim 8, wherein the method is represented by the formula (2) The method of reacting a compound to form a compound of formula (la) or formula (lb) is:
在避光条件下, 于水溶液中, 通过银离子除去式 (2)中的卤离子, 然后与式(la)所定义的 Y的碱金属盐或铵盐反应生成式(la)所示的铂(Π )配合物, 或与式(lb)所定义的 Z的碱金属 盐或铵盐反应生成式(lb)所示的铂( II )配合物; The halogen ion in the formula (2) is removed by silver ions in an aqueous solution under light shielding conditions, and then reacted with an alkali metal salt or an ammonium salt of Y defined by the formula (la) to form a platinum represented by the formula (la). (Π) complex, or reacted with an alkali metal salt or ammonium salt of Z as defined by formula (lb) to form a platinum (II) complex of formula (lb);
或者, Or,
在避光条件下, 于水溶液中, 通过式(la)所定义的 Y的银盐与式 (2)所示的铂(Π )配合物 反应生成式(la)所示的铂( II )配合物,或通过式(lb)所定义的 Z的银盐与式 (2)所示的铂( II ) 配合物反应生成式(lb)所示的铂( II )配合物。 In a light-protected condition, a silver salt of Y defined by the formula (la) is reacted with a platinum (ruthenium) complex represented by the formula (2) in an aqueous solution to form a platinum (II) complex represented by the formula (la). The platinum salt of the formula (b) is reacted with a platinum (II) complex represented by the formula (2) to form a platinum (II) complex represented by the formula (lb).
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