LU501930B1 - Tripyridine iron/ruthenium compound containing nitrogen mustard, synthesis method and application thereof - Google Patents
Tripyridine iron/ruthenium compound containing nitrogen mustard, synthesis method and application thereof Download PDFInfo
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- LU501930B1 LU501930B1 LU501930A LU501930A LU501930B1 LU 501930 B1 LU501930 B1 LU 501930B1 LU 501930 A LU501930 A LU 501930A LU 501930 A LU501930 A LU 501930A LU 501930 B1 LU501930 B1 LU 501930B1
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- Prior art keywords
- iron
- tripyridine
- nitrogen mustard
- compound containing
- ruthenium compound
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 41
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960004961 mechlorethamine Drugs 0.000 title claims abstract description 41
- 150000003304 ruthenium compounds Chemical class 0.000 title claims abstract description 32
- DRGAZIDRYFYHIJ-UHFFFAOYSA-N 2,2':6',2''-terpyridine Chemical compound N1=CC=CC=C1C1=CC=CC(C=2N=CC=CC=2)=N1 DRGAZIDRYFYHIJ-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 241000219198 Brassica Species 0.000 claims abstract 2
- 235000003351 Brassica cretica Nutrition 0.000 claims abstract 2
- 235000003343 Brassica rupestris Nutrition 0.000 claims abstract 2
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 claims abstract 2
- 235000010460 mustard Nutrition 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 239000002246 antineoplastic agent Substances 0.000 claims description 11
- 229940041181 antineoplastic drug Drugs 0.000 claims description 11
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 9
- OJPDDQSCZGTACX-UHFFFAOYSA-N 2-[n-(2-hydroxyethyl)anilino]ethanol Chemical compound OCCN(CCO)C1=CC=CC=C1 OJPDDQSCZGTACX-UHFFFAOYSA-N 0.000 claims description 7
- 239000005457 ice water Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 claims description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- JFJNVIPVOCESGZ-UHFFFAOYSA-N 2,3-dipyridin-2-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CN=C1C1=CC=CC=N1 JFJNVIPVOCESGZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 32
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- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
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- 238000012795 verification Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 15
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 14
- 230000000259 anti-tumor effect Effects 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
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- 238000000034 method Methods 0.000 description 8
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- 230000012292 cell migration Effects 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000003446 ligand Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000003698 anagen phase Effects 0.000 description 4
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- 230000008859 change Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- -1 ethyleneimine ions Chemical class 0.000 description 4
- 238000004896 high resolution mass spectrometry Methods 0.000 description 4
- 150000002736 metal compounds Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
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- 229910021645 metal ion Inorganic materials 0.000 description 3
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- 150000002506 iron compounds Chemical class 0.000 description 2
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- 230000004048 modification Effects 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PXUFHXLGUJLBMI-UHFFFAOYSA-N 4-[bis(2-chloroethyl)amino]benzaldehyde Chemical compound ClCCN(CCCl)C1=CC=C(C=O)C=C1 PXUFHXLGUJLBMI-UHFFFAOYSA-N 0.000 description 1
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- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 101000911513 Homo sapiens Uncharacterized protein FAM215A Proteins 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102100026728 Uncharacterized protein FAM215A Human genes 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 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
- C07F15/0073—Rhodium compounds
- C07F15/008—Rhodium 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- 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
- C07F15/02—Iron compounds
- C07F15/025—Iron compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (9)
1. Eine Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, dadurch gekennzeichnet, dass die Strukturformel wie folgt lautet: 2+ / \ / \ | 2CT A, _ EN JT _ HA N \ NT MTN] / N of” $ Th wobei M eines von Fe oder Ru ist.
2. Fin Verfahren zur Synthese der Terpyridin-Fisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 1, das die folgenden Schritte umfasst: (1) Synthese von 4-[Bi-(B-chlorethyl)amino]benzaldehyd: unter Eiswasserbad, tropfenweise Zugabe von POCI; in DMF, Rühren während des Abtropfens, und Fortsetzen der Reaktion im Fiswasserbad für 25-35 min, um eine erste Lösung zu erhalten, dann Zugabe der DMF-Lôsung, enthaltend N,N-Bi-(2-hydroxyethyl)-anilin, in die erste Lôsung und Reaktion für 2-4 h bei 90-110°C, Abkühlung auf Raumtemperatur, um eine zweite Lösung zu erhalten, Gießen der zweiten Losung in Eiswasser, Einstellung zur Neutralität mit Alkalilauge, Saugfiltrieren, Waschen des Filterkuchens und Umkristallisieren, um einen hellgelben Feststoff zu erhalten, nämlich 4-[Bi-(B-chlorethyl)amino]benzaldehyd; (2) Synthese von 4-(4-[ Bi-(P-chlorethyl) amino] phenyl) -2,2',6',2-Tripyridin: 4-[ Bi-(B-chlorethyl) amino] benzaldehyd, 2-Acetylpyridin und NaOH werden in Ethanol zugegeben, und dann Ammoniakwasser nach der Reaktion fur 25-35 Minuten bei Raumtemperatur zugesetzt, Zugabe von Ammoniakwasser, Reaktion 10-15 Stunden lang, um eine dritte Losung zu erhalten, Konzentrieren der dritten Lôsung auf 1/3 der ursprünglichen Lösung, Filtrieren, Trocknen von Filterkuchen nach dem Waschen, und Umkristallisieren, um einen hellgelben Feststoff zu erhalten, nämlich 4-(4-[ Bi-beta-chlorethyl)amino]phenyl) -2,2',6',2-terpyridin; (3) Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf: Auflôsen von 4-(4-[ Bi-(B-chlorethyl) amino] phenyl)-2,2',6',2- Tripyridin in Ethylenglykolmethylether, Zugabe von Eisen-/Rutheniumchlorid während des Rührens und ZurückflieBen bei 120-130°C für 6-10 Stunden, Waschen nach dem Entfernen von Lôsungsmittel und Trocknen, um die,501930 Tripyridin-Fisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, zu erhalten.
3. Das Verfahren zur Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 2, dadurch gekennzeichnet, dass das molare Verhältnis von DMF zu POCI; in Schritt (1) (2-2,5):1 beträgt, das molare Verhältnis von N,N- Bi-(2-hydroxyethyl)-anilin in DMF-Lôsung, enthaltend N,N-Bi-(2-hydroxyethyl)-anilin, zu DMF beträgt 1:1.
4. Das Verfahren zur Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 2, dadurch gekennzeichnet, dass die Alkalilauge in Schritt (1) NaOH, KOH, Na,COs, K:CO; oder Natriumethanolat umfasst.
5. Das Verfahren zur Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 2, dadurch gekennzeichnet, dass in Schritt (1) die Umkristallisation unter Verwendung einer Mischlôsung aus Ethanol und Dichlormethan durchgeführt wird, und das Volumenverhältnis von Ethanol zu Dichlormethan in der Mischlôsung ist 1:1.
6. Das Verfahren zur Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 2, dadurch gekennzeichnet, dass in Schritt (2) das molare Verhältnis von 4-[Bi-(B-chlorethyl) amino] benzaldehyd, 2-Acetylpyridin und NaOH 1:2:2 beträgt.
7. Das Verfahren zur Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 2, dadurch gekennzeichnet, dass in Schritt (2) die Mischungslösung aus Methanol und Dichlormethan zur Umkristallisation verwendet wird, und das Volumenverhältnis von Methanol zu Dichlormethan in der Mischungslösung ist 1:1.
8. Das Verfahren zur Synthese der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 2, dadurch gekennzeichnet, dass in Schritt (3) das Molverhältnis von 4-(4-[Bi-(B-chlorethyl) amino] phenyl)-2,2',6',2- tripyridin zu Eisen/Rutheniumchlorid 2:1 beträgt.
9. Eine Anwendung der Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, zur Herstellung von = Antitumor-Medikamenten, dadurch gekennzeichnet, dass die Antitumor-Medikamente die Tripyridin-Eisen/Ruthenium-Verbindung, enthaltend Stickstoffsenf, nach Anspruch 1 oder ein pharmazeutisch akzeptables Salz davon umfassen.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110178589.4A CN112940046B (zh) | 2021-02-09 | 2021-02-09 | 一种含氮芥的三联吡啶铁/钌配合物、合成方法与应用 |
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