WO2025061216A1 - Coordination compounds of ruthenium and osmium for use in the treatment of lung cancer - Google Patents

Coordination compounds of ruthenium and osmium for use in the treatment of lung cancer Download PDF

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WO2025061216A1
WO2025061216A1 PCT/CZ2024/050060 CZ2024050060W WO2025061216A1 WO 2025061216 A1 WO2025061216 A1 WO 2025061216A1 CZ 2024050060 W CZ2024050060 W CZ 2024050060W WO 2025061216 A1 WO2025061216 A1 WO 2025061216A1
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general formula
coordination compound
pcym
ionic coordination
compounds
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French (fr)
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Ivan NEMEC
Pavel Starha
Jan HOSEK
Katerina PENCIKOVA
Nicol STRAKOVA
Renata HEZOVA
Pavlina SIMECKOVA
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Univerzita Palackeho V Olomouci
Vyzkumny Ustav Veterinarniho Lekarstvi, V. V. I.
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    • 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
    • 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
    • C07F15/0046—Ruthenium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • 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
    • C07F15/002—Osmium compounds

Definitions

  • Coordination compounds of ruthenium and osmium for use in the treatment of lung cancer Field of Art
  • the invention relates to the field of anticancer drugs based on the platinum metals ruthenium and osmium, and relates to half-sandwich coordination compounds containing a complex cation of the general formula [Ru( ⁇ 6 -pcym)Cl(L)] + and [Os( ⁇ 6 -pcym)Cl(L)] + , wherein L represents an N,N-donor bidentate aliphatic ligand based on ethane-1,2-diamine substituted by two polycyclic aromatic substituents.
  • the invention further relates to use of such compounds for the treatment of lung cancer.
  • Cancer is a genetic disease that is caused by DNA damage or faulty DNA repair. Cancer is currently one of the leading causes of death worldwide. In recent years, one of the most dangerous types of cancer is lung cancer, which is one of the most frequently newly diagnosed oncological diseases and at the same time the most common cause of death from cancer (approx. 20% of all cancer-related deaths). It is therefore evident that conventional anticancer therapies are not completely effective against lung cancer and it is essential to look for new therapeutics in this field. From the point of view of cancer classification, two main types of lung cancer can be distinguished - small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • NSCLC In oncological practice (often due to the late diagnosis of this disease), NSCLC in particular is one of the most problematic and difficult- to-treat cancer types.
  • Chemotherapy continues to be an integral part of lung cancer treatment, usually combined with surgery and/or radiotherapy.
  • one of the first approved anticancer drugs is cisplatin (Formula A), which has shown clinical activity against a wide range of solid tumors, including lung cancer.
  • Combination therapy for lung cancer containing platinum-based drugs e.g., cisplatin
  • negative side effects e.g., nephrotoxicity or myelosuppression
  • the problem with patients treated with platinum-based drugs is the emergence of resistance to such chemotherapy.
  • ruthenium(III) coordination compounds [RuCl(NH 3 ) 4 (OH)]Cl and fac-[RuCl 3 (NH 3 ) 3 ], the latter exhibiting cisplatin-like activity, inducing filamentous growth in E. coli (Durig et al., Chem.-Biol. Interact. 13 (1976) 287).
  • ruthenium-based coordination compounds reached the stage of clinical trials for the treatment of various types of tumors, including lung cancer, in human oncology patients.
  • These compounds were the tetrachlorido-bis(indazole)ruthenium(III) complex (under various code names - KP1019, NKP-1339, IT-139; formula B; Burris et al., ESMO Open 1 (2016) e000154) and the structurally similar tetrachlorido-(dimethylsulfoxido)(imidazole)ruthenium(III) complex (NAMI-A; formula C; Leijen et al., Invest. New Drugs 33 (2015) 201).
  • the second article described the synthesis and biological and catalytic activity of ruthenium(II) coordination compounds of this type containing N,N ⁇ -bis ⁇ (E)-[4-(1- methylethyl)phenyl]methylene ⁇ ethane-1,2-diamine (L a ) and N,N ⁇ -bis(1-pyrenylmethylene)ethane-1,2- diamine (L b ) (Gopalakrishnan et al., Appl. Organometal. Chem.33 (2019) e4756). Both compounds were tested for in vitro antiproliferative activity against human breast adenocarcinoma (MCF-7) and human hepatocellular carcinoma (HepG2) cell lines.
  • MCF-7 breast adenocarcinoma
  • HepG2 human hepatocellular carcinoma
  • An aspect of the present invention are ionic half-sandwich coordination compounds of ruthenium or osmium in oxidation state +II of general formula I, wherein: - the central atom M is ruthenium or osmium; - each substituent R is a polycyclic aryl which is independently selected from the group naphthyl, anthracenyl, phenanthrenyl or pyrenyl; - wherein when the central atom M is ruthenium, the substituent R is other than 1-pyrenyl, optionally in the form of pharmaceutically acceptable solvates.
  • solvates are especially solvates with solvents selected from the group of water, primary alcohol, secondary alcohol, dichloromethane, acetone, n-hexane, diethyl ether, and mixtures thereof. Typically, solvates are formed with one to four solvent molecules. Compounds of general formula I may also form solvates in the form of crystal solvates.
  • the coordination compounds according to the present invention are cationic, so they will occur in compounds with a counterion.
  • the counterion is a pharmaceutically acceptable anion, preferably selected from acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hexafluorophosphate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfonate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, theoclate, to
  • the central atom M is osmium.
  • each substituent R is independently selected from the group consisting of 2- naphthyl, 9-anthracenyl, 9-phenanthrenyl and 1-pyrenyl.
  • An aspect of the present invention are ionic half-sandwich coordination compounds of ruthenium or osmium in oxidation state +II of general formula I, wherein: - the central atom M is ruthenium or osmium; - each substituent R is a polycyclic aryl which is independently selected from the group naphthyl, anthracenyl, phenanthrenyl or pyrenyl; optionally in the form of pharmaceutically acceptable solvates; for use as medicaments, in particular for use in the treatment of cancer, more preferably for use in the treatment of lung cancer (lung carcinomas, such as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • An aspect of the present invention is a method for preparation of ionic half-sandwich coordination compounds of ruthenium or osmium in their oxidation state +II of the general formula I, by a procedure starting from dinuclear coordination compound [Ru( ⁇ -Cl)( ⁇ 6 -pcym)Cl] 2 or [Os( ⁇ -Cl)( ⁇ 6 -pcym)Cl] 2 , which reacts with an N,N'-dimethylideneethane-1,2-diamine derivative of general formula II and with ammonium or potassium hexafluorophosphate to form the desired coordination compound of general formula I with PF 6 – anion, which can be further converted to a compound of general formula I with any pharmaceutically acceptable anion by generally known procedures for the preparation of salts
  • the reaction for the preparation of a coordination compound of general formula I is preferably carried out in a microwave reactor at a temperature of 100 °C for 1 min.
  • the reaction is preferably carried out in a solvent selected from the group: primary alcohol, dichloromethane, and mixtures thereof.
  • the product (coordination compound of general formula I in the form of a salt with PF 6 – anion) is precipitated or crystallized and separated from the mother liquor by filtration or centrifugation. Subsequently, the separated product can preferably be washed with water and a solvent selected from the group: water, primary alcohol, secondary alcohol, dichloromethane, acetone, n-hexane, diethyl ether, and their mixtures.
  • the isolated product can then be dried in a desiccator or under an infrared lamp.
  • Compounds of general formula II are prepared by Schiff reaction of ethane-1,2-diamine with aldehydes of the respective polycyclic aromatic hydrocarbons in methanol in a microwave reactor, preferably at a temperature of about 60 °C, preferably for about 3 min.
  • the coordination compound of formula I, wherein M is ruthenium and R is 1-pyrenyl, has already been described in the literature and can therefore also be prepared according to the literature procedure, but its antiproliferative activity against human lung cancer has not yet been examined (Gopalakrishnan et al., Appl. Organometal. Chem. 33 (2019) e4756).
  • An aspect of the invention is a pharmaceutical composition containing a therapeutically effective amount of an ionic half-sandwich coordination compound of ruthenium or osmium in oxidation state +II of general formula I, and at least one excipient.
  • Auxiliary substances can be in particular fillers, binders, solvents, glidants, disintegrants, stabilizers, and/or taste and smell masking agents.
  • the pharmaceutical composition is preferably a liquid composition, for example in the form of an injection or infusion solution or preparation for oral administration.
  • a therapeutically effective amount is an amount which leads to stopping or reversing the development of the cancer disease in a patient.
  • Fig.10 are pictures from confocal microscopy showing 3D spheroids from A549 cells treated with complexes 1 and 5, and cisplatin.
  • Fig.11 shows the effect of complexes 1 and 5, and cisplatin on cell apoptosis/death detected in the A549 cell line.
  • Fig.12 shows the effect of complexes 1 and 5, and cisplatin on the cell cycle detected in the A549 cell line.
  • Fig.13 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with early cell stress in the A549 cell line after 5 h incubation.
  • Fig.14 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with oxidative stress and heat shock response in the A549 cell line after 5 h incubation.
  • Fig.15 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with DNA damage response in the A549 cell line after 5 h incubation.
  • Fig.16 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with endoplasmic reticulum stress in the A549 cell line after 5 h incubation.
  • Fig.17 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with xenobiotic response and immunomodulation in the A549 cell line after 5 h incubation.
  • Fig.18 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with early cell stress in the A549 cell line after 24 h incubation.
  • Fig.19 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with oxidative stress and heat shock response in the A549 cell line after 24 h incubation.
  • Fig.20 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with DNA damage response in the A549 cell line after 24 h incubation.
  • Fig.21 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with endoplasmic reticulum stress in the A549 cell line after 24 h incubation.
  • Fig.22 shows the effect of complexes 1 and 5, and cisplatin on changes in transcription of genes connected with xenobiotic response and immunomodulation in the A549 cell line after 24 h incubation.
  • the prepared coordination compounds of ruthenium and osmium were characterized by the following analytical techniques: • elemental analysis (Flash 2000 CHNS). • nuclear magnetic resonance (NMR; Varian-400 spectrometer) - 1 H and gs-COSY experiments were performed at a temperature of 298 K.
  • the geometry of the coordination polyhedron of the complex particle is the so-called "piano stool” type with the pcym ligand providing six Ru–C bonds (2.16– 2.24 ⁇ ).
  • the Ru–Cl bond is the longest one (2.3994(7) ⁇ ), while the Ru–N bonds with the L3 ligand are the shortest bonds (2.097(2) and 2.125(2) ⁇ ).
  • RT room temperature.
  • L3 derivative is novel.
  • Ethane-1,2-diamine (1 mmol) is added to a suspension of a stoichiometric amount (2 mmol) of the aldehyde of the corresponding polycyclic aromatic hydrocarbon in 10 mL of methanol.
  • the reaction mixture is acidified with four drops of concentrated acetic acid and then reacts in a microwave reactor at a temperature of 60 °C for 3 min.
  • the reaction mixture was heated to 100 °C for 1 min in a Monowave 300 microwave reactor. After cooling to room temperature (ca.22 °C), the resulting mixture was filtered and an excess of NH 4 PF 6 (40.8 mg; 0.25 mmol) was added. The mixture was stirred for 15 min. Subsequently, the solvent volume was reduced to 1–2 mL. The resulting solid product was filtered off and redissolved in 3 mL of dichloromethane. An equal volume of water was added to this solution and the resulting mixture was thoroughly shaken. After separation of the dichloromethane phase, this solution was dried by adding MgSO 4 and after subsequent filtration, the filtrate was concentrated (nitrogen gas) to approx.1 mL volume.
  • coordination compounds 1 to 8 can be prepared according to Scheme 3.
  • the starting coordination compound [Ru( ⁇ -Cl)( ⁇ 6 -pcym)Cl] 2 (30.6 mg; 0.05 mmol; for compounds 1–4) or [Os( ⁇ - Cl)( ⁇ 6 -pcym)Cl] 2 (39.5 mg; 0.05 mmol; for compounds 5–8) was mixed with an organic compound of general formula II, which is one of the ligands L1 to L4 (0.15 mmol; 50.5 mg for L1, 65.5 mg for L2 and L3, and 72.7 mg for L4) in 5 mL of methanol. The reaction mixture was stirred at room temperature for 24 h. Then the resulting mixture was filtered and NH 4 PF 6 (40.8 mg; 0.25 mmol) was added to the filtrate.
  • an organic compound of general formula II which is one of the ligands L1 to L4 (0.15 mmol; 50.5 mg for L1, 65.5 mg for L2 and L3, and 72.7 mg for L4
  • Example 2 In vitro antiproliferative activity of compounds of formulas 1 to 8 against cell lines derived from lung tumors Microtitration colorimetric analysis using 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4- disulfophenyl)-2H-tetrazolium sodium (CCK-8) was used to determine in vitro antiproliferative activity of coordination compounds 1 to 8 against human lung cancer-derived cell lines A549, MOR and MOR/CPR. The test spectrophotometrically determines the absorbance of the orange dye (i.e. reduced CCK-8), which corresponds to the number of metabolically active (i.e.
  • the human cell line A549 is an adherent line obtained from the European Collection of Authenticated Cell Cultures (catalog number 86012804). It was derived from lung cancer of a 58-year-old Caucasian man. Functionally, they are epithelial cells.
  • the human cell line MOR is an adherent line obtained from the European Collection of Authenticated Cell Cultures (catalog number 84112312). It was derived from lung adenocarcinoma. These are epithelial-like cells that grow in colonies.
  • the MOR/CPR cell line was obtained from the European Collection of Authenticated Cell Cultures (catalog number 96042333).
  • MOR line (ECACC catalog number 84112312) and is characterized by resistance to cisplatin. It grows adherently in colonies and as aggregates in suspension.
  • A549 cells were grown in DMEM medium with a higher glucose content (4.5 g/L) supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and 1% penicillin-streptomycin antibiotic.
  • MOR and MOR/CPR cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine and 1% penicillin-streptomycin antibiotic.
  • the medium for MOR/CPR cells additionally contained cisplatin at a concentration of 1 ⁇ g/mL.
  • the tested coordination compounds 1 to 8 were dissolved in N,N'-dimethylformamide (DMF) to prepare 20.0 mM stock solutions.
  • DMF N,N'-dimethylformamide
  • the stock solutions were diluted with medium to concentrations of 20 ⁇ M, 10 ⁇ M, 5 ⁇ M, 2.5 ⁇ M, 1.25 ⁇ M, 0.63 ⁇ M, 0.31 ⁇ M and 0.16 ⁇ M.
  • the concentration of DMF was constant in all tested concentrations, namely 0.1% (v/v).
  • A549, MOR and MOR/CPR cell suspensions were pipetted into a 96-well microtiter plate in a volume of 100 ⁇ L and an amount of 1 ⁇ 10 4 cells per well. Subsequently, the cells were allowed to adhere for 16 h, after which the non-adherent cells were aspirated together with the culture medium. In fresh medium (note the medium for MOR/CPR did not contain cisplatin at this stage of testing), coordination compounds 1 to 8 were added to the cells at concentrations of 20 ⁇ M, 10 ⁇ M, 5 ⁇ M, 2.5 ⁇ M, 1.25 ⁇ M, 0, 63 ⁇ M, 0.31 ⁇ M and 0.16 ⁇ M.
  • cell viability was calculated according to the formula for each sample: ⁇ 100 wherein A 450 is absorbance at 450 nm, A 630 is absorbance at 630 nm and n.c. is a negative control treated by only 0.1% (v/v) DMF. Cell viability was calculated for all concentrations of the tested coordination compounds 1 to 8. Three independent experiments (each in triplicate) were performed from freshly passaged cells. The half- maximal inhibitory concentration (IC 50 ) of the test compounds, which corresponds to the concentration of the tested compounds required to inhibit the growth of 50% of the treated cancer cells, was calculated from the dose curves and is shown in Table 1.
  • Table 1 Results of in vitro antiproliferative activity testing of coordination compounds 1 to 8 against human cancer cell lines A549, MOR and MOR/CPR determined using the CCK-8 assay. Results are expressed as IC 50 inhibitory concentration values ⁇ standard error of the mean (SEM).
  • A549 cells resuspended in serum-free DMEM were seeded at a density of 16 ⁇ 10 3 cells/well into a 96-well U-shaped bottom microtitre plate with a low cell binding surface (Thermo Scientific, Roskilde, Denmark). After 4 days, the medium was exchanged for medium containing 10% FBS, and the spheroids were cultivated for another 3 days. Then, the grown spheroids (diameter of 0.5– 1.0 mm) were transferred to a 96-well plate with a flat bottom, which was covered with Vitrogel matrix, forming a wide U-shaped bed. During the transfer, the medium was exchanged.
  • Example 4 In vitro cell cycle and apoptosis evaluation of compounds 1 and 5 on A549 cells Flow cytometry was used to evaluate the number of cells in the particular phases of the cell cycle and subsequently to analyse cell death. Vindel's solution prepared as follows was used for cell cycle staining: 5 mg propidium iodide (Merck; USA), 1 mg RNase (Sigma-Aldrich, USA), 100 ⁇ L TRITON X-100 (Sigma-Aldrich, USA), 60 mg NaCl (Merck, USA), 1 mL 1M TRIS (pH 8.0; Merck, USA) diluted in 100 mL water.
  • Vindel's solution prepared as follows was used for cell cycle staining: 5 mg propidium iodide (Merck; USA), 1 mg RNase (Sigma-Aldrich, USA), 100 ⁇ L TRITON X-100 (Sigma-Aldrich, USA), 60 mg NaCl (Merck, USA), 1 mL 1M TRIS
  • A549 cell suspension (3 ⁇ 10 5 cells per well) were pipetted into a 6-well microtiter plate (TPP, Switzerland) in 3 mL DMEM medium with a higher glucose content (4.5 g/L) supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and 1% penicillin-streptomycin antibiotic.
  • the cells adhered for 16 h, next the non-adherent cells were aspirated together with the culture medium.
  • coordination compounds 1 and 5 were added to the cells at concentrations corresponding to their 0.5 ⁇ , 1 ⁇ , and 3 ⁇ IC 50 values obtained from 2D experiments (i.e., 3, 6, and 18 ⁇ M for 1; 0.6, 1.2, and 3.6 ⁇ M for 5).
  • samples were washed twice by 5 mL PBS (Merck, USA), centrifuged (500 g, 5 min, 4 °C) and stained by 100 ⁇ L Vindel's solution for 20 min at room temperature and analysed by flow cytometer Amnis CellStream (Luminex, USA). Moreover, Annexin V-FITC with viability staining were used for the detection of live, apoptotic, necrotic cells. The treated cells were stained with an ApoflowEx FITC Kit (Exbio, Czech Republic) at a dilution of 1:20 and a LIVE/DEAD Fixable Violet Dead Cell Stain Kit (ThermoFisher Scientific, USA) at a dilution of 1:1000 for 20 min.
  • ApoflowEx FITC Kit Exbio, Czech Republic
  • LIVE/DEAD Fixable Violet Dead Cell Stain Kit ThermoFisher Scientific, USA
  • Live cells live cells/Annexin V negative; low left quadrant; LL
  • early apoptotic cells live cells/Annexin V positive; low right quadrant; LR
  • late apoptotic cells dead cells/Annexin V positive; upper right quadrant; UR
  • necrotic/dead cells dead cells/Annexin V negative; upper left quadrant; UL
  • Example 5 In vitro evaluation of the effect of compounds 1 and 5 on transcription of stress-related genes on A549 cells Changes in the gene expression of cellular stress markers were determined by quantitative real-time PCR (qRT–PCR) using A549 cells. Cells were seeded at the density of 2 ⁇ 105 cells into 24-well plates and treated with compounds 1 and 5 at the indicated concentrations for 5 and 24 h, respectively. After exposure, cells were washed and harvested into cell lysis buffer from the NucleoSpin RNA II Purification Kit (Macherey-Nagel, Düren, Germany). Total RNA was isolated according to the manufacturer's instructions.
  • RNA levels were normalized using Hydroxymethylbilane synthase (HMBS, NM_000190) and beta-2-microglobulin (B2M, NM_004048) in predesigned qRT-PCR assay 3032-F (Generi Biotech, Hradec Králové, Czech Republic). Changes in gene expression were calculated using the comparative threshold cycle method.
  • HMBS Hydroxymethylbilane synthase
  • B2M beta-2-microglobulin

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PCT/CZ2024/050060 2023-09-18 2024-09-17 Coordination compounds of ruthenium and osmium for use in the treatment of lung cancer WO2025061216A1 (en)

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WO1996023010A2 (en) 1995-01-24 1996-08-01 E.I. Du Pont De Nemours And Company α-OLEFINS AND OLEFIN POLYMERS AND PROCESSES THEREFOR
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