WO2017205879A2 - Processes for preparing phosphorodiamidate morpholino oligomers - Google Patents
Processes for preparing phosphorodiamidate morpholino oligomers Download PDFInfo
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- WO2017205879A2 WO2017205879A2 PCT/US2017/040311 US2017040311W WO2017205879A2 WO 2017205879 A2 WO2017205879 A2 WO 2017205879A2 US 2017040311 W US2017040311 W US 2017040311W WO 2017205879 A2 WO2017205879 A2 WO 2017205879A2
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- 150000005829 chemical entities Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- DSTOQIFCRHYSBA-UHFFFAOYSA-N chloro-N-(dimethylamino)phosphonamidic acid Chemical group CN(C)NP(O)(Cl)=O DSTOQIFCRHYSBA-UHFFFAOYSA-N 0.000 description 1
- MCKANBCWFDYIJO-UHFFFAOYSA-N chloro-dihydroxy-imino-$l^{5}-phosphane Chemical group NP(O)(Cl)=O MCKANBCWFDYIJO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- ANCLJVISBRWUTR-UHFFFAOYSA-N diaminophosphinic acid Chemical compound NP(N)(O)=O ANCLJVISBRWUTR-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 125000000371 nucleobase group Chemical group 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 208000035139 partial with pericentral spikes epilepsy Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000008298 phosphoramidates Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- UIDUKLCLJMXFEO-UHFFFAOYSA-N propylsilane Chemical compound CCC[SiH3] UIDUKLCLJMXFEO-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 210000001324 spliceosome Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000010200 validation analysis 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
Definitions
- Antisense technology provides a means for modulating the expression of one or more specific gene products, including alternative splice products, and is uniquely useful in a number of therapeutic, diagnostic, and research applications.
- the principle behind antisense technology is that an antisense compound, e.g., an oligonucleotide, which hybridizes to a target nucleic acid, modulates gene expression activities such as transcription, splicing or translation through any one of a number of antisense mechanisms.
- the sequence specificity of antisense compounds makes them attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in disease.
- Duchenne muscular dystrophy is caused by a defect in the expression of the protein dystrophin.
- the gene encoding the protein contains 79 exons spread out over more than 2 million nucleotides of DNA. Any exonic mutation that changes the reading frame of the exon, or introduces a stop codon, or is characterized by removal of an entire out of frame exon or exons, or duplications of one or more exons, has the potential to disrupt production of functional dystrophin, resulting in DMD.
- oligonucleotides for the treatment of DMD are based on SSO technology to induce alternative splicing of pre-mRNAs by steric blockade of the spliceosome (Cirak et al., 2Q ⁇ ⁇ ; Goemans et al., 2011; Kinali et al., 2009; van Deutekom et al., 2007).
- SSOs oligonucleotides
- Casimersen is a phosphorodiamidate morpholino oligomer (PMO) designed to skip exon 45 of the human dystrophin gene in patients with DMD who are amendable to exon 45 skipping to restore the read frame and produce a functional shorter form of the dystrophin protein.
- PMO phosphorodiamidate morpholino oligomer
- PMOs phosphorodiamidate morpholino oligomers
- the oligomeric compound of the disclosure including, for example, some embodiments of an oligomeric compound of Formula (C), is an oligomeric compound of Formula (XII):
- Fig. 1 and Fig. 2 show representative analytical high performance liquid
- Fig. 3 and Fig. 4 show a representative analytical HPLC chromatogram of a purified casimersen drug substance solution (see Example 5).
- Fig. 5 and Fig. 6 show a representative analytical HPLC chromatogram of a desalted and lyophilized casimersen drug substance (see Example 5).
- morpholino oligomer described herein displays stronger affinity for DNA and RNA without
- the morpholino oligomer of the disclosure minimizes or prevents cleavage by RNase H. In some embodiments, the morpholino oligomer of the disclosure does not activate RNase H.
- the processes described herein are advantageous in an industrial-scale process and can be applied to preparing quantities of a morpholino oligomer in high yield and scale (e.g., about 1 kg, about 1-10 kg, about 2-10 kg, about 5-20 kg, about 10-20 kg, or about 10-50 kg).
- Base-protected or “base protection” refers to protection of the base-pairing groups, e.g., purine or pyrimidine bases, on the morpholino subunits with protecting groups suitable to prevent reaction or interference of the base-pairing groups during stepwise oligomer synthesis.
- An example of a base-protected morpholino subunit is the activated C subunit Compound (C) having a CBZ protecting group on the cytosine amino group depicted below.
- activated phosphoramidate group is typically a chlorophosphoramidate group, having substitution at nitrogen which is desired in the eventual phosphorodiamidate linkage in the oligomer.
- support-bound refers to a chemical entity that is covalently linked to a support-medium.
- support-medium refers to any material including, for example, any particle, bead, or surface, upon which an oligomer can be attached or synthesized upon, or can be modified for attachment or synthesis of an oligomer.
- Representative substrates include, but are not limited to, inorganic supports and organic supports such as glass and modified or functionalized glass, plastics (including acrylics, polystyrene and copolymers of styrene and other materials, polypropylene, polyethylene, polybutylene, polyurethanes, TEFLON, etc.), polysaccharides, nylon or nitrocellulose, ceramics, resins, silica or silica- based materials including silicon and modified silicon, carbon, metals, inorganic glasses, plastics, optical fiber bundles, and a variety of other polymers.
- Particularly useful support- medium and solid surfaces for some embodiments are located within a flow cell apparatus.
- the support-medium comprises polystyrene with 1% cross
- representative support-medium comprise at least one reactive site for attachment or synthesis of an oligomer.
- a support-medium of the disclosure comprises one or more terminal amino or hydroxyl groups capable of forming a chemical bond with an incoming subunit or other activated group for attaching or synthesizing an oligomer.
- CPG controlled pore glass
- oxalyl- controlled pore glass see, e.g., Alul, et al., Nucleic Acids Research 1991, 19, 1527
- silica- containing particles such as porous glass beads and silica gel such as that formed by the reaction of trichloro-[3-(4-chloromethyl)phenyl]propylsilane and porous glass beads (see Parr and Grohmann, Angew. Chem. Internatl. Ed. 1972, 11, 314, sold under the trademark
- PORASIL E by Waters Associates, Framingham, Mass., USA
- a mono ester of 1,4- dihydroxymethylbenzene and silica see Bayer and Jung, Tetrahedron Lett, 1970, 4503, sold under the trademark "BIOPAK” by Waters Associates
- TENTAGEL see, e.g., Wright, et al., Tetrahedron Lett.
- POROS cross-linked styrene/divinylbenzene copolymer beaded matrix
- POROS cross-linked styrene/divinylbenzene copolymer beaded matrix
- POROS cross-linked styrene/divinylbenzene copolymer beaded matrix
- soluble support-medium such as polyethylene glycol PEG's (see Bonora et al., Organic Process Research & Development, 2000, 4, 225-231);
- PEPS support which is a polyethylene (PE) film with pendant long-chain polystyrene (PS) grafts (see Berg, et al., J. Am. Chem.
- flow cell apparatus refers to a chamber comprising a surface (e.g., solid surface) across which one or more fluid reagents (e.g., liquid or gas) can be flowed.
- a surface e.g., solid surface
- fluid reagents e.g., liquid or gas
- deblocking agent refers to a composition (e.g., a solution) comprising a chemical acid or combination of chemical acids for removing protecting groups.
- exemplary chemical acids used in deblocking agents include halogenated acids, e.g., chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and
- a deblocking agent removes one or more trityl groups from, for example, an oligomer, a support-bound oligomer, a support-bound subunit, or other protected nitrogen or oxygen moiety.
- halogen and halo refer to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine.
- capping agent refers to a composition (e.g., a solution) comprising an acid anhydride (e.g., benzoic anhydride, acetic anhydride, phenoxyacetic anhydride, and the like) useful for blocking a reactive cite of, for example, a support-medium forming a chemical bond with an incoming subunit or other activated group.
- an acid anhydride e.g., benzoic anhydride, acetic anhydride, phenoxyacetic anhydride, and the like
- cleavage agent refers to a composition (e.g., a liquid solution or gaseous mixture) comprising a chemical base (e.g., ammonia or l,8-diazabicycloundec-7-ene) or a combination of chemical bases useful for cleaving, for example, a support-bound oligomer from a support-medium.
- a chemical base e.g., ammonia or l,8-diazabicycloundec-7-ene
- a combination of chemical bases useful for cleaving, for example, a support-bound oligomer from a support-medium.
- deprotecting agent refers to a composition (e.g., a liquid solution or gaseous mixture) comprising a chemical base (e.g., ammonia, l,8-diazabicycloundec-7-ene or potassium carbonate) or a combination of chemical bases useful for removing protecting groups.
- a deprotecting agent in some embodiments, can remove the base protection from, for example, a morpholino subunit, morpholino subunits of a morpholino oligomer, or support-bound versions thereof.
- solvent refers to a component of a solution or mixture in which a solute is dissolved.
- Solvents may be inorganic or organic (e.g., acetic acid, acetone, acetonitrile, acetyl acetone, 2-aminoethanol, aniline, anisole, benzene, benzonitrile, benzyl alcohol, 1- butanol, 2-butanol, i-butanol, 2-butanone, t-butyl alcohol, carbon disulfide,
- acetoacetate, ethyl benzoate ethylene glycol, glycerin, heptane, 1-heptanol, hexane, 1- hexanol, methanol, methyl acetate, methyl t-butyl ether, methylene chloride, 1-octanol, pentane, 1-pentanol, 2-pentanol, 3-pentanol, 2-pentanone, 3-pentanone, 1-propanol, 2- propanol, pyridine, tetrahydrofuran, toluene, water, p-xylene).
- morpholino refers to a phosphorodiamidate morpholino oligomer of the following general structure:
- Morpholinos as described herein are intended to cover all stereoisomers and configurations of the foregoing general structure.
- the synthesis, structures, and binding characteristics of morpholino oligomers are detailed in U.S. Patent Nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166,315, 5,521,063, 5,506,337, 8,076,476, and 8,299,206, all of which are incorporated herein by reference.
- a morpholino is conjugated at the 5' or 3' end of the oligomer with a "tail" moiety to increase its stability and/or solubility.
- exemplary tails include:
- EG3 tail refers to triethylene glycol moieties conjugated to the oligomer, e.g., at its 3'- or 5'-end.
- EG3 tail conjugated to the 3' end of an oligomer can be of the structure:
- Synthesis is generally performed, as described herein, on a support-medium.
- a first synthon e.g. a monomer, such as a morpholino subunit
- the oligomer is then synthesized by sequentially coupling subunits to the support-bound synthon. This iterative elongation eventually results in a final oligomeric compound.
- Suitable support-media can be soluble or insoluble, or may possess variable solubility in different solvents to allow the growing support-bound polymer to be either in or out of solution as desired.
- R 1 is a support-medium
- R 1 is a support-medium and R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- R 1 is a support-medium
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and tnmethoxytntyl
- R 4 is selected from the group consisting of:
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytntyl
- R 4 is, independently for each occurrence, selected from the group consisting of:
- R 1 is a support-medium; with a compound of Formula (A4):
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethox trityl and tnmethox tntyl
- R 4 is selected from the group consisting of:
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
- R 4 is selected from the group consisting of:
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 4 is, independently for each occurrence, selected from the group consisting of:
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytntyl
- R 4 is, independently for each occurrence, selected from the group consisting of:
- n is an integer from 1 00ttoo440, and R 4 is, for each occurrence independently selected from the group consisting of:
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 4 is, independently for each occurrence, selected from the group consisting of:
- n is an integer from 10 to 40, aanndd eeeach R 2 is, independently for each occurrence, selected from the group consisting of:
- rocess comprises contacting a compound of Formula (Al 1)
- n is an integer from 1 00 ttoo 440, and R 4 is, independently for each occurrence, selected from the group consisting of:
- n is an integer from 10 to 40, and each R is, independently for each occurrence, selected from the group consisting of:
- R 1 is a support-medium and R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethox trityl and tnmethox tntyl
- R 4 is selected from the group consisting of:
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
- R 4 is selected from the group consisting of:
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl
- R 4 is, independently for each compound of Formula (A8 selected from the group consisting of:
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytntyl
- R 4 is, independently for each occurrence, selected from the group consisting of:
- n is an integer from 10 to 40, and R 4 is, independently for each occurrence, selected from the group consisting of:
- step (d) or step (e2) further comprises contacting the compound of Formula (IV) or the compound formed by the immediately prior step, respectively, with a capping agent.
- each step is performed in the presence of at least one solvent.
- the deblocking agent used in each step is a solution comprising a halogenated acid.
- the deblocking agent used in each step is cyanoacetic acid.
- the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.
- the halogenated acid is trifluoroacetic acid.
- at least one of steps (a), (c), (el), and (f) further comprise the step of contacting the deblocked compound of each step with a neutralization agent.
- each of steps (a), (c), (el), and (f) further comprise the step of contacting the deblocked compound of each step with a neutralization agent.
- the neutralization agent is in a solution comprising dichloromethane and isopropyl alcohol.
- the neutralization agent is a monoalkyl, dialkyl, or trialkyl amine.
- the neutralization agent is N,N-diisopropylethylamine.
- the deblocking agent used in each step is a solution comprising 4-cyanopyridine, dichloromethane, trifluoroacetic acid, trifluoroethanol, and water.
- the capping agent is in a solution comprising
- the capping agent is an acid anhydride.
- the acid anhydride is benzoic anhydride.
- the compounds of Formula (A4) and Formula (A8) are each, independently, in a solution comprising ethylmorpholine and dimethylimidazolidinone.
- the cleavage agent comprises dithiothreitol and 1,8- diazabicyclo[5.4.0]undec-7-ene.
- the cleavage agent is in a solution comprising N-methyl- 2-pyrrolidone.
- the deprotecting agent comprises NH 3 .
- the deprotecting agent is in an aqueous solution.
- the support-medium comprises polystyrene with 1% crosslinked divinylbenzene.
- the compound of Formula (A4) is of Formula (A4a):
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
- R 4 is selected from:
- the compound of Formula (A5) is of Formula (A5a):
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytntyl and trimethoxytrityl, and
- R 4 is selected from:
- the compound of Formula (A8) is of Formula (A8a):
- R 1 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
- R 4 is, independently at each occurrence of the compound of Formula (A8a), selected from the group consisting of:
- the compound of formula (A9) is of Formula (A9a):
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl, and
- R 4 is, independently for each occurrence, selected from the group consisting of:
- the compound of Formula (AlO) is of Formula (AlOa):
- n is an integer from 10 to 40
- R 1 is a support-medium
- R 4 is independently for each occurrence, selected from the group consisting of:
- the compound of Formula (Al 1) is of Formula (Al la):
- n is an integer from 10 to 40
- R 4 is, independently for each occurrence, selected from the group consistin
- n is 22, and R 2 is at each position from 1 to 22 and 5' to 3' :
- oligomeric compound of Formula (A) is a compound of Formula (C ):
- Casimersen formerly known by its code name “SPR-4045,” is a PMO having the base sequence 5 ' -C AATGCC ATCCTGGAGTTCCTG-3 ' (SEQ ID NO: l). Casimersen is registered under CAS Registry Number 1422958-19-7. Chemical names include:
- the oligomeric compound of Formula (A) is a compound of Formula (C):
- the oligomeric compound of Formula (C) is an oligomeric compound of Formula (XII):
- R 1 is a support-medium, with a deblocking agent to form the compound of Formula (II):
- R 1 is a support-medium
- R 1 is a support-medium; (c) contacting the compound of Formula (III) with a deblocking agent to form a compound of Formula (IV):
- R 1 is a support-medium
- R 1 is a support-medium
- R 1 is a support-medium
- R 1 is a support-medium
- R 2 is:
- R 1 is a support-medium
- R is, independently for each occurrence, selected from the group consisting of:
- R 2 is at each position from 1 to 22 and 5' to 3' :
- R 1 is a support-medium
- R is, independently for each occurrence, selected from the group consisting of
- w erein R is at each position from 1 to 22 and 5' to 3'
- R 2 is, independently for each occurrence, selected from the group consisting of
- R 2 is at each position from 1 to 22 and 5' to 3' :
- step (d), step (f), step (g2), or combinations thereof further comprises contacting the compound of Formula (IV), Formula (VI), or the compound formed by the immediately prior step, respectively, with a capping agent.
- each of step (d), step (f) and step (g2) further comprises contacting the compound of Formula (IV), Formula (VI), or the compound formed by the immediately prior step, respectively, with a capping agent.
- each step is performed in the presence of at least one solvent.
- the deblocking agent used in each step is a solution comprising a halogenated acid.
- the deblocking agent used in each step is cyanoacetic acid.
- the halogenated acid is selected from the group consisting of chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid.
- the halogenated acid is trifluoroacetic acid.
- steps (c), (e), and (gl) further comprise the step of contacting the deblocked compound of each step with a neutralization agent.
- each of steps (c), (e), and (gl) further comprise the step of contacting the deblocked compound of each step with a neutralization agent.
- the neutralization agent is in a solution comprising dichloromethane and isopropyl alcohol.
- the neutralization agent is a monoalkyl, dialkyl, or trialkyl amine.
- the neutralization agent is N,N-diisopropylethylamine.
- the deblocking agent used in each step is a solution comprising 4-cyanopyridine, dichloromethane, trifluoroacetic acid, trifluoroethanol, and water.
- the capping agent is in a solution comprising
- the capping agent is an acid anhydride.
- the acid anhydride is benzoic anhydride.
- the compound of Formula (VIII), Formula (D), and Formula (F) are each, independently, in a solution comprising ethylmorpholine and dimethylimidazolidinone.
- the cleavage agent comprises dithiothreitol and 1,8- diazabicyclo[5.4.0]undec-7-ene. In yet another embodiment, the cleavage agent is in a solution comprising N-methyl- 2-pyrrolidone.
- the deprotecting agent comprises H 3 .
- the deprotecting agent is in an aqueous solution.
- the support-medium comprises polystyrene with 1% crosslinked divinylbenzene.
- the compound of Formula (V) is of Formula (Va):
- R 1 is a support-medium.
- the compound of Formula (F) is of Formula (Fl):
- the compound of Formula (VII) is of Formula (Vila):
- R 1 is a support-medium.
- the compound of Formula (VIII) is of Formula (Villa):
- R 2 is, in iddeeppeennddeennttllyy ffoorr eeaach compound of Formula (Villa), selected from the group consisting of:
- the compound of Formula (IX) is of Formula (IXa):
- R 1 is a support-medium
- R 2 is, independently at each occurrence, selected from the group consisting of
- R 2 is at each position from 1 to 22 and 5' to 3' :
- the compound of Formula (X) is of Formula (Xa): (Xa),
- R 1 is a support-medium
- R 2 is independently at each occurrence, selected from the group consisting of
- R 2 is at each position from 1 to 22 and 5' to 3' :
- the compound of Formula (XI) is of Formula (XIa):
- R 2 is at each position from 1 to 22 and 5' to 3' :
- the compound of Formula (VI) is of Formula (Via):
- R 1 is a support-medium.
- the oligomeric compound of Formula (C) is an oligomeric compound of Formula (XII):
- R 1 is a support-medium.
- the compound of Formula (V) is of Formula (Va):
- R 1 is a support-medium
- R 3 selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethox trityl
- R 4 is selected from:
- the compound of Formula (A5) is of Formula (A5a):
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl
- R 4 is selected from:
- the compound of Formula (VI) is of Formula (Via):
- the compound of Formula (VII) is of Formula (Vila):
- R 1 is a support-medium
- R 2 is, independently at each occurrence, selected from the group consisting of:
- R 2 is at each position from 1 to 22 and 5' to 3' :
- R 1 is a support-medium
- R 2 is independently at each occurrence, selected from the group consisting of
- R 2 is at each position from 1 to 22 and 5' to 3' :
- n is an integer from 10 to 40;
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- R 4 is, independently at each occurrence, selected from the group consisting of:
- the compound of Formula (A9) is of Formula (A9a):
- n is an integer from 10 to 40;
- R 1 is a support-medium
- R 3 is selected from the group consisting of trityl, monomethoxytrityl, dimethoxytrityl and trimethoxytrityl;
- R 4 is, independently at each occurrence, selected from the group consisting of: (X);
- R 1 is a support-medium
- R 2 is independently at each occurrence, selected from the group consisting of
- R 2 is at each position from 1 to 22 and 5' to 3' :
- the compound of Formula (X) is of Formula (Xa): (Xa),
- R 1 is a support-medium
- R 2 is, independently at each occurrence, selected from the group consisting of
- R is at each position from 1 to 22 and 5' to 3'
- n is an integer from 10 to 40;
- R 1 is a support-medium
- R 4 is, independently at each occurrence, selected from the group consisting of:
- n is an integer from 10 to 40;
- R 1 is a support-medium
- R 4 is independently at each occurrence, selected from the group consisting of
- the support-medium compri polystyrene with 1% crosslinked divinylbenzene.
- R 2 is, independently at each occurrence, selected from the group consisting of:
- R 2 is at each position from 1 to 22 and 5' to 3' :
- the compound of Formula (XI) is of Formula (XIa):
- R 2 is at each position from 1 to 22 and 5' to 3' :
- n is an integer from 10 to 40;
- R 4 is, independently at each occurrence, selected from the group consisting of:
- n is an integer from 10 to 40;
- R 4 is, independently at each occurrence, selected from the group consisting of:
- Important properties of morpholino-based subunits include: 1) the ability to be linked in an oligomeric form by stable, uncharged or positively charged backbone linkages; 2) the ability to support a nucleotide base (e.g. adenine, cytosine, guanine, thymidine, uracil, 5- methyl-cytosine and hypoxanthine) such that the polymer formed can hybridize with a complementary-base target nucleic acid, including target RNA; 3) the ability of the oligomer to be actively or passively transported into mammalian cells; and 4) the ability of the oligomer and oligomenRNA heteroduplex to resist RNAse and RNase H degradation, respectively.
- a nucleotide base e.g. adenine, cytosine, guanine, thymidine, uracil, 5- methyl-cytosine and hypoxanthine
- the antisense oligomers contain base modifications or substitutions.
- certain nucleo-bases may be selected to increase the binding affinity of the antisense oligomers described herein.
- 5-methyl cytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2°C, and may be incorporated into the antisense oligomers described herein.
- at least one pyrimidine base of the oligomer comprises a 5-substituted pyrimidine base, wherein the pyrimidine base is selected from the group consisting of cytosine, thymine and uracil.
- the 5-substituted pyrimidine base is 5-methylcytosine.
- at least one purine base of the oligomer comprises hypoxanthine.
- Morpholino-based oligomers are detailed, for example, in U.S. Patent Nos. 5,698,685, 5,217,866, 5, 142,047, 5,034,506, 5, 166,315, 5, 185,444, 5,521,063, 5,506,337, 8,299,206, and 8, 076,476, International Patent Application Publication Nos. WO/2009/064471 and WO/2012/043730, and Summerton et al. (1997, Antisense and Nucleic Acid Drug Development, 7, 187-195), each of which are hereby incorporated by reference in their entirety.
- Oligomenc compounds of the disclosure may have asymmetric centers, chiral axes, and chirai planes (as described, for example, in: E. L. Eli el and S. H. Wilen. Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1 1 1.9-1 190, and March, J., Advanced Organic Chemistry, 3d. Ed., Chap. 4, John Wiley & Sons, New York (1985)), and may occur as racemates, racemic mixtures, and as individual diastereomers, with ail possible isomers and mixtures thereof, including optical isomers. Oligomeric compounds of the disclosure herein specifically mentioned, without any indication of its stereo-chemistry, are intended to represent all possible isomers and mixtures thereof.
- oligomeric compounds of the disclosure are prepared, as discussed herein, from activated morpholino subiinits including such non-limiting examples such as a compound of Formula (VIII):
- Each of the above-mentioned compounds of Formula (VIII), may be prepared, for example, from the corresponding beta-D-ribofuranosyl as depicted below:
- each morpholino subunit may be produced based on selection of, for example, an alpha-L- ribofuranosyl, alpha-D- ribofuranosyl, beta-L-ribofuranosyl, or beta-D-ribofuranosyl starting material.
- a compound of Formula (VIII) of the disclosure may be of Formula (Villa):
- R 2 is, independently for each compound of Formula (Villa), selected from the group consisting of:
- incorporation of 10 to 40 compounds of Formula (VIII), for example, into an oligomeric compound of the disclosure may result in numerous possible stereoisomers.
- oligomeric compounds of the disclosure comprise one or more phosphorous-containing intersubunits, which create a chiral center at each phosphorus, each of which is designated as either an "Sp" or "Rp"
- this chirality creates stereoisomers, which have identical chemical composition but different three-dimensional arrangement of their atoms.
- each phosphorous intersubunit linkage occurs randomly during synthesis of, for example, oligomeric compounds of the disclosure.
- the synthesis process generates an exponentially large number of stereoisomers of an oligomeric compound of the disclosure because oligomeric compounds of the disclosure are comprised of numerous phosphorous intersubunit linkages - with each phosphorous intersubunit linkage having a random chiral configuration.
- each intersubunit linkage of an additional morpholino subunit doubles the number of stereoisomers of the product, so that a conventional preparation of an oligomeric compound of the disclosure is in fact a highly heterogeneous mixtures of 2 N stereoisomers, where N represents the number of phosphorous intersubunit linkages.
- N represents the number of phosphorous intersubunit linkages.
- Table 1 depicts various embodiments of morpholino subunits provided in the processes described herein.
- Table 1 Various embodiments of morpholino subunits.
- the solid filter cake was triturated with 14.8kg of purified water, filtered, triturated again with 14.8kg of purified water, and filtered.
- the solid was returned to the 100L flask with 39.9kg of DCM and refluxed with stirring for 1 hour. 1.5kg of purified water was added to dissolve the remaining solids.
- the bottom organic layer was split to a pre-warmed 72L flask, then returned to a clean dry 100L flask.
- the solution was cooled to 0° C, held for 1 hour, then filtered.
- the solid filter cake was washed twice each with a solution of 9.8kg DCM and 5kg heptane, then dried on the funnel.
- the solid was transferred to trays and dried to a constant weight of 1.855kg 3-Nitro-4-(2-oxopropyl)benzoic Acid. Overall yield 42% from compound 1. HPLC 99.45%.
- N-Tritylpiperazine Succinate N-Tritylpiperazine Succinate
- the combined organic layers were washed with a solution of 1.08kg sodium chloride in 4.08kg purified water.
- the organic layers were dried over 1.068kg of sodium sulfate and filtered.
- the sodium sulfate was washed with 1.3kg of DCM.
- the combined organic layers were slurried with 252g of silica gel and filtered through a filter funnel containing a bed of 252g of silica gel.
- the silica gel bed was washed with 2kg of DCM.
- the combined organic layers were evaporated on a rotovap.
- the organic layer was separated and the aqueous was twice more extracted with 4.7kg of DCM each.
- the combined organic layers were washed with a solution of about 800g of sodium chloride in about 3kg of water, then dried over 2.7kg of sodium sulfate.
- the suspension was filtered and the filter cake was washed with 2kg of DCM.
- the combined filtrates were concentrated to 2.0 volumes, diluted with about 360g of ethyl acetate, and evaporated.
- the crude product was loaded onto a silica gel column of 4kg of silica packed with DCM under nitrogen and eluted with 2.3kg ethyl acetate in 7.2kg of DCM.
- the combined fractions were evaporated and the residue was taken up in 11.7kg of toluene.
- the combined solids were charged to a 100L jacketed flask and dissolved in 28kg of DCM and washed with a solution of 900g of potassium carbonate in 4.3kg of water. After 1 hour, the layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with 10kg of water, separated, and dried over 3.5kg of sodium sulfate. The DCM was filtered, evaporated, and dried under vacuum to 6.16kg of NCP2 Anchor (114% yield).
- the resin was treated and stirred with 1 ⁇ 2 the DEDC Capping Solution for 30 minutes, drained, and was treated and stirred with the 2 nd 1 ⁇ 2 of the DEDC Capping Solution for 30 minutes and drained.
- the resin was washed six times with 39L of DCM per wash then dried in an oven to constant weight of 3573.71g of Anchor Loaded Resin.
- N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide HONB
- DMAP 4-dimethylaminopyridine
- EDC l-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
- the dichloromethane solution underwent solvent exchange to acetone and then to ⁇ , ⁇ -dimethylformamide, and the product was isolated by precipitation from acetone/N,N-dimethylformamide into saturated aqueous sodium chloride.
- R 1 is a support-medium.
- Anchor Loaded Resin 750 g of Anchor Loaded Resin and 10.5 L of NMP were charged to a 50 L silanized reactor and stirred for 3 hours. The NMP was drained and the Anchor Loaded Resin was washed twice with 5.5L each of DCM and twice with 5.5 L each of 30% TFE/DCM.
- the Anchor Loaded Resin was washed three times with 5.5 L each of 30% TFE/DCM and drained, washed with 5.5 L of CYFTA solution for 15 minutes and drained, and again washed with 5.5 L of CYTFA Solution for 15 minutes without draining to which 122 mL of 1 : 1 NEM/DCM was charged and the suspension stirred for 2 minutes and drained.
- the resin was washed once with 5.5L Neutralization Solution for 10 minutes and drained, twice with 5.5 L of Neutralization Solution for 5 minutes and drained, then twice with 5.5 L each of DCM and drained.
- the resin Prior to each coupling cycle as described in Table 4, the resin was: 1) washed with 30% TFE/DCM; 2) a) treated with CYTFA Solution 15 minutes and drained, and b) treated with CYTFA solution for 15 minutes to which was added 1 : 1 NEM/DCM, stirred, and drained; 3) stirred three times with Neutralization Solution; and 4) washed twice with DCM. See Table 4
- the resin was: 1) washed with DCM; and 2) washed three times with 30% TFE/DCM. If the resin was held for a time period prior to the next coupling cycle, the third TFE/DCM wash was not drained and the resin was retained in said TFE/DCM wash solution. See Table 4.
- the resin was washed 8 times with 19.5 L each of IPA, and dried under vacuum at room temperature for about 63.5 hours to a dried weight of 4523 g.
- the above resin bound Casimersen Crude Drug Substance was divided into two lots, each lot was treated as follows. Two 2261.5 g lots of resin were each: 1) stirred with 10L of NMP for 2hrs, then the NMP was drained; 2) washed tree times with 10L each of 30% TFE/DCM; 3) treated with 10L CYTFA Solution for 15 minutes; and 4) 10L of CYTFA Solution for 15 minutes to which 130ml 1 : 1 NEM/DCM was then added and stirred for 2 minutes and drained. The resin was treated three times with 10L each of Neutralization
- the combined Cleaving Solution and NMP wash were transferred to a pressure vessel to which was added 39.8L of NH 4 OH ( ⁇ 3 ⁇ 2 0) that had been chilled to a temperature of - 10° to -25° C in a freezer.
- the pressure vessel was sealed and heated to 45° C for 16hrs then allowed to cool to 25° C.
- This deprotection solution containing the Casimersen crude drug substance was diluted 3 : 1 with purified water prior to solvent removal. During solvent removal, the deprotection solution was pH adjusted to 3.0 with 2M phosphoric acid, then to pH 8.03 with NH 4 OH.
- HPLC C18 80.93% (Fig. 1) and SCX-10 84.4% (Fig. 2).
- Example 4 The deprotection solution from Example 4, part E, containing the Casimersen crude drug substance was loaded onto a column of ToyoPearl Super-Q 650S anion exchange resin (Tosoh Bioscience) and eluted with a gradient of 0-35% B over 17 column volume (Buffer A: 10 mM sodium hydroxide; Buffer B: 1 M sodium chloride in 10 mM sodium hydroxide) and fractions of acceptable purity (CI 8 and SCX HPLC) were pooled to a purified drug product solution. HPLC: 97.74% (C18; Fig. 3) 94.58% (SCX; Fig. 4).
- the purified drug substance solution was desalted and lyophilized to 1477.82 g purified Casimersen drug substance. Yield 63.37%; HPLC: 96.045% (Fig. 5; C18) 96.346% (Fig. 6; SCX).
Abstract
Description
Claims
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US16/302,018 US10947533B2 (en) | 2016-05-24 | 2017-06-30 | Processes for preparing phosphorodiamidate morpholino oligomers |
BR112018074330-5A BR112018074330B1 (en) | 2016-05-24 | 2017-06-30 | PROCESS FOR PREPARING AN OLIGOMER COMPOUND AND MORPHOLINE PHOSPHORODIAMIDATE OLIGOMER COMPOUNDS |
EP17803760.2A EP3463389A4 (en) | 2016-06-30 | 2017-06-30 | Processes for preparing phosphorodiamidate morpholino oligomers |
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CONC2018/0013831A CO2018013831A2 (en) | 2016-05-24 | 2018-12-19 | Processes for preparing morpholino phosphorodiamidate oligomers |
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US10385092B2 (en) | 2010-09-01 | 2019-08-20 | Nippon Shinyaku Co., Ltd. | Antisense nucleic acids |
EP4230196A1 (en) | 2022-02-21 | 2023-08-23 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of dystrophinopathies |
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EP3657604A1 (en) | 2018-11-26 | 2020-05-27 | TE Connectivity Germany GmbH | Cable terminating assembly with electrically insulating cutting blades |
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KR20190020674A (en) | 2019-03-04 |
JP7022079B2 (en) | 2022-02-17 |
KR102523522B1 (en) | 2023-04-20 |
EP3463389A4 (en) | 2020-02-19 |
CA3024153A1 (en) | 2017-11-30 |
AU2017270598A1 (en) | 2019-01-17 |
MX2018014160A (en) | 2019-04-01 |
JP2019518748A (en) | 2019-07-04 |
AU2017270598B2 (en) | 2022-12-01 |
SG11201809502YA (en) | 2018-12-28 |
CO2018013831A2 (en) | 2018-12-28 |
EP3463389A2 (en) | 2019-04-10 |
WO2017205879A3 (en) | 2018-01-18 |
CN109152792A (en) | 2019-01-04 |
CN109152792B (en) | 2021-09-14 |
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