WO2021198725A1 - Fosalvudine and fozivudine tidoxil for use in the treatment of covid-19, and use of the structurally simplified derivatives thereof - Google Patents
Fosalvudine and fozivudine tidoxil for use in the treatment of covid-19, and use of the structurally simplified derivatives thereof Download PDFInfo
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- WO2021198725A1 WO2021198725A1 PCT/IB2020/052996 IB2020052996W WO2021198725A1 WO 2021198725 A1 WO2021198725 A1 WO 2021198725A1 IB 2020052996 W IB2020052996 W IB 2020052996W WO 2021198725 A1 WO2021198725 A1 WO 2021198725A1
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- WIPO (PCT)
- Prior art keywords
- methyl
- propyl
- preparation
- covid
- acid
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- 208000025721 COVID-19 Diseases 0.000 title claims abstract description 18
- JHXLLEDIXXOJQD-VBWFMVIDSA-N [(2r)-2-decoxy-3-dodecylsulfanylpropyl] [(2r,3s,5r)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl hydrogen phosphate Chemical compound C1[C@H](F)[C@@H](COP(O)(=O)OC[C@H](CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 JHXLLEDIXXOJQD-VBWFMVIDSA-N 0.000 title abstract description 3
- IBHARWXWOCPXCR-WELGVCPWSA-N [(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl (2-decoxy-3-dodecylsulfanylpropyl) hydrogen phosphate Chemical compound C1[C@H](N=[N+]=[N-])[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 IBHARWXWOCPXCR-WELGVCPWSA-N 0.000 title abstract description 3
- 229950003232 fosalvudine tidoxil Drugs 0.000 title abstract description 3
- 229950011117 fozivudine tidoxil Drugs 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- -1 Nucleoside phospholipids Chemical class 0.000 claims description 25
- JHXLLEDIXXOJQD-WELGVCPWSA-N (2-decoxy-3-dodecylsulfanylpropyl) [(2r,3s,5r)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl hydrogen phosphate Chemical compound C1[C@H](F)[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 JHXLLEDIXXOJQD-WELGVCPWSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- 159000000007 calcium salts Chemical class 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000002777 nucleoside Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- UJQBOUAGWGVOTI-XSSZXYGBSA-N 1-[(2r,4s,5r)-4-azido-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@](O)(N=[N+]=[N-])C1 UJQBOUAGWGVOTI-XSSZXYGBSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- NCVBROIPVZPARB-UHFFFAOYSA-N 5-decoxy-2-phenyl-1,3-dioxane Chemical compound O1CC(OCCCCCCCCCC)COC1C1=CC=CC=C1 NCVBROIPVZPARB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- GRJCIXKOALIDNC-UHFFFAOYSA-N (2-decoxy-3-dodecylsulfanylpropyl) dihydrogen phosphate Chemical compound CCCCCCCCCCCCSCC(COP(O)(O)=O)OCCCCCCCCCC GRJCIXKOALIDNC-UHFFFAOYSA-N 0.000 claims description 3
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000001639 calcium acetate Substances 0.000 claims description 3
- 229960005147 calcium acetate Drugs 0.000 claims description 3
- 235000011092 calcium acetate Nutrition 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- OIFWQOKDSPDILA-XLPZGREQSA-N [(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl dihydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 OIFWQOKDSPDILA-XLPZGREQSA-N 0.000 claims description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
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- 239000011734 sodium Substances 0.000 claims description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims 2
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 claims 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
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- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- HABLENUWIZGESP-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O HABLENUWIZGESP-UHFFFAOYSA-N 0.000 description 1
- JHAYEQICABJSTP-UHFFFAOYSA-N decoquinate Chemical group N1C=C(C(=O)OCC)C(=O)C2=C1C=C(OCC)C(OCCCCCCCCCC)=C2 JHAYEQICABJSTP-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- WLGSIWNFEGRXDF-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O.CCCCCCCCCCCC(O)=O WLGSIWNFEGRXDF-UHFFFAOYSA-N 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- JLRBNGCMXSGALP-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O.CCCCCCC(O)=O JLRBNGCMXSGALP-UHFFFAOYSA-N 0.000 description 1
- KYYWBEYKBLQSFW-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O KYYWBEYKBLQSFW-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- YAQXGBBDJYBXKL-UHFFFAOYSA-N iron(2+);1,10-phenanthroline;dicyanide Chemical compound [Fe+2].N#[C-].N#[C-].C1=CN=C2C3=NC=CC=C3C=CC2=C1.C1=CN=C2C3=NC=CC=C3C=CC2=C1 YAQXGBBDJYBXKL-UHFFFAOYSA-N 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- BMQNWLUEXNQIGL-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O.CCCCCCCCC(O)=O BMQNWLUEXNQIGL-UHFFFAOYSA-N 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 1
- ACXGEQOZKSSXKV-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O.CCCCCCCC(O)=O ACXGEQOZKSSXKV-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940042443 other antivirals in atc Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- MHZDONKZSXBOGL-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound CCCOP(O)(O)=O MHZDONKZSXBOGL-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- ZTUXEFFFLOVXQE-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCC(O)=O ZTUXEFFFLOVXQE-UHFFFAOYSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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 Table
- 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
- C07F9/65586—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 at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Definitions
- the invention relates to fosalvudine and fozivudintidoxil for use in the treatment of the disease Covid-19 and the use of their structurally simplified derivatives for the production of a medicament against Covid-19.
- Fosalviudine [(2S, 3S, 5f?) -3-fluoro-5- (5-methyl-2,4-dioxo-pyrimidin-1-yl) tetrahydrofuran-2-yl] methyl [(2RS) -decoxy- 3-dodecylsulfanyl-propyl] hydrogen phosphate, depending on the substitution also fozivudintidoxil, [(2S, 3S, 5R) -3-azido-5- (5-methyl-2,4-di-oxo-pyrimidin-1-yl) tetrahydrofuran 2-yl] methyl [(2F?
- Fozivudintidoxil is structurally similar to remdesivir in the pharmacologically active area. Remdesevir with the structural formula below
- the subject of the present invention is the second medical indication of the substances known per se fosalvudin and fozivudintidoxil for application in the treatment of the disease Covid-19 and the use of it structurally simplified derivatives for the production of a drug against Covid-19.
- Fosalvudine and fozivudintidoxil are characterized by a combination of zidovudine (also azidothymidine, AZT for short), namely a chemical derivative of the nucleoside thymidine with a phospholipid. Fosalvudine and fozivudintidoxil therefore have three different areas:
- Fluorine-substituted fosalvudine is shown in the structure diagram. In the left part there is the lipid residue on the left, in the middle a phosphate group as a link and on the right the fluorine-substituted zidovudine residue.
- zidovudine belongs to the nucleoside reverse transcriptase inhibitors (NRTIs), a group of antiretroviral substances. Zidovudine is used to treat HIV-1 infected patients as part of combination antiretroviral therapy.
- NRTIs nucleoside reverse transcriptase inhibitors
- Fosalvudine and fozivudintidoxil improve the effect of the zidovudine residue through the phospholipid group.
- the common belief is that the phospholipid accumulates on the surface of living cells. The nature of the phospholipid residue thus determines the affinity for certain cell types. The affinity for lung tissue once observed makes this substance a candidate for the treatment of Covid-19.
- the phoshpolipid residue supplies the virus to be combated with zidovudine by bringing the zidovudine into spatial proximity to the virus at the location of the virus adhering to the cell surface.
- the amount of the substance to be administered as a drug is between 50 mg and 800 mg in one to two doses per day.
- particularly large quantities of the active ingredient are necessary in order to be able to supply the sick population with enough active ingredient.
- the multi-step synthesis of fosalvudine and fozivudintidoxil not inconsiderable problems arise in the area of the sulfur-containing lipid residue, since the sulfanyl sulfur has a strong tendency to oxidize and sulfoxides are formed in the process. The purification of the synthesized fosalvudine is possible, but complicates the synthesis with a considerable expenditure of time. Because of the suspected high toxicity, residues of the sulfoxides have to be removed quantitatively from the pharmaceutically active substance as an impurity during the synthesis.
- a structural change is proposed in the area of the phospholipid residue, in which the decoxy group and the dodecylsulfanyl group are replaced by an ester group, whereby the esters can be based on linear alkanoic acids, namely caproic acid (n-hexanoic acid), enanthic acid (n-heptanoic acid), Caprylic acid (n-octanoic acid), pelargonic acid (n-nonanoic acid), capric acid (n-decanoic acid), undecanoic acid, lauric acid (n-dodecanoic acid), tridecanoic acid, myristic acid (n-tetradecanoic acid), pentadecanoic acid, palmitic acid (n-hexadecanoic acid) acid), heptadecanoic acid, stearic acid (n-octadecanoic acid)
- linear alkanoic acids namely caproic acid (n-hexanoic
- the carbon residues on the lipid chains can range from C6H 13 , hexyl, via C 7 H 15 (heptyl), CsH (octyl), C9H 19 (nonyl), C 10 H 21 (decyl), C11H23 (undecyl), C12H25 (dodecyl) , C13H27 (tridecyl), C14H29 (Tetrade- cyl), C15H31 (pentadecyl), C16H33 (hexadecyl), C17H35 (heptadecyl) to C 18 H3 5 (octadecyl) rich.
- the solution was cooled to 0 to 5 ° C and 180 liters of isohexane were added over a period of 30 to 45 minutes. For crystallization, the suspension was stirred at 0 ° to 5 ° C. for 3 hours. After adding 60 l of 50% strength NaOH solution and 120 l of toluene, the isohexane-toluene-water mixture was distilled off under reduced pressure until the steam temperature was 80.degree. This produced 200 l of distillate.
- the organic phase was separated off and extracted 3 times with 180 l of demineralized water.
- the toluene phase was evaporated in vacuo and the residue was treated in a thin-film evaporator at 1 mbar and 150 ° C. operating temperature in order to remove decanol and bromodecane.
- the separated crystals were washed with 51 cold isohexane and dried at 15 ° to 20 ° C.
- the crude oil obtained was used for the next stage and stored at 0 ° to 5 ° C. Storage should not exceed 2 days.
- the emulsion was treated with 12 l of methyl tert-butyl ether and heated to 50 ° to 60 °. The organic phase was separated off and the solvent was removed in vacuo. The remaining oil was dissolved in 450 l of ethyl methyl ketone. 5.4 kg of calcium acetate in 33 l of demineralized water were added to the vigorously stirred solution over a period of 1.5 hours. The suspension was stirred for at least 8 hours and then filtered. The obtained calcium salt was washed with 50 l of ethyl methyl ketone and 100 l of demineralized water.
- the moist calcium salt is used for the next step without drying. Yield: 22.5 kg calcium salt (based on dry matter)
- the crude calcium salt was dissolved in 30 l of methyl tert-butyl ether and 3.5 l of 6M hydrochloric acid with stirring. The organic phase was then separated off, concentrated in vacuo and redissolved in 136 l of methanol. 12 liters of water and 40 g of sodium acetate were added. The pH was adjusted to 5.0-5.5 by adding concentrated NaOH solution. The mixture was filtered to remove any remaining cloudiness and saved for further HPLC purification.
- the previously prepared solution was applied in portions of 4 l to an HPLC column (200-350 mm, Merck, LiChroprep RP 18, 15-25 ⁇ m) and eluted with approximately 50 l methanol / 0.02M Na acetate solution 87 .5 / 12.5 as the mobile phase.
- the column was rinsed with 20 l of methanol between two runs.
- the eluate from about 40 runs (700 to 800 l) was collected, diluted with 130 l of demineralized water and treated with a solution of 1.15 kg of calcium acetate in 22 l of water.
- the resulting suspension was stirred for 5 hours at ambient temperature and the calcium salt was filtered and washed with 50 liters of demineralized water.
- the pure calcium salt was used for the next step without further drying.
- the stirrer was stopped, the organic phase was separated off and extracted with 20 l of demineralized water. The organic phase was filtered and the solvent was removed in vacuo. The residue was dissolved in 60 l of toluene and 30 l of toluene was distilled off to remove traces of water. The remaining solution was adjusted to a pH of 6.9 to 7.1 with sodium methylate solution while stirring at 20 ° to 25 ° C.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention relates to fosalvudine and fozivudine tidoxil for use in the treatment of the coronavirus disease 2019 and to the use of the structurally simplified derivatives thereof for manufacturing a drug against Covid-19.
Description
Fosalvudin und Fozivudintidoxil zur Anwendung bei der Behandlung der Krankheit Covid-19 und die Verwendung von deren strukturvereinfachten Derivaten Fosalvudine and fozivudintidoxil for use in the treatment of the disease Covid-19 and the use of their structurally simplified derivatives
Die Erfindung betrifft Fosalvudin und Fozivudintidoxil zur Anwendung bei der Be handlung der Krankheit Covid-19 und die Verwendung von deren strukturverein fachten Derivaten zur Herstellung eines Medikaments gegen Covid-19. The invention relates to fosalvudine and fozivudintidoxil for use in the treatment of the disease Covid-19 and the use of their structurally simplified derivatives for the production of a medicament against Covid-19.
Fosalviudin [(2S,3S,5f?)-3-Fluoro-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydro- furan-2-yl]methyl[(2RS)-decoxy-3-dodecylsulfanyl-propyl]hydrogenphosphat, je nach Substitution auch Fozivudintidoxil, [(2S,3S,5R)-3-Azido-5-(5-methyl-2,4-di- oxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2F?S)-decoxy-3-dodecylsulfanyl- propyljhydrogenphosphat mit der folgenden Struktur
wurden in den 1990er Jahren als potentielle Virostatika zur Behandlung von HIV, AIDS, eingehend untersucht (im Bild das fluorsubstituierte Derivat Fosalvudin).Fosalviudine [(2S, 3S, 5f?) -3-fluoro-5- (5-methyl-2,4-dioxo-pyrimidin-1-yl) tetrahydrofuran-2-yl] methyl [(2RS) -decoxy- 3-dodecylsulfanyl-propyl] hydrogen phosphate, depending on the substitution also fozivudintidoxil, [(2S, 3S, 5R) -3-azido-5- (5-methyl-2,4-di-oxo-pyrimidin-1-yl) tetrahydrofuran 2-yl] methyl [(2F? S) -decoxy-3-dodecylsulfanyl propyl hydrogen phosphate having the following structure were investigated in detail in the 1990s as potential antivirals for the treatment of HIV, AIDS (the fluorine-substituted derivative fosalvudine in the picture).
Im Vergleich zu anderen Virostatika (AZT) haben Fosalvudin und Fozivudintidoxil eine mehrfach höhere Wirkung in HIV-1 -infizierten CEM-SS-Zellen (eine Zellli nie). In-vitro wurden synergistische Effekte mit Proteaseinhibitoren beschrieben, wie sie auch bei anderen Inhibitoren der reversen Transkriptase Vorkommen.
Eine in vivo-Studie zeigte bei Makaken eine antivirale Wirkung in vivo und in vitro. Eine vierwöchige Gabe von 7 mg/kg (äquivalent von 150 mg für Menschen) wurde von Makaken mit minimaler hämatologischer Auffälligkeit und nicht be obachteter Lebertoxizität gut vertragen. Diese Substanz wurde in einer Phase I Studie mit einer einmaligen Gabe von 5 mg bis 40 mg untersucht. (Cahn P et al, Int Conf AIDS. 2006, Abstract No. ThPE0025). Fosalvudin wurde gut vertragen, zeigte ein lineares Dosisverhältnis für AUC und für Cmax. Dabei wurde ein Halb wertszeit von 4 bis 7 Stunden beobachtet, die eine tägliche Gabe ohne Akkumu lation bei wiederholter Einnahme ermöglicht. Compared to other antivirals (AZT), fosalvudine and fozivudintidoxil are several times more effective in HIV-1 -infected CEM-SS cells (one cell line). In-vitro synergistic effects with protease inhibitors have been described, as they also occur with other inhibitors of reverse transcriptase. An in vivo study showed an antiviral effect in macaques in vivo and in vitro. A four-week dose of 7 mg / kg (equivalent to 150 mg for humans) was well tolerated by macaques with minimal haematological abnormalities and unobserved liver toxicity. This substance was investigated in a phase I study with a single dose of 5 mg to 40 mg. (Cahn P et al, Int Conf AIDS. 2006, Abstract No. ThPE0025). Fosalvudine was well tolerated, showing a linear dose ratio for AUC and for Cmax. A half-life of 4 to 7 hours was observed, which enables daily administration without accumulation with repeated ingestion.
Die Entwicklung des Fozivudintidoxil wurde aufgrund der beobachteten Vertei lung im Körper und der daraus abgeleiteten Dosis aufgrund der Toxizität für Zel len des Knochenmarks und der Leber eingestellt. (A. C. Venhoff, D. Lebrecht, F. U. Reuss, B. Heckl-Ostreicher, R. Wehr, U. A. Walker, N. Venhoff: Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside re- verse transcriptase inhibitor prodrug. In: Antimicrobial agents and chemotherapy. Band 53, Nummer 7, Juli 2009, S. 2748-2751). Die nicht akzeptable Toxizität ergab sich vor allem aufgrund der für HIV notwendigen sehr hohen Dosis, damit sämtliche Gewebetypen im Körper mit einer genügenden Konzentration des Wirkstoffs versorgt sind. The development of fozivudintidoxil was discontinued due to the observed distribution in the body and the dose derived therefrom due to the toxicity for cells of the bone marrow and the liver. (AC Venhoff, D. Lebrecht, FU Reuss, B. Heckl-Ostreicher, R. Wehr, UA Walker, N. Venhoff: Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcriptase inhibitor prodrug. In : Antimicrobial agents and chemotherapy. Volume 53, Number 7, July 2009, pp. 2748-2751). The unacceptable toxicity was mainly due to the very high dose required for HIV so that all tissue types in the body are supplied with a sufficient concentration of the active ingredient.
Fozivudintidoxil hat eine in der pharmakologisch wirksamen Gegend strukturelle Ähnlichkeit mit Remdesivir. Remdesevir mit der nachstehenden Strukturformel
Fozivudintidoxil is structurally similar to remdesivir in the pharmacologically active area. Remdesevir with the structural formula below
Der prinzipähnliche Wirkmechanismus bei Fosalvudin und Fozivudintidoxil lässt die Erwartung zu, dass die nachgewiesenen virostatischen Eigenschaften auch bei Covid-19 wirken. The mechanism of action of fosalvudine and fozivudintidoxil, which is similar in principle, allows the expectation that the proven virostatic properties also work with Covid-19.
Eine Besonderheit, die hinzukommt, ist die Beobachtung der Tatsache aus älte ren Studien zur Wirksamkeit bei HIV, dass bei einer Gabe von 15mg/kg Körper gewicht bei Mäusen mit radioaktiven, isotopenmarkierten Substanzen der Wirk stoff mit folgenden Konzentrationen wie folgt in den Organen der untersuchten Mäuse nachgewiesen werden konnte:
A special feature that is added is the observation of the fact from older studies on the effectiveness of HIV that when mice are given 15 mg / kg body weight with radioactive, isotope-labeled substances, the active substance in the following concentrations in the organs of the examined Mice could be detected:
Quelle: Reuss F., Kulke M., Braspenning J., Heckl-Östreicher B., Opitz H.-G. Hei delberg Pharma GmbH, Ladenburg, Deutschland Source: Reuss F., Kulke M., Braspenning J., Heckl-Östreicher B., Opitz H.-G. Hei delberg Pharma GmbH, Ladenburg, Germany
Es zeigt sich also, dass die Substanz eine starke Affinität zum Lungengewebe hat. Gerade diese in der HlV-Studie eher als nachrangig und auch nachteilig be trachtete Affinität zur Lunge hilft, dass dieses Virostatikum bei der Behandlung von Covid-19 erfolgreich eingesetzt werden kann. So it turns out that the substance has a strong affinity for lung tissue. It is precisely this affinity to the lungs, which in the HIV study was considered to be of secondary importance and also disadvantageous, that this antiviral agent can be used successfully in the treatment of Covid-19.
In der internationalen Patentanmeldung WO 1992/003462 A1 werden erstmals neue Phospholipid-Derivate von Nucleosiden, deren Herstellung sowie die Ver wendung als antivirale Arzneimittel gelehrt. Die dort gelehrten Substanzen zeich nen sich aus durch eine Kopplung der Alkylreste im Phospholipid-Teil der Mole kularstruktur über ein Schwefel-Atom. In the international patent application WO 1992/003462 A1, new phospholipid derivatives of nucleosides, their production and their use as antiviral drugs are taught for the first time. The substances taught there are characterized by a coupling of the alkyl radicals in the phospholipid part of the molecular structure via a sulfur atom.
In der internationalen Patentanmeldung WO 95/20596 wird ein Verfahren zur Herstellung von unsymmetrischen Phosphorsäurediestern offenbart. Die dort ge lehrten Substanzen zeichnen sich aus durch eine Kopplung der Alkylreste im Phospholipid-Teil der Molekularstruktur über einer Verbindung einer Methylen gruppe mit Kohlenstoff über Alkoxyreste, Alkylthioreste, Alkylsulfinylreste oder Al- kylsulfonylreste. In the international patent application WO 95/20596 a process for the production of asymmetrical phosphoric acid diesters is disclosed. The substances taught there are distinguished by a coupling of the alkyl radicals in the phospholipid part of the molecular structure via a compound of a methylene group with carbon via alkoxy radicals, alkylthio radicals, alkylsulfinyl radicals or alkylsulfonyl radicals.
Gegenstand der vorliegenden Erfindung ist die zweite medizinische Indikation der an sich bekannten Substanzen Fosalvudin und Fozivudintidoxil zur Anwendung bei der Behandlung der Krankheit Covid-19 und die Verwendung von dessen
strukturvereinfachten Derivaten zur Herstellung eines Medikaments gegen Covid- 19. The subject of the present invention is the second medical indication of the substances known per se fosalvudin and fozivudintidoxil for application in the treatment of the disease Covid-19 and the use of it structurally simplified derivatives for the production of a drug against Covid-19.
Fosalvudin und Fozivudintidoxil zeichnen sich aus durch eine Verbindung von Zidovudin (auch Azidothymidin, kurz AZT), nämlich ein chemisches Derivat des Nukleosids Thymidin mit einem Phospholipid. Fosalvudin und Fozivudintidoxil weisen demnach drei unterschiedliche Bereiche auf:
Fosalvudine and fozivudintidoxil are characterized by a combination of zidovudine (also azidothymidine, AZT for short), namely a chemical derivative of the nucleoside thymidine with a phospholipid. Fosalvudine and fozivudintidoxil therefore have three different areas:
Im Strukturbild ist Fluor-substituiertes Fosalvudin abgebildet. Im linken Teil befin det sich links der Lipidrest, in der Mitte eine Phosphatgruppe als Bindeglied und rechts der Fluor-substitutierte Zidovudinrest. Fluorine-substituted fosalvudine is shown in the structure diagram. In the left part there is the lipid residue on the left, in the middle a phosphate group as a link and on the right the fluorine-substituted zidovudine residue.
Pharmakologisch gehört Zidovudin zu den nukleosidischen Reverse-Transkrip- tase-lnhibitoren (NRTI), einer Gruppe antiretroviraler Substanzen. Zidovudin dient zur Behandlung HIV-1 -infizierter Patienten im Rahmen einer antiretroviralen Kombinationstherapie. Pharmacologically, zidovudine belongs to the nucleoside reverse transcriptase inhibitors (NRTIs), a group of antiretroviral substances. Zidovudine is used to treat HIV-1 infected patients as part of combination antiretroviral therapy.
Fosalvudin und Fozivudintidoxil verbessern die Wirkung des Zidovudinrestes durch die Phospholipid-Gruppe. Die gängige Vorstellung ist, dass sich das Phos pholipid auf der Oberfläche lebender Zellen anreichert. Die Beschaffenheit des Phospholipidrestes bestimmt damit die Affinität zu bestimmten Zelltypen. Die einst beobachtete Affinität zum Lungengewebe macht diese Substanz zu einem Kandidaten für die Behandlung von Covid-19. Auf der Oberfläche der Zelle
angereichert, liefert der Phoshpolipidrest dem zu bekämpfenden Virus das Zidovudin, in dem es am Ort des auf der Zelloberfläche anhaftenden Virus das Zidovudin in räumliche Nähe zum Virus bringt. Fosalvudine and fozivudintidoxil improve the effect of the zidovudine residue through the phospholipid group. The common belief is that the phospholipid accumulates on the surface of living cells. The nature of the phospholipid residue thus determines the affinity for certain cell types. The affinity for lung tissue once observed makes this substance a candidate for the treatment of Covid-19. On the surface of the cell Enriched, the phoshpolipid residue supplies the virus to be combated with zidovudine by bringing the zidovudine into spatial proximity to the virus at the location of the virus adhering to the cell surface.
Die Menge der als Medikament zu verabreichenden Substanz beträgt beim Men schen zwischen 50 mg und 800 mg in ein bis zwei Dosen pro Tag. Bei einer Pan demie sind besonders große Mengen des Wirkstoffs notwendig, um die erkrankte Bevölkerung mit genügend Wirkstoff versorgen zu können. Bei der vielstufigen Synthese von Fosalvudin und Fozivudintidoxil treten im Bereich des schwefelhal tigen Lipidrests nicht unerhebliche Probleme auf, da der Sulfanyl-Schwefel stark zur Oxidation neigt und dabei bilden sich Sulfoxide. Die Aufreinigung des synthe tisierten Fosalvudins ist zwar möglich, erschwert aber die Synthese unter nicht unerheblichem Zeitaufwand. Reste der Sulfoxide müssen wegen der vermuteten starken Toxizität als Verunreinigung bei der Synthese quantitativ aus der pharma kologisch wirksamen Substanz entfernt werden. The amount of the substance to be administered as a drug is between 50 mg and 800 mg in one to two doses per day. In the case of pandemic, particularly large quantities of the active ingredient are necessary in order to be able to supply the sick population with enough active ingredient. In the multi-step synthesis of fosalvudine and fozivudintidoxil, not inconsiderable problems arise in the area of the sulfur-containing lipid residue, since the sulfanyl sulfur has a strong tendency to oxidize and sulfoxides are formed in the process. The purification of the synthesized fosalvudine is possible, but complicates the synthesis with a considerable expenditure of time. Because of the suspected high toxicity, residues of the sulfoxides have to be removed quantitatively from the pharmaceutically active substance as an impurity during the synthesis.
In der bekannten Struktur von Fosalvudin und Fozivudintidoxil befindet sich au ßerdem ein chirales Kohlenstoff-Atom im Phospholipid. Der Unterschied der Wir kung der beiden in Bezug auf dieses Kohlenstoffatom enatiomeren Formen wurde bei den bereits durchgeführten Phase Il-Studien nicht näher untersucht.In the known structure of fosalvudine and fozivudintidoxil there is also a chiral carbon atom in the phospholipid. The difference in the effect of the two enantiomeric forms with regard to this carbon atom was not investigated in more detail in the phase II studies that have already been carried out.
Die Synthese von Fosalvudin und Fozivudintidoxil verläuft über eine Vielzahl von chemischen Zwischenstufen. Dabei sind manche Zwischenstufen stark oxida tionsempfindlich. The synthesis of fosalvudine and fozivudintidoxil proceeds through a large number of chemical intermediates. Some intermediate stages are very sensitive to oxidation.
Es wird daher vorgeschlagen, die Struktur des bekannten Fosalvudin und Fozivu dintidoxil abzuändern und als Derivat als Medikament zur Verwendung bei der Behandlung von Covid-19 zur Verfügung zu stellen. It is therefore proposed to modify the structure of the known Fosalvudin and Fozivu dintidoxil and make them available as a derivative as a drug for use in the treatment of Covid-19.
Vorgeschlagen wird eine Strukturänderung im Bereich des Phospholipidrestes, in dem die Decoxy-Gruppe und die Dodecylsulfanylgruppe ersetzt werden durch eine Estergruppe, wobei die Ester basieren können auf lineyren Alkansäuren, nämlich der Capronsäure (n-Hexansäure), Önanthsäure (n-Heptansäure),
Caprylsäure (n-Octansäure), Pelargonsäure (n-Nonansäure), Caprinsäure (n-De- cansäure), Undecansäure, Laurinsäure (n-Dodeacnsäure), Tridecansäure, Myris tinsäure (n-Tetradecansäure), Pentadecansäure, Palmitinsäure (n-Hexadecan- säure), Heptadecansäure, Stearinsäure (n-Octadecansäure)
A structural change is proposed in the area of the phospholipid residue, in which the decoxy group and the dodecylsulfanyl group are replaced by an ester group, whereby the esters can be based on linear alkanoic acids, namely caproic acid (n-hexanoic acid), enanthic acid (n-heptanoic acid), Caprylic acid (n-octanoic acid), pelargonic acid (n-nonanoic acid), capric acid (n-decanoic acid), undecanoic acid, lauric acid (n-dodecanoic acid), tridecanoic acid, myristic acid (n-tetradecanoic acid), pentadecanoic acid, palmitic acid (n-hexadecanoic acid) acid), heptadecanoic acid, stearic acid (n-octadecanoic acid)
Anstelle der Fluorsubstitution im Zidovudinrest kann auch eine Substitution mit Azid, Brom oder mit Chlor vorliegen. Die Kohlenstoffreste an den Lipidketten kön nen von C6H13, Hexyl, über C7H15 (Heptyl), CsH (Octyl), C9H19 (Nonyl), C10H21 (Decyl), C11H23 (Undecyl), C12H25 (Dodecyl), C13H27 (Tridecyl), C14H29 (Tetrade- cyl), C15H31 (Pentadecyl), C16H33 (Hexadecyl), C17H35 (Heptadecyl) bis hin zu C18H35 (Octadecyl) reichen.
Instead of fluorine substitution in the zidovudine residue, substitution with azide, bromine or with chlorine can also be present. The carbon residues on the lipid chains can range from C6H 13 , hexyl, via C 7 H 15 (heptyl), CsH (octyl), C9H 19 (nonyl), C 10 H 21 (decyl), C11H23 (undecyl), C12H25 (dodecyl) , C13H27 (tridecyl), C14H29 (Tetrade- cyl), C15H31 (pentadecyl), C16H33 (hexadecyl), C17H35 (heptadecyl) to C 18 H3 5 (octadecyl) rich.
Darstellung von Fozivudintidoxil Presentation of fozivudine doxil
1. Darstellung von 5-Decyloxy-2-phenyl-1,3-dioxan
1. Preparation of 5-decyloxy-2-phenyl-1,3-dioxane
Eine Lösung von 19,1 kg Benzaldehyd, 16,6 kg Glycerin und 534 g Methansul fonsäure in 60 I Toluol wurde unter Rückfluss ca. 4 h lang erhitzt bis 3,2 I Wasser abgetrennt werden konnten. A solution of 19.1 kg of benzaldehyde, 16.6 kg of glycerol and 534 g of methanesulfonic acid in 60 I of toluene was heated under reflux for about 4 hours until 3.2 I of water could be separated off.
Die Lösung wurde auf 0 bis 5°C gekühlt und 180 I Isohexan wurden in einem Zeit raum von 30 bis 45 min hinzugefügt. Zur Kristallisierung wurde die Suspension bei 0° bis 5°C 3h lang gerührt.
Nach Hinzufügen von 60 I 50%iger NaOH-Lösung und 120 I Toluol wurde das Isohexan-Toluol-Wasser-Gemisch unter vemindertem Druck abdestilliert bis die Dampftemperatur 80°C betrug. Dabei entstanden 200 I Destillat. The solution was cooled to 0 to 5 ° C and 180 liters of isohexane were added over a period of 30 to 45 minutes. For crystallization, the suspension was stirred at 0 ° to 5 ° C. for 3 hours. After adding 60 l of 50% strength NaOH solution and 120 l of toluene, the isohexane-toluene-water mixture was distilled off under reduced pressure until the steam temperature was 80.degree. This produced 200 l of distillate.
60 I 1-Bromdecan und 2,1 kg Aliquat 336 (Starks' Katalysator, ein Quartärammo niumsalz) wurden hinzugefügt und die Mischung wurde 3 h lang auf 85° bis 90°C erwärmt. 60 liters of 1-bromodecane and 2.1 kg of Aliquat 336 (Starks' catalyst, a quaternary ammonium salt) were added and the mixture was heated to 85 ° to 90 ° C. for 3 hours.
Nach Abkühlung auf Raumtemperatur und Verdünnung mit 220 I demineralisier- tem Wasser wurde die organische Phase abgetrennt und 3 mal mit 180 I demine- ralisiertem Wasser extrahiert. Die Toluolphase wurde im Vakuum verdampft und der Rückstand wurde in einem Dünnschicht-Verdampfer bei 1 mbar und 150°C Betriebstemperatur behandelt, um Decanol und Bromdecan zu entfernen. After cooling to room temperature and dilution with 220 l of demineralized water, the organic phase was separated off and extracted 3 times with 180 l of demineralized water. The toluene phase was evaporated in vacuo and the residue was treated in a thin-film evaporator at 1 mbar and 150 ° C. operating temperature in order to remove decanol and bromodecane.
58 kg des rohes Produkts wurden in 370 I Isohexan gelöst und aufgereinigt mit 2 kg Aktivkohle. Nach Filtrierung wurde die Lösung übernacht auf -20°C gekühlt.58 kg of the crude product were dissolved in 370 l of isohexane and purified with 2 kg of activated charcoal. After filtration, the solution was cooled to -20 ° C. overnight.
Die abgetrennten Kristalle wurden mit 5I kaltem Isohexan gewaschen und bei 15° bis 20°C getrocknet. The separated crystals were washed with 51 cold isohexane and dried at 15 ° to 20 ° C.
Ausbeute: 44 kg (76% basierend auf eingesetztem Benzaldehyd) Yield: 44 kg (76% based on benzaldehyde used)
Reinheit (GC): 98% Purity (GC): 98%
2. Darstellung von 3-Bromo-2-decyloxy-1-propyl)benzoat
2. Preparation of 3-bromo-2-decyloxy-1-propyl) benzoate
Eine Mischung von 7kg 5-decyloxy-2-phenyl-1,3-dioxan und 3,06 kg 1,3-Dibrom- 5,5-dimethylhydantoin in 87 I Isohexan wurde auf 50°C erwärmt. Nach 4 Stunden
io wurde die Suspension auf Raumtemperatur gekühlt, durch einen Aktivkohlefilter gefiltert und im Vakuum bei max. 30°C aufkonzentriert. A mixture of 7 kg of 5-decyloxy-2-phenyl-1,3-dioxane and 3.06 kg of 1,3-dibromo-5,5-dimethylhydantoin in 87 l of isohexane was heated to 50.degree. After 4 hours The suspension was cooled to room temperature, filtered through an activated carbon filter and concentrated in vacuo at a maximum of 30.degree.
Das rohe, erhaltene Öl wurde für die nächste Stufe verwendet und bei 0°bis 5°C gelagert. Lagerung sollte 2 Tage nicht überschreiten. The crude oil obtained was used for the next stage and stored at 0 ° to 5 ° C. Storage should not exceed 2 days.
Ausbeute: 8,9 kg Yield: 8.9 kg
Reinheit (GC): ca. 90% Purity (GC): approx. 90%
3. Darstellung von 3-Dodecylthio-2-deyloxy-1-propanol
3. Preparation of 3-dodecylthio-2-deyloxy-1-propanol
5,4 I 1-Dodecylmercaptan in 6,3 I Methanol wurden behandelt mit 4,19 I einer Natriummethylat-Lösung (30%) in 32 I Methanol wobei die Temperatur unter 30°C gehalten wurde. Danach wurde das rohe Öl von (3-Bromo-2-decyloxy-1- propyl)benzoat (8,7 kg, 90%iger Reinheit) in 15 I Methanol hinzugefügt bei Raum temperatur und die Lösung wurde 15 h lang gerührt. 5.4 l of 1-dodecyl mercaptan in 6.3 l of methanol were treated with 4.19 l of a sodium methylate solution (30%) in 32 l of methanol, the temperature being kept below 30.degree. The crude oil of (3-bromo-2-decyloxy-1-propyl) benzoate (8.7 kg, 90% purity) in 15 l of methanol was then added at room temperature and the solution was stirred for 15 hours.
Danach wurden 3,4 I NaOH-Lösung (50%) hinzugefügt, wobei die Temperatur unter 45°C gehalten wurde. Danach wurde die Lösung auf 40° bis 45°C zwei Stunden lang erwärmt. Thereafter, 3.4 l of NaOH solution (50%) were added, the temperature being kept below 45 ° C. The solution was then heated to 40 ° to 45 ° C. for two hours.
50 I Methanol/Wasser wurden in Vakuum abgezogen und 60 I demineralisiertes Wasser wurde hinzugefügt. Erneut wurden 30 I Methanol/Wasser abdestilliert.50 l of methanol / water were removed in vacuo and 60 l of demineralized water was added. Another 30 l of methanol / water were distilled off.
Der Rückstand wurde 30 min lang gerührt mit 47 I Methyl-tert-butylether. Die or ganische Phase wurde abgetrennt und einmal mit 14 I gesättigter Natriumchlorid lösung gewaschen und aufkonzentriert im Vakuum.
Der Rückstandwurde einer Dünnschichtverdampfer-Destillation ausgesetzt bei weniger als 1mbar Druck und 200°C. Das nicht verflüchtigbare Öl wurde im nächsten Schritt ohne weitere Reinigung verwendet. The residue was stirred with 47 liters of methyl tert-butyl ether for 30 minutes. The organic phase was separated off and washed once with 14 l of saturated sodium chloride solution and concentrated in vacuo. The residue was subjected to a thin film evaporator distillation at less than 1 mbar pressure and 200 ° C. The non-volatile oil was used in the next step without further purification.
Ausbeute: 8,8 kg Yield: 8.8 kg
Reinheit (GC): > 85% Purity (GC):> 85%
Didodecyldisulfid: 1 ,5-2 % Didodecyl disulfide: 1.5-2%
4. Darstellung von (3-Dodecylthio-2-decyloxy-1-propyl)dihydrogen-phos- phat
4. Preparation of (3-dodecylthio-2-decyloxy-1-propyl) dihydrogen phosphate
Eine Lösung von 18,8 kg 3-Dodecylthion-2-decyloxy-1-propanol und 6,9 kg 2,6- Lutidin in 92 I Toluol wurden bei 0° bis 3°C über einen Zeitraum von 2 Stunden zu 10 kg Phophoroxychlorid in 92 I Toluol gegeben. Das Reaktionsgemisch wurde weitere 3 Stunden bei 0° bis 3°C gerührt, um die Reaktion ausreagieren zu las sen. Das ausgefallene Hydrochlorid wurde durch Filtration entfernt, mit 96 I Toluol gewaschen und das Filtrat wurde unter Kühlung langsam in 109 1 demineralisier- tes Wasser gegeben, wobei die Temperatur zwischen 25° und 30°C gehalten wurde. Nach etwa 6 Stunden Rühren bei Raumtemperatur wurde die Emulsion mit 12 I Methyl-tert-butylether behandelt und auf 50° bis 60° erwärmt. Die organi sche Phase wurde abgetrennt und das Lösemittel wurde im Vakuum abgezogen. Das verbleibende Öl wurde in 450 I Ethylmethylketon gelöst. Zur heftig gerührten Lösung wurden über einen Zeitraum von 1 ,5 Stunden 5,4 kg Calciumacetat in 33 I demineralisiertem Wasser hinzugefügt. Die Suspension wurde mindestens 8 Stunden gerührt und anschließend filtriert. Das erhaltene Calciumsalz wurde mit 50 I Ethylmethylketon und 100 I demineralisierte Wasser gewaschen. A solution of 18.8 kg of 3-dodecylthione-2-decyloxy-1-propanol and 6.9 kg of 2,6-lutidine in 92 l of toluene were converted into 10 kg of phosphorus oxychloride at 0 ° to 3 ° C. over a period of 2 hours given in 92 l of toluene. The reaction mixture was stirred for a further 3 hours at 0 ° to 3 ° C. in order to allow the reaction to react to completion. The precipitated hydrochloride was removed by filtration, washed with 96 l of toluene and the filtrate was slowly added to 109 l of demineralized water with cooling, the temperature being kept between 25 ° and 30 ° C. After stirring for about 6 hours at room temperature, the emulsion was treated with 12 l of methyl tert-butyl ether and heated to 50 ° to 60 °. The organic phase was separated off and the solvent was removed in vacuo. The remaining oil was dissolved in 450 l of ethyl methyl ketone. 5.4 kg of calcium acetate in 33 l of demineralized water were added to the vigorously stirred solution over a period of 1.5 hours. The suspension was stirred for at least 8 hours and then filtered. The obtained calcium salt was washed with 50 l of ethyl methyl ketone and 100 l of demineralized water.
Das feuchte Calciumsalz wird für den nächsten Schritt ohne Trocknung verwen det.
Ausbeute: 22,5 kg Calciumsalz (basierend auf der Trockensubstanz) The moist calcium salt is used for the next step without drying. Yield: 22.5 kg calcium salt (based on dry matter)
5. Darstellung von 3'-azido-3'-deoxy -5'-Thymidylsäure, mono(3-dode- cylthio-2decyloxypropyl)ester Calciumsalz
5. Preparation of 3'-azido-3'-deoxy -5'-thymidylic acid, mono (3-dodecylthio-2decyloxypropyl) ester calcium salt
8,3 kg feuchtes (3-dodecylthio-2-decyloxy-1-propyl)dihydrogenphosphat als Cal ciumsalz aus dem vorherigen Schritt 4 (basierend auf der Trockensubstanz) wur den in 30 I Methyl-tert-butylether und 6 I 6M Salzsäure gelöst und gerührt. Da nach wurde die organische Phase abgetrennt, in Vakuum aufkonzentriert und mit 10 I trockenem Pyridin mitverdampft, um Spuren von Wasser zu entfernen. Der Rückstand wurde gelöst in 42 I trockenem Pyridin und 6,92 kg 2,4,6- triisobutylbenolsulfonylchlorid und 4,06 kg 3'-Azidothymidin (Zidovudin, auch Azidothymidin, kurz AZT) wurden hinzugefügt. Die Mischung wurde gerührt für 4
Stunden bei 20° bis 25°C unter einer Stickstoffatmosphäre. Das Pyridin wurde entfernt im Vakuum bei einer Höchsttemperatur von 60°C (Vakuum < 5 mbar über eine Stunde) 8.3 kg of moist (3-dodecylthio-2-decyloxy-1-propyl) dihydrogen phosphate as calcium salt from the previous step 4 (based on the dry matter) WUR dissolved in 30 l of methyl tert-butyl ether and 6 l of 6M hydrochloric acid and touched. Then the organic phase was separated off, concentrated in vacuo and evaporated with 10 l of dry pyridine in order to remove traces of water. The residue was dissolved in 42 l of dry pyridine and 6.92 kg of 2,4,6-triisobutylbenolsulfonyl chloride and 4.06 kg of 3'-azidothymidine (zidovudine, also azidothymidine, AZT for short) were added. The mixture was stirred for 4 Hours at 20 ° to 25 ° C under a nitrogen atmosphere. The pyridine was removed in vacuo at a maximum temperature of 60 ° C (vacuum <5 mbar for one hour)
Der Rückstand wurde bei 50° bis 55°C in 33 I Methyl-tert-butylether suspendiert und auf 20° bis 25°C abgekühlt. Das ausgefallene Salz wurde abgefiltert und ge waschen mit 20 I Methyl-tert-butylether. (10 kg Triisobutylbenzolsulfonyl-pyridin- salz). The residue was suspended in 33 l of methyl tert-butyl ether at 50 ° to 55 ° C. and cooled to 20 ° to 25 ° C. The precipitated salt was filtered off and washed with 20 l of methyl tert-butyl ether. (10 kg triisobutylbenzenesulfonylpyridine salt).
Das Filtrat wurde im Vakuum abgedampft. Das verbleibende viskose Öl wurde in 75 I Aceton gelöst und unter heftigem Rühren in eine Lösung von 2 kg Calciu macetat-Hydrat in 15 I demineralisiertem Wasser gegeben. Es wurde für eine weitere Stunde gerührt und das Salz wurde abfiltriert und gewaschen mit 20 L Aceton und 100 I demineralisiertem Wasser. Das rohe Calciumsalz wurde gela gert ohne vorherige Trocknung. The filtrate was evaporated in vacuo. The remaining viscous oil was dissolved in 75 l of acetone and, with vigorous stirring, added to a solution of 2 kg of calcium acetate hydrate in 15 l of demineralized water. It was stirred for an additional hour and the salt was filtered off and washed with 20 L acetone and 100 L demineralized water. The crude calcium salt was stored without prior drying.
Ausbeute: 9,5 kg rohes Calciumsalz, basierend auf der Trockensubstanz Yield: 9.5 kg of crude calcium salt based on dry matter
6. Vorbereitung der HPLC-Lösung 6. Prepare the HPLC solution
Das rohe Calciumsalz wurde in 30 I Methyl-tert-butylether und 3,5I 6M Salzsäure unter Rühren gelöst. Danach wurde die organische Phase abgetrennt, im Va kuum aufkonzentriert und erneut in 136 1 Methanol gelöst. 12 I Waser und 40 g Natriumacetat wurden hinzugegeben. Der pH-Wert wurde auf 5,0 bis 5,5 durch Hinzufügen von konzentrierter NaOH-Lösung eingestellt. Die Mischung wurde ge filtert, um eine verbliebene Trübung zu entfernen und für die weitere HPLC- Reinigung aufbewahrt. The crude calcium salt was dissolved in 30 l of methyl tert-butyl ether and 3.5 l of 6M hydrochloric acid with stirring. The organic phase was then separated off, concentrated in vacuo and redissolved in 136 l of methanol. 12 liters of water and 40 g of sodium acetate were added. The pH was adjusted to 5.0-5.5 by adding concentrated NaOH solution. The mixture was filtered to remove any remaining cloudiness and saved for further HPLC purification.
7. HPLC-Chromatografie 7. HPLC chromatography
Die zuvor erstellte Lösung wurde in Portionen von 4 I auf eine HPLC-Säule (200 - 350 mm, Merck, LiChroprep RP 18, 15 - 25 pm) und eluiert mit ungefähr 50 I Me thanol/ 0,02M Na-Acetat-Lösung 87,5/12,5 als mobile Phase. Zwischen zwei Durchläufen wurde die Säule mit 20 I Methanol gespült.
Das Eluat von ca 40 Durchläufen (700 bis 800 I) wurde gesammelt, verdünnt mit 130 I demineralisiertem Wasser und behandelt mit einer Lösung von 1,15 kg Cal cium Acetat in 22 I Wasser. Die erhaltene Suspension wurde 5 Stunden lang bei Umgebungstemperatur gerührt und das Calciumsalz wurde filtriert und gewa schen mit 50 I demineralisiertem Wasser. Das reine Calciumsalz wurde für den nächsten Schritt ohne weitere Trocknung verwendet. The previously prepared solution was applied in portions of 4 l to an HPLC column (200-350 mm, Merck, LiChroprep RP 18, 15-25 μm) and eluted with approximately 50 l methanol / 0.02M Na acetate solution 87 .5 / 12.5 as the mobile phase. The column was rinsed with 20 l of methanol between two runs. The eluate from about 40 runs (700 to 800 l) was collected, diluted with 130 l of demineralized water and treated with a solution of 1.15 kg of calcium acetate in 22 l of water. The resulting suspension was stirred for 5 hours at ambient temperature and the calcium salt was filtered and washed with 50 liters of demineralized water. The pure calcium salt was used for the next step without further drying.
Ausbeute: 6,0 bis 7,0 kg Calciumsalz, basierend auf der TrockensubstanzYield: 6.0 to 7.0 kg calcium salt based on dry matter
8. Darstellung von S'-Azido-S'-deoxy-S'-thymidylsäure, mono(3-dodecylthio- 2-decyloxypropyl)ester-Natriumsalz
10,0 kg gereinigtes Calciumsalz wurden in 65 I Methyl-tert-butylether suspendiert und gerührt 1 Stunde lang bei Raumtemperatur gerührt. 14,4 I 2M Salzsäure wurde hinzugefügt und das Rühren wurde fortgeführt bis sämtlicher Niederschlag aufgelöst war. 8. Preparation of S'-azido-S'-deoxy-S'-thymidylic acid, mono (3-dodecylthio-2-decyloxypropyl) ester sodium salt 10.0 kg of purified calcium salt were suspended in 65 l of methyl tert-butyl ether and stirred for 1 hour at room temperature. 14.4 liters of 2M hydrochloric acid was added and stirring was continued until all of the precipitate had dissolved.
Der Rührer wurde gestoppt, die organische Phase wurde abgetrennt und extra hiert mit 20 I demineralisiertem Wasser. Die organische Phase wurde gefiltert und das Lösemittel wurde im Vakuum abgezogen. Der Rückstand wurde gelöst in 60 I Toluol und 30 I Toluol wurden abdestilliert, um Spuren von Wasser zu entfernen. Die verbleibende Lösung wurde unter Rühren bei 20° bis 25°C auf einen pH- Wert von 6,9 bis 7,1 mit Natriummethylat-Lösung eingestellt. The stirrer was stopped, the organic phase was separated off and extracted with 20 l of demineralized water. The organic phase was filtered and the solvent was removed in vacuo. The residue was dissolved in 60 l of toluene and 30 l of toluene was distilled off to remove traces of water. The remaining solution was adjusted to a pH of 6.9 to 7.1 with sodium methylate solution while stirring at 20 ° to 25 ° C.
Der Toluol Lösung wurde langsam und unter Rühren 240 I kochendes Aceton hinzugefügt. Rückfluss wurde aufrechterhalten für 15 Minuten. Danach wurde die Suspension auf 0° bis 5°C innerhalb von 3 Stunden gekühlt und bei dieser Tem peratur für weitere 2 Stunden gerührt. Das Natriumsalz wurde abfiltriert, gewa schen mit 40 I Aceton, getrocknet, gemahlen und erneut getrocknet. 240 l of boiling acetone were added slowly and with stirring to the toluene solution. Reflux was maintained for 15 minutes. The suspension was then cooled to 0 ° to 5 ° C. within 3 hours and stirred at this temperature for a further 2 hours. The sodium salt was filtered off, washed with 40 l of acetone, dried, ground and dried again.
Ausbeute: 9,5 kg
Yield: 9.5 kg
B E Z U G S Z E I C H E N L I S T E keine
B E Z U G S Z E I C H E N L I S T E none
Claims
1 . Nucleosid-Phospholipide aufweisend die folgende Strukturformel
mit Ri gleich Fluor (Fosalviudin [(2S,3S,5R)-3-Fluoro-5-(5-methyl-2,4-dioxo- pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2F?S)-decoxy-3-dodecylsulfanyl- propyl]hydrogenphosphat), Chlor, Brom oder Azid (Fozivudintidoxil, [(2S,3S,5F?)-3-Azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2- yl]methyl[(2RS)-decoxy-3-dodecylsulfanyl-propyl]hydrogenphosphat) zur Anwendung bei der Behandlung der Krankheit Covid-19.
1 . Nucleoside phospholipids having the following structural formula with Ri being fluorine (fosalviudine [(2S, 3S, 5R) -3-fluoro-5- (5-methyl-2,4-dioxopyrimidin-1-yl) tetrahydrofuran-2-yl] methyl [(2F? S ) -decoxy-3-dodecylsulfanyl-propyl] hydrogen phosphate), chlorine, bromine or azide (fozivudintidoxil, [(2S, 3S, 5F?) - 3-azido-5- (5-methyl-2,4-dioxo-pyrimidine- 1-yl) tetrahydrofuran-2-yl] methyl [(2RS) -decoxy-3-dodecylsulfanyl-propyl] hydrogen phosphate) for use in the treatment of Covid-19.
2. Nucleosid-Phospholipide der Struktur
mit Ri Fluor, Chlor, Brom oder Azid, mit R2 C6H13, Hexyl, C7H15 (Heptyl), CsHi (Octyl), C9H192. Nucleoside phospholipids of the structure with Ri fluorine, chlorine, bromine or azide, with R2 C6H13, hexyl, C7H15 (heptyl), CsHi (octyl), C9H19
(Nonyl), C10H21 (Decyl), C11H23 (Undecyl), C12H25 (Dodecyl), C13H27 (Tridecyl), C14H29 (Tetradecyl), C15H31 (Pentadecyl), C16H33 (Hexadecyl), C17H35 (Heptadecyl) oder C18H35 (Octadecyl) und mit R3 C6H13, Hexyl, C7H15 (Heptyl), CsH (Octyl), C9H19 (Nonyl), C10H21 (decyl), C11H23 (undecyl), C12H25 (dodecyl), C13H27 (tridecyl), C14H29 (tetradecyl), C15H31 (pentadecyl), C16H33 (hexadecyl), C17H35 (heptadecyl) or C 18 H3 5 (octadecyl ) and with R3 C6H 13 , hexyl, C 7 H 15 (heptyl), CsH (octyl), C9H 19
(Nonyl), C10H21 (Decyl), C11H23 (Undecyl), C12H25 (Dodecyl), C13H27 (Tridecyl), C14H29 (Tetradecyl), C15H31 (Pentadecyl), C16H33 (Hexadecyl), C17H35 (Heptadecyl) oder C18H35 (Octadecyl), und dem chiralen Kohlenstoffatom * in R-Konfiguration o- der S-Konfiguration.
(Nonyl), C10H21 (decyl), C11H23 (undecyl), C12H25 (dodecyl), C13H27 (tridecyl), C14H29 (tetradecyl), C15H31 (pentadecyl), C16H33 (hexadecyl), C17H35 (heptadecyl) or C 18 H3 5 (octadecyl ), and the chiral carbon atom * in R-configuration or S-configuration.
3. Verwendung von Nucleosid-Phospholipiden nach Anspruch 2 zur Herstel lung eines Medikaments gegen Virenerkrankungen. 3. Use of nucleoside phospholipids according to claim 2 for the produc- tion of a drug against viral diseases.
4. Verwendung von Nucleosid-Phospholipiden nach Anspruch 2 zur Herstel lung eines Medikaments gegen SARS (SARS-CoV), MERS (MERS-CoV). 4. Use of nucleoside phospholipids according to claim 2 for the produc- tion of a drug against SARS (SARS-CoV), MERS (MERS-CoV).
5. Verwendung von Nucleosid-Phospholipiden nach Anspruch 2 zur Herstel lung eines Medikaments gegen Covid-19. 5. Use of nucleoside phospholipids according to claim 2 for the production of a medicament against Covid-19.
6. Nucleosid-Phospholipide nach Anspruch 2 zur Anwendung bei der Behand lung von Covid-19. 6. nucleoside phospholipids according to claim 2 for use in the treatment of Covid-19.
7. Verfahren zur Herstellung von Fozivudintidoxil, [(2S,3S,5R)-3-Azido-5-(5- methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2RS)-decoxy-3- dodecylsulfanyl-propyl]hydrogenphosphat), aufweisend die folgenden Schritte 7. Process for the preparation of fozivudintidoxil, [(2S, 3S, 5R) -3-azido-5- (5-methyl-2,4-dioxo-pyrimidin-1-yl) tetrahydrofuran-2-yl] methyl [(2RS ) -decoxy-3-dodecylsulfanyl-propyl] hydrogen phosphate), comprising the following steps
Darstellung von 5-Decyloxy-2-phenyl-1,3-dioxan durch Preparation of 5-decyloxy-2-phenyl-1,3-dioxane by
Umsetzen von Benzaldehyd mit Glycerin in Gegenwart von Säure, bevorzugt in Gegenwart von Merthansulfonsäure und anschließender Umsetzung des zuvor erhaltenen Produkts mit 1- Bromdecan in Gegenwart eines Katalysators, bevorzugt in Ge genwart einer Quartärammoniumsalzes
in einem ersten Schritt, Reacting benzaldehyde with glycerol in the presence of acid, preferably in the presence of merthanesulfonic acid and subsequent reaction of the previously obtained product with 1-bromodecane in the presence of a catalyst, preferably in the presence of a quaternary ammonium salt in a first step,
Darstellung von 3-Bromo-2-decyloxy-1-propyl)benzoat durch Umset zen des im ersten Schritt erhaltenen 5-Decyloxy-2-phenyl-1 ,3-dioxans mit N-Bromsuccinimid in einem zweiten Schritt, Preparation of 3-bromo-2-decyloxy-1-propyl) benzoate by reacting the 5-decyloxy-2-phenyl-1,3-dioxane obtained in the first step with N-bromosuccinimide in a second step,
Darstellung von 3-Dodecylthio-2-deyloxy-1-propanol durch Umsetzen des im zweiten Schritt erhaltenen 3-Bromo-2-decyloxy-1-propyl)ben- zoats mit 1-Dodeycylmercaptan in basischer Umgebung in einem dritten Schritt, Preparation of 3-dodecylthio-2-deyloxy-1-propanol by reacting the 3-bromo-2-decyloxy-1-propyl) benzoate obtained in the second step with 1-dodecyl mercaptan in a basic environment in a third step,
Darstellung von (3-Dodecylthio-2-decyloxy-1 -propyl)dihydrogen-phos- phat durch Umsetzen des im dritten Schritt erhaltenen 3-Dodecylthio- 2-deyloxy-1-propanols mit Phosphoroxychlorid in einem vierten Schritt, Preparation of (3-dodecylthio-2-decyloxy-1-propyl) dihydrogen phosphate by reacting the 3-dodecylthio-2-deyloxy-1-propanol obtained in the third step with phosphorus oxychloride in a fourth step,
Darstellung von 3'-azido-3'-deoxy -5'-Thymidylsäure, mono(3-dode- cylthio-2decyloxypropyl)ester durch Preparation of 3'-azido-3'-deoxy -5'-thymidylic acid, mono (3-dodecylthio-2decyloxypropyl) ester by
Umsetzen des im vierten Schritt erhaltenen (3-Dodecylthio-2-de- cyloxy-1-propyl)dihydrogen-phosphats mit 3'-Azidothymidin und anschließender Umsetzung mit Calciumacetat in einem fünften Schritt.
Reacting the (3-dodecylthio-2-de-cyloxy-1-propyl) dihydrogen phosphate obtained in the fourth step with 3'-azidothymidine and subsequent reaction with calcium acetate in a fifth step.
8. Verfahren nach Anspruch 7, gekennzeichnet durch Tauschen der Calcium-Kationen durch Natrium-Kati onen durch Umsetzen des im fünften Schritt erhaltenen Calcium-Salzes mit Salzsäure. 8. The method according to claim 7, characterized by exchanging the calcium cations by sodium Kati onen by reacting the calcium salt obtained in the fifth step with hydrochloric acid.
9. Verfahren zur Herstellung von Fosalviudin [(2S,3S,5R)-3-Fluoro-5-(5-me- thyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2F?S)-decoxy-3- dodecylsulfanyl-propyl]hydrogenphosphat mit den Verfahrensschritten in Anspruch 7, wobei im fünften Schritt 3'-Flourothymidin anstelle von 3'- Azidothymidin eingesetzt wird. 9. Process for the preparation of fosalviudin [(2S, 3S, 5R) -3-fluoro-5- (5-methyl-2,4-dioxo-pyrimidin-1-yl) tetrahydrofuran-2-yl] methyl [( 2F? S) -decoxy-3-dodecylsulfanyl-propyl] hydrogen phosphate with the process steps in claim 7, wherein in the fifth step 3'-fluorothymidine is used instead of 3'-azidothymidine.
10. Verfahren zur Herstellung von [(2S,3S,5R)-3-Chloro-5-(5-methyl-2,4-dioxo- pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2F?S)-decoxy-3-dodecylsulfanyl- propyl]hydrogenphosphat mit den Verfahrensschritten in Anspruch 7, wobei im fünften Schritt 3'-Chlorothymidin anstelle von 3'-Azidothymidin eingesetzt wird.
10. Process for the preparation of [(2S, 3S, 5R) -3-chloro-5- (5-methyl-2,4-dioxopyrimidin-1-yl) tetrahydrofuran-2-yl] methyl [(2F? S ) -decoxy-3-dodecylsulfanyl propyl] hydrogen phosphate with the process steps in claim 7, wherein in the fifth step 3'-chlorothymidine is used instead of 3'-azidothymidine.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE112020006626.6T DE112020006626A5 (en) | 2020-03-30 | 2020-03-30 | Fosalvudine and fozivudintidoxil for use in the treatment of the disease Covid-19 and the use of their structurally simplified derivatives |
| PCT/IB2020/052996 WO2021198725A1 (en) | 2020-03-30 | 2020-03-30 | Fosalvudine and fozivudine tidoxil for use in the treatment of covid-19, and use of the structurally simplified derivatives thereof |
| TW110102544A TW202140041A (en) | 2020-03-30 | 2021-01-22 | Fosalvudine and fozivudintidoxil for use in the treatment of the disease covid-19 and the use of their of structurally simplified derivatives thereof |
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| PCT/IB2020/052996 WO2021198725A1 (en) | 2020-03-30 | 2020-03-30 | Fosalvudine and fozivudine tidoxil for use in the treatment of covid-19, and use of the structurally simplified derivatives thereof |
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| WO1992003462A1 (en) | 1990-08-20 | 1992-03-05 | Boehringer Mannheim Gmbh | New phospholipid derivatives of nucleosides, their preparation and their use as antiviral drugs |
| WO1995020596A1 (en) | 1994-01-28 | 1995-08-03 | Boehringer Mannheim Gmbh | Method of preparing unsymmetrical phosphoric acid diesters |
| WO2008118879A2 (en) * | 2007-03-23 | 2008-10-02 | Ardea Biosciences, Inc. | Antiviral compositions comprising 2 compounds |
-
2020
- 2020-03-30 DE DE112020006626.6T patent/DE112020006626A5/en active Pending
- 2020-03-30 WO PCT/IB2020/052996 patent/WO2021198725A1/en active Application Filing
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2021
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| WO1992003462A1 (en) | 1990-08-20 | 1992-03-05 | Boehringer Mannheim Gmbh | New phospholipid derivatives of nucleosides, their preparation and their use as antiviral drugs |
| WO1995020596A1 (en) | 1994-01-28 | 1995-08-03 | Boehringer Mannheim Gmbh | Method of preparing unsymmetrical phosphoric acid diesters |
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