WO2016074596A1 - Dérivé de phosphoramidate de nucléoside et son application - Google Patents

Dérivé de phosphoramidate de nucléoside et son application Download PDF

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Publication number
WO2016074596A1
WO2016074596A1 PCT/CN2015/094101 CN2015094101W WO2016074596A1 WO 2016074596 A1 WO2016074596 A1 WO 2016074596A1 CN 2015094101 W CN2015094101 W CN 2015094101W WO 2016074596 A1 WO2016074596 A1 WO 2016074596A1
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compound
group
formula
solvate
hydrate
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PCT/CN2015/094101
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English (en)
Chinese (zh)
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倪帅健
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南京曼杰生物科技有限公司
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention belongs to the technical field of medicinal chemistry, and more particularly to a novel nucleoside phosphoramidate derivative, a pharmaceutically acceptable acid salt, solvate or hydrate, and their preparation for mammalian infectivity Use in diseases, prevention or treatment of drugs for hepatitis C, cirrhosis, and liver cancer.
  • HCV infection is a serious health problem that causes chronic liver disease in a large number of infected individuals, which in turn develops into cirrhosis and liver cancer.
  • WHO World Health Organization
  • Current therapeutics for HCV infection include recombinant interferon, therapy alone or in combination with the nucleoside analog ribavirin, and Girard-listed sofosbuvir. While sofosbuvir is metabolized in the body by nearly 90% into inactive metabolites. Therefore, HCV infection treatment drugs with high bioavailability, good liver selectivity and high efficacy are still urgent clinical needs.
  • a second object of the present invention is to provide a pharmaceutical composition comprising the above nucleoside phosphoramidate derivative.
  • a third object of the present invention is to provide a use of the above-described nucleoside phosphoramidate derivative or pharmaceutical composition for preventing or treating infectious diseases in a mammal, particularly for preventing or treating hepatitis C, liver cirrhosis, and liver cancer-related diseases. .
  • nucleoside phosphoramidate derivative such as a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
  • R 1 is a C 1-4 alkyl group
  • R 2 is an optionally substituted phenyl or naphthyl group, the substituent of which is selected from a C 1-4 alkyl group, a C 1-4 alkoxy group;
  • R 3 is an amino acid acyl group or a polypeptide acyl group.
  • R 1 in the compound of the formula I according to the invention is methyl, ethyl or isopropyl; further preferably isopropyl.
  • R 2 in the compound of the formula I according to the invention is a phenyl or naphthyl group; further preferably a phenyl group.
  • R 3 in the compounds of the formula I according to the invention is a natural amino acid acyl group, a non-natural amino acid acyl group or a dipeptidyl group.
  • R 3 in the compounds of the formula I according to the invention is a natural amino acid acyl group.
  • R 3 in the compound of the formula I according to the invention is glycyl, alanyl, prolyl, leucyl, isoleucyl, phenylalanyl, tryptophanyl , tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, methionyl, seryl, threonyl, cysteinyl, prolyl, Histidine or arginyl.
  • R 1 in the compound of formula I according to the invention is methyl, ethyl or isopropyl;
  • R 2 is phenyl or naphthyl;
  • R 3 is glycyl, alanyl , prolyl, leucyl, isoleucyl, phenylalanyl, tryptoyl, tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, A methionyl group, a seryl group, a threonyl group, a cysteinyl group, a prolyl group, a histidine group, and an arginyl group.
  • R 1 in the compound of formula I of the invention is isopropyl;
  • R 2 is phenyl;
  • R 3 is glycyl, alanyl, prolyl, leucyl , isoleucyl, phenylalanyl, tryptoyl, tyrosyl, aspartyl, asparaginyl, glutamyl, glutaminyl, lysyl, methionyl, seryl , threonyl, cysteinyl, prolyl, histidyl, arginyl.
  • the compounds provided herein are selected from one of the following compounds, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
  • the derivative provided by the invention comprises an enantiomer and a racemate of a compound of formula I.
  • the derivative of the invention comprises a compound of formula I or a pharmaceutically acceptable acid salt thereof, including but not limited to a salt of a compound with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid or succinic acid.
  • a salt of a compound with the following acids hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxa
  • C 1-4 alkyl group in the present invention means a linear or branched saturated hydrocarbon group having 1, 2, 3 or 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl or isopropyl. Base, n-butyl and the like.
  • the "optionally substituted" in the present invention means having a substituent or having no substituent.
  • C 1-4 alkoxy group in the present invention means a linear or branched alkyl-substituted oxy group having 1 , 2, 3 or 4 carbon atoms, that is, “C 1-4 alkyl-O"-”.
  • the amino acids referred to herein include 20 kinds of natural amino acids, and also include various unnatural amino acids, such as: alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), Proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), cysteine (Cys ), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg) ), histidine (His), and the like.
  • the small molecule compound formed by the bond is preferably a dipeptide including, but not limited to, a glycoglutapeptide, a glycyrrhizin, a propionol dipeptide, a propyl dipeptide, and the like.
  • the present invention provides a process for the preparation of the above nucleoside phosphoramidate derivative of the compound of formula I or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, comprising the steps of:
  • the compound of the formula II is reacted with a compound of the formula III under a condensing agent or a compound of the formula II with a compound of the formula IV, followed by removal of the amino protecting group to give a compound of the formula I
  • the condensing agent may be carbonyl diimidazole (CDI), N, N'-diisopropyl Carbodiimide (DIC), N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ( EDC ⁇ HCl), O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N, N', N'-tetramethylurea hexafluorophosphate (HBTU), the Cbz group is a benzyloxycarbonyl protecting group that protects the amino group.
  • CDI carbonyl diimidazole
  • DIC N, N'-diisopropyl Carbodiimide
  • DCC N,N'-dicyclohexylcarbod
  • the present invention provides a process for the preparation of the above nucleoside phosphoramidate derivative of the compound of formula I or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, which comprises formula II
  • the compound or a salt thereof is dissolved in an organic solvent, and the base is added in a batchwise manner, and then reacted with the compound of the formula IV, and then the Cbz protecting group is removed by catalytic hydrogenation to obtain a compound of the formula I; or the compound of the formula III is reacted with a condensing agent, and added.
  • the base is reacted with an organic solvent of the compound of the formula II or a salt thereof, and then Cbz is removed by catalytic hydrogenation.
  • the protecting group provides a compound of formula I which can be further purified by conventional methods such as recrystallization, column chromatography and the like if necessary.
  • the base may be an inorganic base or an organic base, and may be selected from sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, or N,N-diisopropylethylamine.
  • the compound of formula I is salted with an aqueous solution or aqueous solution of an acid to give the acid salt of the compound of formula I.
  • the corresponding side chain is added in the present invention. Protection, adding a deprotection step after the condensation reaction.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned nucleoside phosphoramidate derivative of Formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, the pharmaceutical composition
  • a pharmaceutically acceptable carrier or diluent may also be included, and the pharmaceutical composition may also include other active ingredients to form a combination or a synergistic composition.
  • the pharmaceutical composition can be administered by intravenous injection, by injection into tissue, intraperitoneally, orally or intranasally.
  • the pharmaceutical composition may be in the form of a solution, a dispersion, a suspension, a powder, a capsule, a tablet, a pill, a time release capsule, a time release tablet, and a time release pill.
  • the pharmaceutical composition is administered at a dose of 5 to 5000 mg/day.
  • the present invention provides the above nucleoside phosphoramidate derivative, such as a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, for use in the preparation of a medicament for preventing or treating infectious diseases in a mammal, in particular It is used in the preparation of drugs for preventing or treating hepatitis C, liver cirrhosis and liver cancer.
  • the novel nucleoside phosphoramidate derivatives of the present invention have significant anti-HCV activity, and the concentration of liver active metabolites, which is a key indicator of anti-HCV activity, is even higher than that of sofosbuvir.
  • Figure 1 shows the concentration (ng/g) of the liver active metabolite GS-461203 after administration of 80 mg/kg of the compound of the present invention and sofosbuvir to the SD rats.
  • the source of the compound starting material used in the examples was: all reagents were purchased from a reagent company, and the compound of formula II was synthesized by the method of sofosbuvir with reference to J. Org. Chem. 2011, 76, 8311-8319.
  • Nuclear magnetic resonance spectroscopy data was collected and processed by a Bruker AV-300 NMR spectrometer.
  • the target compound was obtained in the same manner as in Example 3, using benzyloxycarbonyl-protected amino group as the starting material. The yield was 51.3%. MS (m/z): 643.2 [M + 1] + .
  • the target compound was obtained in the same manner as in Example 3, using the benzyloxycarbonyl-protected amino-isoleucine as a starting material, yield 41.1%. MS (m/z): 643.2 [M + 1] + .
  • the target compound was obtained in the same manner as in Example 3, using benzyloxycarbonyl-protected amino-aspartic acid as the starting material. The yield was 52.7%. MS (m/z): 644.2 [M + 1] + .
  • the target compound was obtained in the same manner as in Example 3, using benzyloxycarbonyl-protected amino-amino glutamine as a starting material in a yield of 45.2%. MS (m/z): 658.2 [M+1] + .
  • the target compound was obtained in the same manner as in Example 3, using a benzyloxycarbonyl-protected amino group aspartic acid side chain carboxybenzyl ester as a starting material. The yield was 39.9%. MS (m/z): 645.2 [M + 1] + .
  • the target compound was obtained in the same manner as in Example 3, using the benzyloxycarbonyl-protected amino group as the starting material of the glutamic acid side chain carboxybenzyl ester. The yield was 41.5%. MS (m/z): 659.2 [M + 1] + .
  • the target compound was obtained in the same manner as in Example 3 using benzyloxycarbonyl bis-protected amino lysine as a starting material in a yield of 53.5%. MS (m/z): 658.2 [M+1] + .
  • the methionine protecting the amino group with a benzyloxycarbonyl group as a starting material was similar to that of Example 3 except that the catalytic hydrogenation was carried out using Raney Ni as a catalyst to obtain a target compound in a yield of 31.3%.
  • the target compound was obtained in the same manner as in Example 3, using a benzyloxycarbonyl group to protect the aminobenzyl group to protect the hydroxyl group as a starting material, and the yield was 43.6%.
  • the target compound was obtained in the same manner as in Example 3, using benzyloxycarbonyl as a starting material to protect the aminobenzyl group to protect the hydroxy group.
  • the yield was 39.1%.
  • a benzyloxycarbonyl group-protected aminotrityl-protected thiol-containing cysteine was used as a starting material, and a method similar to that of Example 10 was carried out except that catalytic hydrogenation was carried out using Raney Ni as a catalyst to obtain a target compound in a yield of 23.1%.
  • the target compound was obtained in the same manner as in Example 10 by the benzyloxycarbonyl-protected aminotrityl group-protected side chain heterocyclic nitrogen histidine as a starting material in a yield of 27.3%. MS (m/z): 667.2 [M + 1] + .
  • the target compound was obtained in the same manner as in Example 10 by using benzyloxycarbonyl-protected aminotrityl-protected arginine as a starting material, and the yield was 29.6%. MS (m/z): 686.2 [M + 1] + .
  • GS-461203 is an active metabolite formed by the anti-hepatitis drug sofosbuvir in vivo. It passes NS5B polymerase. It can be incorporated into the RNA of hepatitis C virus and exerts an antiviral effect like a chain terminator. The content of GS-461203 in the liver after administration can reflect the strength of the compound against hepatitis C virus.
  • Rat liver samples were added with ice bath 70% aqueous methanol solution (including EDTA, etc.), homogenized, centrifuged, and the supernatant was taken in an appropriate amount, evaporated, and dissolved in an aqueous solution of acetonitrile containing 0.1% formic acid, which was used as a test solution.
  • aqueous methanol solution including EDTA, etc.
  • the content of GS-461203 was determined by LC/MS/MS method, and the liver exposure (AUC) was calculated.
  • the test compound liver GS-461203AUC was higher than sofosbuvir, MJ10702 group and MJ10703 group were significantly higher than sofosbuvir group. The results are shown in Table 1.
  • GS-331007 is an inactive metabolite formed by the anti-hepatitis drug sofosbuvir in vivo. It is also the main metabolite of sofosbuvir. Its presence indirectly reflects the bioavailability of sofosbuvir in vivo, and the patented compounds undergo metabolism in vivo. As a process of nucleoside monophosphate and then dephosphorylation to GS-331007, the amount of GS-331007 in the test plasma can reflect the overall absorption of the inventive compound in vivo.
  • SD rats were divided into several groups, with 27 rats in each group.
  • the test solutions of sofosbuvir and patented compounds were administered orally at a dose of 50 mg/kg, respectively, and 0.5, 1, 2, 3, 4 after administration. At 6, 8, 10, and 12 hours, animal plasma was collected (3/time/group).
  • the concentration of metabolite GS-331007 in rat plasma was quantitatively determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the pharmacokinetic parameters were calculated by WinNonlin 6.2 software according to the non-compartmental model. The results are shown in Table 2.
  • Sofosbuvir does not form salts under acidic and basic conditions, and is almost insoluble in neutral aqueous solutions.
  • the patented compounds can form salts with acids, increase their solubility in water, and provide convenience in formulation.
  • the sample to be tested is dissolved in water, precipitated at the bottom, filtered, and the absorbance coefficient is determined by ultraviolet spectrophotometry. The sample concentration is calculated. The test shows that the solubility of the patented compound is greater than 6 mg/ml, and the results of MJ10702 and MJ10703 are shown in Table 4.

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Abstract

La présente invention concerne un dérivé de phosphoramidate de nucléoside et son application, lequel est plus précisément un composé représenté par la formule I ou un sel acide pharmaceutiquement acceptable, un solvate ou un hydrate de ce dernier. Dans la formule, R1 représente un groupe alkyle en C1 - 4; R2 représente un quelconque groupe phényle ou naphtyle substitué et un groupe substituant de ce dernier est choisi parmi les groupes alkyle en C1 - 4 et alcoxy en C1 - 4; et R3 représente un groupe acyle d'acide aminé ou acyle de peptide. Le composé selon la présente invention peut être utilisé pour préparer un médicament pour la prévention ou le traitement de maladies infectieuses chez des mammifères et, en particulier, il peut être utilisé pour préparer des médicaments pour la prévention ou le traitement de l'hépatite C, de la cirrhose du foie et d'un cancer du foie.
PCT/CN2015/094101 2014-11-10 2015-11-09 Dérivé de phosphoramidate de nucléoside et son application WO2016074596A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN111051326A (zh) * 2017-10-23 2020-04-21 四川科伦博泰生物医药股份有限公司 核苷磷酸类化合物及其制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1891710A (zh) * 2005-07-01 2007-01-10 博瑞生物医药技术(苏州)有限公司 L－核苷的前体药物
US20070167353A1 (en) * 2003-10-24 2007-07-19 John Hilfinger Prodrug composition
WO2010135569A1 (fr) * 2009-05-20 2010-11-25 Pharmasset, Inc. Ester de n-[(2 ' r) -2' -désoxy-2' -fluoro-2' -méthyl-p-phényl-5' -uridylyl]-l-alanine 1-méthyléthyle et son procédé de production
WO2011039221A2 (fr) * 2009-09-29 2011-04-07 Centocor Ortho Biotech Products L.P. Dérivés phosphoramidates nucléosides
WO2014209983A1 (fr) * 2013-06-26 2014-12-31 Alios Biopharma, Inc. Nucléosides substitués, nucléotides et analogues de ceux-ci

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964580B2 (en) * 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US9828409B2 (en) * 2014-03-19 2017-11-28 Minghong Zhong Bridged-cyclo-ProTides as prodrugs of therapeutic nucleosides and nucleotides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070167353A1 (en) * 2003-10-24 2007-07-19 John Hilfinger Prodrug composition
CN1891710A (zh) * 2005-07-01 2007-01-10 博瑞生物医药技术(苏州)有限公司 L－核苷的前体药物
WO2010135569A1 (fr) * 2009-05-20 2010-11-25 Pharmasset, Inc. Ester de n-[(2 ' r) -2' -désoxy-2' -fluoro-2' -méthyl-p-phényl-5' -uridylyl]-l-alanine 1-méthyléthyle et son procédé de production
WO2011039221A2 (fr) * 2009-09-29 2011-04-07 Centocor Ortho Biotech Products L.P. Dérivés phosphoramidates nucléosides
WO2014209983A1 (fr) * 2013-06-26 2014-12-31 Alios Biopharma, Inc. Nucléosides substitués, nucléotides et analogues de ceux-ci

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