WO2019052359A1 - Effet antitumoral et utilisation d'analogue de ribavirine dihétérocyclique - Google Patents

Effet antitumoral et utilisation d'analogue de ribavirine dihétérocyclique Download PDF

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WO2019052359A1
WO2019052359A1 PCT/CN2018/103763 CN2018103763W WO2019052359A1 WO 2019052359 A1 WO2019052359 A1 WO 2019052359A1 CN 2018103763 W CN2018103763 W CN 2018103763W WO 2019052359 A1 WO2019052359 A1 WO 2019052359A1
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pyrazolo
triazin
hydroxymethyl
oxo
dihydro
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徐利锋
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辽宁利锋科技开发有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

  • the present invention relates to the use of bicyclic heterocyclic ribavirin analogs for the treatment, prevention and or amelioration of anti-tumor activity and novel indications.
  • the invention also relates to the use of such compounds for the treatment of diseases such as anti-tumor and preparation methods thereof.
  • An object of the present invention is to provide a compound containing a bicyclic heterocyclic triazole nucleoside analog compound, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a double salt or a solvate having the following structural formula I,
  • the X 1 and X 2 are absent and or independently selected from, but not limited to: H, -C-, -S-, -O-, -NH-;
  • the S 1 and S 2 are absent and or independently selected from, but not limited to: H, halogen, aryl, -CN, -CF 3 , -OH, -NH 2 , fluorenyl, fluorenyl, -C (O)OH,P(O)(OH) 2 ,-C 1,2,3,4,5,6- alkyl, -C 2,3,4,5,6 alkenyl, -C 2,3, 4,5,6 alkynyl, -C 3,4,5,6,7,8,9,10 cycloalkyl, -C 3,4,5,6,7,8,9,10 cycloalkenyl, Aryl, -C 3,4,5,6,7,8,9,10 heterocyclyl, -C 3,4,5,6,7,8,9,10heteroaryl , -CN,-CF 3 , -OH, -OC 1,2,3,4,5,6- alkyl, -NH 2 , -NHC 1,2,3,4,5,6- alkyl, -N(
  • the structure is not present and or is selected from, but not limited to:
  • the structure is not present and or is selected from, but not limited to:
  • the R is absent and or independently selected from, but not limited to: H, halogen, -CN, -CF 3 , -OH, -NH 2 , fluorenyl, fluorenyl, -SH, -P(O) ( OH) 2 , C 3,4, 5,6,7,8 amino acid group, -OC 1,2,3,4,5,6 alkyl, -OC 2,3,4,5,6 alkenyl,- OC 2,3,4,5,6 alkynyl, -OC 3,4,5,6,7,8,9,10 cycloalkyl, -OC 3,4,5,6,7,8,9, 10 cycloalkenyl, O-aryl, -OC 3,4,5,6,7,8,9,10 heterocyclyl, -OC 3,4,5,6,7,8,9,10 heteroaryl Base, -NHC 1,2,3,4,5,6- alkyl, -NHC 2,3,4,5,6 alkenyl, -NHC 2,3,4,5,6 alkynyl, -NHC 3,
  • the bicyclotriazinone analog A and the acetylated sugar are subjected to a reflux reaction in the presence of a NH 4 SO 4 and a SnCl 4 catalyst to obtain a bicyclic ring.
  • Triazinone nucleoside analog B the five-membered heterocyclic compound C is reacted with NaNO 2 in the presence of a base catalyst in a dilute HCl solution to obtain a compound D to form a triazinone.
  • 2-cyanoacetamide E is reacted with an azide reagent to give a substituted triazole carboxamide compound F.
  • compound G is nitrated by nitric acid and then reduced with H 2 /Pd to give compound H by formation of an amino group.
  • the compound J is provided by the formation of an amino group by the same general method.
  • the compound K is reacted with a chlorophosphonamine compound in the presence of a base to form a compound L by forming a PO bond.
  • Method I To a mixture of an aryl heterocyclic compound (10 mmol) and concentrated sulfuric acid (15 mmol) in 20 mL of a tetrahydrofuran solution, concentrated nitric acid (15 mmol) was added, and the mixture was stirred until the reaction was completed, and the reaction solution was filtered, and the crude product was passed through silica gel column chromatography. Separating the nitrated compound;
  • Acetic anhydride (12 mmol) was added to a mixture of a mixture of carbamide (10 mmol) and pyrimidine (20 mL), and the mixture was refluxed for 4 hours. The reaction solution was extracted with EtOAc.
  • intermediate compound (I) 2-(acetoxy)-5-(7-cyano-5-hydroxy-4-oxo-4,5-dihydro-3H-pyrazole [4,3-d][1,2,3]triazin-3-yl)3,4-diacetoxytetrahydrofuran; using general procedure E, from intermediate compound (I) 4.36 g (10 mmol) and methanol /
  • the target compound was prepared by dissolving 20 mL (1 mol/L) of sodium methoxide solution. The mixture was reacted for 5 hours and acetic acid was added to pH 7. The reaction solution was extracted with ethyl acetate.
  • the crude product is purified by flash chromatography to give the intermediate compound (I) 2-(acetoxy)-5-(5-hydroxy-4-oxo-7-(piperidin-1-yl)-4,5-dihydro -3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)3,4-diacetoxytetrahydrofuran; using general procedure E, from intermediate compound (I) 4.94 g
  • the title compound was prepared (20 mmol) and methanol / sodium methoxide solution 20 mL (1 mol / L). The mixture was reacted for 5 hours and acetic acid was added to pH 7. The reaction solution was extracted with ethyl acetate.
  • the crude product is purified by flash chromatography to give the intermediate compound (I) 2-((3-(3,4-diacetoxy-5-(acetoxymethyl)tetrahydrofuran-2-yl)-5-methyl 4-oxo-4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-7-yl)(methyl)amino)-2-(diethyl
  • the oxyphosphoryl)acetic acid was prepared from the intermediate compound (I) 6.32 g (10 mmol) and methanol/methanol sodium solution 20 mL (1 mol/L). The mixture was reacted for 5 hours and acetic acid was added to pH 7. The reaction solution was extracted with ethyl acetate.
  • Example 25 N-(3-(3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methyl-4-oxo-4,5-dihydro-3H-pyridyl Preparation of oxazo[4,3-d][1,2,3]triazin-7-yl)-3-(dimethylamino)propanamide
  • intermediate compound (I) 2-(acetoxy)-5-(5-methyl-7-nitro-4-oxo-4,5-dihydro-3H-pyridin Zizo[4,3-d][1,2,3]triazin-3-yl)3,4-diacetoxytetrahydrofuran; using general procedure C, from intermediate compound (I) and 5-(acetyloxy) Preparation of intermediate compound (II) 2-(acetoxy)-5-(5-methyl-7-nitro-4-oxo-4,5 by methyl)-2,3,4-triacetoxytetrahydrofuran -Dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)3,4-diacetoxytetrahydrofuran; using general procedure E, from intermediate compound (II
  • the target compound was prepared in an amount of 4.54 g (10 mmol) and a methanol/methanol solution (20 m
  • Example 38 2-((5-Cyclopropyl-3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,5-dihydro-3H -Preparation of pyrazolo[4,3-d][1,2,3]triazin-7-yl)amino)-2-(diethoxyphosphoryl)acetic acid
  • Example 42 N-(5-Cyclopropyl-3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,5-dihydro-3H- Preparation of pyrazolo[4,3-d][1,2,3]triazin-7-yl)-3-(dimethylamino)propanamide
  • Example 48 5-(2-Amino-2-oxoethyl)-3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,5- Preparation of dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-7-carboxylic acid ethyl ester
  • the title compound was prepared from Intermediate Compound (II) 4.70 g (10 mmol) and methanol/methanol sodium solution 20 mL (1 mol/L) using General Method E. The mixture was reacted for 5 hours and acetic acid was added to pH 7. The reaction solution was extracted with ethyl acetate. The crude product was separated by silica gel column chromatography to give the title compound.
  • Example 51 N-(5-(2-Amino-2-oxoethyl)-3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4 ,5-Dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-7-yl)-3-(dimethylamino)propanamide
  • Example 65 2-(Diethoxyphosphoryl)-2-(3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-7- (piperider Preparation of pyridin-1-yl)-3H-pyrazolo[4,3-d][1,2,3]triazin-5(4H)-yl)acetic acid
  • the title compound was prepared from the intermediate compound (II) 3.53 g (10 mmol) and methanol/methanol sodium solution 20 mL (1 mol/L) using General Method E. The mixture was reacted for 5 hours and acetic acid was added to pH 7. The reaction solution was extracted with ethyl acetate. The crude product was separated by silica gel column chromatography to give the title compound.
  • Example 70 7-Cyano-3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-3H-pyrazolo[4,3-d][ Preparation of 1,2,3]triazine-5(4H)-formamidine
  • Example 76 N-(5-Thiocarbamido-3-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,5-dihydro- Preparation of 3H-pyrazolo[4,3-d][1,2,3]triazin-7-yl)-3-(dimethylamino)propanamide
  • Example 102 2-(Bis(isopropylamino)phosphoryl)-2-((5-(7-(ethoxycarbonyl)-5-hydroxy-4-oxo-4,5-dihydro-3H-pyridyl) Preparation of oxazo[4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 103 2-(Bis(isopropylamino)phosphoryl)-2-((3,4-dihydroxy-5-(5-hydroxy-4-oxo-7-propyl-4,5-dihydro) Preparation of -3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • intermediate compound (I) 2-(bis(isopropylamino) from 6-butyryl-1,2,3-triazinyl-4,5(3H,6H)-dione and hydroxyindole by the general method C Phosphoryl)-2-((3,4-diacetoxy-5-(4-butyryl-5,6-dioxo-5,6-dihydro-1,2,3-triazine-1 ( 4H)-yl)tetrahydrofuran-2-yl)methoxy)acetic acid; intermediate compound (II) 2-(bis(isopropylamino)phosphoryl)-prepared from intermediate compound (I) and hydroxyindole using general procedure J 2-((3,4-Diacetoxy-5-(5-hydroxy-4-oxo-7-propyl-4,5-dihydro-3H-pyrazolo[4,3-d][1 , 2,3]triazin-3-yl)tetrahydrofuran-2-yl)meth
  • Example 104 2-((5-(7-Amino-5-hydroxy-4-oxo-4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3]3 Preparation of pyrazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(bis(isopropylamino)phosphoryl)acetic acid
  • Intermediate compound (I) 2-(double) was prepared by the general method C from 5,6-dioxo-1,4,5,6-tetrahydro-1,2,3-triazin-4-carbonitrile and hydroxyindole (isopropylamino)phosphoryl)-2-((3,4-diacetoxy-5-(4-cyano-5,6-dioxo-5,6-dihydro-1,2,3- Triazine-1(4H)-yl)tetrahydrofuran-2-yl)methoxy)acetic acid; intermediate compound (II) 2-(bis(isopropylamino) prepared from intermediate compound (I) and hydroxyindole using general procedure J Phosphoryl)-2-((3,4-diacetoxy-5-(7-amino-5-hydroxy-4-oxo-4,5-dihydro-3H-pyrazolo[4,3- d][1,2,3]triazin-3-yl)tetrahydrofuran-2-
  • Example 105 2-(Bis(isopropylamino)phosphoryl)-2-((5-(7-(ethoxycarbonyl)-5-methyl-4-oxo-4,5-dihydro-3H- Preparation of pyrazolo[4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 106 2-(Bis(isopropylamino)phosphoryl)-2-((3,4-dihydroxy-5-(5-methyl-4-oxo-7-propyl-4,5-di) Preparation of hydrogen-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 109 2-(Bis(isopropylamino)phosphoryl)-2-((5-(7-(ethoxycarbonyl))-5-(hydroxymethyl)-4-oxo-4,5-dihydro Preparation of -3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 110 2-(Bis(isopropylamino)phosphoryl)-2-((3,4-dihydroxy-5-(5-(hydroxymethyl)-4-oxo-7-propyl-4, Preparation of 5-dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 111 2-(Bis(isopropylamino)phosphoryl)-2-((5-(5-cyclopropyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrazole) Preparation of [4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 113 2-((5-(7-Amino-5-(2-amino-2-oxoethyl)-4-oxo-4,5-dihydro-3H-pyrazolo[4,3- Preparation of d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(bis(isopropylamino)phosphoryl)acetic acid
  • Example 114 2-(Bis(isopropylamino)phosphoryl)-2-((5-(5-carbamoyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrazole) Preparation of [4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 116 2-((Cyanomethoxy)(isopropylamino)phosphino)-2-((5-(7-(ethoxycarbonyl)-5-hydroxy-4-oxo-4,5- Preparation of dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 117 2-((Cyanomethoxy)(isopropylamino)phosphino)-2-((3,4-dihydroxy-5-(5-hydroxy-4-oxo-7-propyl-) Preparation of 4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 120 2-((Cyanomethoxy)(isopropylamino)phosphino)-2-((3,4-dihydroxy-5-(5-methyl-4-oxo-7-propyl) Preparation of -4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 122 2-((Cyanomethoxy)(isopropylamino)phosphino)-2-((5-(5-cyclopropyl-4-oxo-7-propyl-4,5-di) Preparation of hydrogen-3H-pyrazolo[4,3-d][1,2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 124 2-((5-(5-Mercapto-4-oxo-7-propyl-4,5-dihydro-3H-pyrazolo[4,3-d][1,2, 3] Preparation of triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-((cyanomethoxy)(isopropylamino)phosphino)acetic acid
  • Example 125 2-((5-(5-Thiocarbyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrazolo[4,3-d][1, Preparation of 2,3]triazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-((cyanomethoxy)(isopropylamino)phosphino)acetic acid
  • Example 128 2-((5-(2-Amino-2-oxoethyl)-3-(((1,3-dihydroxypropan-2-yl)oxy)methyl)-4-oxo- Preparation of 4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-7-yl)amino)-2-(diethoxyphosphoryl)acetic acid
  • Example 129 N-(5-(2-Amino-2-oxoethyl)-3-(((1,3-dihydroxypropan-2-yl)oxy)methyl)-4-oxo-4 ,5-Dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-7-yl)-3-(dimethylamino)propanamide
  • Example 140 (5-(5-Mercapto-4-oxo-7-propyl-4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3] Of pyrazin-3-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrotriphosphate
  • Example 150 2-(Bis(isopropylamino)phosphoryl)-2-((5-(7-oxo-1-propyl-1H-[1,2,3]triazolo[4,5 -d][1,2,3] Preparation of triazine-6(7H)-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 154 2-(Bis(isopropylamino)phosphoryl)-2-((5-(7-oxo-3-propyl-3H-[1,2,3]triazolo[4,5 -d][1,2,3] Preparation of triazine-6(7H)-yl)tetrahydrofuran-2-yl)methoxy)acetic acid
  • Example 157 2-(Diethoxyphosphoryl)-2-((5-(hydroxymethyl)-4-oxo-3-(3,4,5-trihydroxy-6-(hydroxymethyl)). Tetrahydro-2H-pyran-2-yl)-4,5-dihydro-3H-pyrazolo[4,3-d][1,2,3]triazin-7-yl)amino)acetic acid preparation
  • 1-methyl-3-propyl-1H-pyrazole was prepared by the general method B from 5-amino-1-methyl-3-propyl-1H-pyrazole-4-carboxamide and sodium nitrite [ 3,4-d][1,2,3]triazin-4(5H)-one; using general methods C and E from 1-methyl-3-propyl-1H-pyrazolo[3,4 -d][1,2,3]triazin-4(5H)-one and 6-(acetoxy)-2,3,4,5-tetraacetoxytetrahydro-2H-pyran to prepare the target compound .
  • Example 165 1-(Hydroxymethyl)-5-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-[1,2 , 3] Preparation of triazolo[4,5-d][1,2,3]triazine-4(5H)-one
  • Example 166 7-carbamoyl-1-oxo-2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2,7- Preparation of dihydro-1H-pyrazolo[4,3-d][1,2,3]triazine-5-carboxylic acid ethyl ester
  • Example Compound 14 5.0 mg of Example Compound 14, 600 mL (95%) of ethanol, 600 mL of 1,2-propanediol and 100 mL of Tween (80) were dissolved, and water for injection was added to a total volume of 5000 mL. The solution was filtered through a 0.22 ⁇ m membrane filter and sterilized at 100 ° C for 30 minutes to obtain 1000 mg of an injection solution of 5 mg/5 mL.
  • Example compound 15 8.0 g, DMSO 50 mL, 1,2-propanediol 100 mL and Tween 80 100 mL were dissolved, and water was added to a total volume of 5000 mL. The solution was filtered through a 0.22 ⁇ m membrane filter and sterilized at 100 ° C for 30 min to obtain an injection dose of 1000 mg of 8 mg/5 mL.
  • the human pancreatic cancer cell line Panc-1, human colorectal cancer cell line HT-29, human lung cancer cell line NCI-H460 and breast cancer cell line MCF7 were selected; the medium was DMEM (Gibco BRL) containing 10% fetal bovine serum ( Gibco BRL) and 2 mM L-glutamine (Gibco BRL).
  • DMEM Gibco BRL
  • Gibco BRL 10% fetal bovine serum
  • the above sample was dissolved in dimethyl sulfoxide (DMSO, Sigma, USA), and then diluted with the medium, and the final concentration of DMSO in the medium was 0.5%. This concentration has been confirmed to be non-cytotoxic, cyclophosphorus.
  • DMSO dimethyl sulfoxide
  • the amide preparation was a positive control (Aldrich, USA, purity > 96%) and was diluted with medium.
  • the cells were dispersed into individual cells and suspended in the above medium containing penicillin (25 U/ml) and streptomycin (25 ⁇ g/ml), and the cells were seeded in 96-well culture plates (Corning Incorporated). After incubating at 37 ° C, air containing 5% CO 2 at a humidity of 100%, the culture solution is discarded, and a culture solution containing a series of concentrated C is added, and each concentrated C is provided with parallel holes. After 48 hours of culture, the culture medium containing the test substance was discarded, and the culture medium containing thioindigo blue (MTT, Sigma) was used.
  • penicillin 25 U/ml
  • streptomycin 25 ⁇ g/ml
  • the final concentration of MTT was 0.5 g/L, and the acidification was continued after 4 hours of incubation. After isopropyl alcohol solution, the purple crystal was completely dissolved after 1 h, and the light density °C (OD) at 570 nm/630 nm was measured by a SK601 type microplate reader (product of Seikagaku Co., Japan), and the cell survival rate was calculated by the following formula:
  • the positive control drug CTX was treated in the same manner as the above test substance.
  • Inhibition of colorectal cancer cell line HT-29 As shown in Table 2, seven test compounds showed anti-proliferative effects on HT29.
  • Example 15 Compound displayed on HT29 value is closely related to the antiproliferative composition of CTX, IC 50 values and 95% confidence limit of 3.92 (1.99-5.46) ⁇ g / mL ( P ⁇ 0.05), CTX the IC 50 value The 95% confidence limit was 2.26 (2.08-4.89) ⁇ g/mL (P ⁇ 0.05); the anti-proliferative effects of compounds 7,89,82 and 135 were relatively weak, and the IC 50 value and 95% confidence limit were 18.81, respectively.
  • Panc-1 pancreatic cancer cells As shown in Table 2, seven kinds of test compounds on Panc-1 show antiproliferative effect of the different, Compound 15 and Compound 11 650 Panc-l value of the IC 95 and The % confidence limits were 2.66 (1.25-3.51) ⁇ g/ml, 2.19 (0.89-3.45) ⁇ g/ml, IC 50 (P ⁇ 0.05), and Compound 7, Compound 82, Compound 89 and Compound 135 were half of pancreatic cancer.
  • Inhibitory concentration (IC 50 ) and 95% confidence limit were 51.32 (48.95-55.51) ⁇ g/ml (P ⁇ 0.05), 10.01 (7.24-12.91) ⁇ g/ml (P ⁇ 0.05), 52.97 (50.20-54.41), respectively. Gg/ml and 53.45 (45.32-58.67) ⁇ g/ml (P ⁇ 0.05).
  • Inhibition of breast cancer cell MCF7 As shown in Table 2, the IC 50 and 95% confidence limits of the test compound, compound 15, compound 82, compound 89, compound 116 and compound 135 on breast cancer MCF7 cells, respectively The IC 50 of the positive control CTX was 6.18 (3.42-8.03), 2.73 (1.21-4.02), 34.33 (30.54-40.78), 67.45 (58.89-79.51), 12.94 (9.78-15.13) and 5.70 (4.22-6.96). And 95% confidence limit was 0.92 (0.03-2.02) ⁇ g / mL, MCF7 cells were sensitive to compound 15, IC 50 (P ⁇ 0.05).
  • test compounds in this test were compound 7, compound 15, compound 82, compound 89, compound 116 and compound 135, and the selected cell lines were colorectal cancer HT-29, pancreatic cancer Panc-1, lung cancer NCI-H460, breast cancer cell line MCF7. After two trials, the results were very reproducible. The results showed that colorectal cancer and pancreatic cancer cells were sensitive to this compound, and compound 15 and compound 116 had stronger inhibitory effects on colorectal cancer and pancreatic cancer.
  • Test sample Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 20, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31 Compound 32, Compound 36, Compound 40, Compound 48, Compound 49, Compound 50, Compound 54, Compound 55, Compound 56, Compound 58, Compound 59, Compound 60, Compound 61, Compound 68, Compound 70, Compound 72, Compound 73.
  • Test animals Kunming healthy mice, weighing 19-21 g, divided into male and female, 10 in each group, provided by the Animal Center of the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
  • Tumor strain mouse sarcoma S 180 is a type of ascites, derived from the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
  • tumor animal model aseptically aspirated 7-day sarcoma S 180 passaged mice ascites, diluted with physiological saline to a tumor cell suspension with a density of 4 ⁇ 10 7 cell ⁇ ml -1 , 0.2 ml per mouse Inoculated in the right forelimb of the right axilla, 7 days after inoculation, a relatively uniform tumor was grown in the right axilla of the modeled mice, which was successful in modeling. To ensure the viability of the inoculated cells, the cell suspension was placed during the experiment. In an ice-containing beaker, the entire molding process was completed in 230 minutes.
  • mice 24 h after inoculation were randomly divided into group control group, positive drug cyclophosphamide (CTX) control group 15 mg/kg, paclitaxel 20 mg/kg; the dose of each compound is shown in Table 3, and each group of animals was administered once a day. After 7 days of continuous administration, the tumor mice were sacrificed the next day, the tumor pieces were removed, the weight of the mice and the tumor mass were weighed, and the tumor inhibition rate and body weight change were calculated.
  • CTX positive drug cyclophosphamide
  • Example compound Mode of administration Mg/kg Tumor inhibition rate (%) Blank control - - CTX Iv 15 ++ Paclitaxel Ip 20 ++ Compound 14 Iv 12.5 ++ Compound 15 Iv 50 ++ Compound 16 Ip 100 + Compound 17 Iv 25 ++ Compound 18 Ip 200 + Compound 20 Ip 200 + Compound 22 Ip 200 ++ Compound 23 Ip 100 ++ Compound 24 Ip 300 ++ Compound 25 Ip 200 ++ Compound 26 Ip 70 ++ Compound 27 Iv 15 + Compound 28 Iv 20 ++ Compound 29 Iv 15 + Compound 30 Ip 400 ++ Compound 31 Ip 100 ++ Compound 32 Iv 30 ++ Compound 36 Ip 200 ++ Compound 40 Iv 50 + Compound 48 Iv 50 ++ Compound 49 Ip 100 ++ Compound 50 Iv 15 ++ Compound 54 Ip 150 ++ Compound 55 Ip 100 ++ Compound 56 Ip 100 ++ Compound 58 Ip 100 ++ Compound 59 Iv 50 + Compound 60 Iv
  • Table 3 gives in vitro anti-cancer experimental data, especially the compounds 14, 15, 17, 22, 23, 24, 25, 26, 28, 30, 31, 32, 36, 48, 49, 50, 54, The statistical differences were significant at 55, 56, 58, 60, 68, 70, 72, 73, 74, 76, 77, 81, 88, 89, 91, 94, 95, 97, 100, 116, 117, 120 and 135.

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Abstract

Le but de la présente invention est de fournir un composé contenant un analogue de ribavirine dihétérocyclique, un stéréoisomère, un promédicament, un sel pharmaceutiquement acceptable, un sel de composé et/ou un composé solvaté de formule générale structurale suivante (I), et/ou un stéréoisomère, un tautomère, un promédicament, un sel pharmaceutiquement acceptable, un sel de composé et/ou un solvate de celui-ci, qui ont un effet antitumoral ainsi qu'une utilisation.
PCT/CN2018/103763 2017-09-14 2018-09-03 Effet antitumoral et utilisation d'analogue de ribavirine dihétérocyclique WO2019052359A1 (fr)

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