WO2023195529A1 - ウイルス増殖阻害活性を有するウラシル誘導体およびそれらを含有する医薬組成物 - Google Patents

ウイルス増殖阻害活性を有するウラシル誘導体およびそれらを含有する医薬組成物 Download PDF

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WO2023195529A1
WO2023195529A1 PCT/JP2023/014316 JP2023014316W WO2023195529A1 WO 2023195529 A1 WO2023195529 A1 WO 2023195529A1 JP 2023014316 W JP2023014316 W JP 2023014316W WO 2023195529 A1 WO2023195529 A1 WO 2023195529A1
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substituted
unsubstituted
group
compound
aromatic heterocyclic
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PCT/JP2023/014316
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English (en)
French (fr)
Japanese (ja)
Inventor
淳 佐藤
啓允 芝山
啓一朗 平井
佑斗 宇納
彰太 上原
秀爾 米澤
香菜 倉橋
栄一 児嶋
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to CN202311441304.7A priority Critical patent/CN117510472B/zh
Priority to EP23784813.0A priority patent/EP4506342A1/en
Priority to CN202380010896.9A priority patent/CN117203195A/zh
Priority to US18/554,130 priority patent/US12545687B2/en
Priority to JP2023560417A priority patent/JPWO2023195529A1/ja
Publication of WO2023195529A1 publication Critical patent/WO2023195529A1/ja
Anticipated expiration legal-status Critical
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • R 2 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group is a cyclic group or substituted or unsubstituted alkyl;
  • R 3c is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocycl
  • (100) A compound or its compound according to any of the above items (1) to (11), (1') to (11'), (1'') to (12'') and (1''') A pharmaceutical composition for the prevention and/or treatment of coronavirus infection, containing a pharmaceutically acceptable salt.
  • (100') A pharmaceutical composition for the prevention and/or treatment of coronavirus infection, containing the compound described in item (13'') above, its deuterium, or a pharmaceutically acceptable salt thereof.
  • (101) The pharmaceutical composition according to the above item (100) or (100') for preventing and/or treating new coronavirus infection (COVID-19).
  • (102) The pharmaceutical composition according to item (100) or (100') above, for preventing and/or treating infectious diseases caused by SARS-CoV-2.
  • Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
  • Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like.
  • the two-ring aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members.
  • Trialkylsilyl means a group in which three of the above “alkyl” groups are bonded to a silicon atom.
  • the three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and the like.
  • Substituent group D halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ Alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ Alkylsulfanyl which may be substituted with substituent group ⁇ , alkenylsulfanyl which may be substituted with substituent group ⁇ , alkynylsulfanyl which may be substituted with substituent group ⁇ , alkylsulfinyl which may be substituted with substituent group ⁇ , Alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇
  • substituents for the "substituted or unsubstituted aromatic heterocyclic group" in R 2 include: halogen; Substituted alkyl (as a substituent, halogen; may be substituted with one or more groups selected from these); can be mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted or unsubstituted aromatic carbocyclic oxy" in R 3c and R 3 include: halogen; substituted or unsubstituted alkyloxy; can be mentioned. It may be substituted with one or more groups selected from these.
  • substituents for the "substituted or unsubstituted non-aromatic heterocyclic group" in R 1 include: halogen; Oxo; Substituted alkyl (as a substituent, halogen; may be substituted with one or more groups selected from these); unsubstituted alkyl; can be mentioned. It may be substituted with one or more groups selected from these.
  • substituents of "substituted or unsubstituted carbamoyl” and “substituted or unsubstituted amino" in R 1 include substituted alkyl (halogen as a substituent); unsubstituted alkyl; It may be substituted with one or more groups selected from these.
  • Substituents for "substituted or unsubstituted alkyl" in R 4a and R 4b include, for example, halogen; oxo; substituted alkyl (substituents include halogen; ); unsubstituted alkyl; can be mentioned. It may be substituted with one or more groups selected from these.
  • R 2 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group Examples include cyclic groups (hereinafter referred to as D-1).
  • R 2 is an aromatic carbocyclic group substituted or unsubstituted with substituent group G, a non-aromatic carbocyclic group substituted or unsubstituted with substituent group G, or substituted with substituent group G; (hereinafter referred to as D-20).
  • R 2 examples include a 6-membered aromatic carbocyclic group substituted with 1, 2 or 3 substituents selected from substituent group G' or unsubstituted (hereinafter referred to as D-8) .
  • Substituent group G' halogen, haloalkyl and cyano.
  • Examples of R 2 include a 6-membered aromatic carbocyclic group substituted with one or two substituents selected from substituent group G or unsubstituted (hereinafter referred to as D-9).
  • D-10 6-membered aromatic carbocyclic group substituted with one or two substituents selected from substituent group G
  • R 1 is a 5- to 9-membered aromatic heterocyclic group substituted or unsubstituted with substituent group ⁇ 1 or a 5- to 9-membered non-aromatic heterocyclic group substituted or unsubstituted with substituent group ⁇ 2; (hereinafter referred to as H-7).
  • R 1 include a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group or a substituted or unsubstituted 6-membered non-aromatic heterocyclic group (hereinafter referred to as H-8).
  • R 5a each independently represents a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as K-1). Each R 5a independently includes a hydrogen atom (hereinafter referred to as K-2).
  • R 5b each independently represents a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as L-1).
  • R 5b each independently includes a hydrogen atom (hereinafter referred to as L-2).
  • R 7a and R 7b are each independently a hydrogen atom, halogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxycarbonyl; or R 7a and R 7b taken together with the bonding carbon atom may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as O-1).
  • R 7a and R 7b each independently include a hydrogen atom, halogen, carboxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkyloxycarbonyl (hereinafter referred to as O-2).
  • ring A is the following formula: (In the formula, each symbol has the same meaning as above), X is a single bond, -CR 4a R 4b - or -O-, and R 3 is a non-aromatic heterocyclic group, an aromatic carbon When it is ring oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, amino or alkyloxy (In the formula, Hal is a halogen (chlorine atom, bromine atom, iodine atom, etc.), Alk is a C1-C3 alkyl, Lg is a leaving group, and other symbols have the same meanings as above) (1st step) Compound (A-1) in the presence of methanol, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, DMF, etc.
  • phosphine ligands examples include Xantphos, P(2-furyl) 3 , PPh 3 , P(o-tol) 3 , P(OPh) 3 , P(OMe) 3 , dppp, dppb, dppf, dtbpf, BINAP, X-Phos, P(t-Bu) 3 , P(Oi-Pr) 3 , P(p-MeOPh) 3 or DPEPhos, etc. can be used.
  • As the solvent 1,4-dioxane, tetrahydrofuran, water, etc. can be used.
  • the reaction temperature may range from room temperature to a temperature at which the solvent refluxes, preferably under heating to reflux.
  • Compound (IE) can be produced by reacting compound (E-3) and compound (A-5) in the same manner as the third step of method A above.
  • Compound (H-10) is treated with an acid such as trifluoroacetic acid or trifluoromethanesulfonic acid at 0°C to 120°C, preferably 80°C to 120°C, for 0.1 to 24 hours, preferably 4 hours to Compound (H-11) can be produced by reacting for 6 hours.
  • Anisole or the like may be added as an additive.
  • Step 4 Synthesis of Compound 13
  • Compound 12 (523 mg, 2.20 mmol) was suspended in DMF (5.2 mL), and potassium carbonate (912 mg, 6.60 mmol) and 2-bromoacetonitrile (440 ⁇ L, 6.60 mmol) were added. and stirred at room temperature for 20 hours.
  • the reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. The solid was filtered off, dried under reduced pressure, and purified by silica gel column chromatography (ethyl acetate 100%) to obtain Compound 13 (89 mg, 0.321 mmol, yield 14.6%).

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US12091420B2 (en) 2022-08-05 2024-09-17 Gilead Sciences, Inc. SARS-COV2 main protease inhibitors
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WO2025074997A1 (ja) * 2023-10-02 2025-04-10 塩野義製薬株式会社 ウイルス増殖阻害活性を有する縮合複素環誘導体およびそれらを含有する医薬組成物
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