WO2017088730A1 - Composé contenant une silicone pour résister à une infection par le virus de l'hépatite c - Google Patents

Composé contenant une silicone pour résister à une infection par le virus de l'hépatite c Download PDF

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Publication number
WO2017088730A1
WO2017088730A1 PCT/CN2016/106781 CN2016106781W WO2017088730A1 WO 2017088730 A1 WO2017088730 A1 WO 2017088730A1 CN 2016106781 W CN2016106781 W CN 2016106781W WO 2017088730 A1 WO2017088730 A1 WO 2017088730A1
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Prior art keywords
compound
formula
bis
phenyl
independently selected
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PCT/CN2016/106781
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English (en)
Chinese (zh)
Inventor
张寅生
刘保民
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正大天晴药业集团股份有限公司
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Publication of WO2017088730A1 publication Critical patent/WO2017088730A1/fr

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    • 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
    • A61K31/695—Silicon compounds
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present application belongs to the field of medicinal chemistry, and in particular to a silicon-containing compound for use against hepatitis C virus infection, a process for the preparation thereof, and a pharmaceutical composition containing the same.
  • the application also relates to the use of these compounds and pharmaceutical compositions for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • HCV is a positive-strand RNA virus belonging to the genus Hepatitis C in the Flaviviridae family. At least six major genotypes have been identified, including more than 50 subtypes.
  • the single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of approximately 3000 amino acids. In infected cells, the polyprotein is cleaved by cellular and viral proteases at multiple sites, resulting in both structural and non-structural (NS) proteins. In the case of HCV, the formation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B) is achieved by two viral proteases.
  • Treatment options for chronic HCV infection include: peginterferon- ⁇ combined with ribavirin in the treatment of HCV-infected patients and patients with cirrhosis, if the treatment fails, the interferon-containing treatment regimen is used again, and the sustained virological response rate will be As low as 14%, in addition, interferon-containing treatment regimens have increased toxic side effects in patients with cirrhosis; treatment with peginterferon- ⁇ , ribavirin and telaprevir or boceprevir may lead to serious deaths including death Complications, this program is not suitable for patients with cirrhosis with platelet count ⁇ 100000/ml and albumin level ⁇ 35g/L. Therefore, there is a need for a direct acting antiviral combination regimen that does not contain interferon to improve the efficacy and safety of patients with cirrhosis who are treated for HCV infection.
  • Ombitasvir (ABT-267) is an HCV NS5A protease inhibitor and a number of HCV NS5A inhibitors similar in structure to ABT-267 are currently under development.
  • the present application specifically selects ombitasvir as the mother nucleus to obtain a more excellent compound against hepatitis C virus infection.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof:
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, alkyl or aryl;
  • X is selected from -C(R 6 R 7 )- or -Si(R 6 R 7 )-;
  • Y is selected from -C(R' 6 R' 7 )- or -Si(R' 6 R' 7 )-;
  • R 4 is selected from -C(R 8 R 9 R 10 ) or -Si(R 8 R 9 R 10 );
  • R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 );
  • R 6 , R 7 , R' 6 and R' 7 are each independently selected from hydrogen or C 1-6 alkyl;
  • R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, and one or more A pharmaceutically acceptable carrier.
  • the application provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, for use in the manufacture of a medicament for the treatment of hepatitis C virus infection .
  • the present application provides the use of the above pharmaceutical composition for the manufacture of a medicament for the treatment of hepatitis C virus infection.
  • the application provides a method of treating a hepatitis C virus infection, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a pharmaceutically acceptable salt thereof A drug or a stereoisomer and a mixture thereof or a pharmaceutical composition as described above.
  • the application provides a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, for use in the treatment of hepatitis C virus infection, and combinations of the foregoing Things.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, alkyl or aryl;
  • X is selected from -C(R 6 R 7 )- or -Si(R 6 R 7 )-;
  • Y is selected from -C(R' 6 R' 7 )- or -Si(R' 6 R' 7 )-;
  • R 4 is selected from -C(R 8 R 9 R 10 ) or -Si(R 8 R 9 R 10 );
  • R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 );
  • R 6 , R 7 , R' 6 and R' 7 are each independently selected from hydrogen or C 1-6 alkyl;
  • R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the relative stereochemistry of the 2 and 5 positions of the pyrrole ring (where N is the 1 position) to which the three benzene rings are directly attached may be cis or trans.
  • the 2- and 5-position configurations on the pyrrole ring include (2S, 5S), (2S, 5R), (2R, 5S), (2R, 5R).
  • the compound of formula I may be a stereoisomer or a mixture of two or more stereoisomers in any ratio.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl. In the above embodiment, R 1 , R 2 and R 3 may be the same or different, and different cases include that all three are different and the two are different. For example, in the case where the two are different, R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • X is selected from -C (R 6 R 7) -
  • Y is selected from -C (R '6 R' 7 ) - or -Si (R '6 R' 7 ) -.
  • X is selected from -Si (R 6 R 7) -
  • Y is selected from -C (R '6 R' 7 ) - or -Si (R '6 R' 7 ) -.
  • R 4 is selected from -C(R 8 R 9 R 10 ), and R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ). In some embodiments, R 4 is selected from -Si(R 8 R 9 R 10 ); R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ).
  • R 6 , R 7 , R′ 6 and R′ 7 are each independently selected from hydrogen or C 1-4 alkyl. In some embodiments, R 6 , R 7 , R′ 6 and R′ 7 are each independently selected from hydrogen, methyl or ethyl. In the above embodiment, R 6 and R 7 may be the same or different, and R' 6 and R' 7 may be the same or different.
  • R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, methyl, ethyl, methoxy or ethoxy. In the above embodiment, R 8 , R 9 and R 10 may be the same or different, and R' 8 , R' 9 and R' 10 may be the same or different.
  • X and Y are both -CH 2 -; or X and Y are both -Si (CH 3) 2 -.
  • X is different from Y, for example, X is -Si(CH 3 ) 2 -, Y is -CH 2 -; or X is -CH 2 -; Y is -Si(CH 3 ) 2 -.
  • R 4 and R 5 are the same, for example, R 4 and R 5 are both -CH(CH 3 ) 2 ; or both -Si(CH 3 ) 3 ; or both -C(CH 3 ) 3 Or both are -CH(CH 3 )(OCH 3 ). In some embodiments, R 4 and R 5 are different, for example, R 4 is —C(CH 3 ) 3 ; R 5 is —CH(CH 3 ) 2 ; or R 4 is —Si(CH 3 ) 3 ; R 5 Is -CH(CH 3 ) 2 .
  • X is the same as Y, for example, at the same time -CH 2 -;
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or -CH (C 1-4) Alkyl)(C 1-4 alkoxy);
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl.
  • X is the same as Y, for example, simultaneously -CH 2 -;
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH (C 1 -4 alkyl)(C 1-4 alkoxy);
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl.
  • X is the same as Y, for example, simultaneously -CH 2 -;
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH (C 1 -4 alkyl)(C 1-4 alkoxy);
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, Isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different. For example, the two are different.
  • R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X and Y are both -CH 2 -;
  • R 4 is -C(C 1-4 alkyl) 3 ;
  • R 5 is -CH(C 1-4 alkyl) 2 or -C(C 1-4 alkyl) 3 ;
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X is -Si(C 1-4 alkyl) 2 -
  • Y is -CH 2 - or -Si(C 1-4 alkyl) 2 -
  • R 4 and R 5 are simultaneously -CH (C 1-4 alkyl) 2
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or benzene base.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X and Y are both -CH 2 -;
  • R 4 is -Si(C 1-4 alkyl) 3 ;
  • R 5 is -CH(C 1-4 alkyl) 2 or -Si(C 1-4 alkyl) 3 ;
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • X and Y are independently selected from -CH 2 - or -Si (CH 3) 2 -;
  • R 4 and R 5 are independently selected from -CH (CH 3) 2, -C (CH 3) 3 , -Si(CH 3 ) 3 or -CH(CH 3 )(OCH 3 );
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and tertiary Butyl, n-butyl, isobutyl or phenyl.
  • X and Y are both -CH 2 -;
  • R 4 and R 5 are both -CH(CH 3 ) 2 , or both -C(CH 3 ) 3 , or both -Si(CH 3 3 or all are -CH(CH 3 )(OCH 3 ); and
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, and Butyl, isobutyl or phenyl.
  • X is -Si(CH 3 ) 2 -; Y is -CH 2 - or -Si(CH 3 ) 2 -; R 4 and R 5 are both -CH(CH 3 ) 2 ; 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • X and Y are both -CH 2 -;
  • R 4 is -C (CH 3) 3 or -Si (CH 3) 3;
  • R 5 is -CH (CH 3) 2; and
  • R 1, R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • the application provides a compound of Formula Ia, Formula Ib, Formula Ic, Formula Id, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • R 1 , R 2 , R 3 , X, Y, R 4 and R 5 in formula Ia, formula Ib, formula Ic and formula Id are as described above for R 1 , R 2 , R 3 , X, Y in formula I
  • the detailed descriptions of R 4 and R 5 are the same.
  • the application provides a compound of Formula II, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, alkyl or aryl;
  • R 4 is selected from -C(R 8 R 9 R 10 ) or -Si(R 8 R 9 R 10 );
  • R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 );
  • R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • the relative stereochemistry of the 2 and 5 positions of the pyrrole ring (where N is 1 position) directly linked to the three benzene rings It is cis or trans.
  • the 2- and 5-position configurations on the pyrrole ring include (2S, 5S), (2S, 5R), (2R, 5S), (2R, 5R).
  • the compound of formula II may be a stereoisomer or a mixture of two or more stereoisomers in any ratio.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl. In some embodiments, R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl. In the above embodiment, R 1 , R 2 and R 3 may be the same or different, and different cases include that all three are different and the two are different. For example, in the case where the two are different, R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • R 4 is selected from -C(R 8 R 9 R 10 ), and R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ). In some embodiments, R 4 is selected from -Si(R 8 R 9 R 10 ); R 5 is selected from -C(R' 8 R' 9 R' 10 ) or -Si(R' 8 R' 9 R' 10 ).
  • R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy. In some embodiments, R 8 , R 9 , R 10 , R′ 8 , R′ 9 and R′ 10 are each independently selected from hydrogen, methyl, ethyl, methoxy or ethoxy. In the above embodiment, R 8 , R 9 and R 10 may be the same or different, and R' 8 , R' 9 and R' 10 may be the same or different.
  • R 4 and R 5 are the same, for example, R 4 and R 5 are both -CH(CH 3 ) 2 ; or both -Si(CH 3 ) 3 ; or both -C(CH 3 ) 3 Or both are -CH(CH 3 )(OCH 3 ). In some embodiments, R 4 and R 5 are different, for example, R 4 is —C(CH 3 ) 3 ; R 5 is —CH(CH 3 ) 2 ; or R 4 is —Si(CH 3 ) 3 ; R 5 Is -CH(CH 3 ) 2 .
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH(C 1-4 alkyl)(C 1-4 alkoxy); R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl or C 6-12 aryl. In some specific embodiments, R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH(C 1-4 alkyl)(C 1-4 alkoxy) R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-4 alkyl, phenyl or naphthyl.
  • R 4 and R 5 are the same, for example, both -CH(C 1-4 alkyl) 2 or both -CH(C 1-4 alkyl)(C 1-4 alkoxy)
  • R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different. For example, the two are different.
  • R 1 is the same as R 2 and R 3 is different from R 1 and R 2 .
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • R 4 is -C(C 1-4 alkyl) 3
  • R 5 is -CH(C 1-4 alkyl) 2 or -C(C 1-4 alkyl) 3
  • R 1 R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, tert-butyl or Phenyl.
  • R 4 is -Si(C 1-4 alkyl) 3
  • R 5 is -CH(C 1-4 alkyl) 2 or -Si(C 1-4 alkyl) 3
  • R 1 R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl, isobutyl or phenyl.
  • R 1 , R 2 and R 3 may be the same or different, and the different cases include that the three are different and the two are different.
  • R 1 , R 2 and R 3 are the same, both methyl or all ethyl; or R 1 is the same as R 2 , both methyl or ethyl, and R 3 is isopropyl, t-butyl or Phenyl.
  • R 4 and R 5 are both -CH(CH 3 ) 2 , or both -C(CH 3 ) 3 , or both -Si(CH 3 ) 3 , or both -CH(CH 3 ) (OCH 3 ); and R 1 , R 2 and R 3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl or phenyl.
  • R 4 is -C(CH 3 ) 3 or -Si(CH 3 ) 3
  • R 5 is -CH(CH 3 ) 2
  • R 1 , R 2 and R 3 are each independently selected from Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl or phenyl.
  • the present application provides a compound of Formula IIa, Formula IIb, Formula IIc, Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof,
  • the present application provides the following compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or stereoisomers thereof, and mixtures thereof:
  • Me is a methyl group
  • Et is an ethyl group
  • Ph is a phenyl group
  • t-Bu is a tert-butyl group
  • i-Pr is an isopropyl group.
  • compositions comprising a therapeutically effective amount of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula A compound of IId, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, and one or more pharmaceutically acceptable carriers.
  • compositions of the present application can be prepared by combining a compound of the present application, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, with a suitable pharmaceutically acceptable carrier.
  • a suitable pharmaceutically acceptable carrier for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, Microspheres and aerosols, etc.
  • Typical routes for administration of a compound of the present application, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, Administered by the intestine, or topical, transdermal, inhaled, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers.
  • pharmaceutically acceptable carriers such carriers.
  • These carriers enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules.
  • the core of a tablet or dragee. Suitable accessory package include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compound of the present application comprises a compound having a specific structure having hepatitis C virus (HCV) NS5A inhibitory activity, and can be used as an HCV NS5A inhibitor for the treatment of hepatitis C virus infection, specifically for causing hepatitis C virus infection. Treatment of liver diseases such as hepatitis and cirrhosis.
  • HCV hepatitis C virus
  • the compound of the present application includes a compound having a specific structure having hepatitis C virus (HCV) NS5A inhibitory activity, in particular, having excellent inhibitory activity against various gene subtypes of HCV, and these gene subtypes include 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 6a are preferably 1b, 3a, 4a, 5a, 6a.
  • HCV hepatitis C virus
  • the compounds of the present application including compounds of specific structure, also have excellent pharmacokinetic parameters, including stability in liver microsomes, good half-life and bioavailability, and good liver targeting.
  • the compounds of the present application include anti-HCV viral activity of compounds of specific structure and have significant advantages in terms of pharmacokinetics compared to ombitasvir; compounds of the present application include inhibitory activities of compounds of specific structure on various genetic subtypes of HCV and Compared with ombitasvir, it has significant advantages.
  • the present application provides a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate thereof, Use of prodrugs or stereoisomers and mixtures thereof for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present application provides a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate thereof, Use of prodrugs or stereoisomers and mixtures thereof with at least one other active compound for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present application provides a compound comprising Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • a pharmaceutical composition of a prodrug or a stereoisomer and a mixture thereof for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • the present application provides a compound comprising Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, or solvate thereof
  • a pharmaceutical composition of a prodrug or a stereoisomer and a mixture thereof with at least one other active compound for the manufacture of a medicament for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • other active compounds include, but are not limited to, other compounds that are resistant to HCV activity.
  • other active compounds include, but are not limited to, immunomodulatory agents and other antiviral agents.
  • other active compounds include, but are not limited to, interferon or ribavirin, wherein the interferon is selected from the group consisting of interferon alpha 2B, PEGylation Interferon alpha, complex interferon (consensus interferon), interferon alpha 2A, and lymphoblastin interferon tau.
  • other active compounds include, but are not limited to, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of a type 1 helper T cell response, interfering RNA, antisense RNA, Imiqimod, Baverin, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
  • other active compounds are effective to inhibit the function of a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV Entry, HCV assembly, HCV release, HCV NS5A protein and IMPDH.
  • a target selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV Entry, HCV assembly, HCV release, HCV NS5A protein and IMPDH.
  • the HCV includes a plurality of genotypes thereof and a plurality of gene subtypes, such as 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 6a.
  • the application provides a method of treating a hepatitis C virus infection, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or a compound of Formula IIc or Formula IId, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, and mixtures thereof.
  • the therapeutically effective amount of the prodrug or stereoisomer and mixtures thereof is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId is determined by the needs of the individual patient, for example, once or twice per day, Or more times a day.
  • Administration can be intermittent, for example, wherein during a period of several days, the patient receives Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId A daily dose of the compound, followed by a period of several days or more, the patient does not receive Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId The daily dose of the compound.
  • the present application provides a compound of Formula I or Formula Ia or Formula Ib or Formula Ic or Formula Id or Formula II or Formula IIa or Formula IIb or Formula IIc or Formula IId for use in the treatment of hepatitis C virus infection or a pharmaceutically acceptable compound thereof Salts, hydrates, solvates, prodrugs or stereoisomers and mixtures thereof, as well as the above pharmaceutical compositions for the treatment of hepatitis C virus infection.
  • Cbz- means a benzyloxycarbonyl group, specifically PhOCO-.
  • EDCI refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.
  • HOBT refers to 1-hydroxybenzotriazole.
  • Ms- nail sulfonyl group, specifically CH 3 SO 2 -.
  • C mn means having mn carbon atoms in this moiety.
  • C1-6 alkyl means that the alkyl group has from 1 to 6 carbon atoms.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • the "alkyl”, “C 1-6 alkyl” or “C 1-4 alkyl” may be unsubstituted or substituted by one or more substituents selected from alkyl, hydroxy, halogen or amino groups. .
  • C1-6 alkoxy refers to an -O-alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkoxy refers to an -O-alkyl group having from 1 to 4 carbon atoms.
  • the "alkoxy”, “C 1-6 alkoxy” or “C 1-4 alkoxy” may be unsubstituted or selected from one or more selected from the group consisting of an alkyl group, a hydroxyl group, a halogen or an amino group. Substituent substitution.
  • aryl refers to an all-carbon monocyclic or polycyclic fused aromatic ring group having a conjugated ⁇ -electron system, preferably having from 6 to 14 carbon atoms, more preferably from 6 to 12 carbon atoms, most It preferably has 6 carbon atoms.
  • a monocyclic aromatic ring group is selected from phenyl
  • a bicyclic fused aromatic ring group consists of a phenyl group fused to a 4-6 membered aromatic or non-aromatic carbocyclic ring including a naphthyl group.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without biologically adverse effects.
  • a pharmaceutically acceptable salt for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned. .
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • hydrate refers to a complex formed by a compound of the present application and a stoichiometric amount of water molecules.
  • solvate refers to a compound comprising a compound of the present application and a stoichiometric amount of one or more pharmaceutically acceptable solvents.
  • a molecular complex of molecules such as ethanol.
  • prodrug refers to a compound obtained by chemically modifying a drug, which has no activity in vitro, and is converted into an original drug in an organism or a human body to exert a pharmacological effect; the original drug (original drug) is referred to as a parent drug, The structurally modified compound is a prodrug.
  • stereoisomer refers to isomers of the same molecular structure of the compound, but which differ in stereostructure, such as enantiomers and diastereomers.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • the compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • the compounds of the present application may contain asymmetrically substituted carbon atoms known as chiral centers. These compounds may, without limitation, be a single stereoisomer (eg, a single enantiomer or a single diastereomer), a mixture of stereoisomers (eg, a mixture of enantiomers or diastereomers). Or in the form of a racemic mixture.
  • Compounds identified herein as single stereoisomers are intended to describe compounds that are substantially free of other stereoisomers. "Substantially free” means that at least 95%, 96%, 97%, 98% or 99% of the compound in the composition is the stereoisomer described.
  • R 4 and R 5 may contain a chiral carbon atom, specifically When R 4 and R 5 are -CH(C 1-4 alkyl)(C 1-4 alkoxy), at least one of the chiral carbon atoms is -C*H(C 1-4 alkyl) (C 1-4 alkoxy), wherein C* is a chiral carbon atom, which may be in the S configuration or the R configuration, respectively, more specifically, R 4 and R 5 are -CH(CH 3 ) (OCH 3 ) When the specific configuration is:
  • stereoisomers of the compounds of the present application can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, enantiomeric enantiomeric conversion of enantiomeric mixtures to diastereomers, and subsequent diastereomeric chromatography. Separation and regeneration of individual enantiomers, as well as enzymatic resolution.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the following Specific embodiments, their implementations in combination with other chemical synthesis methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments include, but are not limited to, embodiments of the present application.
  • reaction materials and reaction reagents of the present application can be obtained by purchase unless otherwise stated.
  • the compounds of formula I of the present application can be prepared by the following general methods in the art: wherein R 1 , R 2 , R 3 , X, Y, R 4 , R 5 , R 6 , R 7 , R' 6 , R' 7 , R 8 , R 9 , R 10 , R' 8 , R' 9 and R' 10 are as defined above.
  • Compound 5 reacts with compound 8 under the action of a base to form compound 9; compound 9 is reacted by reduction (using a catalyst such as platinum oxide) to form compound 10, compound 10 is reacted with amino acid derivative 11 to obtain compound 12; and compound 12 is deprotected from Cbz (The reaction conditions are, for example, under the action of a palladium carbon catalyst and hydrogen to give compound 13; compound 13 is then amidated with amino acid derivative 14 to give a compound of formula I.
  • Compound 5 is reacted with compound 8 under the action of a base to form compound 9; compound 9 is subjected to a reduction reaction (using a catalyst such as platinum oxide) to give compound 10, and compound 10 is reacted with amino acid-derived fragment 15 to give a compound of formula I.
  • a reduction reaction using a catalyst such as platinum oxide
  • the obtained compound 10 is sequentially reacted with the amino acid derivative 11X and the amino acid derivative 11Y to obtain a compound 12, which is then subjected to reduction and amidation to give a compound of the formula I.
  • the obtained compound 13 is sequentially reacted with the amino acid derivative 14-R4 and the amino acid derivative 14-R5 to prepare a compound of the formula I.
  • the obtained compound 10 is sequentially reacted with the amino acid derivative 11X and the amino acid derivative 11Y to obtain the compound 12, which is then subjected to a reduction reaction, and is sequentially amidated with the amino acid derivative 14-R4 and the amino acid derivative 14-R5 to obtain a compound of the formula I. .
  • the compound 10 can be subjected to chromatography to obtain an optically active compound 10a, a compound 10b, and a compound 10c.
  • Compound 1 reacts with Compound 2 under Lewis acid mediated conditions to form Compound 3;
  • Compound 3 can be, for example, boron Reduction of sodium hydride produces compound 4, which reacts with methylsulfonyl chloride to form compound 5 under the action of a base.
  • Compound 5 is a mixture of various configurations comprising 5a (RR), 5b (SS), 5c (SR). It can be synthesized according to the preparation methods reported in the literature (J. Med. Chem, 2014, 57, 2047-2057; Synthesis, 2009, 1739-1743; Synthesis, 2000, 1259-1262).
  • Compound 5 can be subjected to chiral column chromatography to give optically active compound 5a, compound 5b, and compound 5c.
  • the preparation method of the intermediate compound 8 is as follows:
  • the synthesis of the silicon-containing aniline compound 8 can be carried out according to the preparation method reported in the literature (Journal of Organic Chemistry, 73 (17), 2008, 6671-6678). Different methods may use different silane derivatives such as Me 3 SiMe 3 , Et 3 SiH, Me 3 SiCl, Et 3 SiCl, Me 2 EtSiCl, Me 2 PhSiH, Me 2 PhSiCl and the like, which are commercially available.
  • Intermediate 11 (including 11X and 11Y) can be prepared according to methods reported in the literature.
  • the intermediate 11 containing silicon can be obtained by a method reported in the literature (Eur. J. Org. Chem. 2000, 8072811 J. Am. Chem. Soc. 2006, 128, 8479-8483), (ICH 2 ) 2 Si (R) 6 R 7 ) can be obtained, for example, from the purchase of Aldrich.
  • Intermediate 14 (including 14-R4 and 14-R5) can be prepared according to methods reported in the literature.
  • the intermediate 14 containing silicon can be reported in the literature (Tetrahedron, 61(1), 43-50; 2005, Angew. Chem. Int. ed. 2009, 39, 2288-2290).
  • the method is then obtained by further chiral separation. Examples are as follows:
  • the starting material compound 21 and other silane analogs which are differently substituted on the silicon atom can be obtained, for example, from Aldrich.
  • the intermediate 25 may be purchased or obtained by a method disclosed in the literature, or may be obtained by removing the protecting group from the intermediate 11.
  • the present application also provides a process for the preparation of the compounds of Formula Ia, Formula Ib, Formula Ic, and Formula Id.
  • the compounds of the formula Ia, the formula Ib, the formula Ic and the formula Id of different configurations can be obtained directly by chromatography column chromatography.
  • the compound of the formula Ia, the formula Ib, the formula Ic and the formula Id can be further synthesized by the optically active compound 10a, the compound 10b, and the compound 10c, respectively, in a similar manner to the above-mentioned preparation of the compound of the formula I.
  • the compound of the formula Ia, the formula Ib, the formula Ic and the formula Id can be further synthesized by the optically active compound 5a, the compound 5b, and the compound 5c, respectively, in a similar manner to the above-mentioned preparation of the compound of the formula I.
  • a mixture of the optically active compound 10a and the compound 10b may be isolated to obtain a mixture of the compound of the formula Ia and the compound of the formula Ib, which is then chromatographed to obtain a compound of the formula Ia of different configuration but of the same structure, formula Ib.
  • Compound. Methods of preparation of such similar means are included within the scope of the present application.
  • the compound of formula Ic is prepared using compound 10c or compound 5c, which will first give the cis configuration of the compound of formula I, which can be further isolated to give a compound of formula Ic, formula Id.
  • the corresponding compound of formula II (compound of formula IIa, formula IIb, formula IIc, formula IId) can be prepared according to the process for the preparation of a compound of formula I (compounds of formula Ia, formula Ib, formula Ic, formula Id).
  • a mixture of trans isomers 10a (SS) and 10b (RR) is reacted with amino acid derivative 11 to obtain a mixture of 12a (SS) and 12b (RR); a mixture of 12a (SS) and 12b (RR) is Removal of Cbz protecting group by palladium-carbon catalyst and hydrogen to obtain a mixture of 13a (SS) and 13b (RR); 13a (SS), 13b (RR) and amidation of amino acid derivative 14 to obtain a mixture of Ia and Ib Ia and Ib can be separated by column chromatography to obtain a compound of a single configuration of Ia and Ib.
  • Nuclear magnetic resonance chromatography was measured using a Varian VNMR S-400 nuclear magnetic resonance spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18, Mm, 5 microns, 35 ° C), using ESI (+) ion mode.
  • THF refers to tetrahydrofuran.
  • DCM dichloromethane.
  • DMSO means dimethyl sulfoxide.
  • DIPEA means N,N-diisopropylethylamine.
  • DMF means N,N-dimethylformamide.
  • MOC-L-proline means N-(methoxycarbonyl)-L-proline.
  • Room temperature means that the reaction temperature is between 25 and 30 °C.
  • Step 1 Add p-chloronitrobenzene (30 g, 190.4 mmol), hexamethyldisilane (119.57 g, 86.82 mmol), tetrakis-(triphenylphosphine)palladium (8.8 g, 7.616 mmol) to a pressure tube. The reaction was stirred at 170 ° C under a nitrogen atmosphere with xylene (90 mL). After 7 hours, the reaction was completed, and the reaction mixture was cooled to room temperature, then celite was filtered, and the filtrate was concentrated to give trimethyl(4-nitrophenyl)-silane (32 g).
  • Step 2 Add trimethyl(4-nitrophenyl)-silane (32 g, 163.86 mmol), absolute ethanol (500 mL), 10% Pd/C (4.78 g, 4.5 mmol) in a single-neck flask, and pass nitrogen. The substitution was carried out 3 times, the hydrogen was replaced 3 times to remove the air, and the reaction was carried out at room temperature overnight under a hydrogen pressure of 1 atm. After the completion of the reaction, the reaction mixture was filtered with EtOAc EtOAc (EtOAc)EtOAc.
  • Step 1 Toluene (300 mL), anhydrous zinc chloride (54.6 g, 0.4 mol) were added to a three-necked flask, and the reaction was stirred at room temperature under nitrogen atmosphere, then triethylamine (32 mL) and tert-butanol (28 mL) were slowly added. Stirring was continued for 1.5 hours at room temperature. Then, 2-bromo-4-nitroacetophenone (48.8 g, 0.2 mol) and 4-nitroacetophenone (49.6 g, 0.3 mol) were further added, and stirred at room temperature overnight.
  • Step 2 Add 1,4-bis-(4-nitrophenyl)butane-1,4-dione (30 g, 91.39 mmol) and THF (500 mL) in a one-neck flask, under nitrogen, at 0 ° C Sodium borohydride (10.72 g, 283.3 mmol) was added, and after reacting for 30 minutes, the mixture was heated to 60 ° C to react overnight. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with water, and the mixture was washed with water, and then the mixture was added with 500 ml of water, and the mixture was extracted with ethyl acetate. (4-Nitrophenyl)butane-1,4-diol (13.2 g), a mixture of three configurations of SS, RR, and SR.
  • Step 3 Add a mixture of three configurations of SS, RR, SR of 1,4-bis(4-nitrophenyl)butane-1,4-diol in a three-necked flask (13 g, 39.12 mmol), DCM (300 mL), triethylamine (16.31 mL, 117.36 mmol) was added dropwise at 0 ° C under nitrogen atmosphere. After stirring, stirring was continued for 20 minutes, then methanesulfonyl chloride (7.57 mL, 97.8 mmol) was slowly added dropwise. The reaction was continued for 2.5 hours to 3.5 hours after completion.
  • Butane-1,4-disubstituted dimethoyl ester (10.5 g) is a mixture of three configurations of SS, RR, SR.
  • Step 1 Add sodium hydroxide (2.4 g, 60.08 mmol) to 60 mL water, then add O-methyl-L-threonine (8.0 g, 60.08 mmol) and sodium carbonate (3.30 g, 31.2 mmol), 0 ° C Stirring to dissolve the solid, the solution became clarified and then became turbid. Methyl chloroformate (8.48g, 90.12mmol) was slowly added to the reaction solution. After the addition was completed, it was moved to room temperature overnight. After the reaction, the ice water bath was cooled.
  • Step 2 Add (2S,3R)-3-methoxy-2-((methoxy)amino)butyric acid (11.5 g, 60.15 mmol) to 150 mL of ethyl acetate and then add N-hydroxysuccinyl Imine (6.92g, 60.15mmol), stirred at 0 ° C, solid dissolved, diisopropylcarbodiimide (7.59g, 60.15mmol) was slowly added to the reaction solution, resulting in white turbidity, after the end of the addition, 0 ° C After stirring for 1 hour, the reaction mixture was allowed to react to room temperature overnight.
  • Step 3 L-valine (4.98 g, 43.37 mmol) was added to a mixed solvent of 40 mL of water and 40 mL of acetonitrile, then N,N-diisopropylethylamine (10.68 g, 82.60 mmol) was added and stirred at room temperature The solid was dissolved by (2S,3R)-2,5-dioxopyrrolidin-1-yl-3-methoxy-2-((methoxy)amino)butyrate (11.90 g, 41.30 mmol Dissolved in 40 mL of acetonitrile, and then slowly added to the above reaction solution.
  • Example 1 Dimethyl((2S,2'S)-((2S,2'S)-2,2'-((((2S,5S)-1-(4-(trimethylsilyl))phenyl) Pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl)) bis ( 3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ia-1)
  • Step 1 Add a mixture of 1,4-bis(4-nitrophenyl)butane-1,4-disubstituted dimesyl ester SS, RR, SR in a three-necked flask (4.5 g, 9.2mmol), DMF (24mL), triethylamine (9.32g, 92.1mmol), the mixture was heated to 60 ° C under nitrogen, then slowly added trimethylsilylaniline (10.66g, 64.47mmol), and the reaction was stirred overnight. . After completion of the reaction, the reaction mixture was cooled, and then added with 50 mL of water and ethyl acetate.
  • Step 2 Add 2,5-bis-(4-nitro-phenyl)-1-(4-trimethylsilyl-phenyl)-pyrrolidine SS, RR, SR to the autoclave.
  • the celite was filtered, and the filter cake was washed with dichloromethane.
  • Step 3 Add 4,4'-(1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine trans isomer SS, RR in a single vial Mixture (450 mg, 1.12 mmol), DMF (15 mL), N-benzyloxycarbonyl-L-valine (1.34 g, 5.6 mmol), EDCI (869.34mg, 5.6mmol), HOBT (756.67mg, 5.6mmol) N-methylmorpholine (566.44 mg, 5.6 mmol) was stirred at room temperature under nitrogen overnight.
  • Step 4 Add (2S,2'S)-dibenzyl-2,2'-((((2S,5S)-1-(4-(trimethylsilyl)phenyl)pyrrolidine) to the autoclave. 2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) and (2S,2'S)-di Benzyl-2,2'-((((2R,5R)-1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis(4,1- sub) a mixture of phenyl))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate) (790 mg, 0.914 mmol), then ethanol (30 mL), partially dissolved, then added Methanol (5 mL), all solids were dissolved, then 10% anhydrous
  • Step 5 Compound (Ia-1) and Compound (Ib-1)
  • Example 2 Dimethyl ((2S, 2S')-((2S, 2S')-2, 2'-((((2S,5R)-1-(4-(trimethylsilyl)) Phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1-diyl) )) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ic-1)
  • Step 1 (2S, 2'S)-dibenzyl-2,2'-((((2S,5R)-1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5- Diyl) bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate)
  • Step 2 (2S,2'S)-N,N'-(((2S,5R)-1-(4-(Trimethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis (4 , 1-phenylene)) bis(pyrrolidine-2-carboxamide)
  • Example 3 dimethyl ((2S, 2S')-((2S, 2S')-2, 2'-(((((2S,5S)-1-(4-(triethylsilyl))) Phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1-diyl) )) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ia-2)
  • Step 1 Referring to Step 1 in Example 1, trimethylsilylaniline was replaced with triethylsilylaniline (13.37 g, 64.47 mmol) to give 2,5-bis-(4-nitro-phenyl)- A mixture of three configurations of 1-(4-triethylsilyl-phenyl)-pyrrolidine SS, RR, SR. HRMS (ESI) m/z 504.2312 (M+H) + .
  • Step 2 Referring to Step 2 in Example 1, 4,4'-(1-(4-(trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine is trans isomerized. Bulk SS, RR mixture (850 mg), cis single isomer SR (1.0 g).
  • step 5 of Example 1 a mixture of Ia-2 and Ib-2 was obtained, a total of 490 mg, and the ratio of the two isomers was 1:1.
  • the two isomers were separated on a C-18 column, and Ia-2 was isolated first, and then Ib-2 was isolated.
  • Example 4 dimethyl ((2S, 2S')-((2S, 2S')-2, 2'-((((2S,5R)-1-(4-(triethylsilyl))) Phenyl) Pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1-diyl)) double (3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ic--2)
  • Step 1 (2S,2'S)-dibenzyl-2,2'-((((2S,5R)-1-(4-(triethylsilyl)phenyl)pyrrolidine-2,5- Diyl) bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-1-carboxylate)
  • Step 2 (2S, 2'S)-N,N'-(((2S,5R)-1-(4-(Triethylsilyl)phenyl)pyrrolidine-2,5-diyl) bis (4 , 1-phenylene)) bis(pyrrolidine-2-carboxamide)
  • Example 5 Dimethyl((2S,2S')-((2S,2S')-2,2'-(((((2S,5S)-1-(4-(tert-butyldimethyl)) Silyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1 -diyl)) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ia-3)
  • step 1
  • (2S, 2'S)-N,N'-((2S,5S)-1-(4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2 was obtained.
  • 2,5-diyl)bis(4,1-phenylene))bis(pyrrolidine-2-carboxamide) and (2S,2'S)-N,N'-((2R,5R)-1-( a mixture of 4-(tert-butyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene)bis(pyrrolidine-2-carboxamide) 350mg.
  • Step 5 Compound (Ia-3) and Compound (Ib-3)
  • a mixture of Ia-3 and Ib-3 was obtained in a total of 350 mg, and the ratio of the two isomers was 1:1.
  • the two isomers were separated by a C-18 column, and Ia-3 was isolated and then separated to obtain Ib-3.
  • Example 6 Dimethyl((2S,2S')-((2S,2S')-2,2'-(((((2S,5R)-1-(4-(tert-butyldimethyl)) Silyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1 -diyl)) bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (Ic-3)
  • step 1
  • Example 7 Dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2S,5S))) Ethylsilyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2 ,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-15)
  • step 1
  • Example 8 dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2), 5S)) Butyl dimethyl Silyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2,1 -diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-16)
  • Step 1 (2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-tert-butyldimethylsilyl-phenyl)-pyrrolidine
  • Example 9 dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2), 5S)) Dimethylsilyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl) -2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-17)
  • Step 1 (2S,5S)-2,5-bis-(4-nitro-phenyl)-1-(4-ethyldimethylsilyl-phenyl)-pyrrolidine
  • Step 2 4,4'-((2S,5S)-1-(4-(ethyldimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine
  • Example 10 dimethyl ((2S, 2S', 3R, 3R')-((2S, 2S')-2, 2'-(((((2S,5S)-1-(4-(3) Methylsilyl)phenyl)pyrrolidinyl-2,5-diyl)bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidinyl-2 ,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl))dicarbamate (Ia-18)
  • Step 2 4,4'-((2S,5S)-1-(4-(Trimethylsilyl)phenyl)pyrrolidine-2,5-diyl)diphenylamine
  • Example 11 In vitro drug efficacy test and cytotoxicity test
  • the Huh7 cell line is stably transferred into the HCV genotype 1a replicon or the 1b replicon.
  • Test compound 10 mM mother liquor prepared with 100% DMSO was temporarily stored in a nitrogen cabinet, and the compound list is shown in Table 2.
  • the compound DMSO stock solution was diluted according to the dilution information of the compound of Table 2 and added to a 96-well experimental plate at a final concentration of 0.5% DMSO.
  • HCV 1a replicon cells or 1b replicon cells were seeded in the above 96-well cell plates, followed by incubation at 37 ° C for 3 days in a 5% CO 2 incubator.
  • the cell viability test can be carried out by adding a cell growth fluorescent titration detection reagent to each well. After incubating the cells for 1 hour at 37 ° C in a 5% CO 2 incubator, the Luminescence signal value is detected by a spectrophotometer detection system Envision, and the raw data is used for the calculation of the compound cytotoxicity. .
  • the inhibitory effect of the compound of the present application on HCV replication can be determined by measuring the activity of the luciferase reporter gene. The luciferase luminescent substrate Bright-Glo was added to each well, and the Luminescence signal value was detected within 5 minutes using the chemiluminescence detection system Envision. The raw data was used for the calculation of the compound inhibitory activity.
  • the raw data is processed as a percentage of cell viability using the following formula:
  • the raw data is processed as a percent inhibition using the following formula:
  • CPD represents the signal value of the compound pore
  • HPE Haundred percent effect
  • ZPE Zero percent effect
  • CPD represents the signal value of the compound pore
  • HPE Haundred percent effect
  • HPE 100% effective control well signal value, only DMEM medium in the well
  • ZPE Zero percent effect
  • the percentage of cell viability, the percent inhibition were introduced into GraphPad Prism software for data processing and the curve corresponding compound derived cytotoxicity (CC 50) and the replicon inhibitory activity against HCV (EC 50) values.
  • Ic-1 >1 0.008 nM 4
  • Ia-2 >1 0.003 nM 5
  • Ib-2 >1 0.006 nM 6
  • Ic-2 >1 0.007 nM 7
  • Ia-3 >1 0.003 nM
  • Example 12 Inhibitory activity of HCV different genotype NS5A chimeric replicon and determination of anti-infective disease hepatitis virus (HCVcc, JFH-1, GT2a) activity
  • DMEM cell culture solution Invitrogen Fetal bovine serum Corning L-glutamine Invitrogen Penicillin-streptomycin Invitrogen Phosphate buffer Corning Trypsin Invitrogen Dimethyl sulfoxide (DMSO) Sigma Plasmid extraction kit Qiagen SpeI-HF enzyme NEB PCR product purification kit Qiagen In vitro transcription kit Promega RNA purification kit Qiagen DEPC treatment of water Invitrogen Phosphate buffer PBS pH 7.4 (Ca2+Mg2+free) Invitrogen Bright-Glo detection reagent Promega
  • the HCV replicon RNA was transiently transfected into huh7 cells by electroporation; the cells were then seeded into 96-well plates (10,000 cells/well), and then placed in a 37 ° C, 5% CO 2 incubator. 3 days.
  • Anti-HCV replicon activity assay The luciferase luminescent substrate Bright-Glo was added to each well, and the Luminescence signal value was detected by the chemiluminescence detection system Envision within 5 minutes. The raw data (RLU) was used for the calculation of the compound inhibitory activity.
  • CPD Signal value of the compound well.
  • HPE 100% effective control well signal value, only DMEM medium in the well.
  • ZPE Zero percent effect: Ineffective control cell signal value, with 0.5% DMSO instead of compound.
  • Huh-7.5.1 cells were seeded into 96-well plates (7,000 cells/well) and subsequently cultured overnight at 37 ° C in a 5% CO 2 incubator.
  • HCVcc was added to a 96-well assay plate at a concentration of MOI 0.1 per well. It was then placed in a 37 ° C, 5% CO 2 incubator for 3 days. The luciferase luminescent substrate was added to each well, and the Luminescence signal value was detected by the chemiluminescence detection system Envision. The raw data (RLU) was used for the calculation of the compound inhibitory activity.
  • the raw data was processed as percent inhibition activity using the following formula:

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Abstract

La présente invention concerne un composé contenant une silicone pour résister à une infection par le virus de l'hépatite C, et concerne en particulier un nouveau composé qui est représenté par la formule I et présente une activité d'inhibition de la protéase NS5A du VHC, des sels, des hydrates, des solvates, des promédicaments ou des stéréoisomères pharmaceutiquement acceptables du nouveau composé ainsi qu'un mélange de sels, d'hydrates, de solvates, de promédicaments et de stéréoisomères pharmaceutiquement acceptables de ce nouveau composé, et un procédé de préparation et une composition pharmaceutique de ce nouveau composé. La présente invention concerne également l'utilisation du composé, des sels, des hydrates, des solvates, des promédicaments ou des stéréoisomères pharmaceutiquement acceptables du composé, d'un mélange de sels, d'hydrates, de solvates, de promédicaments et de stéréoisomères pharmaceutiquement acceptables du composé et d'une composition pharmaceutique du composé dans le traitement d'une infection par le virus de l'hépatite C.
PCT/CN2016/106781 2015-11-23 2016-11-22 Composé contenant une silicone pour résister à une infection par le virus de l'hépatite c WO2017088730A1 (fr)

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CN201510814757 2015-11-23
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114656389A (zh) * 2022-04-27 2022-06-24 河南大学 一种1-苯基吡咯烷的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5214176A (en) * 1988-04-20 1993-05-25 Rhone-Poulenc Chimie Organosilicon compounds
CN103172620A (zh) * 2009-06-11 2013-06-26 雅培制药有限公司 抗病毒化合物
CN103209686A (zh) * 2010-06-10 2013-07-17 雅博维巴哈马有限公司 固体组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5214176A (en) * 1988-04-20 1993-05-25 Rhone-Poulenc Chimie Organosilicon compounds
CN103172620A (zh) * 2009-06-11 2013-06-26 雅培制药有限公司 抗病毒化合物
CN103209686A (zh) * 2010-06-10 2013-07-17 雅博维巴哈马有限公司 固体组合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114656389A (zh) * 2022-04-27 2022-06-24 河南大学 一种1-苯基吡咯烷的合成方法
CN114656389B (zh) * 2022-04-27 2023-12-15 河南大学 一种1-苯基吡咯烷的合成方法

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