WO2015197006A1 - Composé thioester d'acide aminé substitué, et composition et application de celui-ci - Google Patents

Composé thioester d'acide aminé substitué, et composition et application de celui-ci Download PDF

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WO2015197006A1
WO2015197006A1 PCT/CN2015/082294 CN2015082294W WO2015197006A1 WO 2015197006 A1 WO2015197006 A1 WO 2015197006A1 CN 2015082294 W CN2015082294 W CN 2015082294W WO 2015197006 A1 WO2015197006 A1 WO 2015197006A1
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group
compound
pharmaceutically acceptable
alkyl
methyl
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PCT/CN2015/082294
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Chinese (zh)
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魏用刚
余彦
邱关鹏
雷柏林
祝国智
卢泳华
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四川海思科制药有限公司
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Priority to CN201580001775.3A priority Critical patent/CN105518012B/zh
Publication of WO2015197006A1 publication Critical patent/WO2015197006A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a substituted amino acid thioester compound, a composition thereof and use thereof, and in particular, the present invention relates to a substituted amino acid thioester compound represented by the formula (I), a stereoisomer thereof or Pharmaceutically acceptable salts and pharmaceutical compositions containing them and use in the manufacture of a medicament for the treatment of viral infectious diseases.
  • Hepatitis B is one of the world's diseases, it is caused by hepatitis B virus. A third of the world's population is infected with hepatitis B virus to some extent, including 350 million chronic carriers. In some Asian and African countries, hepatitis B has become a pandemic, especially in China. Hepatitis B virus can cause acute and chronic infections. Acute infections are usually accompanied by inflammation of the liver, vomiting, jaundice, and very few deaths. Chronic infections may induce cirrhosis and liver cancer. Although hepatitis B virus infection can be prevented by vaccines at present, there is no effective method for treating chronic hepatitis B disease.
  • Hepatitis B virus is a hemorrhagic DNA (DNA) virus with a circular partially double-stranded DNA genome.
  • the shorter one chain has 1700 to 2800 nucleotides, the longer one chain has 3020 to 3320 nucleotides, and this long chain encodes the viral DNA polymerase.
  • the genome of the hepatitis B virus encodes four known genes - C, X, P and S.
  • Gene C encodes a nuclear protein (HBcAg)
  • gene S encodes a surface antigen (HBsAg)
  • gene P encodes a DNA polymerase.
  • the function of the protein encoded by gene X is unclear, but it is thought to be related to the occurrence of liver cancer because it activates A gene that induces cell proliferation and inactivates growth regulators.
  • hepatitis B virus The life cycle of hepatitis B virus is complex, enters cells through unknown receptors and endocytosis, and its genome is transferred to the nucleus by the host protein chaperones.
  • hepatitis B virus converts part of the double-stranded DNA into intact double-stranded DNA by the DNA polymerase of the host cell, and changes the morphology to a circular DNA (cccDNA) that is bound by a covalent bond.
  • cccDNA was used as a template to transcribe four viral mRNAs. These four transcripts are used as templates to be transported into the cytoplasm and translated into viral membrane proteins, nuclear proteins and DNA polymerases.
  • the longest mRNA (3.5 kb, longer than the viral genome) replicates as a template a new genomic copy, a transcriptional nucleocapsid protein and a viral DNA polymerase. At the same time, this 3.5 kb long RNA will be reverse transcribed from the antisense strand of hepatitis B virus DNA, followed by completion of the viral sense strand. Double-stranded DNA will be exported as a new sub-virus or returned to the nucleus to form a new cccDNA.
  • hepatitis B virus DNA polymerase The synthesis of hepatitis B virus RNA and DNA depends on the hepatitis B virus DNA polymerase, and hepatitis B virus DNA polymerase is essential for viral replication.
  • the polymerase has four domains: the beginning of replication of hepatitis B virus and the nucleocapsid The assembly is important for terminal proteins, spacer proteins, reverse transcriptase, and the RNaseH domain used to degrade pre-genomic RNA templates. Despite this, the lack of proofreading results in a high mutation rate of hepatitis B virus DNA polymerase.
  • DNA polymerase inhibitors as anti-HBV drugs has become an attractive option.
  • a particular viral polymerase inhibitor belongs to the family of nucleoside analogs.
  • Treatment for patients with chronic hepatitis B has been improved by oral administration of anti-HBV nucleoside analog drugs.
  • nucleoside analogs can rapidly reduce HBV DNA to unpredictable levels, and the mechanism of action is clear: nucleoside analogs competitively inhibit the activity of viral DNA polymerase.
  • nucleoside analogs showed good tolerance and fewer adverse reactions than interferon IFN- ⁇ .
  • hepatitis B virus DNA polymerase inhibitors have been marketed as drugs for the treatment of chronic hepatitis B in the United States and Europe, including: lamivudine, and fosfovir dipivoxil. Entecavir, telbivudine and tenofovir disoproxil fumarate, as well as several other drugs at the stage of research.
  • long-term antiviral therapy may cause viral resistance and selectivity due to virus residues in the liver and mutations caused by viral polymerases, including mutations in the viral polymerase amino acid. This puts requirements on the development of new antiviral drugs.
  • Tenofovir chemical name [(1R)-2-(6-aminofluoren-9-yl)-1-methyl-ethoxy]methyl phosphate (PMPA)
  • PMPA 2-aminofluoren-9-yl-1-methyl-ethoxy]methyl phosphate
  • An acid reverse transcriptase inhibitor has anti-HBV and HIV; however, it has disadvantages such as having a phosphoric acid group, having a large polarity, a poor biofilm penetrating ability, and poor bioavailability in a living body.
  • a phosphonate or phosphonamide prodrug form can be made.
  • Viread (Tinofovir dipivoxil fumarate), a drug developed by Gilead in 2002, is a prodrug of PMPA, and the prodrug form of the phosphonate is greatly improved in bioavailability. Viread plays an important role in the treatment of HIV and HBV. The transformation of the form of tenofovir prodrugs has become a hot topic of research.
  • EP206459 describes a structure comprising tenofovir for 9- (methoxy phosphate alkyl) adenine derivatives, and their use for antiviral drugs, in which R 1 selected from hydrogen, methyl, hydroxymethyl, R 2 is selected from substituted or unsubstituted ethylene, methylene, propylene, and the like.
  • R 1 selected from hydrogen, methyl, hydroxymethyl
  • R 2 is selected from substituted or unsubstituted ethylene, methylene, propylene, and the like.
  • EP 481214 describes a novel oral phosphate nucleoside analog prodrug comprising adefovir dipivoxil, and its antiviral medical use, in particular anti-RNA, DNA virus, can also be used for the treatment of tumors, etc., wherein B is selected from ⁇ , cytosine, uracil, thymine, ornithril, etc., R 3 is selected from substituted or unsubstituted C 1 -C 20 alkyl, R 1 , R 2 are independently selected from substituted or unsubstituted amino, OR 4 , R 4 is selected from CH 2 C (O) N ( R 5) 2, CH 2 C (O) OR 5, CH2OC (O) R 5, CH (R 5) OC (O) R 5, CH 2 C ( R 5 ) 2 CH 2 OH or CH 2 OR 5 , R 5 is selected from C 4 -C 20 alkyl, aryl or aryl-alkyl groups which are unsubstituted or substituted by hydroxy,
  • WO0208241 describes compositions comprising a derivative of adenine for disoproxil structure, in which R 1 selected from hydrogen, methyl.
  • R 1 selected from hydrogen, methyl.
  • WO02057288 describes substituted amino acid thioesters and their use in antiviral drugs, wherein Q is selected from the group consisting of purines or pyrimidines, R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, etc., R 1 , R 2 , R 3 , R 7 , and R 8 are independently selected from the group consisting of a hydroxyl group, a halogen, a hydrogen, an amino group, an alkyl group, an alkoxy group, and an alkylamino group.
  • Q is selected from the group consisting of purines or pyrimidines
  • R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, etc.
  • R 1 , R 2 , R 3 , R 7 , and R 8 are independently selected from the group consisting of a hydroxyl group, a halogen, a hydrogen, an amino group, an alkyl group, an alkoxy group, and an alkylamino group.
  • CN200410024276.X describes 9-((phosphate)methoxyalkyl)adenine derivatives and their use in antiviral drugs, wherein R 1 and R 2 are independently selected from hydrogen or substituted biphenylmethyl .
  • R 1 and R 2 are independently selected from hydrogen or substituted biphenylmethyl .
  • CN200710041280.0 describes substituted amino acid thioester compounds and their use in antiviral drugs, wherein R 1 is selected from the group consisting of hydrogen, halogen, amino, cyclopropylamino, methoxy, ethoxy, etc., R 2 is selected From hydrogen or an amino group, R 5 is selected from methyl or hydrogen, and R 3 and R 4 are independently selected from (substituted aminocarbonyloxy)alkyl.
  • R 1 is selected from the group consisting of hydrogen, halogen, amino, cyclopropylamino, methoxy, ethoxy, etc.
  • R 2 is selected From hydrogen or an amino group
  • R 5 is selected from methyl or hydrogen
  • R 3 and R 4 are independently selected from (substituted aminocarbonyloxy)alkyl.
  • CN200410088840.4 describes substituted amino acid thioester compounds and their use in antiviral drugs, wherein R is hydrogen or methyl, R 2 is selected from hydrogen or camphoryl, and R 1 is selected from 3-8 carbons.
  • R is hydrogen or methyl
  • R 2 is selected from hydrogen or camphoryl
  • R 1 is selected from 3-8 carbons.
  • WO2011069322 describes substituted amino compounds and thioesters useful for the treatment and prevention of diseases associated with viral infections medical uses, in which R 1 is selected from hydrogen or methyl, R 2 is selected from -R 3 or -OR 3, R 3 It is selected from a C 1-8 alkyl group and a C 3-8 cycloalkyl group.
  • R 1 is selected from hydrogen or methyl
  • R 2 is selected from -R 3 or -OR 3
  • R 3 It is selected from a C 1-8 alkyl group and a C 3-8 cycloalkyl group.
  • the invention designs a compound represented by the general formula (I) on the basis of tenofovir disoproxil to provide a novel structure, better medicine, safer, less toxic and side effects, good solubility or high bioavailability.
  • the present invention provides a compound of the formula (A), a stereoisomer thereof, a pharmaceutically acceptable salt or a eutectic, wherein:
  • A is selected from a 6 to 10 membered aromatic ring or a 6 to 10 membered heteroaryl ring, and the heteroaryl group contains 1 to 4 hetero atoms selected from N, O, and S, and the aromatic ring or heteroaryl ring is Further selected from 0 to 5 selected from H, F, Cl, Br, I, CN, amino, hydroxy, carboxy, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy or -C ( Substituted by a substituent of OC 1-4 alkyl;
  • E is selected from -CH 2 CH(CH 3 )OCH 2 - or -CH 2 CH 2 OCH 2 -;
  • R N is selected from H or C 1-4 alkyl
  • R 1 and R 2 are each independently selected from the group consisting of H, C 1-6 alkyl or a side chain of a natural or pharmaceutically acceptable amino acid, and if the side chain contains a carboxyl group, the carboxyl group may be optionally esterified with an alkyl group or an aryl group;
  • R 1 , R 2 may form a C 3-6 cycloalkyl group together with the carbon atom to which they are attached;
  • R 3 is selected from H, C 1-6 alkyl, 6 to 10 membered aromatic ring or 6 to 10 membered heteroaryl ring, and the heteroaryl group contains 1 to 4 hetero atoms selected from N, O, and S,
  • the alkyl, aromatic or heteroaryl ring is optionally further selected from 0 to 5 selected from the group consisting of H, F, Cl, Br, I, CN, amino, hydroxy, carboxy, C 1-4 alkyl or C 1- Substituted by a 4 -alkoxy substituent.
  • A is selected from phenyl or naphthyl, and the phenyl or naphthyl group is further optionally further selected from 0 to 5 selected from the group consisting of H, F, Cl, Br, I, CN, amino, hydroxy, carboxy, C 1-4 alkane. Substituted by a substituent of a C 1-4 alkoxy group;
  • E is selected from -CH 2 CH(CH 3 )OCH 2 - or -CH 2 CH 2 OCH 2 -;
  • R N is selected from H or C 1-4 alkyl
  • R 2 is a side chain of a natural or pharmaceutically acceptable amino acid, and if the side chain contains a carboxyl group, the carboxyl group may be optionally esterified with an alkyl group or an aryl group;
  • R 3 is a C 1-6 alkyl group.
  • a preferred embodiment of the present invention a thioester compound of the amino acid of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl or naphthyl, preferably phenyl;
  • the phenyl or naphthyl group is optionally further substituted with from 0 to 5 substituents selected from the group consisting of H, F, Cl, Br, I, CN, amino, hydroxy, carboxy, methyl, ethyl, methoxy or ethoxy.
  • the substitution is further preferably substituted with 0 to 5 substituents selected from H, F, Cl, Br, CN, amino or methoxy.
  • the amino acids thereof are preferably glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methionine, tryptophan, serine, glutamine, threonine.
  • cysteine histidine, asparagine, tyrosine, aspartic acid, glutamic acid, naphthyl acid or arginine, further preferably glycine, alanine, leucine, phenylalanine Acid, asparagine or arginine, more preferably glycine, alanine or phenylalanine.
  • an amino acid thioester compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein R 3 is a C 1-6 alkyl group, preferably a C 1-4
  • the alkyl group is further preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group.
  • R 2 is selected from the side chain of glycine, alanine, leucine, phenylalanine, asparagine or arginine, preferably a side chain of glycine, alanine or phenylalanine.
  • E is selected from -CH 2 CH(CH 3 )OCH 2 -;
  • R 3 is a C 1-4 alkyl group.
  • R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 2 is selected from the side chain of glycine, alanine, leucine, phenylalanine, asparagine or arginine, preferably a side chain of glycine, alanine or phenylalanine, further preferably alanine Side chain
  • R 3 is C 1-4 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • A is selected from a 6 to 10 membered aromatic ring or a 6 to 10 membered heteroaryl ring, and the heteroaryl group contains 1 to 4 hetero atoms selected from N, O, and S, and the aromatic ring or heteroaryl ring is Further selected from 0 to 5 selected from H, F, Cl, Br, I, CN, amino, hydroxy, carboxy, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy or -C ( Substituted by a substituent of OC 1-4 alkyl;
  • E is selected from -CH 2 CH(CH 3 )OCH 2 - or -CH 2 CH 2 OCH 2 -;
  • R 1 and R 2 are each independently selected from a C 1-6 alkyl group
  • R 1 , R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 3 is selected from H, C 1-6 alkyl, 6 to 10 membered aromatic ring or 6 to 10 membered heteroaryl ring, and the heteroaryl group contains 1 to 4 hetero atoms selected from N, O, and S,
  • the aromatic or heteroaryl ring is optionally further selected from 0 to 5 selected from the group consisting of H, F, Cl, Br, I, CN, amino, hydroxy, carboxy, C 1-4 alkyl or C 1-4 alkoxy Substituted by a substituent.
  • a preferred embodiment of the invention a compound of the formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt or a eutectic, wherein:
  • A is selected from a substituted or unsubstituted phenyl, pyridyl or naphthyl group, and when substituted, optionally further 1 to 3 are selected from the group consisting of H, F, Cl, Br, I, CN, methoxy, methyl Substituted by a substituent of a trifluoromethyl or ethoxycarbonyl group;
  • E is selected from -CH 2 CH(CH 3 )OCH 2 -;
  • R 1 and R 2 are each independently selected from a methyl group and an ethyl group.
  • R 1 , R 2 together with the carbon atom to which they are attached form a cyclopropyl group
  • R 3 is selected from methyl, ethyl, isopropyl, monofluoromethyl or difluoromethyl.
  • a preferred embodiment of the invention a compound of the formula (A), a stereoisomer thereof, a pharmaceutically acceptable salt or a eutectic, wherein:
  • A is selected from phenyl
  • R N is selected from H
  • R 1 and R 2 are each independently selected from methyl or ethyl
  • R 3 is selected from methyl, ethyl or isopropyl.
  • the amino acid thioester compound represented by the formula (I) is a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is:
  • the compound is a compound obtained by resolution of compound 1:
  • the separation conditions were: instrument, MGII preparative SFC; column, ChiralPak AS-H, 250 ⁇ 30 mm I.D.; mobile phase, A is CO 2 and B is Methanol; gradient, B 40%; flow rate, 40 mL/min; back pressure , 100 bar; column temperature 38 ° C; wavelength, 220 nm; period, 5.5 min;
  • the compound having a short retention time is Compound 1-1 retention time of 2.21 ⁇ 0.5 min;
  • the compound in which the retention time is long is the compound 1-2 retention time of 3.82 ⁇ 0.5 min.
  • the compound is a compound obtained by resolution of compound 2:
  • the separation conditions were: instrument: Thar 200prepararive SFC, column: ChiralPak AS-10u, 300 ⁇ 50 mm I.D., mobile phase: A is CO 2 and B is ethanol, gradient: B 45%, flow rate: 200 mL/min, back Pressure: 100 bar, column temperature: 38 ° C, wavelength: 220 nm, cycle: ⁇ 15 min;
  • the compound having a short retention time is a compound 2-1 retention time of 2.32 ⁇ 0.5 min;
  • the compound in which the retention time is long is the compound 2-2 retention time of 3.98 ⁇ 0.5 min.
  • the compound is a compound obtained by resolution of compound 5:
  • the separation conditions were: instrument: Thar 200prepararive SFC, column: ChiralCel OD-10u, 300 ⁇ 50 mm I.D, mobile phase: A is CO 2 and B is ethanol, gradient: B 25%, flow rate: 200 mL/min, back pressure 100 bar, column temperature: 38 ° C, wavelength: 220 nm, period: ⁇ 5 min;
  • the compound having a short retention time is Compound 5-1 retention time of 3.38 ⁇ 0.5 min;
  • the compound in which the retention time is long is the retention time of the compound 5-2 of 3.77 ⁇ 0.5 min.
  • the compound is a compound obtained by resolution of compound 6:
  • the compound having a short retention time is a compound 6-1 retention time of 1.93 ⁇ 0.5 min;
  • the compound in which the retention time is long is the retention time of the compound 6-2 of 2.87 ⁇ 0.5 min.
  • the compound is a compound obtained by resolution of compound 7:
  • the separation conditions were: instrument: waters SFC, column: Chiralpak AS-3 (4.6 ⁇ 100 mm), mobile phase: A is methanol and B is CO 2 , gradient: B 10-40%, flow rate: 2 mL/min, back pressure : 2000 psi, column temperature: 35 ° C, wavelength: 260 nm; period: ⁇ 6 min;
  • the compound having a short retention time is a compound 7-1 retention time of 1.62 ⁇ 0.5 min;
  • the compound in which the retention time is long is the retention time of the compound 7-2 of 2.52 ⁇ 0.5 min.
  • the present invention also provides a compound of the formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the salt is a fumarate.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, and a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or Shape agent.
  • the present invention provides the use of the compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a viral infectious disease.
  • the viral infectious disease comprises an infectious disease caused by hepatitis B virus, hepatitis C virus and HIV virus.
  • the present invention provides a method of treating a viral infectious disease, wherein the method comprises administering a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt or eutectic thereof or the Pharmaceutical composition.
  • the viral infectious disease comprises an infectious disease caused by hepatitis B virus, hepatitis C virus and HIV virus.
  • the present invention relates to the substitution of a plurality of substituents, which may be the same or different.
  • the present invention relates to the inclusion of a plurality of heteroatoms, each of which may be the same or different.
  • the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements, carbon, hydrogen and oxygen involved in the groups and compounds of the present invention.
  • Sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N
  • the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, positive a mercapto group, and various branched isomers thereof; more preferred are lower alkyl groups having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, isopropyl, and Butyl, isobutyl or tert-butyl.
  • Amino means -NH 2, may be substituted or unsubstituted. When substituted, the substituent is preferably 1 to 3, independently selected from alkyl, alkenyl, alkynyl, alkoxy, Thio, hydroxy, amino, alkylamino, alkyl acylamino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxylic acid or Carboxylic acid ester.
  • Aryl means a substituted or unsubstituted 6 to 14 membered all carbon monocyclic or fused polycyclic group having a polycyclic group of a conjugated ⁇ -electron system, preferably a 6 to 10 membered aromatic ring, Non-limiting examples include phenyl or naphthyl; the aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, and the moiety attached to the parent structure is an aryl group, non-limiting examples of which include benzo Furan, benzocyclopentyl or benzothiazole.
  • Natural or pharmaceutically acceptable amino acids The basic skeleton of a protein molecule is an amino acid sequence, and there are 20 basic amino acids constituting a protein. These 20 basic amino acids are the basis for biological late modification of proteins, and in addition, based on these basic amino acids. The organism also synthesizes amino acid types derived from hydroxyproline, hydroxylysine, etc. These biosynthesized amino acids are collectively referred to as “natural amino acids”; artificially synthesized are “unnatural amino acids”. "Pharmaceutically acceptable amino acid” refers to a pharmaceutically acceptable natural or unnatural amino acid.
  • “Pharmaceutically acceptable salt” means a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases.
  • Crystal refers to a combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, of which API and CCF The pure state is solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
  • the "eutectic former” includes, but is not limited to, various pharmaceutically acceptable acid, base, nonionic compounds.
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • “Pharmaceutical composition” means one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or mixture of prodrugs thereof with other chemical components, such as physiological/pharmaceutically acceptable carriers and excipient.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • Prodrug means a compound of the invention which can be converted to biological activity under physiological conditions or by solvolysis.
  • Prodrugs of the invention are prepared by modifying functional groups in the compound which can be removed by conventional procedures or in vivo to provide the parent compound.
  • a prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention.
  • the prodrug is cleaved to form a free hydroxyl group, respectively. , free amino or free sulfhydryl.
  • Examples of prodrugs include However, it is not limited to a compound formed by a hydroxyl group or an amino functional group in the compound of the present invention and formic acid, acetic acid or benzoic acid.
  • aryl substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the aryl group is substituted with an alkyl group and the case where the aryl group is not substituted with an alkyl group.
  • Substituted or unsubstituted refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.
  • “As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.
  • substitution refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom.
  • the group is substituted, for example, amino, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H
  • substituent of F, Cl, Br, I, hydroxy, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy the groups formed include, but are not limited to, methyl, chloromethyl, Trichloromethyl, hydroxymethyl, -CH 2 OCH 3 , -CH 2 SH, -CH 2 CH 2 CN, -CH 2 NH 2 , -NHOH, -NHCH 3 , -OCH 2 Cl, -OCH 2 OCH 2 CH 3 , -
  • the compound (A-1) is reacted with a thiol under an ester condensing agent to obtain a compound (A-2) including, but not limited to, dicyclohexylcarbodiimide, N,N-carbonyldiimidazole, N,N. '-disuccinimidyl carbonate, 1-p-methylbenzenesulfonylimidazole, 4,5-dicyanoimidazole, preferably N,N-carbonyldiimidazole;
  • Compound (A-1) can be purchased or prepared by reference to CN201080036406.5 literature;
  • Compound (A-4) is prepared with reference to EP0206459B1, CN01813161.1 or WO2013052094;
  • R a is selected from an amino protecting group, wherein the amino protecting group includes, but is not limited to, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, three Methylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-biphenyl-2-propoxycarbonyl, tert-butoxy, phthaloyl, p-toluenesulfonyl, o-nitrophenylsulfonyl , p-nitrophenylsulfonyl, pivaloyl, formyl, trifluoroacetyl, benzoyl, benzyl, trityl, p-methoxybenzyl or 2,4-dimethoxybenzyl, Preferred is tert-butoxycarbonyl;
  • Compound (IA) is reacted with a thiol under an ester condensing agent to give compound (IB), including but not limited to dicyclohexylcarbodiimide, N,N-carbonyldiimidazole, N,N'-diamidium Imidyl carbonate, 1-p-methylbenzenesulfonylimidazole, 4,5-dicyanoimidazole, preferably N,N-carbonyldiimidazole;
  • Compound (I-B) deprotects the amino group to give compound (I-C); the deprotection is carried out using conventional amino protecting group deprotection methods including, but not limited to, deprotection under acidic conditions, such as using trifluoroacetic acid;
  • Compound (I-A) can be purchased or prepared by reference to CN201080036406.5 literature;
  • Compound (A-4) is prepared with reference to EP0206459B1, CN01813161.1 or WO2013052094;
  • R a is selected from an amino protecting group, wherein the amino protecting group includes, but is not limited to, tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, three Methylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-biphenyl-2-propoxycarbonyl, tert-butoxy, phthaloyl, p-toluenesulfonyl, o-nitrophenylsulfonyl , p-nitrophenylsulfonyl, pivaloyl, formyl, trifluoroacetyl, benzoyl, benzyl, trityl, p-methoxybenzyl or 2,4-dimethoxybenzyl, Preferred is tert-butoxycarbonyl;
  • Compound (A-4) can be purchased or prepared by the method of WO2014088923 or WO2012154698.
  • Compound (IV-B) can be purchased or prepared by methods such as WO2012075456, WO2011014973 or WO2012084794;
  • Compound (IV-C) can be prepared by referring to the methods of the present invention, WO0208241 or WO2013052094;
  • Compound (IV) is obtained by transesterification of compound (IV-C) with a thiol;
  • R 4 is selected from H or C 1-6 alkyl
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • N-tert-butoxycarbonyl-L-alanine (1A) (5 g, 26.4 mmol) was dissolved in tetrahydrofuran (40 mL), and N,N'-carbonyldiimidazole (CDI) (4.7 g, 29.1 mmol) was added. Stir at room temperature for 2 hours. Thioisopropanol (6.2 g, 79.3 mmol) was added and allowed to react at room temperature overnight. 4 mol/L of sodium hydroxide solution (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL ⁇ 4).
  • CDI N,N'-carbonyldiimidazole
  • reaction mixture was concentrated under reduced pressure to dryness to ethyl acetate.
  • ethyl acetate (10mL) and water (15mL) were added to the residue, and the aqueous layer was extracted with ethyl acetate (10mL ⁇ 2).
  • Separation analysis method instrument, Thar analytical SFC; column, ChiralPak AS-H, 250 ⁇ 4.6 mm; mobile phase, A is CO 2 and B is Methanol (0.05% DEA); gradient, B 40%; flow rate, 2.4 mL/ Min; back pressure, 100 bar; column temperature, 35 ° C; wavelength, 220 nm.
  • Preparation separation method instrument, MGII preparative SFC; column, ChiralPak AS-H, 250 ⁇ 30 mm I.D.; mobile phase, A is CO 2 and B is Methanol; gradient, B 40%; flow rate, 40 mL/min; back pressure, 100 bar; column temperature 38 ° C; wavelength, 220 nm; period, 5.5 min.
  • N-tert-butoxycarbonyl-L-alanine (2A) (50,264 mmol) was dissolved in tetrahydrofuran (400 mL), and N,N'-carbonyldiimidazole (CDI) (47 g, 291 mmol) was added and stirred at room temperature 1 Ethyl thiol (18 g, 291 mmol) was added at rt overnight. Water (100 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj The mixture was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc:EtOAc 2B), white solid (46 g, yield 74.6%).
  • (2S)-2-Aminopropionic acid thioethyl ester (2C) (25g, 98.57mmol) was dissolved in dry dichloromethane (150mL), under nitrogen, dry ice-ethanol cooled to -50 ° C, add three Ethylamine (36.6 g, 361.6 mmol), [[(1R)-2-(6-aminofluoren-9-yl)-1-methylethoxy]methyl]phenoxyphosphoryl chloride (1F) 23 g, 60.24 mmol), naturally heated to room temperature for 1 hour. After completion of the reaction, water (50 mL) was added, and the mixture was evaporated.
  • Preparation Separation method Instrument: Thar 200prepararive SFC, column: ChiralPak AS-10u, 300 ⁇ 50 mm I.D., mobile phase: A is CO 2 and B is ethanol, gradient: B 45%, flow rate: 200 mL/min, back pressure : 100 bar, column temperature: 38 ° C, wavelength: 220 nm, period: ⁇ 15 min,
  • Preparation Separation method Instrument: Thar 200prepararive SFC, column: ChiralCel OD-10u, 300 ⁇ 50 mm I.D, mobile phase: A is CO 2 and B is ethanol, gradient: B 25%, flow rate: 200 mL/min, back pressure 100 bar , column temperature: 38 ° C, wavelength: 220 nm, period: ⁇ 5 min,
  • Trimethylaluminum (67 ml, 134.4 mmol, 2 mol/L) was dissolved in dichloromethane (100 mL), ethanethiol (8.33 g, 10 mmol) was added at 0 ° C, and reacted for 15 minutes, and 2-[[[(1R) was added. )-2-(6-Amino-7H-indol-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]-2-methyl-propionic acid ethyl ester ( 5B) (8.0 g, 16.8 mmol), allowed to react at room temperature overnight. After being added to a saturated aqueous solution of ammonium chloride, the mixture was evaporated.
  • Preparation separation method Instrument: MGII preparative SFC-1, column: ChiralCel OD-5u, 250 ⁇ 30 mm I.D.
  • Mobile phase A is CO2 and B is isopropanol, gradient: 30%, flow rate: 60 mL/min, back Pressure: 100 bar, column temperature: 38 ° C, wavelength: 220 nm, period: ⁇ 4 min,
  • Trimethylaluminum (2 mol/L) (33.7 ml, 67.5 mmol) was dissolved in 50 mL of dichloromethane, and diisopropyl mercaptan (5.13 g, 67.5 mmol) was added under ice-cooling under ice, and then ice bath Stir for 30 minutes, add 7B (4.0g, 8.4mmol), warm to room temperature for 4 days, add 50mL of saturated aqueous solution of saturated ammonium chloride to quench the reaction, separate the liquid, and extract with dichloromethane (50mL ⁇ 3 ), the organic phase is combined, the organic phase is washed with water (50 mL ⁇ 2), anhydrous sulfur The sodium salt was dried and concentrated to give the title compound ⁇ RTIgt;
  • Test Example 1 Screening for anti-hepatitis B virus activity
  • HepG 2.2.15 cells Compounds were tested for anti-HBV activity using HepG 2.2.15 cells.
  • the materials and instruments used were as follows: HepG2.2.15 cells, RPMI 1640 medium, fetal bovine serum, 96-well plates, DMSO, QIAamp 96 DNA Blood Kit, Cell-titer blue, microplate reader, Applied Biosystems 7900 real-time PCR system.
  • Each compound was dissolved in DMSO at 20 mM and stored at -20 ° C, and a 20 mM stock solution of each compound was diluted with a DMSO 3 fold gradient for a total of 9 concentrations. It was further diluted 200-fold with RPMI 1640 medium containing 2.0% FBS. The highest test final concentration of the compound was 100M.
  • Experimental Procedure The compounds were tested for anti-HBV activity by qPCR method and the EC 50 (half effective inhibitory concentration) was calculated by following the QIAamp 96 DNA Blood Kit (QIAGEN 51161) instructions.
  • inhibition rate (%) (total amount of HBV in the DMSO control group - total amount of HBV in the test sample group) / total amount of HBV in the DMSO control group ⁇ 100.
  • EC 50 values were calculated using GraphPad Prism software compound.
  • Table 1 EC 50 values and CC 50 values for each compound
  • test compounds all showed good anti-HBV activity, comparable anti-HBV activity compared to the control, and no cytotoxicity over the range of concentrations tested.
  • a standard solution of the test compound is prepared and added to the blank plasma, liver and kidney homogenate.
  • the concentration of the standard is 10000 ng/ml, 5000 ng/ml, 2500 ng/ml, 1000 ng/ml, 250 ng/ml, 50 ng/ml, 25 ng/ml, 10 ng/ml, 5 ng/ml, 2 ng/ml.
  • 30 ⁇ l of each concentration solution was added, 200 ⁇ l of acetonitrile containing internal standard was added, shaken at 2500 rpm for 2 min, then centrifuged at 13,000 rpm for 10 min at 4 ° C, and the supernatant was taken to prepare a standard curve of the test compound in blank plasma, liver and kidney homogenate.
  • the whole blood of ICR mice, SD rats, Beagle dogs, cynomolgus monkeys and healthy people used in this experiment was collected freshly before the experiment (male and female).
  • the test compound will be co-incubated with various genus whole blood, the incubation system is 400 ⁇ L, and the final concentration is 1 ⁇ M.
  • 40 ⁇ L of the incubated whole blood sample was taken and added to 200 ⁇ L of acetonitrile containing the internal standard. After the protein was precipitated, the supernatant was centrifuged, and the test compound in the supernatant was analyzed by the LC-MS/MS method, and the sample was parallelized in two portions.
  • Analyte/AIS analyte/internal standard peak area ratio
  • %Control the remaining percentage
  • the Average T 1/2 value of the compound 1-1, 1-2 of the present invention is more than 30 times that of the control compound, and its stability is obviously superior to the control compound, so the exposure of PMPA in human plasma is observed.
  • the lower amount significantly reduces the toxic side effects of the compounds of the invention due to the metabolism of PMPA in plasma.

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Abstract

L'invention concerne un composé thioester d'acide aminé substitué représenté par la formule générale (A), et une composition et une application de celui-ci.
PCT/CN2015/082294 2014-06-25 2015-06-25 Composé thioester d'acide aminé substitué, et composition et application de celui-ci WO2015197006A1 (fr)

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CN106928080A (zh) * 2015-12-31 2017-07-07 四川海思科制药有限公司 稠合环γ‑氨基酸衍生物及其制备方法和在医药上的应用
WO2017133517A1 (fr) * 2016-02-03 2017-08-10 四川海思科制药有限公司 Dérivé de phosphamide, son procédé de fabrication et ses utilisations
CN109485676A (zh) * 2017-12-21 2019-03-19 深圳市塔吉瑞生物医药有限公司 用于抗病毒的新型核苷类逆转录酶抑制剂
CN109942632A (zh) * 2017-12-20 2019-06-28 上海博志研新药物技术有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN109942633A (zh) * 2017-12-20 2019-06-28 上海博志研新药物技术有限公司 替诺福韦艾拉酚胺中间体的制备方法
JP2020504733A (ja) * 2016-12-22 2020-02-13 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． テノホビルの抗ウイルス性脂肪族エステルプロドラッグ

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CN106928080A (zh) * 2015-12-31 2017-07-07 四川海思科制药有限公司 稠合环γ‑氨基酸衍生物及其制备方法和在医药上的应用
CN106928080B (zh) * 2015-12-31 2020-12-25 四川海思科制药有限公司 稠合环γ-氨基酸衍生物及其制备方法和在医药上的应用
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JP2020504733A (ja) * 2016-12-22 2020-02-13 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． テノホビルの抗ウイルス性脂肪族エステルプロドラッグ
CN109942633B (zh) * 2017-12-20 2021-08-31 上海新礼泰药业有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN109942632B (zh) * 2017-12-20 2021-08-31 上海博志研新药物研究有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN109942632A (zh) * 2017-12-20 2019-06-28 上海博志研新药物技术有限公司 替诺福韦艾拉酚胺中间体的制备方法
CN109942633A (zh) * 2017-12-20 2019-06-28 上海博志研新药物技术有限公司 替诺福韦艾拉酚胺中间体的制备方法
WO2019120084A1 (fr) * 2017-12-21 2019-06-27 深圳市塔吉瑞生物医药有限公司 Inhibiteur nucléosidique de la transcriptase inverse antiviral
EP3730503A4 (fr) * 2017-12-21 2021-05-05 Shenzhen TargetRx, Inc. Inhibiteur nucléosidique de la transcriptase inverse antiviral
JP2021506938A (ja) * 2017-12-21 2021-02-22 深▲チェン▼市塔吉瑞生物医薬有限公司Ｓｈｅｎｚｈｅｎ ＴａｒｇｅｔＲｘ， Ｉｎｃ． 新規抗ウイルス性ヌクレオシド系逆転写酵素阻害剤
CN109485676A (zh) * 2017-12-21 2019-03-19 深圳市塔吉瑞生物医药有限公司 用于抗病毒的新型核苷类逆转录酶抑制剂
JP7076158B2 (ja) 2017-12-21 2022-05-27 深▲チェン▼市塔吉瑞生物医薬有限公司 新規抗ウイルス性ヌクレオシド系逆転写酵素阻害剤
CN109485676B (zh) * 2017-12-21 2022-07-15 深圳市塔吉瑞生物医药有限公司 用于抗病毒的新型核苷类逆转录酶抑制剂
US11447512B2 (en) 2017-12-21 2022-09-20 Shenzhen Targetrx, Inc. Antiviral nucleoside reverse transcriptase inhibitor

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