WO2018133846A1 - Composé de cyclothiouréa et utilisation de celui-ci - Google Patents

Composé de cyclothiouréa et utilisation de celui-ci Download PDF

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WO2018133846A1
WO2018133846A1 PCT/CN2018/073460 CN2018073460W WO2018133846A1 WO 2018133846 A1 WO2018133846 A1 WO 2018133846A1 CN 2018073460 W CN2018073460 W CN 2018073460W WO 2018133846 A1 WO2018133846 A1 WO 2018133846A1
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group
substituted
unsubstituted
alkyl
compound
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PCT/CN2018/073460
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Chinese (zh)
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王喆
王晓光
范国钦
卢涔宾
杨赛
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上海长森药业有限公司
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Publication of WO2018133846A1 publication Critical patent/WO2018133846A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention pertains to the field of medicine, and in particular, to the use of cyclic thiourea compounds for the treatment of hepatitis B and uses thereof.
  • Hepatitis B virus is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene.
  • the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed.
  • the pre-genomic RNA which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
  • hepatitis B virus The spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
  • direct treatment is currently limited to interferon as well as the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.
  • heteroaryldihydropyrimidines have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) . Also disclosed are WO sulfonyl-aryl amide compounds which are resistant to HBV activity, as disclosed in WO 2013/006394 and WO 2013/096744.
  • HBV antiviral drugs may encounter various problems such as toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.
  • a compound of formula A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • the R 11 and R 12 together with the adjacent C atoms constitute a substituted or unsubstituted 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, wherein
  • Y is a substituted or unsubstituted C 1 -C 7 alkylene group or a C 2 -C 7 alkenylene group, and in the Y, the substitution means one or more selected from the group consisting of (for example, 2, 3) Substituted by four, four, etc. substituents: C 1 -C 4 alkyl, halogen, -OH, preferably C 1 -C 4 alkyl or -OH;
  • Z is selected from the group consisting of NH, O or a bond
  • Ring C is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S and O, wherein said ring C is selected from the group consisting of Substituted by one or more (eg, 2, 3, 4, etc.) substituents: C 1 -C 3 alkyl (preferably methyl), C 3 -C 4 cycloalkyl, -CN or halogen ;
  • Ring B is a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O;
  • the substitution refers to being substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl , -CN or halogen;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted Or unsubstituted 3-10 membered heterocycloalkyl having 1 to 30 hetero atoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted a 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, wherein in R 1 , R 2 the substitution is replaced by one or more selected from the group consisting of Substituted by: -OH, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -O-;
  • R a , R b , R c and R d are substituents at any position on the benzene ring, as defined above.
  • R 12 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 10 alkyl, preferably H, substituted or unsubstituted C 1 -C 6 alkyl, more preferably The ground is H or methyl.
  • ring C is a substituted or unsubstituted 5 or 6 membered heteroaryl group, said substitution being selected from one or more selected from the group consisting of (eg, 2, 3, 4, etc.) Substituted by a substituent: methyl, -CN or halogen.
  • Ring B is phenyl or a substituted or unsubstituted 6-membered heteroaryl group, preferably a phenyl or pyridyl group.
  • the R a , R b , R c , R d are each independently selected from the group consisting of H, halogen, —CHF 2 , —CF 2 —methyl, —CH 2 F, —CF. 3 , -OCF 3 , -CN, -C 3 -C 4 cycloalkyl, or -C 1 -C 4 alkyl.
  • the ring C is among them
  • R 4 is H, -C 1 -C 3 alkyl (preferably methyl), -C 3 -C 4 cycloalkyl;
  • R 5 is H or halogen (preferably F);
  • R 6 is selected from H, methyl, -CN or halogen.
  • the Z is O or a bond.
  • the R 7 is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-2 heteroatoms selected from the group consisting of N, S and O.
  • the compound of formula A is selected from the group consisting of:
  • a process for the preparation of a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof The compound of formula A is a compound of formula VII-1, and the method comprises the step (I):
  • the compound of formula A shown is a compound of formula VIII-1, said method comprising step (II):
  • R 2 , R a , R b , R c , R d , ring C, and ring B are as defined above, and m and n are each a positive integer of 1-5. ;
  • a pharmaceutical composition comprising the compound of the first aspect, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, Or a solvate; (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference) Au- ⁇ ) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
  • an immunomodulator eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference
  • Au- ⁇ e.g, PEGylation interference
  • a stimulant of the innate immune system such as Toll-like receptor 7 and/or 8 agonists
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.
  • the fifth aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a third aspect of the invention.
  • the inventors have conducted extensive and intensive research and found a novel class of cyclic thiourea compounds which have an excellent therapeutic effect on hepatitis B.
  • the compounds of the present invention have novel cores in structure, especially those having a cyclic thiourea, and therefore have not only excellent anti-HBV activity but also lower cytotoxicity (especially for liver cells). On this basis, the inventors completed the present invention.
  • alkyl as used herein includes a straight or branched alkyl group.
  • C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
  • alkynyl includes a straight or branched alkynyl group.
  • C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
  • C 3 -C 10 cycloalkyl means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
  • C 1 -C 8 alkylamino refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
  • C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are A saturated or partially saturated cyclic group selected from the group consisting of heteroatoms of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A cyclic aromatic group of the following group of heteroatoms of N, S and O. It may be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo” means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond.
  • a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • proton transfer such as 1H-carbazole and 2H-carbazole.
  • Valence tautomers include interconversion through some bonding electron recombination.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
  • hydrate refers to a complex formed by the coordination of a compound of the invention with water.
  • a compound of the invention refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A).
  • pharmaceutically acceptable salt refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer.
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • other pharmaceutically acceptable compounds e.g., anti-HBV agents.
  • the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound e.g, an anti-HBV agent
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.
  • the compounds of the invention are very toxic to normal cells.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B virus-related diseases for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • step 1
  • the preparation of the compound 6b was carried out in the same manner as in the step 1-5 of Example 1, except that in step 3, 1,3-dibromopropane was used instead of 1,4-dibromobutane.
  • the preparation of the compound 6g is carried out in the same manner as in the step 1-5 of the embodiment 1, except that the 1-isopropyl-1,4-dibromohexane is substituted for the 1,4-dibromobutane in the step 3, and the step 5 is used. 3,4-Difluoro-aniline instead of 4-fluoro-3-cyanoaniline.
  • the preparation of the compound 6h is carried out by referring to the steps 1-5 of the first embodiment, except that the 1-isopropyl-1,4-dibromohexane is substituted for the 1,4-dibromobutane in the step 3, and the step 5 is used.
  • 4-Fluoro-3-difluoromethylaniline instead of 4-fluoro-3-cyanoaniline.
  • the chlorosulfonic acid isocyanate (2 g) was dissolved in dichloromethane (40 mL), the temperature of the system was lowered to 0 °, then tert-butanol (1.3 g) was added to the reaction system, stirred for 30 min, triethylamine (3 g) and compound 12(2.0g) was added to the reaction system at 0 degree. After the addition was completed, the temperature was raised to room temperature and the reaction was stirred for 2 h.
  • the compound 14 (400 mg) was dissolved in dichloromethane (400 mL), then the catalyst CatB (42 mg) was added to the reaction system, and the reaction was carried out at 30 degrees for 12 hours.
  • the compound 17 (40 mg) was dissolved in dichloromethane (2 mL) and then 4N HCl (1 mL) was added to the reaction system, and the reaction was carried out at 30 °C for 2 h, the reaction solution was spun dry, and the saturated sodium hydrogen carbonate solution was adjusted to pH 7-8, acetic acid. Ethyl ester (3*10 mL) was extracted, dried over anhydrous sodium sulfate, and then evaporated to dryness.
  • the preparation of the compound 17d is carried out by referring to the step 11-16 of Example 9, except that in Step 13, 4-methylisoxazole benzyl-1-pentene was used instead of propylene bromide.
  • the preparation of the compound 17e is carried out by referring to the steps 11-16 of Example 9, except that in step 13, 1-isopropyl-1-propene is used instead of propylene bromide, and in step 16, 3,4-difluoro-aniline is used instead of 4- Fluoro-3-cyanoaniline.
  • the compound 26 (40 mg) was dissolved in dichloromethane (2 mL) and then 4N HCl (1 mL) was added to the reaction system, and the reaction was carried out at 30 °C for 2 h, the reaction solution was spun dry, and the saturated sodium hydrogen carbonate solution was adjusted to pH 7-8, acetic acid. Ethyl acetate (3*10 mL) was extracted, dried over anhydrous sodium sulfate, and then evaporated to dryness.
  • the chlorosulfonic acid isocyanate (2 g) was dissolved in dichloromethane (40 mL), the temperature of the system was lowered to 0 °, then tert-butanol (1.3 g) was added to the reaction system, stirred for 30 min, triethylamine (3 g) and compound 32 (2.0 g) was added to the reaction system at 0 °C. After the addition was completed, the mixture was warmed to room temperature and stirred for 2 h.
  • the compound 37 (40 mg) was dissolved in dichloromethane (2 mL) and then 4N HCl (1 mL) was added to the reaction system, and the reaction was carried out at 30 °C for 2 h, the reaction solution was spun dry, and the saturated sodium hydrogen carbonate solution was adjusted to pH 7-8. Ethyl ester (3*10 mL) was extracted, dried over anhydrous sodium sulfate, and then evaporated to dryness.
  • step 32 1-isopropyl-1-propene is used in place of propylene bromide, and in step 35, 3,4-difluoro-aniline is substituted for 4- Fluoro-3-cyanoaniline.
  • step 32 1-isopropyl-1-propene is used in place of propylene bromide, and in step 35, 3-difluoromethyl-4-fluoro- is used.
  • Aniline replaces 4-fluoro-3-cyanoaniline.
  • [C150Bo] represents the concentration of a fluorescently labeled protein
  • A504 represents an absorbance value of a wavelength of 504 nM
  • A280 represents an absorption value of a wavelength of 280 nM
  • M -1 represents the reciprocal of the molar concentration.
  • the mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 ⁇ M with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
  • C150Bo was diluted to 2 ⁇ M with 50 mM HEPES. 37.5 ⁇ L of C150Bo and 2.5 ⁇ L of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 ⁇ l of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
  • Control wells were assembled with 0% protein, 10 ⁇ L of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
  • Control wells were assembled with 100% protein and 10 ⁇ L of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
  • the final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 ⁇ M, and the final concentration of C150Bo was 1.5 ⁇ M. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
  • % protein assembly [1 - (sample fluorescence value - 1 M NaCl fluorescence value) / (0 M NaCl fluorescence value - 1 M NaCl fluorescence value)] ⁇ 100.
  • the IC 50 value is calculated by the prism software and the equation is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • Bottom represents the bottom of the curve
  • Top represents the top of the curve
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • HepG2.2.15 cells (4 x 10 4 cells/well) were inoculated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
  • the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15.
  • the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
  • the activity calculation formula is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • Bottom represents the bottom of the curve
  • Top represents the top of the curve
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • test compounds The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
  • A1 indicates IC50 ( ⁇ M) at ⁇ 1;
  • A2 indicates that the IC50 ( ⁇ M) is between 1 and 100;
  • A3 indicates that the IC50 ( ⁇ M) is >100
  • control compound is:

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Abstract

La présente invention porte sur un composé de cyclothiouréa et sur son utilisation. La présente invention concerne particulièrement un composé ayant la structure telle que représentée dans la formule (A) qui peut être utilisée en tant qu'inhibiteur de la réplication du VHB ou un stéréoisomère ou un tautomère de celui-ci, ou un sel pharmaceutiquement acceptable, un hydrate ou un solvate de celui-ci. La présente invention concerne également une composition pharmaceutique comprenant le composé et son utilisation dans le traitement de l'hépatite B.
PCT/CN2018/073460 2017-01-23 2018-01-19 Composé de cyclothiouréa et utilisation de celui-ci WO2018133846A1 (fr)

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WO2018011163A1 (fr) * 2016-07-14 2018-01-18 F. Hoffmann-La Roche Ag Composés 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine and 6,7-dihydro-4h-triazolo[1,5-a]pyrazine pour le traitement des maladies infectieuses

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3909957A4 (fr) * 2019-01-11 2022-09-07 Shanghai Longwood Biopharmaceuticals Co., Ltd. Composé amide arylamide cyclique interne de sulphiamidine et son utilisation dans le traitement de l'hépatite b

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