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WO2011003365A1 - Inhibiteurs de l’histone désacétylase possédant une structure ramifiée synthétisée par click chemistry - Google Patents

Inhibiteurs de l’histone désacétylase possédant une structure ramifiée synthétisée par click chemistry Download PDF

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Publication number
WO2011003365A1
WO2011003365A1 PCT/CN2010/075097 CN2010075097W WO2011003365A1 WO 2011003365 A1 WO2011003365 A1 WO 2011003365A1 CN 2010075097 W CN2010075097 W CN 2010075097W WO 2011003365 A1 WO2011003365 A1 WO 2011003365A1
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group
compound
inhibitor
histone deacetylase
bridging
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PCT/CN2010/075097
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English (en)
Chinese (zh)
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王鹏
沈杰
尹正
侯静丽
李中华
冯丛然
方清洪
古国贤
曹雪峰
王辉辉
张鹏飞
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天津尚德药缘科技有限公司
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Priority to CN201080030609.3A priority Critical patent/CN102438996B/zh
Publication of WO2011003365A1 publication Critical patent/WO2011003365A1/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
    • A61K31/33—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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/423—Oxazoles condensed with carbocyclic 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic 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
    • C07D417/02—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
    • C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to the field of biomedical technology, and in particular to a histone deacetylase inhibitor having a "branched" structure synthesized by click chemistry.
  • Inhibitors can be used as a medicament for the preparation of drugs for the treatment of cardiovascular diseases, immune diseases and neurodegenerative diseases.
  • HDAC histone deacetylase
  • HAT histone acetyltransferase
  • HDAC/HAT Known substrate proteins for HDAC/HAT include: histones, tubulin, Hsp90 and transcription factors (such as p53, F-B, Ku70 and Stat3). Among them, histone is the earliest and most abundant substrate protein in research, and the naming of HDAC and HAT is also derived from it. The acetylation of histones by HDAC and HAT is an important means of regulating gene expression in epigenetics.
  • HDAC histone deacetylase inhibitors selectively kill cancer cells and have a good synergistic effect with many anticancer drugs.
  • suberic anilide hydroxamic acid developed by Merck USA became the first approved HDAC targeted drug.
  • the technical problem to be solved by the present invention is to provide a novel click-chemically synthesized histone deacetylase inhibitor having a "branched” structure, the disclosure of which includes: structure, preparation method and application of the compound.
  • the innovations of the present invention are: 1) enhancing the biological activity of histone deacetylase inhibitors by introducing a "branched” structure; 2) conveniently synthesizing histones having a chiral "branched” structure by using chiral amino acids An acetylase inhibitor.
  • the present invention provides a histone deacetylase inhibitor (ie, a parent drug molecule) having a "branched" structure synthesized by click chemistry, the inhibitor being a compound having the following structural formula:
  • A is a dC 6 alkyl chain
  • Ri and R 2 are a substituted or unsubstituted alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group, an alkenyl group, a cycloalkenyl group, a heteroalkenyl group, a heterocycloalkenyl group, an alkynyl group, a cycloalkynyl group, a heteroalkynyl group, a cycloheteroalkynyl group, an aryl group, or a heteroaryl group, wherein the sum may be the same or different;
  • the substituent is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heteroalkynyl , cycloheteroalkynyl, aryl, heteroaryl, halogen, -CF 3 , -OCF3, carboxy (-COOH), sulfonic acid (-S0 3 H), cyano (-CN), hydroxy (-OH) Or an amino group (-H 2 ), or a nitro group (-N0 2 ); preferably, a bridging group may be inserted in the middle of at least one single bond, and the bridging group is selected from a thioether group (-S-), Ether group (-0-), imino group (-HN-), carbonyl group (-(CO)-), sulfony
  • the compound of the formula Mi is a compound having the structural formula M 2 as follows:
  • Xi, X 2 , X 3 and X 4 are N or CR 3 ; may be NR 3 , S or O; Q 2 may be N or CR 3 .
  • R 3 is selected from the group consisting of H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heteroalkyne , cycloheteroalkynyl, aryl, heteroaryl, halogen, -CF 3 , -OCF3, carboxy (-COOH), sulfonic acid (-S0 3 H), cyano (-CN), hydroxy (-OH , an amino group (-H 2 ), or a nitro group (-N0 2 ); preferably R 3 is H wherein a bridge group is inserted between C, N and R 3 in CR 3 and NR
  • Mercapto group refers to a linear or branched aliphatic hydrocarbon group; preferably an alkyl group of dC 14 ; a more preferred choice is an alkyl group of 1 () ; the most preferred option is dC 6 .
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl, and the like.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused or spiro carbon ring. A ring consisting of 3-9 carbon atoms is preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Heteroquinone refers to a group having a straight chain or a branched alkyl group, and contains at least one or more hetero atoms selected from S, 0 and N in the main chain. A chain containing 2-14 atoms is preferred.
  • Heteroalkyl groups include, but are not limited to: ethers, thioethers, alkanes Base esters, second or third alkylamines, alkylsulfinic acids, and the like.
  • Heterocyclic fluorenyl means a cycloalkyl group containing at least one hetero atom selected from N, S, 0. It preferably contains 1-3 hetero atoms.
  • the preferred ring is a 3-14 membered ring and the more preferred ring is a 4-7 membered ring.
  • Heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, dihydropyrrolyl, tetrahydropyrrolyl, dihydropyrazolyl, piperidinyl, morpholinetetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyran Base.
  • Alkenyl As a part of a group, it means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, and may be either a straight chain or a branched chain. Alkenyl groups having C 2 -C 14 are preferred. 12 is even better; the most preferred is a C 2 -C 6 alkenyl group. The group may contain multiple double bonds in its backbone and its conformation may each be £ or 2. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, and the like.
  • Cycloalkenyl means that at least one carbon-carbon single bond in a cycloalkyl group is substituted by a carbon-carbon double bond.
  • Heteroalkenyl means that at least one carbon-carbon single bond in a heteroalkyl group is replaced by a carbon-carbon double bond.
  • Heterocyclenyl means that at least one carbon-carbon single bond in a heterocycloalkyl group is substituted by a carbon-carbon double bond.
  • Alkynyl group As a part of a group, it means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, and may be either a straight chain or a branched chain. Alkynyl groups having C 2 -C 14 are preferred. 12 is even better; the most preferred is a C 2 -C 6 alkynyl group. The group may contain multiple double bonds in its backbone and its conformation may each be £ or 2. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • Cycloalkynyl group means that at least one carbon-carbon single bond in a cycloalkyl group is substituted by a carbon-carbon triple bond.
  • Heteroalkynyl group means that at least one carbon-carbon single bond in a heteroalkyl group is substituted by a carbon-carbon triple bond.
  • Heterocyclic alkynyl group means that at least one carbon-carbon single bond in a heterocycloalkyl group is substituted by a carbon-carbon triple bond.
  • Aryl A moiety as a group or a group means: (1) an aromatic monocyclic or fused ring: an aromatic carbocyclic ring having 5 to 12 carbon atoms is preferred (rings in which the ring atoms are all carbon) Structure).
  • aryl groups include, but are not limited to: phenyl, naphthyl; (2) may be attached to a partially saturated carbocyclic ring, for example: phenyl and C 5 _ 7 cycloalkyl or C 5 -7 cycloalkenyl group They are fused to each other to form a ring structure. Examples include, but are not limited to, tetrahydronaphthyl, anthracenyl or hydroquinone. An aryl group can be substituted with one or more substituents.
  • Heteroaryl means a monocyclic or fused polycyclic aromatic heterocycle. Preference is given to a 5-7 member aromatic ring containing one or more heteroatoms selected from N, 0 or / and S.
  • Typical heteroaryl substituents include, but are not limited to, furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, pyridine, pyrimidine, pyrazine, indole, benzimidazole and the like.
  • Halogen fluorine, chlorine, bromine and iodine.
  • Acyl refers to the [R-CO-] group, R is alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkyne Base, cycloalkynyl, heteroalkynyl, cycloheteroalkynyl, aryl, heteroaryl.
  • Examples of the acyl group include, but are not limited to, acetyl, propionyl, isobutyryl, benzoyl and the like.
  • Substituted imino group a group obtained by substituting a hydrogen atom in an imino group (-NH-) with a substituent group (-NR -),
  • R is an alkyl group, a cycloalkyl group, a heteroalkyl group, a heterocycloalkyl group Alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heteroalkynyl, cycloheteroalkynyl, aryl, heteroaryl.
  • Examples of acyl groups include, but are not limited to, acetyl, propionyl, isobutyryl, benzoyl and the like.
  • R further includes at least one of the above substituent groups being bridge-derived to obtain Substituents.
  • Substitution Derivatization The process by which one or more hydrogen atoms of a parent compound are replaced by a "substituent group".
  • Bridging group refers to a substituent (-A -) having two linking sites, which can be inserted into a single bond X-Y to form
  • Bridging groups include, but are not limited to, thioether (-S-), ether (-0-), imino (-HN-), substituted imino (-R-), carbonyl (-(CO)- ), sulfonyl (-(S0 2 )-), sulfinyl (-(SO)-).
  • Bridging Derivatization refers to the process of obtaining a new molecular structure by inserting a "bridged group" by one or more single bonds.
  • the single bond to which the bridging group is inserted may be located within the substituent or at the junction of the substituent with other fragments of the molecule.
  • Histone deacetylase inhibitor A compound that inhibits histone deacetylase with an IC50 value of 100 ⁇ M or less.
  • the compounds which are available for reference include, but are not limited to, the molecules shown below:
  • the compound of the above structural formula M 2 is preferably a compound having the following structure:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above inhibitor or a salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above inhibitor for the preparation of a medicament for treating a disease associated with cell differentiation or proliferation, a cardiovascular disease, an immune disease and a neurodegenerative disease or cancer.
  • the invention also provides prodrug compounds of the above inhibitors, various isomeric forms of prodrug compounds, pharmaceutically active metabolites of the inhibitors, metabolites in pharmaceutically acceptable salts, wherein the isomeric forms include non-image isomerism E, Z isomer of the body, mirror image isomer, tautomer, double bond.
  • the present invention also provides pharmaceutically acceptable salts and prodrugs of the above compounds, as well as pharmaceutically active metabolites, and pharmaceutically acceptable salts of these metabolites.
  • the invention also provides various solvated forms of all of the above compounds, particularly hydrated forms of related compounds. And complexes obtained by combining all of the above compounds with a pharmaceutically acceptable dispersant or carrier material, including but not limited to liposomes, nanoparticles, high molecular weight polymers, microemulsions and the like.
  • Prodrug molecules of all of the above compounds are also provided, and prodrugs are converted to the corresponding drug molecules in vivo by means of in vivo metabolism.
  • a pharmaceutically acceptable salt based on the above compound or prodrug compound, and a pharmaceutically active metabolite, and a pharmaceutically acceptable salt of these metabolites refers to certain salts of the drug molecule which are capable of maintaining or partially retaining the original biological activity and which are suitable for medical use.
  • One is the above-mentioned compound or prodrug compound with an acid including but not limited to: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, Arginine, citric acid, fumaric acid, fumaric acid, alkylsulfonic acid, arylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, malonic acid, salicylic acid, gentisic acid, etc. a salt formed by the corresponding anion;
  • an acid including but not limited to: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, Arginine, citric acid, fumaric acid, fumaric acid, alkylsulfonic acid, arylsulfonic acid, hydroch
  • the other is a compound or prodrug compound described above with a certain cation (these cations include but are not limited to ammonium groups, quaternary ammonium cations, lithium ions, sodium ions, potassium ions, magnesium ions, calcium ions, aluminum ions, zinc). a salt formed by an ion or the like;
  • the third is a salt formed by the above-described compound or prodrug compound and a cation formed by protonation of an organic amine, including but not limited to: choline, ethylene glycol amine, morpholine and the like.
  • the present invention also encompasses various isomeric forms of all of the compounds represented by the parent drug molecules or prodrug compounds and salts thereof as described above. Including non-Spiegelmers, Spiegelmers, tautomers, E/Z isomers of double bonds. Any of the above-mentioned optically pure or stereoisomerically pure compounds can be isolated by any chemist with a certain foundation.
  • the present invention also includes the possible elimination of the compound represented by the parent drug molecule or the prodrug compound and the salt thereof as described above.
  • a pharmaceutical composition comprising: the parent drug molecule or prodrug compound of any of the above, and a pharmaceutically acceptable carrier.
  • the present invention includes the parent drug molecule, prodrug compound, salt, stereoisomer or composition of any of the above, as but not limited to a de-histone acetylase inhibitor, alone or in combination with other drugs, diluents
  • excipients and/or other pharmaceutical carriers in combination as a medicament for the preparation of a treatment-related disease.
  • Many of these diseases are known to be involved or partially regulated by HDAC activity.
  • HDAC activity is known to play a role in promoting the onset of the disease, or can be treated by the compounds of the present invention.
  • proliferative disorders eg, cancer
  • neurodegenerative diseases eg, Huntington's disease, polyglutamine disease, Parkinson's disease, Alzheimer's disease, epileptic seizures, striatum substantia nigra, Progressive supranuclear palsy, torsion insufficiency, spastic torticollis and dyskinesia, familial tremor, Tourette syndrome, diffuse Lewy body disease, Pico disease, intracranial hemorrhage, primary lateral sclerosis, spinal cord Muscular muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy-Drager syndrome, etc.
  • metabolism Sexual diseases eg, type 2 diabetes
  • ocular degenerative diseases including glaucoma, age-related macular degeneration, iris red degeneration glaucom
  • the invention is particularly useful as a medicament for the preparation of a tumor for treatment, including but not limited to: breast cancer, lung cancer, ovarian cancer, prostate cancer, head cancer, cervical cancer, rectal cancer, gastric cancer, brain cancer, leukemia and the like.
  • histone deacetylase inhibitor of the parent drug molecule, prodrug compound, salt, stereoisomer or composition according to any of the above may be administered by gastrointestinal administration (oral or rectal administration), or non-stomach Intestinal administration (including but not limited to subcutaneous, intramuscular, intravenous and intradermal).
  • Solid dosage forms for administration include, but are not limited to, capsules, tablets, tablets, powders, granules and microcapsules.
  • a histone deacetylase inhibitor comprising a parent drug molecule, prodrug compound, salt, stereoisomer or composition of any of the above, together with at least one inert and pharmaceutically acceptable excipient or carrier Mix the agents.
  • excipients and carriers include sodium citrate or dicalcium phosphate, and/or: 1) fillers (eg, starch, lactose, sucrose, glucose, mannitol, and salicylic acid); 2) binding agents (eg, carboxy Methylcellulose, alginate, gelatin polyvinylpyrrolidone, sucrose and gum arabic); 3) disintegrants (eg, acacia, calcium carbonate, potato or tapioca, alginic acid, certain silicates and Sodium carbonate); 4) dissolution retarder (eg, paraffin); 5) absorption accelerator (eg, quaternary ammonium compound); 6) wetting agent (eg, Cetyl alcohol, glyceryl monostearate); 7) Adsorbents (eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycol).
  • the solid dosage form can be prepared to have a coating or outer shell.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable inert diluents (e.g., water or other solvents), stabilizers and emulsifiers (e.g., ethyl alcohol, ethyl carbonate, in addition to the active compound).
  • pharmaceutically acceptable inert diluents e.g., water or other solvents
  • stabilizers and emulsifiers e.g., ethyl alcohol, ethyl carbonate, in addition to the active compound.
  • Ethyl acetate benzoic acid alcohol, benzyl benzoate, propylene glycol, 1, 3-butanediol, dimethylformamide, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil, glycerin , tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitan, etc., suspending agents (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitan esters, etc.), wetting agents, sweeteners, Spices, flavoring agents, etc.
  • suspending agents eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitan esters, etc.
  • wetting agents sweeteners, Spices, flavoring agents, etc.
  • compositions for rectal or vaginal administration include, but are not limited to, suppositories; suppositories may be derived from the parent drug molecule, prodrug compound, salt, stereoisomer or composition described in any of the above, with appropriate non-irritating
  • the agent or carrier is obtained by mixing.
  • Dosage forms for topical administration include, but are not limited to, powders, patches, sprays, ointments and inhalants.
  • the parent drug molecule, prodrug compound, salt, stereoisomer or composition according to any of the above is obtained by mixing under sterile conditions with a pharmaceutically acceptable carrier and any adjuvant required.
  • adjuvants include, but are not limited to, any preservatives, buffers and/or mixtures, and the like.
  • Formulations for parenteral administration include, but are not limited to, pharmaceutically acceptable sterile aqueous or nonaqueous solvents, dispersing agents, suspending or emulsifying agents, and powder solutions for injectable sterile aqueous solutions before use.
  • the preferred range of measurement is about 0.01 to 300 mg per kg of body weight per day; a more preferred measurement range is about 0.2 to 80 mg per kg of body weight per day. It is also possible to select an appropriate metering dose for multiple doses per day. Advantages and positive effects of the present invention:
  • histone deacetylase inhibitor having the "branched" structure proposed by the present invention has better biological activity than the existing non-branched compound.
  • Histone deacetylase is a newly established anti-cancer target protein; histone deacetylase inhibitors can also be used as a medicament for the treatment of cardiovascular diseases, immune diseases and neurodegenerative diseases. detailed description:
  • the synthetic route and method used in the present invention can be widely applied to the synthesis of analogs.
  • the following examples are merely illustrative of the synthetic methods of the particular compounds invented. However, there are no restrictions on the synthesis method.
  • the synthesis of the compound which is not described in detail in the examples herein, as long as the appropriate starting material is replaced, according to the chemical common sense, the reaction conditions may be slightly changed if necessary, and the synthesis of the compound is in the art for those skilled in the art. The knowledge within the scope of knowledge is fully achievable.
  • the reagents and materials used in the reaction are mainly from, but not limited to, the following suppliers: Aldrich Chemical Company, Lancaster Synthesis Ltd, and the like.
  • the reaction product was isolated by flash chromatography to give the title compound (J. Org. Chem., 1978, 43: 2923).
  • the reaction product uses 1 H-MR to confirm the structure; in general, s represents a single peak, d represents a doublet, t represents a triplet, m represents a multiplet, br represents a broad peak, dd represents a doublet, and dt represents a doublet. Heavy peak; the unit of coupling constant is Hz. Synthetic route one (the synthesis method of the following embodiment 1 is shown in the synthetic route one.)
  • EDC hydrochloride (287 mg, 1.5 mmol), 2-aminophenol Dl (131 mg, 1.2 mmol), HOBt (270 mg, 2.0 mmol) and P D2 (217 mg, 1 mmol) were added to 5 ml at room temperature In a DMF solvent, triethylamine (144 ⁇ M, 1.0 mmol) was then added. The reaction was stirred at room temperature for 1 hour. 25 mL of ethyl acetate was added to the reaction mixture, followed by washing with 25 ml of a 1 M hydrochloric acid solution, 25 mL of a saturated sodium hydrogen carbonate solution, and 25 mL of a saturated aqueous sodium chloride solution.
  • Enzyme activity assays can be tested using BIOMOL's HDACi test kit (see Journal of Medicinal Chemistry, 2008, 7417-7427.). The experiment was performed on a 96-well plate. The experimental setup included a blank control, a negative control, a positive control, and a compound 5 dose groups (100 nM, 200 nM, 500 nM, 1.0 uM, and 10 uM). The experimental determination was carried out in two stages. The reaction solution in the first stage includes: HDAC enzyme solution (15 uL, 1 U), histone deacetylase inhibitor solution (10 ⁇ L) and HDAC enzyme fluorescent peptide substrate melt (25 uL).
  • Tris buffer solutions containing 50 mM Tris pH 8.0, 137 mM sodium chloride, 2.7 mM potassium chloride, 1 mM magnesium chloride and 1 mg/mL BSA.
  • the reaction solution was reacted at 30 ° C for 45 minutes.
  • second stage first add 50 uL of the "developer” solution in the kit, then react at room temperature for 30 minutes, then read the fluorescence data on the reader (absorbed light: 350 nm, emission: 450 nm).
  • IC50 values were obtained from a series of data using analytical software Prism 4.0.
  • Compounds 1-12 inhibit histone deacetylase with an IC50 value of less than 1 ⁇ . It is therefore capable of acting as an inhibitor of histone deacetylase.
  • Example 3 Histone deacetylase inhibitor inhibits tumor fineness Determination of GI50 value
  • Inoculate the cells Inoculate a single cell suspension with 10% fetal bovine serum, and inoculate 96 to 10000 cells per cell (A549 (uM), HepG2 (uM), MDA-MB-231). Orifice plates, 100 ul per well, 37 ° C, 5% (3 ⁇ 4 cultured for 24 h).
  • Cultured cells cultured at 37 ° C, 5% CO 2 culture, for 72 h.
  • Colorimetric Select the wavelength of 570 nm, measure the absorbance of each well on an enzyme-linked immunosorbent monitor, and record the results.

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Abstract

La présente invention a pour objet des inhibiteurs de l’histone désacétylase possédant une structure ramifiée synthétisée par click chemistry. Les inhibiteurs sont représentés par la formule M1, A étant une chaîne alkyle en C1 à C6, R1 et R2 étant un alkyle, un cycloalkyle, un hétéroalkyle, un hétérocycloalkyle, un alcényle, un cycloalcényle, un hétéroalcényle, un hétérocycloalcényle, un alcynyle, un cycloalcynyle, un hétéroalcynyle, un hétérocycloalcynyle, un aryle ou un hétéroaryle, R1 et R2 pouvant être identiques ou différents. La présente invention concerne également les composés obtenus par modification substituée ou pontée de A, R1 et/ou R2 des inhibiteurs ci-dessus. En outre, lesdits inhibiteurs de l’histone désacétylase peuvent être également utilisés pour la préparation de médicaments destinés au traitement des maladies cardiovasculaires, des maladies immunitaires et des maladies neurodégénératives.
PCT/CN2010/075097 2009-07-10 2010-07-09 Inhibiteurs de l’histone désacétylase possédant une structure ramifiée synthétisée par click chemistry WO2011003365A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089995A1 (fr) * 2010-01-21 2011-07-28 公立大学法人名古屋市立大学 Dérivé de l'acide hydroxamique et inhibiteur de hdac8 l'utilisant
CN103613585A (zh) * 2013-12-05 2014-03-05 天津尚德药缘科技股份有限公司 一种无定型组蛋白去乙酰酶抑制剂,及制备方法和用途

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CN102311398A (zh) * 2011-07-01 2012-01-11 中国科学院广州生物医药与健康研究院 三氮唑类化合物及其制备方法和在制备组蛋白去乙酰化酶i抑制剂中的应用

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WO2004082638A2 (fr) * 2003-03-17 2004-09-30 Syrrx, Inc. Inhibiteurs d'histone deacetylase
WO2005087724A2 (fr) * 2004-03-11 2005-09-22 Altana Pharma Ag Nouvelles hydroxy-6-phenylphenanthridines a substitution amido

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CN1787999A (zh) * 2003-03-17 2006-06-14 塔克达圣地亚哥公司 组蛋白脱乙酰基酶抑制剂

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WO2004082638A2 (fr) * 2003-03-17 2004-09-30 Syrrx, Inc. Inhibiteurs d'histone deacetylase
WO2005087724A2 (fr) * 2004-03-11 2005-09-22 Altana Pharma Ag Nouvelles hydroxy-6-phenylphenanthridines a substitution amido

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089995A1 (fr) * 2010-01-21 2011-07-28 公立大学法人名古屋市立大学 Dérivé de l'acide hydroxamique et inhibiteur de hdac8 l'utilisant
CN103613585A (zh) * 2013-12-05 2014-03-05 天津尚德药缘科技股份有限公司 一种无定型组蛋白去乙酰酶抑制剂,及制备方法和用途

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