WO2011003365A1 - Histone deacetylase inhibitors with branched structure synthesized through click chemistry - Google Patents

Histone deacetylase inhibitors with branched structure synthesized through click chemistry Download PDF

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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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French (fr)
Chinese (zh)
Inventor
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/en
Publication of WO2011003365A1 publication Critical patent/WO2011003365A1/en

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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.

Abstract

Histone deacetylase inhibitors with branched structure synthesized through click chemistry are disclosed. The inhibitors are represented by formula M1, wherein A is a C1-C6 alkyl chain, R1 and R2 are alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heteroalkynyl, heterocycloalkynyl, aryl or heteroaryl, R1 and R2 can be same or different. Compounds obtained by substituted or bridged modifying A, R1 and/or R2 of the above inhibitors are also included. In addition, the said histone deacetylase inhibitors can also be used for preparing medicaments for treating cardiovascular diseases, immune diseases and neurodegenerative diseases.

Description

点击化学合成的具有分支结构的组蛋白去乙酰酶抑制剂 技术领域： 本发明属于生物医药技术领域， 特别涉及一种点击化学合成的具有"分支" 结构的组蛋白去乙酰化酶抑制剂， 该类抑制剂可作为制备治疗心血管疾病， 免疫类疾病和 神经退行性疾病药物的应用。  FIELD OF THE INVENTION 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.
背景技术： 赖氨酸残基的乙酰化和去乙酰化是一对可逆的蛋白质转录后修饰过程。 催 化该可逆过程的两个酶分别是 HDAC(组蛋白去乙酰化酶， histone deacetylase)和 HAT(组蛋 白乙酰基转移酶， histone acetyltransferase)。 HAT和 HDAC通过协同作用， 共同决定底物 蛋白的乙酰化程度，进而调控细胞内众多的理化过程 (如蛋白的结合和转运,信号传导和基因 表达等；)。 已知的 HDAC/HAT的底物蛋白包括： 组蛋白， 微管蛋白， Hsp90和转录因子 (如 p53， F- B, Ku70和 Stat3)等。 其中， 组蛋白是研究的最早和最多的底物蛋白， HDAC和 HAT的命名也由此而来。 HDAC和 HAT对组蛋白的乙酰化修饰是表观遗传学中调控基因 表达的一种重要方式。  BACKGROUND OF THE INVENTION The acetylation and deacetylation of lysine residues is a pair of reversible post-transcriptional modification processes of proteins. The two enzymes that catalyze this reversible process are HDAC (histone deacetylase, histone deacetylase) and HAT (histone acetyltransferase). HAT and HDAC work together to determine the degree of acetylation of substrate proteins, thereby regulating numerous physicochemical processes in the cell (such as protein binding and transport, signal transduction and gene expression;). 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.
现有的临床研究和药理研究表明， HDAC是治疗许多疾病的 (潜在)靶点，这些疾病包括: 癌症， 心血管疾病， 免疫类疾病和神经退行性疾病等。 临床前研究表明， 组蛋白去乙酰化 酶抑制剂可选择性地杀死癌细胞,并且和许多的抗癌药物有很好的增效作用。 2006年十月， 由美国默克公司研发的辛二酰苯胺异羟肟酸成为了第一个获准的 HDAC靶向药物。  Existing clinical studies and pharmacological studies have shown that HDAC is a (potential) target for the treatment of many diseases, including cancer, cardiovascular disease, immune diseases and neurodegenerative diseases. Preclinical studies have shown that histone deacetylase inhibitors selectively kill cancer cells and have a good synergistic effect with many anticancer drugs. In October 2006, suberic anilide hydroxamic acid developed by Merck USA became the first approved HDAC targeted drug.
我们曾发表过用点击化学合成具有 "非分支"结构的组蛋白去乙酰化酶抑制剂的方法 (Journal of Medicinal Chemistry, 2008， 7417-7427)。 其相关的七个化合物的结构如下：  We have published a method for synthesizing a histone deacetylase inhibitor having a "non-branched" structure by click chemistry (Journal of Medicinal Chemistry, 2008, 7417-7427). The structure of its seven related compounds is as follows:
Figure imgf000003_0001
Figure imgf000003_0001
总体而言， 这类"非分支"的组蛋白去乙酰化酶抑制剂分子的生物活性相对较差。  Overall, the biological activity of such "non-branched" histone deacetylase inhibitor molecules is relatively poor.
发明内容：本发明所要解决的技术问题是提供一种新的点击化学合成的具有"分支"结构 的组蛋白去乙酰化酶抑制剂， 所公开的内容包括： 化合物的结构， 制备方法和应用。 本发 明的创新在于： 1 ) 通过引入"分支"结构来增强组蛋白去乙酰化酶抑制剂的生物活性； 2) 通过使用手性氨基酸来方便地合成具有手性"分支"结构的组蛋白去乙酰化酶抑制剂。  SUMMARY OF THE INVENTION 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.
本发明提供的利用点击化学合成的具有"分支"结构的组蛋白去乙酰化酶抑制剂（即母体 药物分子）， 该抑制剂是具有如下结构通式 的化合物：
Figure imgf000004_0001
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:
Figure imgf000004_0001
其中， A是一个 d-C6的烷基链， Ri和 R2是被取代基取代或未被取代的烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂环烯基， 链炔基， 环炔基， 杂炔基， 环 杂炔基， 芳基， 或杂芳基， 其中 和 可以相同或不同； Wherein A is a dC 6 alkyl chain, and 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;
其中， 取代基选自烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂 环烯基， 链炔基， 环炔基， 杂炔基， 环杂炔基， 芳基， 杂芳基， 卤素， -CF3， -OCF3, 羧基 ( -COOH), 磺酸基 (-S03H)， 氰基 (-CN), 羟基 （-OH), 氨基 (- H2)， 或硝基 （-N02); 优选地， 在 、 或 中的至少一个单键中间可以插入桥接基团， 桥接基团选自硫醚 基 （-S-) , 醚基 （-0-)， 亚氨基 （-HN -)， 羰基 （-(CO) -)， 磺酰基 （-(S02)-)， 或亚磺酰基 ( -(SO)-); Wherein 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)-), sulfonyl group (-(S0 2 )-), or sulfinyl group (-(SO)-);
优选地， 结构通式 Mi的化合物是具有如下结构通式 M2的化合物： Preferably, the compound of the formula Mi is a compound having the structural formula M 2 as follows:
Figure imgf000004_0002
Figure imgf000004_0002
其中， Xi、 X2、 X3和 X4是 N或 CR3 ; 可以是 NR3， S或 O; Q2可以是 N或 CR3。 其中 R3选自 H， 烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂环 烯基，链炔基，环炔基，杂炔基，环杂炔基，芳基，杂芳基，卤素， -CF3， -OCF3,羧基（-COOH), 磺酸基 (-S03H)， 氰基 (-CN), 羟基 （-OH), 氨基 (- H2)， 或硝基 （-N02); 优选 R3是 H 其中， CR3和 NR3中的 C、 N与 R3之间插入桥接基团， 或 R3不为 H的取代基时， 该取 代基的至少某一个单键中间插入桥接基团， 桥接基团选自硫醚基 （-S-) , 醚基 （-0-)， 亚 氨基（-HN -)，取代亚氨基（-NR-) , 羰基（-(CO) -)，磺酰基（-(S02)-)，或亚磺酰基（-(SO)-); 本发明中所涉及术语的含义如下： Wherein, 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 . Wherein 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 3 , or R 3 is not When a substituent of H is substituted with at least one single bond of the substituent, a bridging group is selected from a thioether group (-S-), an ether group (-0-), an imino group (-HN-) Substituted imino (-NR-), carbonyl (-(CO)-), sulfonyl (-(S0 2 )-), or sulfinyl (-(SO)-); meaning of terms used in the present invention as follows:
垸基:是指直链或带有支链的脂肪烃基团；优先选择为 d-C14的烷基;更优先的选择为 1() 的烷基； 最优先的选择为 d-C6。 实施例包括但不局限于： 甲基， 乙基， 正丙基， 2—丙基， 正丁基， 异丁基， 特丁基， 己基等。 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.
环烷基: 是指饱和或部分饱和的单环、 稠环或螺环之碳环。 以 3-9个碳原子组成的环为优 先选择。 实例包括但不限于： 环丙基、 环丁基、 环戊基、 环己基等。 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.
杂垸基: 是指直链或含有支链烷基的基团， 并且在主链中， 至少含有一个或多个选自 S， 0 和 N的杂原子。 优先选择含有 2-14个原子的链。 杂烷基包括但不限于： 醚类、 硫醚类、 烷 基酯类， 第二或第三烷基胺类、 烷基亚磺酸等。 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.
杂环垸基: 是指至少含有一个选自 N， S， 0的杂原子的环烷基。 优选含有 1-3个杂原子。 优选的环为 3-14员环， 更优先选择的环为 4-7员环。 杂环烷基包括， 但不限于： 吡咯烷基、 二氢吡咯基、 四氢吡咯基、 二氢吡唑基、 哌啶基、 吗啉四氢呋喃基、 四氢硫代呋喃基、 四 氢吡喃基等。 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.
链烯基: 作为一基团的一部分时是指至少含有一个碳-碳双键的脂肪烃基团， 可以作为直链 也可以带有支链。 优先选择具有 C2-C14的烯基。 12则更好； 最为优先选择的是 C2-C6的 烯基。 该基团可在其主链中含有多个双键且其构象可各自为 £或2。 烯基基团的例子包括， 但不限于： 乙烯基、 丙烯基等。 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.
环烯基: 是指环烷基中至少某一个碳碳单键被一个碳碳双键所取代。 Cycloalkenyl: means that at least one carbon-carbon single bond in a cycloalkyl group is substituted by a carbon-carbon double bond.
杂烯基: 是指杂烷基中至少某一个碳碳单键被一个碳碳双键所取代。 Heteroalkenyl: means that at least one carbon-carbon single bond in a heteroalkyl group is replaced by a carbon-carbon double bond.
杂环烯基: 是指杂环烷基中至少某一个碳碳单键被一个碳碳双键所取代。 Heterocyclenyl: means that at least one carbon-carbon single bond in a heterocycloalkyl group is substituted by a carbon-carbon double bond.
链炔基: 作为一基团的一部分时是指至少含有一个碳-碳三键的脂肪烃基团， 可以作为直链 也可以带有支链。 优先选择具有 C2-C14的炔基。 12则更好； 最为优先选择的是 C2-C6的 炔基。 该基团可在其主链中含有多个双键且其构象可各自为 £或2。 炔基基团的例子包括， 但不限于： 乙炔基、 丙炔基等。 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.
环炔基: 是指环烷基中至少某一个碳碳单键被一个碳碳三键所取代。 Cycloalkynyl group means that at least one carbon-carbon single bond in a cycloalkyl group is substituted by a carbon-carbon triple bond.
杂炔基: 是指杂烷基中至少某一个碳碳单键被一个碳碳三键所取代。 Heteroalkynyl group means that at least one carbon-carbon single bond in a heteroalkyl group is substituted by a carbon-carbon triple bond.
杂环炔基: 是指杂环烷基中至少某一个碳碳单键被一个碳碳三键所取代。 Heterocyclic alkynyl group means that at least one carbon-carbon single bond in a heterocycloalkyl group is substituted by a carbon-carbon triple bond.
芳基: 作为一基团或一基团的部分是指： （1 )芳香性的单环或稠环： 优先选择具有 5-12个 碳原子的芳香性碳环 （环原子均为碳的环状构造）。 芳基的实例包括， 但不限于： 苯基、 萘 基； （2)可以连接部分饱和的碳环， 例如： 苯基和 C5_7环烷基或 C5_7环烯基基团系互相稠合 而形成一环状结构。 实例包括， 但不限于： 四氢萘基、 茚基或氢茚基等。 芳基基团可被一 个或多个取代基取代。 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). Examples of 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.
杂芳基: 是指单环性或稠合的多环芳香杂环。 优先选择含有一个或多个选自 N， 0或 /和 S的 杂原子 5-7员芳香环。 典型的杂芳基取代基包括实例， 但不限于： 呋喃基， 噻吩基， 吡咯， 吡唑， 三唑， 噻唑， 吡啶， 嘧啶， 吡嗪， 吲哚， 苯并咪唑等。 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.
卤素: 氟， 氯， 溴和碘。  Halogen: fluorine, chlorine, bromine and iodine.
酰基: 是指 [R-CO-]基团， R为烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯 基， 杂环烯基， 链炔基， 环炔基， 杂炔基， 环杂炔基， 芳基， 杂芳基。 酰基的实例包括但 不局限于： 乙酰基、 丙酰基、 异丁酰基、 苯甲酰基等。 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.
取代亚氨基： 是指亚氨基 （-NH-) 中的氢原子被取代基团取代后得到的基团 （-NR -)， R为烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂环烯基， 链炔基， 环炔基， 杂炔基， 环杂炔基， 芳基， 杂芳基。 酰基的实例包括但不局限于： 乙酰基、 丙酰 基、 异丁酰基、 苯甲酰基等。 R还包括上述取代基团中至少一个单键被桥接衍生化而得到 的取代基。 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.
取代基团: 包括但不局限于烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂环烯基， 链炔基， 环炔基， 杂炔基， 环杂炔基， 芳基， 杂芳基， 卤素， =0， = S， -CF3，Substituent groups: including but not limited to alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, Heteroalkynyl, cycloheteroalkynyl, aryl, heteroaryl, halogen, =0, = S, -CF 3 ,
-OCF3,羧基（-COOH),磺酸基 (-S03H)，氰基 (-CN)，羟基（-OH)，氨基 (- H2)，硝基（-N02)。 取代衍生化: 母体化合物的一个或多个氢原子被 "取代基团"取代的过程。 -OCF3, carboxy (-COOH), sulfonic acid (-S0 3 H), cyano (-CN), hydroxy (-OH), amino (-H 2 ), nitro (-N0 2 ). Substitution Derivatization: The process by which one or more hydrogen atoms of a parent compound are replaced by a "substituent group".
桥接基团: 是指具有两个连接位点的取代基 （-A -)， 它们可以插入某一单键 X-Y中， 形成Bridging group: refers to a substituent (-A -) having two linking sites, which can be inserted into a single bond X-Y to form
X-A-Y的新结构。 桥接基团包括但不局限于： 硫醚基（-S-) , 醚基（-0-)， 亚氨基（-HN -)， 取代亚氨基 (- R-) ，羰基 (-(CO)-), 磺酰基 (-(S02)-)， 亚磺酰基 (-(SO) -)。 The new structure of XAY. Bridging groups include, but are not limited to, thioether (-S-), ether (-0-), imino (-HN-), substituted imino (-R-), carbonyl (-(CO)- ), sulfonyl (-(S0 2 )-), sulfinyl (-(SO)-).
桥接衍生化: 某一个取代基被桥接衍生化是指， 通过某一个或多个单键被插入"桥接基团" 而得到新分子结构的过程。 被插入桥接基团的单键可以位于取代基内， 或位于该取代基与 分子的其它片段的连接处。 Bridging Derivatization: The derivatization of a substituent by bridging 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.
组蛋白去乙酰化酶抑制剂: 抑制组蛋白去乙酰化酶的 IC50值为 100 μ Μ或更低的化合物。 Histone deacetylase inhibitor: A compound that inhibits histone deacetylase with an IC50 value of 100 μM or less.
根据结构通式 Μ2所述的结构， 其可供参考的化合物包括但不局限于如下所示的分子： According to the structure of the structural formula Μ 2 , the compounds which are available for reference include, but are not limited to, the molecules shown below:
Figure imgf000007_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000013_0001
11
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
11
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000016_0001
≤9€e00/Il0Z OAV i.60S.0/0T0ZN3/13d /s/u O z-z-ososld S9i00iAV ≤9€e00/Il0Z OAV i.60S.0/0T0ZN3/13d /s/u O zz-ososld S9i00iAV
上述结构通式 M2的化合物优选为具有如下结构的化合物: The compound of the above structural formula M 2 is preferably a compound having the following structure:
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000018_0001
Figure imgf000019_0001
本发明还提供了一种药物组合物， 该组合物包含权利要求上述抑制剂或其盐， 以及药 学上可接受的载体。  The present invention also provides a pharmaceutical composition comprising the above inhibitor or a salt thereof, and a pharmaceutically acceptable carrier.
本发明还提供了上述抑制剂在制备治疗与细胞分化或增殖相关的疾病， 心血管疾病， 免疫类疾病和神经退行性疾病或癌症的药物中的用途。  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.
本发明还提供了上述抑制剂的前药化合物， 前药化合物的各种异构形式， 抑制剂的医 药活性代谢物， 代谢物在药学上可接受的盐， 其中异构形式包括非镜像异构体、 镜像异构 体、 互变异构体、 双键的 E/Z异构体。  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.
本发明还提供了以上化合物所相应的药学上可接受的盐和前药， 以及医药活性代谢物， 和这些代谢物在药学上可接受的盐。 本发明还提供了以上所有化合物的各种溶剂化形式， 特别是相关化合物的水合物形式。 以及以上所有化合物通过和药学上可接受的分散剂或载 体物质相结合所得到的复合物， 包括但不局限于脂质体， 纳米颗粒， 高分子聚合物， 微乳 等。 还提供了以上所有化合物的前药分子， 前药是指借助于体内代谢的方式将其于体内转 化为相应的药物分子。  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.
一种基于上述化合物或前药化合物所相应的药学上可接受的盐， 以及医药活性代谢物， 和这些代谢物在药学上可接受的盐。 所述的药学上可接受的盐是指药物分子在能保持或部 分保持原有生物活性， 并且适用于医药用途的某些盐类。  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. The pharmaceutically acceptable salt 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.
这些盐类包括三种形式：  These salts include three forms:
一是以上所述的化合物或前药化合物与某种酸（这些酸包括但不局限于： 甲酸， 乙酸， 丙酸， 琥珀酸， 甘醇酸， 葡萄糖酸， 乳酸， 苹果酸， 酒石酸， 甘氨酸， 精氨酸， 柠檬酸， 反丁烯二酸， 反丁烯二酸， 烷基磺酸， 芳基磺酸， 盐酸， 硫酸， 磷酸， 草酸， 丙二酸， 水 杨酸， 龙胆酸等） 所对应的阴离子所形成的盐；  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;
另一种是以上所述的化合物或前药化合物与某种阳离子 （这些阳离子包括但不局限于 铵基， 季铵基阳离子， 锂离子， 钠离子， 钾离子， 镁离子， 钙离子， 铝离子， 锌离子等） 所形成的盐；  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;
第三种是以上所述的化合物或前药化合物与有机胺质子化后形成的阳离子所形成的 盐， 这些有机胺包括但不局限于： 胆碱， 乙二醇胺， 吗啉等。 立体异构体：  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. Stereoisomers:
本发明还包括以上所述的母体药物分子或前药化合物及其盐所表示的所有化合物的各 种异构形式。 包括非镜像异构体， 镜像异构体， 互变异构体， 双键的 E/Z异构体。 任何具 有一定基础的化学工作者均可分离出上述光学纯或者立体异构纯的化合物。  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.
本发明还包括以上所述的母体药物分子或前药化合物及其盐所表示的化合物的可能消 旋体或 /和镜像异构物或 /和非镜像异构物的混合物。 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 mixture of a polar or/and mirror image isomer or/and a non-an image isomer.
一种药物组合物， 它包含： 以上任一项所述的母体药物分子或前药化合物以及药学上 可接受的载体。  A pharmaceutical composition comprising: the parent drug molecule or prodrug compound of any of the above, and a pharmaceutically acceptable carrier.
上述化合物的医学应用  Medical application of the above compounds
本发明包括以上任一项所述的母体药物分子、 前药化合物、 盐、 立体异构体或组合物 作为但不局限于去组蛋白乙酰化酶抑制剂， 单独， 或者与其它药物， 稀释剂， 赋形剂和 /或 其它药物载体联合使用， 来作为制备治疗相关疾病的药物的应用。 这些疾病已有许多已知 涉及或部分藉由 HDAC活性所调节。在下一段落所列出的疾病中， 已知 HDAC活性对于促 进使疾病发作扮演某种角色， 或者可藉由本发明的化合物加以治疗。  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 The use of 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. In the diseases listed in the next paragraph, 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.
这些病症包括但不限于增生性病症（如癌症）， 神经变性疾病 （如， 亨廷顿病， 聚谷氨 酰胺病， 帕金森病， 阿尔茨海默病， 癫痈发作， 纹状体黑质变性， 进行性核上性麻痹， 扭 转张力不全， 痉挛性斜颈和运动障碍， 家族性震颤， 抽动秽语综合症， 弥漫性 Lewy体疾 病， 皮克病， 颅内出血， 原发性侧索硬化症， 脊髓性肌肉萎缩症， 肌萎缩侧索硬化症， 肥 大性间质性多神经病， 视网膜色素变性， 遗传性视神经萎缩， 遗传性痉挛性截瘫， 进行性 共济失调症和 Shy— Drager症候群等）， 代谢性疾病（如， II型糖尿病）， 眼部退化疾病（包 括， 青光眼， 老年黄斑变性， 虹膜红变性青光眼）， 炎性疾病和 /或免疫系统病症 （如， 类 风湿关节炎， 骨性关节炎， 青少年慢性关节炎， 移植物抗宿主病， 牛皮癣， 哮喘， 脊椎关 节病， 克罗恩病， 炎性肠病， 结肠溃疡， 酒精型肝炎， 糖尿病， Sjoegrens综合症， 多发性 硬化症， 强直性脊椎炎， 膜性肾小球病， 椎间盘性疼痛， 全身性红斑狼疮等）， 涉及血管新 生的疾病 （如， 癌症， 牛皮癣， 类风湿性关节炎等）， 心理疾病 （如， 双向性神经障碍， 精 神分裂症， 躁狂症， 抑郁， 痴呆等）， 心血管疾病 （如， 心力衰竭， 再狭窄， 动脉硬化等）， 纤维化疾病 （如， 肝纤维化， 囊性纤维化， 血管纤维瘤等）， 感染性疾病 （如， 真菌感染， 病毒性感染， 原虫感染等）， 造血性疾病 （如， 海洋性贫血， 镰状细胞性贫血等）。  These conditions include, but are not limited to, 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 glaucoma), inflammatory diseases and/or immune system disorders (eg, rheumatoid arthritis, osteoarthritis) , juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, Crohn , inflammatory bowel disease, colon ulcer, alcoholic hepatitis, diabetes, Sjoegrens syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, intervertebral disc pain, systemic lupus erythematosus, etc.), involving angiogenesis Diseases (eg, cancer, psoriasis, rheumatoid arthritis, etc.), mental illness (eg, two-way neurological disorders, schizophrenia, mania, depression, dementia, etc.), cardiovascular disease (eg, heart failure, Restenosis, arteriosclerosis, etc., fibrotic diseases (eg, liver fibrosis, cystic fibrosis, angiofibroma, etc.), infectious diseases (eg, fungal infections, viral infections, protozoal infections, etc.), hematopoietic diseases (eg, marine anemia, sickle cell anemia, etc.).
本发明尤其是可以作为制备治疗肿瘤的药物的应用， 肿瘤类型包括但不局限于： 乳癌， 肺癌， 卵巢癌， 前列腺癌， 头癌， 颈癌， 直肠癌， 胃癌， 脑癌， 白血病等。  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.
以上任一项所述的母体药物分子、 前药化合物、 盐、 立体异构体或组合物的组蛋白去 乙酰化酶抑制剂可以通过胃肠给药（口服或直肠给药）， 或非胃肠给药（包括但不局限于皮 下， 肌肉， 静脉内和皮肤内等途径）。  The 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).
服给药的固体剂型包括但不局限于： 胶囊， 药锭， 药片， 粉末， 颗粒和微胶囊。 含有 以上任一项所述的母体药物分子、 前药化合物、 盐、 立体异构体或组合物的组蛋白去乙酰 化酶抑制剂与至少一种惰性并且药学上可接受的赋形剂或载剂混合。 这些赋形剂和载剂包 括柠檬酸钠或磷酸二钙， 和 /或： 1 ) 填充剂 （如， 淀粉， 乳糖， 蔗糖， 葡萄糖， 甘露醇和 水杨酸）； 2) 结合剂 （如， 羧甲基纤维素， 褐藻酸盐， 明胶聚乙烯吡咯烷酮， 蔗糖和阿拉 伯胶）； 3 ) 崩解剂 （如， 洋菜胶， 碳酸钙， 马铃薯或树薯淀粉， 褐藻酸， 某些硅酸盐和碳 酸钠）； 4) 溶解延迟剂 （如， 石蜡）； 5 ) 吸收加速剂 （如， 季铵化合物）； 6) 润湿剂 （如， 鲸蜡醇， 单硬脂酸甘油酯）； 7) 吸附剂 （如， 滑石粉， 硬脂酸钙， 硬脂酸镁， 固体聚乙二 醇）。 固体剂型可制备成具有涂层或外壳。 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. These 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.
口服给药的液态剂型除了活性化合物以外， 还包括但不局限于药学上可接受的惰性稀 释剂 （如， 水或其它溶剂）， 稳定剂和乳化剂 （如， 乙基醇， 碳酸乙酯， 乙酸乙酯， 苯甲酸 醇， 苯甲酸苯甲酯， 丙二醇， 1， 3—丁二醇， 二甲基甲酰胺， 棉籽油， 花生油， 玉米油， 胚芽油， 橄榄油， 蓖麻油， 芝麻油， 甘油， 四氢呋喃醇， 聚乙二醇和山梨醇酐的脂肪酸酯 类等）， 悬浮剂 （如， 乙氧化异硬脂基醇类， 聚氧乙烯山梨醇酐酯等）， 润湿剂， 甜味剂， 香料和调香剂等。  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). 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.
用于直肠或阴道给予的优选组合物包括但不仅限于栓剂； 栓剂可由以上任一项所述的 母体药物分子、 前药化合物、 盐、 立体异构体或组合物与适当的非剌激性赋形剂或载体混 合而得。  Preferred 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.
用于局部给药的剂型包括但不局限于粉末， 贴片， 喷剂， 油膏和吸入剂。 以上任一项 所述的母体药物分子、 前药化合物、 盐、 立体异构体或组合物在无菌条件下与药学上可接 受的载体和所需的任何辅剂混合而得。 这些辅剂包括但不限于任何防腐剂， 缓冲剂和 /或混 合剂等。  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. These adjuvants include, but are not limited to, any preservatives, buffers and/or mixtures, and the like.
非肠道注射用药配方包括但不局限于药学上可以接受的无菌水剂或非水溶剂， 分散剂， 悬浮剂或乳化剂以及使用前才配成可注射的无菌水溶液的粉针剂。  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.
优先选择的计量范围为每公斤体重每天约 0.01— 300 毫克； 更优选的计量范围为每公 斤体重每天约 0.2— 80毫克。 也可以选择适当的计量每天多次分剂给药。 本发明的优点和积极效果：  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:
本发明提出的具有"分支"结构的组蛋白去乙酰化酶抑制剂，比已有的非分支化合物具有 更好的生物活性。 组蛋白去乙酰化酶是新近确立的抗癌靶点蛋白； 组蛋白去乙酰化酶抑制 剂也可作为制备治疗治疗心血管疾病， 免疫类疾病和神经退行性疾病药物的应用。 具体实施方式：  The 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:
化学合成实例  Chemical synthesis example
本发明所用的合成路线和方法， 可以广泛应用于类似物的合成。 下面的实施例仅仅是 用来说明所发明的具体化合物的合成方法。 但在合成方法上没有任何限制。 本文实施例没 有详述的化合物的合成， 只要更换合适的原始原料， 依据化学常识， 在有必要时稍微更改 一下反应条件即可， 而对于本领域技术人员， 这种化合物的合成是在其所掌握的知识范围 内完全可以实现的。  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.
反应所使用的试剂和原料主要来自但不仅限于以下供应商： Aldrich Chemical Company, Lancaster Synthesis Ltd等。反应产物通是用快速层析分离得到目标化合物（J. Org. Chem. , 1978， 43： 2923 )。 反应产物使用 1 H- MR来确证结构； 通常， s表示单峰， d表 示双峰， t表示三重峰， m表示多重峰， br表示宽峰， dd表示双重峰， dt表示三重峰的双 重峰； 偶合常数的单位是 Hz。 合成路线一 （以下实施 1的合成方法如合成路线一所示。） 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.)
Figure imgf000022_0001
实施例 1 化合物 1的合成方法 步骤一： 合成化合物 D3
Figure imgf000022_0001
Example 1 Synthesis of Compound 1 Step 1: Synthesis of Compound D3
EDC的盐酸盐 (287 mg, 1.5 mmol), 2-氨基苯酚 Dl(131 mg, 1.2 mmol), HOBt(270 mg, 2.0 mmol)禾 P D2(217 mg, 1 mmol)于室温下加入到 5ml DMF溶剂中， 然后加入三乙基胺（ 144 μΐ, 1.0 mmol). 反应在室温下搅拌 1小时。反应的混合物中加入 25 mL乙酸乙酯，然后用 25 ml 1M的盐酸溶液, 25 mL饱和碳酸氢钠溶液，和 25mL饱和氯化钠水溶液依次洗涤。有机 相溶液用无水硫酸镁干燥后， 减压蒸除溶剂。 所得粗产物使用硅胶柱分离 （流动相： 石油 醚 /乙酸乙酯 = 5/1 ) ， 得到黄色固体产品 D3 275mg (分离产率 90%)。 步骤二： 合成化合物 D4  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 μM, 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. After the organic phase solution was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained crude product was separated using a silica gel column (mobile phase: petroleum ether / ethyl acetate = 5/1) to afford product 353 (yield: 90%). Step 2: Synthesis of compound D4
在室温下，将酰胺 D3(100 mg), 三苯基磷 (206 mg, 0.79 mmol) 禾 P 4A分子筛 （4 g/mmol D3) 溶于 4 mL 四氢呋喃，搅拌 1小时，然后温度降低至 0°C，并滴加 DIAD ( 0.16 ml, 0.79 mmol) 的四氢呋喃 （1 ml)溶液。 反应液的温度逐渐升至室温， 并继续搅拌 8个小时。 减压 旋蒸除去溶剂， 然后加入乙醚 (5 ml)， 并在室温下搅拌 1小时。 过滤， 蒸除溶剂， 使用硅胶 柱分离 （流动相： 石油醚 /乙酸乙酯 = 15/1 )得到白色固体 D4 79 mg， 分离产率 74%。 步骤三： 合成化合物 D5  At room temperature, the amide D3 (100 mg), triphenylphosphine (206 mg, 0.79 mmol) and P 4A molecular sieves (4 g / mmol D3) were dissolved in 4 mL of tetrahydrofuran, stirred for 1 hour, then the temperature was lowered to 0 ° C, and a solution of DIAD (0.16 ml, 0.79 mmol) in tetrahydrofuran (1 ml) was added dropwise. The temperature of the reaction solution was gradually raised to room temperature, and stirring was continued for 8 hours. The solvent was evaporated under reduced pressure and diethyl ether (5 ml). Filtration, evaporation of the solvent, EtOAc (EtOAc:EtOAc:EtOAc) Step 3: Synthesis of compound D5
将 D4(290 mg， lmmol) 的二氯甲烷（ 10mL)溶液冷却至 0°C， 加入催化量的三氟乙酸， 让温度逐渐升至室温， 持续搅拌直至原料 D4 消失。 然后， 反应液用饱和碳酸氢钠溶液洗 涤。 所得到的有机相溶液待用。 在另一个反应瓶中， 加入刚制备的 T©¾ (3 mmol) 试剂的二氯甲烷 （10mL) 溶液和催 化量的硫酸铜固体和碳酸钠溶液。 将前述的有机溶液加入。 在加入甲醇， 直至水相和有机 相互相融合为一相溶液。 在室温下搅拌过夜。 于减压下旋蒸除去溶剂， 然后加入 30mL的 二氯甲烷溶剂， 并用水 （30 mL X 3) 洗涤， 干燥后减压下旋蒸除去溶剂， 使用硅胶柱分 离 （流动相： 石油醚 /乙醚 = 20/1 )得到无色液体 D5 165 mg， 分离产率 80%。 A solution of D4 (290 mg, 1 mmol) in dichloromethane (10 mL) was cooled to <RTI ID=0.0>> Then, the reaction solution was washed with a saturated sodium hydrogen carbonate solution. The resulting organic phase solution is ready for use. In a separate reaction vial, a solution of the T©3⁄4 (3 mmol) reagent in dichloromethane (10 mL) and a catalytic amount of copper sulfate solid and sodium carbonate solution were added. The aforementioned organic solution was added. Methanol was added until the aqueous phase and the organic phase were fused to each other as a one-phase solution. Stir at room temperature overnight. The solvent was evaporated under reduced pressure, and then 30 mL of dichloromethane solvent was added, and washed with water (30 mL X 3), dried and evaporated to remove the solvent under reduced pressure, using silica gel column (mobile phase: petroleum ether / ether = 20/1) gave a colorless liquid D5 165 mg, isolated yield 80%.
步骤四： 合成化合物 D7  Step 4: Synthesis of Compound D7
白色固体 D6Clmmol)溶于 20 mL四氢呋喃中，在这个溶液中，顺序加入 188 mg (1.3 mmol) 叠氮化合物 D6、 350 mg (1 mmol)催化剂 P(OEt)3CuI和 0.33 mL(2 mmol)的二异丙基乙胺。 在室温下搅拌， 反应过夜， 并用 TLC板检验反应完全。 减压蒸熘除去溶剂， 残余的固体用 100 mL的二氯甲烷和 100 mL 1%的硫酸铜溶液分离。 水相再用 100 mL的二氯甲烷萃取两 次。 混合的二氯甲烷用无水硫酸钠干燥， 然后减压蒸熘除去二氯甲烷， 过硅胶柱（展开剂： 甲醇： 二氯甲烷 =1 : 100) 纯化产物， 得到 325 mg白色固体 D7， 分离产率 72%。 White solid D6Clmmol) was dissolved in 20 mL of tetrahydrofuran. In this solution, 188 mg (1.3 mmol) of azide D6, 350 mg (1 mmol) of catalyst P(OEt) 3 CuI and 0.33 mL (2 mmol) were added sequentially. Diisopropylethylamine. Stir at room temperature, react overnight, and verify the reaction with a TLC plate. The solvent was removed by distillation under reduced pressure, and the residual solid was separated with 100 mL of dichloromethane and 100 mL of 1% copper sulfate. The aqueous phase was extracted twice more with 100 mL of dichloromethane. The mixed methylene chloride was dried over anhydrous sodium sulfate, and then dichloromethane was evaporated to dryness, and the product was purified by silica gel column (yield: methanol: methylene chloride = 1:100) to give 325 mg of white solid D. The yield was 72%.
步骤五： 合成化合物 1  Step 5: Synthesis of Compound 1
在含有 20mL二氯甲烷的圆底烧瓶中， 顺序加入 200 mg D7、 1 mL (二氯甲烷体积的 5%) 的三氟乙酸和 0.3 mL的三异丙基硅烷。 混合物在室温下搅拌， 并用 TLC板检测反应 的程度。反应完全后，将反应混合物溶于 50 mL乙腈中，并用 DOWEX MARATHO E WB A 阴离子交换树脂中和。 树脂用 25 mL的乙腈洗涤两次。 混合的乙腈减压蒸熘得到固体。 用 C-18反相柱 (展开剂 水： 乙腈 =5: 1-1： : 1)纯化产物得到白色的化合物 1固体 120 mg  In a round bottom flask containing 20 mL of dichloromethane, 200 mg of D7, 1 mL (5% by volume of dichloromethane) of trifluoroacetic acid and 0.3 mL of triisopropylsilane were sequentially added. The mixture was stirred at room temperature and the extent of the reaction was measured using a TLC plate. After completion of the reaction, the reaction mixture was dissolved in 50 mL of acetonitrile and neutralized with DOWEX MARATHO E WB A anion exchange resin. The resin was washed twice with 25 mL of acetonitrile. The mixed acetonitrile was evaporated under reduced pressure to give a solid. Purify the product with a C-18 reverse phase column (developing solvent water: acetonitrile = 5: 1-1:: 1) to afford white compound 1 solid 120 mg
其它所列化合物均可采用类似的合成路线加以合成， 下面的表格中选择列出了部分合 成化合物的核磁谱图. Other listed compounds can be synthesized using a similar synthetic route. The nucleomagnetic spectra of some of the synthesized compounds are listed in the table below.
表 1: 1-12号化合物的结构和核磁谱 Table 1: Structure and NMR spectra of compounds No. 1-12
Figure imgf000024_0001
Figure imgf000024_0001
Figure imgf000025_0001
.60S.0/0T0ZN3/X3d S9CC00/ll0Z OAV
Figure imgf000025_0001
.60S.0/0T0ZN3/X3d S9CC00/ll0Z OAV
.60S.0/0T0ZN3/X3d S9CC00/ll0Z OAV 实施例 2: 组蛋白去乙酰化酶抑制剂的生物活性测试 .60S.0/0T0ZN3/X3d S9CC00/ll0Z OAV Example 2: Biological activity test of histone deacetylase inhibitor
组蛋白去乙酰基酶活性测定  Histone deacetylase activity assay
酶活测定可用 BIOMOL公司的 HDACi测试试剂盒进行测试（参见 Journal of Medicinal Chemistry, 2008, 7417-7427. )。 实验于 96孔板上进行。 实验设置包括空白对照， 阴性对照， 阳性对照和化合物 5个剂量组（ 100 nM, 200 nM, 500 nM, 1.0 uM和 10 uM)。 实验测定分两 个阶段进行。在第一阶段的反应液包括： HDAC酶溶液（15 uL, 1U)， 组蛋白去乙酰化酶抑 制剂溶液（lO uL)和 HDAC酶的荧光多肽底物融液（25 uL)。 这三个溶液都是 Tris的缓冲 溶液（包含 50 mM Tris pH 8.0， 137 mM氯化钠， 2.7 mM氯化钾， 1 mM氯化镁和 lmg/mL 的 BSA)。该反应液在 30°C进行反应 45分钟。在第二阶段，首先加入试剂盒中的 "developer" 溶液 50 uL， 然后在室温下反应 30分钟， 然后在读板机上读取荧光数据（吸收光： 350 nm， 发射光： 450 nm)。 使用分析软件 Prism 4.0自一系列数据中得到 IC50值。  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 μL) and HDAC enzyme fluorescent peptide substrate melt (25 uL). All three solutions were 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. In the 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.
表 2: 1-12号化合物对 Hela细胞提取混酶的 IC50值  Table 2: IC50 values of compounds 1-12 for extracting mixed enzymes from Hela cells
Figure imgf000027_0001
Figure imgf000027_0001
1-12号化合物抑制组蛋白去乙酰化酶的 IC50值为小于 1 μ Μ。 因此其能够作为组蛋白 去乙酰化酶的抑制剂。  Compounds 1-12 inhibit histone deacetylase with an IC50 value of less than 1 μΜ. It is therefore capable of acting as an inhibitor of histone deacetylase.
实施例 3: 组蛋白去乙酰化酶抑制剂抑制肿瘤细 GI50值的测定  Example 3: Histone deacetylase inhibitor inhibits tumor fineness Determination of GI50 value
药物抑制肿瘤细胞生长的 GI50值的测定：  Determination of GI50 values for drug inhibition of tumor cell growth:
1. 接种细胞： 用含 10 %胎牛血清的培养液配成单个细胞悬液， 以每孔 1000— 10000个细 胞（A549(uM)， HepG2(uM), MDA-MB-231 )接种到 96孔板， 每孔体积 100ul， 37°C， 5%(¾培养条件下培养 24h。  1. 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).
2. 加药： 配置不同浓度的药物， 并分别加入到对应的 96孔板， 每个浓度做 3个复孔。 2. Dosing: Configure different concentrations of drugs and add them to the corresponding 96-well plates, and make 3 duplicate wells for each concentration.
3. 培养细胞： 37°C， 5%C02培养条件下， 培养 72h。 3. Cultured cells: cultured at 37 ° C, 5% CO 2 culture, for 72 h.
4. 呈色： 每孔加 MTT溶液 （5mg/ml) 20ul.继续孵育 4小时， 终止培养， 弃去孔内培养上 4. Coloring: Add MTT solution (5mg/ml) to each well 20ul. Continue to incubate for 4 hours, terminate the culture, discard the culture in the well.
5. 清液， 每孔加 150ul DMS0, 振荡 10分钟， 使结晶物充分融解。 5. Clear the solution, add 150ul DMS0 per well, and shake for 10 minutes to fully melt the crystals.
6. 比色： 选择 570nm波长， 在酶联免疫监测仪上测定各孔光吸收值， 记录结果。  6. Colorimetric: Select the wavelength of 570 nm, measure the absorbance of each well on an enzyme-linked immunosorbent monitor, and record the results.
7. 将数值带入 0rigin75软件计算 IC50值。 表 3 : 1-12号化合物抑制肿瘤细胞生长的 GI50值  7. Bring the value into the 0rigin75 software to calculate the IC50 value. Table 3: GI50 values of compounds No. 1-12 inhibiting tumor cell growth
IC50  IC50
化合物编号  Compound number
A549(uM) HepG2(uM) MDA-MB-231  A549(uM) HepG2(uM) MDA-MB-231
1 < 1 < 1 < 1 2 < 1 < 1 < 1 3 < 10 < 10 < 10 4 < 10 < 10 < 10 5 < 10 < 10 < 10 1 < 1 < 1 < 1 2 < 1 < 1 < 1 3 < 10 < 10 < 10 4 < 10 < 10 < 10 5 < 10 < 10 < 10
6 < 10 < 10 < 10 6 < 10 < 10 < 10
7 < 10 < 10 < 107 < 10 < 10 < 10
8 < 10 < 10 < 108 < 10 < 10 < 10
9 < 10 < 10 < 109 < 10 < 10 < 10
10 >20 >20 >2010 >20 >20 >20
11 >20 >20 >2011 >20 >20 >20
12 >20 <20 < 10 本发明的组蛋白去乙酰化酶抑制剂及其用途和制备方法已经通过具体的实施例进行了 描述。 本领域技术人员可以借鉴本发明的内容适当改变原料、 工艺条件等环节来实现相应 的其它目的， 其相关改变都没有脱离本发明的内容， 所有类似的替换和改动对于本领域技 术人员来说是显而易见的， 都被视为包括在本发明的范围之内。 12 > 20 < 20 < 10 The histone deacetylase inhibitor of the present invention, its use and preparation method have been described by way of specific examples. Those skilled in the art can appropriately change the raw materials, process conditions and the like by referring to the content of the present invention to achieve other related purposes, and the related changes are not deviated from the content of the present invention. All similar substitutions and modifications are known to those skilled in the art. It is obvious that it is included in the scope of the present invention.

Claims

1、一种利用点击化学合成的具有"分支"结构的组蛋白去乙酰化酶抑制剂， 该抑制剂为 具有如下结构通式 Mi的化合物： A histone deacetylase inhibitor having a "branched" structure synthesized by click chemistry, the inhibitor being a compound having the following structural formula Mi:
其中， A是一个 d-C6的烷基链， 1¾和 R2是被取代基取代或未被取代的烷基，环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂环烯基， 链炔基， 环炔基， 杂炔基， 环 杂炔基， 芳基， 或杂芳基， 其中 和 可以相同或不同； Wherein A is a dC 6 alkyl chain, and 13⁄4 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;
其中， 取代基选自烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂 环烯基， 链炔基， 环炔基， 杂炔基， 环杂炔基， 芳基， 杂芳基， 卤素， -CF3， -OCF3, 羧 基， 磺酸基， 氰基， 羟基， 氨基， 或硝基。 Wherein 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, sulfonic acid, cyano, hydroxy, amino, or nitro.
2、 根据权利要求 1所述的抑制剂， 在 、 或 中的至少一个单键中间可以插入桥 接基团， 桥接基团选自硫醚基（-S-) , 醚基， 亚氨基（-NH-)，取代亚氨基（-NR -)， 羰基， 磺酰基， 或亚磺酰基。  2. The inhibitor according to claim 1, wherein a bridging group is interposed in at least one of the single bonds, and the bridging group is selected from the group consisting of a thioether group (-S-), an ether group, and an imino group (-NH) -), substituted imino (-NR-), carbonyl, sulfonyl, or sulfinyl.
3、 根据权利要求 1所述的抑制剂， 结构通式 的化合物是具有如下结构通式 M2的 化合物： 3. The inhibitor according to claim 1, the compound of formula is a compound of the general formula M 2 having the following structure:
Figure imgf000029_0002
Figure imgf000029_0002
其中， Xi、 X2、 X3和 X4是 N或 CR3 ; 可以是 NR3， S或 O; Q2可以是 N或 CR3。 其中 R3选自 H， 烷基， 环烷基， 杂烷基， 杂环烷基， 链烯基， 环烯基， 杂烯基， 杂环 烯基， 链炔基， 环炔基， 杂炔基， 环杂炔基， 芳基， 杂芳基， Μ, -CF3, -OCF3, 羧基， 磺酸基， 氰基， 羟基， 氨基， 或硝基。 Wherein, 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 . Wherein R 3 is selected from the group consisting of H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heteroalkyne Base, cycloheteroalkynyl, aryl, heteroaryl, anthracene, -CF 3 , -OCF3, carboxy, sulfonate, cyano, hydroxy, amino, or nitro.
4、 根据权利要求 3所述的抑制剂， 其中， CR3和 NR3中的 C、 N与 R3之间插入桥接 基团， 或 R3不为 H的取代基时， 该取代基的至少某一个单键中间插入桥接基团， 桥接基 团选自硫醚基， 醚基， 亚氨基， 取代亚氨基， 羰基， 磺酰基， 或亚磺酰基。 4, according to claim inhibitor according to claim 3, wherein the insert, in the NR and CR 3 3 C, N and R 3 between the bridging group, R 3 is not H or a substituent group, the substituent is at least A bridging group is intercalated between a single bond, and the bridging group is selected from the group consisting of a thioether group, an ether group, an imino group, a substituted imino group, a carbonyl group, a sulfonyl group, or a sulfinyl group.
5、 根据权利要求 3所述的抑制剂， 其中 是11。  5. The inhibitor according to claim 3, wherein is 11.
6、 根据权利要求 3所述的抑制剂， 该抑制剂为选自如下结构的化合物：
Figure imgf000030_0001
6. The inhibitor according to claim 3, which is a compound selected from the group consisting of:
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000036_0001
34
Figure imgf000037_0001
/s/u O z-z-ososld S9i00iAV 34
Figure imgf000037_0001
/s/u O zz-ososld S9i00iAV
Figure imgf000038_0001
Figure imgf000038_0001
Li Li
Figure imgf000039_0001
Figure imgf000039_0001
S9C£00/llOZ OAV S9C£00/llOZ OAV
Z.60SZ.O/OlOZM3/X3a Z.60SZ.O/OlOZM3/X3a
Figure imgf000040_0001
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0002
38 38
Figure imgf000041_0001
Figure imgf000041_0001
8、 一种药物组合物， 该组合物包含权利要求 1-7任一项所述的抑制剂或其盐， 以及药 学上可接受的载体。  A pharmaceutical composition comprising the inhibitor of any one of claims 1 to 7 or a salt thereof, and a pharmaceutically acceptable carrier.
9、权利要求 1-7任一项所述的抑制剂在制备治疗与细胞分化或增殖相关的疾病， 心血 管疾病， 免疫类疾病和神经退行性疾病或癌症的药物中的用途。  Use of the inhibitor according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of a disease associated with cell differentiation or proliferation, a cardiovascular disease, an immune disease and a neurodegenerative disease or cancer.
10、 权利要求 1-7任一项所述的抑制剂的前药化合物， 前药化合物的各种异构形式， 抑制剂的医药活性代谢物，代谢物在药学上可接受的盐，其中异构形式包括非镜像异构体、 镜像异构体、 互变异构体、 双键的 E/Z异构体。  10. A prodrug compound of the inhibitor of any of claims 1-7, various isomeric forms of the prodrug compound, a pharmaceutically active metabolite of the inhibitor, a metabolite in a pharmaceutically acceptable salt, wherein The conformation includes the non-Spiegelmer, the Spiegelmer, the tautomer, and the double bond E/Z isomer.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089995A1 (en) * 2010-01-21 2011-07-28 公立大学法人名古屋市立大学 Hydroxamic acid derivative and hdac8 inhibitor using same
CN103613585A (en) * 2013-12-05 2014-03-05 天津尚德药缘科技股份有限公司 Amorphous histone deacetylase inhibitor as well as preparation method and application thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102311398A (en) * 2011-07-01 2012-01-11 中国科学院广州生物医药与健康研究院 Triazole compounds, preparation method thereof, and application thereof in preparing histone deacetylase I inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082638A2 (en) * 2003-03-17 2004-09-30 Syrrx, Inc. Histone deacetylase inhibitors
WO2005087724A2 (en) * 2004-03-11 2005-09-22 Altana Pharma Ag Sulphonylpyrroles as hdac inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1787999A (en) * 2003-03-17 2006-06-14 塔克达圣地亚哥公司 Histone deacetylase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082638A2 (en) * 2003-03-17 2004-09-30 Syrrx, Inc. Histone deacetylase inhibitors
WO2005087724A2 (en) * 2004-03-11 2005-09-22 Altana Pharma Ag Sulphonylpyrroles as hdac inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHEN, JIE ET AL.: "Histone Deacetylase Inhibitors through Click Chemistry", J. MED. CHEM., vol. 51, no. 23, 14 November 2008 (2008-11-14), pages 7417 - 7427, XP055061419, DOI: doi:10.1021/jm8005355 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011089995A1 (en) * 2010-01-21 2011-07-28 公立大学法人名古屋市立大学 Hydroxamic acid derivative and hdac8 inhibitor using same
CN103613585A (en) * 2013-12-05 2014-03-05 天津尚德药缘科技股份有限公司 Amorphous histone deacetylase inhibitor as well as preparation method and application thereof

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