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WO2010135908A1 - Dérivés de n-(2-amino-4-pyridyl)benzamide et leurs utilisations - Google Patents

Dérivés de n-(2-amino-4-pyridyl)benzamide et leurs utilisations Download PDF

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Publication number
WO2010135908A1
WO2010135908A1 PCT/CN2010/000712 CN2010000712W WO2010135908A1 WO 2010135908 A1 WO2010135908 A1 WO 2010135908A1 CN 2010000712 W CN2010000712 W CN 2010000712W WO 2010135908 A1 WO2010135908 A1 WO 2010135908A1
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WO
WIPO (PCT)
Prior art keywords
amino
pyridyl
group
benzamide
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2010/000712
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English (en)
Chinese (zh)
Inventor
李建其
冯娟
蔡王平
张子学
殷涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Pharmaceutical Industry
JIANGSU GOWORTH INVESTMENT CO Ltd
Original Assignee
Shanghai Institute of Pharmaceutical Industry
JIANGSU GOWORTH INVESTMENT CO Ltd
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Publication date
Application filed by Shanghai Institute of Pharmaceutical Industry, JIANGSU GOWORTH INVESTMENT CO Ltd filed Critical Shanghai Institute of Pharmaceutical Industry
Publication of WO2010135908A1 publication Critical patent/WO2010135908A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to N-(2-amino-4-pyridyl)benzamide derivatives, a class of histone deacetylase inhibitors for use in the treatment of cancer, leukemia and diseases associated with differentiation and proliferation. Background technique
  • Histone acetylation and deacetylation of chromatin are one of the key aspects regulating gene expression, and abnormal gene expression is the molecular biological basis for tumors and some genetic and metabolic diseases.
  • the degree of histone acetylation is coordinated by histone acetylase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetylase
  • HDAC histone deacetylase
  • HDAC histone deacetylase
  • HDAC histone deacetylase
  • HDAC histone deacetylase
  • the activity of HDAC is related to the occurrence of cancer, immune diseases, certain mental and cardiovascular diseases.
  • HDAC inhibitors increase the level of chromatin histone acetylation, thus leading to the activation of specific genes, which in turn leads to terminal differentiation of cells or apoptosis of cancer cells.
  • Preliminary clinical studies have shown that humans can safely obtain histone hyperacetylation levels by inhibiting the activity of HDAC. Therefore, HDAC has become the latest and most popular target for the development of cancer chemotherapy drugs.
  • Histone deacetylases are a large family, which can be divided into three categories based on sequence identity, the first being rpd3 Similar proteins HDAC 1, HDAC2, HDAC3, HDAC8, HDAC 1 1 These enzymes contain approximately 400-500 amino acids, mainly in the nucleus; the second is yeast HDA1 similar proteins HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC 10, This kind of protein is a protein containing about 1000 amino acids, and its catalytic site is mainly at the C-terminus of the peptide, but HDAC6 also contains a replication catalytic center at the N-terminus; the third is yeast SIR-2 similar Proteins, such proteins contain nicotinamide purine dinucleotide (NAD+)-phase viability.
  • NAD+ nicotinamide purine dinucleotide
  • Hydroxamic acid such as trichostatin (TSA), Suberolanilide hydroxamic acid (SAHA);
  • Heterocyclic compounds such as Depudecina.
  • the first type is hydroxamic acid, which is a reversible HDAC inhibitor.
  • SAHA histone deacetylase inhibitor.
  • the drug is
  • One of the technical problems to be solved by the present invention is to disclose a class of N-(2-amino-4-pyridyl)benzamide derivatives, which are novel histone deacetylase inhibitors, to meet the needs of clinical applications. ;
  • the second technical problem to be solved by the present invention is to disclose the use of the histone deacetylase inhibitor in the preparation of a medicament for treating malignant tumors and treating diseases related to differentiation and proliferation.
  • the histone deacetylase inhibitor of the present invention is a compound having the following chemical structural formula or a salt thereof:
  • R is hydrogen, a fluorenyl group of 1 to 5 carbon atoms, a C 5 or C 6 aliphatic ring, an aromatic ring or a heterocyclic ring, and the aromatic ring or heterocyclic ring may have 1 to 4 substituents, and the substituent may be Is halogen, amino, hydroxy, nitro, cyano, alkyl of 1 to 4 carbon atoms, decyloxy of 1 to 4 carbon atoms, amino fluorenyl group of 1 to 4 carbon atoms, 1 to 4 carbons a fluorenylamino group of an atom, an acyl group of 2 to 4 carbon atoms, an acylamino group of 2 to 4 carbon atoms, a thioalkyl group of 1 to 4 carbon atoms, a trifluoromethyl group, a carboxyl group of 1 to 4 carbon atoms, Alkoxycarbonyl, phenyl or heterocyclic substituent of 1 to 4 carbon atoms;
  • the "aromatic ring" of the present invention has an aromatic cyclic structure and may have a substituent; the substituted phenyl group has 1 to 4 substituents on the benzene ring, and the substituent may be a halogen or a hydroxyl group. a nitro group, a cyano group, a decyloxy group of 1 to 4 carbon atoms, a fluorenyl group or an amino group of 1 to 4 carbon atoms;
  • heterocycle refers to a saturated or unsaturated heterocyclic ring containing one or more heteroatoms (nitrogen, oxygen, sulfur), such as tetrahydropyrrole, dihydropyrazole, piperidine, morpholine, imidazole or Pyridine or the like; the halogen is preferably fluorine, chlorine, bromine or iodine;
  • the mercapto group of 1 to 4 carbon atoms preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • the methoxy group of 1 to 4 carbon atoms is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group;
  • the aminoalkyl group of 1 to 4 carbon atoms is preferably an aminoethyl group, a 1-aminopropyl group or a 2-aminopropyl group;
  • the mercaptoamino group of 1 to 4 carbon atoms is preferably N-methylamino, N-ethylamino or N-isopropylamino;
  • the acyl group of 2 to 4 carbon atoms is preferably an acetyl group, a propionyl group or an isobutyryl group; and the acylamino group having 2 to 4 carbon atoms is preferably an acetylamino group, a propionylamino group, a butyrylamino group or an isobutyryl group.
  • the thioindenyl group of 2 to 4 carbon atoms is preferably a methylthio group, an ethylthio group or a propylthio group;
  • the salt is a hydrochloride, a hydrobromide, a sulfate, a trifluoroacetate or a methanesulfonate, and the salt contains 0.5 to 3 molecules of water of crystallization.
  • Preferred compounds include:
  • V-18N-(2-Amino-4-pyridyl)-4-(1-acetylaminopropyl)benzamide V-19N-(2-amino-4-pyridyl)-4-(1-acetyl Aminoethyl)benzamide, V-20 N-(2-amino-4-pyridyl)-4-(1-acetylamino-2-phenylethyl)benzamide,
  • V-32N-(2-Amino-4-pyridyl)-4-[(3-phenylbenzoyl)aminomethyl]benzoylamine Its structural formula is as follows:
  • the compounds of the present invention can be synthesized by the following methods:
  • the solvent A is: benzene, toluene, dichloromethane, hydrazine, hydrazine-dimethylformamide or thionyl chloride.
  • Compounds I, 11, VI and HBTU are commercially available;
  • Compound IV is synthesized by the method of Heterocyclic C/zem., 23, 669 (1986).
  • Pharmacological tests have shown that the compound of the present invention or a salt thereof not only has a strong inhibitory effect on histone deacetylase, but also has strong differentiation and anti-proliferative activity against certain tumor cells, and has low oral toxicity. It can be used to treat cancer and diseases related to differentiation and proliferation, especially for blood cancer and solid tumors.
  • the invention also relates to a composition
  • a composition comprising a therapeutically effective amount of said compound or Salts and pharmaceutically acceptable carriers, such as perfumes, sweeteners, liquid or solid fillers or diluents, and the like, are conventionally employed, and are prepared by methods known in the art, such as conventional pharmaceutical preparations, such as a tablet, a capsule, a powder, a sugar, a liquid, a suspension or an injection, the preparation usually contains 1 to 70% by weight of the active ingredient, preferably 5 to 50% by weight;
  • the compounds of the present invention can be administered clinically to mammals, including humans, by oral or injection means, especially in oral form.
  • the dosage is 0.0001 ⁇ 200mg/kg body weight per day.
  • the optimal dose will depend on the individual, usually at the beginning of the dose, and then gradually increase the amount. Animal tests have shown that the compounds of the present invention or salts thereof are less toxic.
  • An advantage of the present invention is that the compound and its medicinal preparation have a good therapeutic effect for treating diseases caused by abnormal gene expression, such as tumors, endocrine disorders, immune system diseases, genetic diseases and nervous system diseases. detailed description
  • N-butyryl chloride (0.106 g, 10 mmol) was slowly added to a solution of p-aminomethylbenzoic acid (1.51 g, 10 mmol) in sodium hydroxide (10 ml, 1 mol/L) at room temperature, and stirred at room temperature overnight. The reaction was stopped, and the pH was adjusted to about 6 by 5N hydrochloric acid to precipitate a large amount of solid. Filtered, dried white Color solid (Medium Carrier M-3) 1.70g, yield 76.7%
  • Acetic anhydride (1.02 g, 10 mmol) was slowly added to a p-aminobenzoic acid (1.37 g, 10 mmol) sodium hydroxide solution (10 ml, 1 mol/L) at room temperature, and stirred at room temperature overnight. The reaction was stopped, and the pH was adjusted to about 6 by 5N hydrochloric acid to precipitate a large amount of solid. It was filtered and dried to give a white solid ( Intermediate M.
  • N-butyryl chloride (0.106 g, 10 mmol) was slowly added to a solution of p-aminobenzoic acid (1.37 g, 10 mmol) in sodium hydroxide (10 ml, 1 mol/L) at room temperature, and stirred at room temperature overnight. The reaction was stopped, and the pH was adjusted to about 6 by 5N hydrochloric acid to precipitate a large amount of solid. It was filtered and dried to give a white solid ( Intermediate M-11) 1.70 g, yield 76.7%.
  • Acetic anhydride (1.02 g, 10 mmol) was slowly added to a solution of p-aminoethylbenzoic acid (1.65 g, 10 mmol) in sodium hydroxide (10 ml, 1 mol/L) at room temperature, and stirred at room temperature overnight. The reaction was stopped, and the pH was adjusted to about 6 by 5N hydrochloric acid to precipitate a large amount of solid. It was filtered and dried to give a white solid ( Intermediate M-17) 1.78 g, yield 86%.
  • Acetic anhydride (1.02 g, 10 mmol) was slowly added to a solution of p-aminopropylbenzoic acid (1.79 g, 10 mmol) in sodium hydroxide (10 ml, 1 mol/L) at room temperature, and stirred at room temperature overnight. The reaction was stopped, and the pH was adjusted to about 6 by 5N hydrochloric acid to precipitate a large amount of solid. It was filtered and dried to give a white solid ( Intermediate M-18) 1.83 g, yield 83%.
  • Acetic anhydride (1.02 g, 10 mmol) was slowly added to a solution of 4-(1-amino-2-phenylethyl)benzoic acid (2.41 g, 10 mmol) in sodium hydroxide (10 ml, 1 mol/L) at room temperature. Stir at room temperature overnight. The reaction was stopped, and the pH was adjusted to about 6 by 5N hydrochloric acid to precipitate a large amount of solid. It was filtered and dried to give a white solid ( Intermediate M-20) 2.09 g, yield 74%.
  • V-27 (0,391 g, lmmol) was dissolved in methanol, stannous chloride dihydrate (0.76 g, 4 mmol) was added, and the mixture was heated under reflux for 3 h. After completion of the reaction, methanol was evaporated to dryness, water (100 ml), and saturated potassium carbonate was adjusted to pH 10 The mixture was extracted with methylene chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated.
  • the in vitro inhibitory activity of the histone deacetylase of the compound was determined by reference to the HDAC inhibitor screening kit (Biovision/Catalog #K340-100).
  • the compounds to be tested were separately prepared into a solution of 200 uM and 40 uM, and the inhibition of the compound at this concentration was examined. The results are as follows:
  • the in vitro inhibitory activity of the compound's histone deacetylase IC 5Q value was determined by reference to the HDAC inhibitor screening kit (Biovision/Catalog #K340-100) instructions.
  • the compound was diluted 4 times with DMSO to obtain 10 dilutions, which were 200 ⁇ , 50 ⁇ , 12.5 ⁇ , 3.125 ⁇ , 0.78 ⁇ , 0.19 ⁇ , 4.88 ⁇ -02 ⁇ , 1.22E-02U ⁇ , 3.05 ⁇ -03 ⁇ , 7.6 ⁇ -04 ⁇ ⁇ .
  • the results of the 5 IC IC 5Q values are as follows - Compound IC 50 values ( ⁇ ⁇ )
  • IC50 values obtained by the CCK-8 method are as follows:
  • mice were tested for LD 50 in mice, and administered by intragastric administration.
  • the experimental method was based on the "Modern Pharmacological Experiment” published by Peking Union Medical College and the Joint Press of Beijing Medical University. Method First edition, LD 5Q values are greater than 2g/kg. Acute toxicity test results of some compounds
  • V-8 found LD 50 >2000mg/kg
  • Calcium stearate 2mg Preparation method: The active ingredient is mixed with sucrose and corn starch, moistened with water, stirred evenly, dried, pulverized and sieved, added with calcium stearate, uniformly mixed, and compressed. Each tablet weighs 200 mg and has an active ingredient content of 10 mg.
  • Preparation method The active ingredient is dissolved in water for injection, uniformly mixed, filtered, and the obtained solution is dispensed under sterile conditions into an ampoule, 10 mg per bottle, and the active ingredient content is 2 mg/bottle.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de N-(2-amino-4-pyridyl)benzamide et leurs utilisations, en tant qu'inhibiteurs de l'histone désacétylase. Les inhibiteurs de l'histone désacétylase sont utiles dans le traitement du cancer, de la leucémie et des maladies associées à une différenciation et une prolifération. Les inhibiteurs de l'histone désacétylase sont les composés ou leurs sels représentés par la formule générale suivante.
PCT/CN2010/000712 2009-05-25 2010-05-20 Dérivés de n-(2-amino-4-pyridyl)benzamide et leurs utilisations Ceased WO2010135908A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910051936.6 2009-05-25
CN2009100519366A CN101899001A (zh) 2009-05-25 2009-05-25 N-(2-氨基-4-吡啶基)-苯甲酰胺衍生物及其应用

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WO2010135908A1 true WO2010135908A1 (fr) 2010-12-02

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850236B (zh) 2011-06-27 2016-05-18 国药一心制药有限公司 新型苯甲酰胺类组蛋白去乙酰化酶抑制剂及其应用
CN103420917B (zh) * 2012-05-18 2015-08-19 国药一心制药有限公司 含稠环结构的苯甲酰胺类化合物及其作为抗肿瘤药物应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11335375A (ja) * 1998-05-20 1999-12-07 Mitsui Chem Inc ヒストン脱アセチル化酵素阻害作用を有するベンズアミド誘導体
CN1513839A (zh) * 2003-07-04 2004-07-21 深圳微芯生物科技有限责任公司 具有分化和抗增殖活性的苯甲酰胺类组蛋白去乙酰化酶抑制剂及其药用制剂
WO2007017728A2 (fr) * 2005-08-05 2007-02-15 Orchid Research Laboratories Limited Nouveaux composes heterocycliques
WO2009152735A1 (fr) * 2008-06-20 2009-12-23 江苏国华投资有限公司 Inhibiteurs d'histone déacétylase et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11335375A (ja) * 1998-05-20 1999-12-07 Mitsui Chem Inc ヒストン脱アセチル化酵素阻害作用を有するベンズアミド誘導体
CN1513839A (zh) * 2003-07-04 2004-07-21 深圳微芯生物科技有限责任公司 具有分化和抗增殖活性的苯甲酰胺类组蛋白去乙酰化酶抑制剂及其药用制剂
WO2007017728A2 (fr) * 2005-08-05 2007-02-15 Orchid Research Laboratories Limited Nouveaux composes heterocycliques
WO2009152735A1 (fr) * 2008-06-20 2009-12-23 江苏国华投资有限公司 Inhibiteurs d'histone déacétylase et leurs utilisations

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