WO2010135908A1 - N-(2-amino-4-pyridyl) benzamide derivatives and uses thereof - Google Patents
N-(2-amino-4-pyridyl) benzamide derivatives and uses thereof Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- pyridyl
- group
- benzamide
- mmol
- Prior art date
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- RCYNMOWBHTWDCA-UHFFFAOYSA-N n-(2-aminopyridin-4-yl)benzamide Chemical class C1=NC(N)=CC(NC(=O)C=2C=CC=CC=2)=C1 RCYNMOWBHTWDCA-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 230000004069 differentiation Effects 0.000 claims abstract description 6
- 230000035755 proliferation Effects 0.000 claims abstract description 5
- -1 amino fluorenyl group Chemical group 0.000 claims description 99
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 52
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000006606 n-butoxy group Chemical group 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
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- 238000002425 crystallisation Methods 0.000 claims description 2
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- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004001 thioalkyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000001212 derivatisation Methods 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 125000003544 oxime group Chemical group 0.000 claims 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 abstract description 15
- 229940121372 histone deacetylase inhibitor Drugs 0.000 abstract description 14
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
- 239000007787 solid Substances 0.000 description 71
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 30
- OYTKINVCDFNREN-UHFFFAOYSA-N amifampridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 description 29
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- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 6
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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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Abstract
N-(2-amino-4-pyridyl) benzamide derivatives and uses thereof, which are histone deacetylase inhibitors. The histone deacetylase inhibitors are useful in the treatment of cancer, leukaemia and the diseases associated with differentiation and proliferation. The histone deacetylase inhibitors are the compounds or salts thereof represented as the general formula (I).
Description
N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物及其应用 技术领域 N-(2-amino-4-pyridyl)benzamide derivative and its application
本发明涉及 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 一类组蛋白去 乙酰化酶抑制剂在治疗癌症、 白血病及与分化和增殖相关疾病方面的 应用。 背景技术 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
染色质的组蛋白乙酰化和去乙酰化是调节基因表达的关键环节之 一， 而异常的基因表达是肿瘤及一些遗传和代谢疾病发生的分子生物 学基础。 组蛋白的乙酰化程度， 有组蛋白乙酰化酶 （HAT) 和组蛋白 去乙酰化酶 （HDAC) 协调控制。 当 HDAC 过度表达并被转录因子募 集， 就会导致特定基因的不正常抑制， 从而导致肿瘤和其它疾病。 据 以下文献报道， HDAC 的活性与癌症、 免疫性疾病、 某些精神类、 心 血管类疾病的发生有关。 实验证明， HDAC 抑制剂会使染色质组蛋白 乙酰化水平提高， 因此导致特定基因激活表达， 相应的导致细胞的末 端分化或癌细胞的调亡。 初步的临床研究表明， 人类可以安全地通过 抑制 HDAC的活性来获得组蛋白高乙酰化水平。 因此， HDAC已成为 目前肿瘤化疗药物研发领域最新、 最热门的靶标。 文献： 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). When HDAC is overexpressed and recruited by transcription factors, it can lead to abnormal inhibition of specific genes, leading to tumors and other diseases. According to the following literature, the activity of HDAC is related to the occurrence of cancer, immune diseases, certain mental and cardiovascular diseases. Experiments have shown that 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. Literature:
(1) British Journal of Pharmacology (2007)， 150(7)， 862-872. (1) British Journal of Pharmacology (2007), 150(7), 862-872.
(2) Bioorganic & Medicinal Chemistry (2008), 16(9), 5254-5265. (2) Bioorganic & Medicinal Chemistry (2008), 16(9), 5254-5265.
(3) WO2003083067 (3) WO2003083067
(4) Cancer Letters (2009) , 280( 2), 154-159. (4) Cancer Letters (2009), 280(2), 154-159.
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(9) J. Med. Chem ( 2009 ) ， 52(2)， 267-277. 组蛋白去乙酰酶是个很大的家族， 基于序列的相同性可以把它分 为三类，第一类是 rpd3相似蛋白 HDAC 1、HDAC2、 HDAC3、 HDAC8、 HDAC 1 1 这类酶含有大约 400〜500个氨基酸， 主要存在于细胞核中； 第二类是酵母 HDA1相似蛋白 HDAC4、 HDAC5、 HDAC6、 HDAC7、 HDAC9、 HDAC 10 ， 这类蛋白是含有约 1000 个氨基酸的蛋白， 其 催化部位主要是在肽的 C-端， 但是其中 HDAC6还含有一个复制的催 化中心在 N-端； 第三类是酵母 SIR-2 类似蛋白， 这类蛋白含有烟酰 胺嘌呤二核苷酸 (NAD+)-相存活性。 上述大多数亚型具有结构相似性。 从原核生物到真核生物都具有这些蛋白， 但是大多数还没有得到定性 的研究。 目前国外已报道了几种类型的组蛋白去乙酰化酶抑制剂， 基于它 们的化学结构将其分为以下几种： (9) J. Med. Chem (2009), 52(2), 267-277. 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. Most of the above subtypes have structural similarities. These proteins are found in prokaryotes to eukaryotes, but most have not been qualitatively studied. Several types of histone deacetylase inhibitors have been reported abroad, and are classified into the following based on their chemical structures:
( 1 )羟肟酸（Hydroxamic acid)类， 如 曲古抑菌素（TSA)， Suberolanilide hydroxamic acid (SAHA) ; (1) Hydroxamic acid, such as trichostatin (TSA), Suberolanilide hydroxamic acid (SAHA);
(2)环肽类， 如 Apicidin; (2) cyclic peptides, such as Apicidin;
(3)苯酰胺 (benzamides)类， 如 MS-275 ; (3) Benzamides, such as MS-275;
(4)短链和芳香脂肪酸类， 如丁酸钠； (4) short-chain and aromatic fatty acids, such as sodium butyrate;
(5)杂环化合物类， 如 Depudecina。 以上各类抑制剂中，第一类即羟肟酸类，属可逆性 HDAC抑制剂。 代表药物 SAHA, 是目前唯一上市的组蛋白去乙酰化酶抑制剂。该药于 (5) Heterocyclic compounds such as Depudecina. Among the above various types of inhibitors, the first type is hydroxamic acid, which is a reversible HDAC inhibitor. The representative drug SAHA is currently the only listed histone deacetylase inhibitor. The drug is
2006年 10月 6 日获得美国 FDA批准， 用于其它药物治疗时或治疗后 仍不能治愈、 或恶化、 或病情反复情况下的转移性皮肤 T淋巴细胞瘤 (CTCL)。 第三类即苯酰胺 （benzamides)类， 体外作用效果较第一类差， 但体内效果较好， 选择性强， 是目前研究的热点。 MS-275 与 CI-994 是其代表药物。
由于组蛋白去乙酰化酶亚型结构的相似性， 现有的大多数组蛋白 去乙酰化酶抑制剂并不具有亚型选择性， 通常同时抑制多个亚型， 造 成一定的毒副反应， 从而影响了成药性。 因此， 设计合成高选择性的 组蛋白去乙酰化酶抑制剂， 以得到疗效好， 毒副作用， 低， 安全性高 的新型抗恶性肿瘤剂是目前该领域的研究热点及技术难点。 发明内容 On October 6, 2006, the company was approved by the US FDA for the treatment of metastatic cutaneous T-lymphoma (CTCL) in the absence or cure of other medications or after treatment. The third class, benzamides, has a worse effect in vitro than the first one, but it has better in vivo effect and strong selectivity, which is a hot topic in current research. MS-275 and CI-994 are representative drugs. Due to the similarity of histone deacetylase subtype structure, most of the existing histone deacetylase inhibitors do not have subtype selectivity, and usually inhibit multiple subtypes at the same time, causing certain side effects. Thereby affecting the drug-forming properties. Therefore, the design and synthesis of highly selective histone deacetylase inhibitors to obtain a new anti-malignant agent with good efficacy, side effects, low safety and high safety is currently a research hotspot and technical difficulty in this field. Summary of the invention
本发明需要解决的技术问题之一是公开一类 N-(2-氨基 -4-吡啶基) 苯甲酰胺衍生物， 其为新型的组蛋白去乙酰化酶抑制剂， 以满足临床 应用的需要； 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. ;
本发明需要解决的技术问题之二是在于公开所述组蛋白去乙酰化 酶抑制剂在制备抗恶性肿瘤及治疗与分化和增殖相关疾病药物中的应 用。 本发明所说的组蛋白去乙酰化酶抑制剂， 为具有如下化学结构通 式的化合物或其盐：
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:
其中， 其中 R为氢、 1至 5个碳原子的垸基、 C5或 C6的脂肪环、 芳环或杂环， 芳环或杂环可以含有 1 至 4个取代基， 其取代基可以是 卤素、 氨基、 羟基、 硝基、 氰基、 1至 4个碳原子的烷基、 1至 4个碳 原子的垸氧基、 1至 4个碳原子的氨垸基、 1至 4个碳原子的垸氨基、 2至 4个碳原子的酰基、 2至 4个碳原子的酰氨基、 1至 4 个碳原子的 硫代烷基、 三氟甲基、 1至 4个碳原子的羧基、 1至 4个碳原子的烷氧 基羰基、 苯基或杂环取代基； Wherein 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;
为氢、 ^〜 5的烷基、 05,或06的脂肪环， 苯基或取代苯基； n = 0,l，2,3。
本发明所述的 "芳环"， 具有芳香性的环状结构， 可含有取代基； 所述的取代苯基为苯环上含有 1至 4个取代基， 其取代基可以是 卤素、 羟基、 硝基、 氰基、 1至 4个碳原子的垸氧基、 1至 4个碳原子 的垸基或氨基基团； Is hydrogen, alkyl ^ ~ 5, 05, 06 or the aliphatic ring, phenyl or substituted phenyl; n = 0, l, 2,3 . 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;
所述的 "杂环"， 是指含一个或多个杂原子 (氮、 氧、 硫)的饱和或不 饱和杂环， 如四氢吡咯、 二氢吡唑、 哌啶、 吗啉、 咪唑或吡啶等； 所述的卤素优选氟、 氯、 溴或碘； The term "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;
所述的 1至 4个碳原子的垸基， 优选甲基、 乙基、 正丙基、 异丙 基、 正丁基、 异丁基或特丁基等； The mercapto group of 1 to 4 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
所述的 1至 4个碳原子的垸氧基优选甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁氧基或异丁氧基等； 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;
所述的 1 至 4个碳原子的氨基烷基优选氨基乙基、 1-氨基丙基或 2-氨基丙基等； The aminoalkyl group of 1 to 4 carbon atoms is preferably an aminoethyl group, a 1-aminopropyl group or a 2-aminopropyl group;
所述的 1 至 4个碳原子的垸基氨基优选 N-甲氨基、 N-乙氨基或 N-异丙氨基； The mercaptoamino group of 1 to 4 carbon atoms is preferably N-methylamino, N-ethylamino or N-isopropylamino;
所述的 2至 4个碳原子的酰基优选乙酰基、丙酰基或异丁酰基等； 所述的 2至 4个碳原子的酰氨基优选乙酰氨基、 丙酰氨基、 丁酰 氨基或异丁酰氨基等； 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. Amino group;
所述的 2至 4个碳原子的硫代垸基优选甲硫基、 乙硫基或丙硫基 等； The thioindenyl group of 2 to 4 carbon atoms is preferably a methylthio group, an ethylthio group or a propylthio group;
所述的盐为盐酸盐、 溴氢酸盐、 硫酸盐、 三氟醋酸盐或甲磺酸盐， 所说的盐含 0.5〜3分子的结晶水。 优选的化合物包括： 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 -l N-(2-氨基 -4-吡啶基 )- 4- (乙酰氨甲基） 苯甲酰胺、 V -l N-(2-amino-4-pyridyl)-4-(acetylaminomethyl)benzamide,
V -2 N-(2-氨基 -4-吡啶基 )- 4- (丙酰氨甲基） 苯甲酰胺、 V -2 N-(2-amino-4-pyridyl)-4-(propionylaminomethyl)benzamide,
V -3 N-(2-氨基 -4-吡啶基 )- 4- (丁酰氨甲基） 苯甲酰胺、 V -3 N-(2-amino-4-pyridyl)-4-(butyrylaminomethyl)benzamide,
V-4 N-(2-氨基 -4-吡啶基 )- 4- (环己酰氨甲基） 苯甲酰胺、 V-4 N-(2-amino-4-pyridyl)-4-(cyclohexanoylaminomethyl)benzamide,
V -5 N-(2-氨基 -4-吡啶基 )- 4- (苯甲酰氨甲基） 苯甲酰胺、 V -5 N-(2-amino-4-pyridyl)-4-(benzoylaminomethyl)benzamide,
V-6 N-(2-氨基 -4-吡啶基) - 4-[ ( 4-甲氧基苯甲酰基） 氨甲基]苯甲
酰胺、 V-6 N-(2-Amino-4-pyridyl)-4-[(4-methoxybenzoyl)aminomethyl]benzamide Amide,
V-7N-(2-氨基 -4-吡啶基 )-4-[ (4-氟苯甲酰基） 氨甲基]苯甲酰胺、 V-8 N-(2-氨基 -4-吡啶基) - 4-[ (3-甲氧基苯甲酰基） 氨甲基]苯甲 酰胺、 V-7N-(2-Amino-4-pyridyl)-4-[(4-fluorobenzoyl)aminomethyl]benzamide, V-8 N-(2-amino-4-pyridyl)- 4-[(3-methoxybenzoyl)aminomethyl]benzamide,
V-9N-(2-氨基 -4-吡啶基 )-4- (乙酰氨基） 苯甲酰胺、 V-9N-(2-amino-4-pyridyl)-4-(acetylamino)benzamide,
V-10N-(2-氨基 -4-吡啶基 )-4- (丙酰氨基） 苯甲酰胺、 V-10N-(2-amino-4-pyridyl)-4-(propionylamino)benzamide,
V-ll N-(2-氨基 -4-吡啶基 )-4- (丁酰氨基） 苯甲酰胺、 V-ll N-(2-amino-4-pyridyl)-4-(butyrylamino)benzamide,
V-12N-(2-氨基 -4-吡啶基 )-4- (环己酰氨基） 苯甲酰胺、 V-12N-(2-amino-4-pyridyl)-4-(cyclohexanoylamino)benzamide,
V-13N-(2-氨基 -4-吡啶基 )-4- (苯甲酰氨基） 苯甲酰胺、 V-13N-(2-amino-4-pyridyl)-4-(benzoylamino)benzamide,
V-14N-(2-氨基 -4-吡啶基 )-4-[ (4-甲氧基苯甲酰基） 氨基]苯甲酰 胺、 V-14N-(2-amino-4-pyridyl)-4-[(4-methoxybenzoyl)amino]benzoylamine,
V-15N-(2-氨基 -4-吡啶基 )-4-[ (4-氟苯甲酰基） 氨基]苯甲酰胺、 V-16N-(2-氨基 -4-吡啶基 )-4-[ (3-甲氧基苯甲酰基） 氨基]苯甲酰 胺、 V-15N-(2-Amino-4-pyridyl)-4-[(4-fluorobenzoyl)amino]benzamide, V-16N-(2-amino-4-pyridyl)-4-[ (3-methoxybenzoyl)amino]benzamide,
V-17N-(2-氨基 -4-吡啶基 )-4- (乙酰氨乙基） 苯甲酰胺、 V-17N-(2-amino-4-pyridyl)-4-(acetylaminoethyl)benzamide,
V-18N-(2-氨基 -4-吡啶基 )-4- (1-乙酰氨丙基) 苯甲酰胺、 V-19N-(2-氨基 -4-吡啶基 )-4- (1-乙酰氨基乙基) 苯甲酰胺、 V-20 N-(2-氨基 -4-吡啶基) - 4- (1-乙酰氨基 2-苯基乙基） 苯甲酰 胺、 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-21N-(2-氨基 -4-吡啶基 )-4- (2-乙酰氨基丙基) 苯甲酰胺、 V-22N-(2-氨基 -4-吡啶基 )-4-[ (3,4-二甲氧基苯甲酰基） 氨甲基] 苯甲酰胺、 V-21N-(2-Amino-4-pyridyl)-4-(2-acetamidopropyl)benzamide, V-22N-(2-amino-4-pyridyl)-4-[ (3, 4-dimethoxybenzoyl)aminomethyl]benzamide,
V -23 N-(2-氨基 -4-吡啶基) - 4-[ ( 3，4，5-三甲氧基苯甲酰基）氨甲基] 苯甲酰胺、 V -23 N-(2-amino-4-pyridyl)-4-[(3,4,5-trimethoxybenzoyl)aminomethyl]benzamide,
V -24 N-(2-氨基 -4-吡啶基) - 4-[ ( 4-吡啶甲酰基）氨甲基]苯甲酰胺、 V-25 N-(2-氨基 -4-吡啶基) - 4-[ (4-吗啉甲酰基）氨甲基]苯甲酰胺、 V-26N-(2-氨基 -4-吡啶基 )-4-[ (3-三氟甲基苯甲酰基） 氨甲基]苯 甲酰胺、 V-24 N-(2-Amino-4-pyridyl)-4-[(4-pyridinecarbonyl)aminomethyl]benzamide, V-25 N-(2-amino-4-pyridyl)- 4-[(4-morpholinyl)aminomethyl]benzamide, V-26N-(2-amino-4-pyridyl)-4-[(3-trifluoromethylbenzoyl)carbamate Benzoylamide,
V-27N-(2-氨基 -4-吡啶基 )-4-[ (3-硝基苯甲酰基） 氨甲基]苯甲酰 胺、
V-28N-(2-氨基 -4-吡啶基 )-4-[ (3-氨基苯甲酰基） 氨甲基]苯甲酰 胺、 V-27N-(2-amino-4-pyridyl)-4-[(3-nitrobenzoyl)aminomethyl]benzamide, V-28N-(2-amino-4-pyridyl)-4-[(3-aminobenzoyl)aminomethyl]benzamide,
V -29 N-(2-氨基 -4-吡啶基) - 4-[ ( 3-氯苯甲酰基）氨甲基]苯甲酰胺、 V-30 N-(2-氨基 -4-吡啶基) - 4-[ (2， 4-二氯苯甲酰基） 氨甲基]苯 甲酰胺、 V -29 N-(2-Amino-4-pyridyl)-4-[(3-chlorobenzoyl)aminomethyl]benzamide, V-30 N-(2-amino-4-pyridyl) - 4-[ (2, 4-dichlorobenzoyl)aminomethyl]benzamide,
V-31N-(2-氨基 -4-吡啶基 )-4-[ (4-苯基苯甲酰基） 氨甲基]苯甲酰 胺或 V-31N-(2-Amino-4-pyridyl)-4-[(4-phenylbenzoyl)aminomethyl]benzoylamine or
V-32N-(2-氨基 -4-吡啶基 )-4-[ (3-苯基苯甲酰基） 氨甲基]苯甲酰 胺。 其结构式如下： V-32N-(2-Amino-4-pyridyl)-4-[(3-phenylbenzoyl)aminomethyl]benzoylamine. Its structural formula is as follows:
编号 结构 Number structure
V-1 V-1
V-2 V-2
0 0
V-3 V-3
0 0
V-4 V-4
V-5 V-5
V-6 V-6
0
0
将原料 1 ( 10 mmol)、 氯化亚砜 (4.72g，40 mmol)溶于 10ml溶剂甲 中， 加热回流 4 小时， 减压蒸出溶剂及未反应的氯化亚砜， 将所得物 在冰浴下滴加至化合物 Π ( l Ommol ) 的和氢氧化钠 （10ml lmol/L ) 的 混合液中， 滴加完毕继续室温搅拌 5小时。 停止反应， 5N盐酸调节 pH 到 6左右， 析出大量固体， 过滤， 干燥得中间体 III； Raw material 1 (10 mmol) and thionyl chloride (4.72 g, 40 mmol) were dissolved in 10 ml of solvent A, heated under reflux for 4 hours, and the solvent and unreacted thionyl chloride were evaporated under reduced pressure, and the obtained material was iced. The mixture was added dropwise to a mixture of the compound hydrazine (10 mmol) and sodium hydroxide (10 ml lmol/L), and the mixture was stirred at room temperature for 5 hours. Stop the reaction, adjust the pH to about 6 with 5N hydrochloric acid, precipitate a large amount of solid, filter, and dry to obtain intermediate III;
将中间体 III ( 1 mmol ) 、 化合物 IV ( lmmol ) 、 O-(IH-苯并三唑 - 1- 基) -Ν,Ν,Ν',Ν'-四甲基异脲六氟化磷 （简称 HBTU ) (0.379g, lmmol)依次 力口入 10ml N，N-二甲基甲酰胺中， 保持冰浴冷却滴加三乙胺 (2mmol)， 再于室温继续搅拌 4小时。 将反应液倒入冰水中， 盐酸调节 pH到 7〜 9左右， 二氯甲烷萃取， 无水硫酸镁干燥。 过滤， 浓缩有机相， 剩余物 经柱层析纯化得产品 V。 上述反应通法中的 R、 Ri、 n同上所述； Intermediate III (1 mmol), compound IV (1 mmol), O-(IH-benzotriazol-1-yl)-oxime, hydrazine, Ν', Ν'-tetramethylisourea hexafluoride ( Abbreviated as HBTU (0.379 g, 1 mmol), 10 ml of N,N-dimethylformamide was added to the mixture, and triethylamine (2 mmol) was added dropwise with ice-cooling, and stirring was continued at room temperature for 4 hours. The reaction solution was poured into ice water, and the pH was adjusted to about 7 to 9 with hydrochloric acid, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. Filtration, concentration of the organic phase, and purification of the residue by column chromatography. R, Ri, n in the above reaction method are the same as described above;
其中， 溶剂甲为： 苯、 甲苯、 二氯甲垸、 Ν,Ν-二甲基甲酰胺或氯 化亚砜等。 化合物 I，11， VI和 HBTU可以通过商业渠道购买； 化合物 IV参 照文献 Heterocyclic C/zem. ,23,669 ( 1986)的方法合成。 药理试验表明， 本发明所述的化合物或其盐， 不仅对组蛋白去乙 酰化酶具有很强的抑制作用， 而且对某些肿瘤细胞具有较强的诱导分 化和抗增殖活性， 口服毒性较低， 可以用于治疗癌症及与分化和增殖 相关的疾病， 尤其对血癌和实体瘤具有优异疗效。 本发明还涉及一种组合物， 包括治疗有效量的所述的化合物或其
盐和医药学上可接受的载体， 所说的载体如香料、 甜味剂、 液体或固 体填料或稀释剂等常用载体物质， 并采用本领域公知的方法， 制成常 见的药用制剂， 如片剂、 胶囊、 粉剂、 糖桨、 液剂、 悬浮剂或针剂， 制剂通常含有重量百分比为 1〜70%的有效成分， 较佳重量含量为 5〜 50%； Among them, 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 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;
本发明所说的化合物在临床上可以通过口服或注射方式对哺乳动 物 （包括人） 进行给药， 其中尤以口服方式最佳。 用药剂量为每日 0.0001~200mg/kg体重。 最佳剂量视个体而定， 通常开始时剂量较小， 然后逐渐增加用量。 动物试验证明， 本发明的化合物或其盐， 毒性较小。 本发明优点在于， 所述化合物及其药用制剂对于治疗基因表达异 常而引起的疾病， 如： 肿瘤、 内分泌紊乱、 免疫系统疾病、 遗传病和 神经系统疾病有很好的疗效。 具体实施方式 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
下面结合实例进一步阐明本发明的内容， 但单本发明的保护范围 并不局限于这些实例。 本发明所述的百分比出特别注明外， 均为重量 百分比。 实施例 1 The contents of the present invention will be further clarified below with reference to examples, but the scope of protection of the present invention is not limited to these examples. The percentages stated in the present invention are all percentages by weight. Example 1
V -l N-(2-氨基 -4-吡啶基 )- 4- (乙酰氨甲基） 苯甲酰胺 V -l N-(2-amino-4-pyridyl)-4-(acetylaminomethyl)benzamide
将乙酸酐（1.02g，10mmol)常温下缓慢加入到对氨甲基苯甲酸 (1.51g，10mmol)的氢氧化钠溶液（10ml,lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 （中间体 M-1) 1.66g， 收率 86.2%。 Acetic anhydride (1.02 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. It was filtered and dried to give a white solid ( Intermediate M-1) 1.66 g.
M-l(0.193g，l mmol)、 3,4-二氨基吡啶 (0.109g, l mmol)、 HBTU(0.379g, l mmol)、 Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3
mmol), 按通法产品 V的方法制备得白色固体 0.147g， 收率 51.9%。 Ml (0.193 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), triethylamine 0.303g, 3 Methyl) 0.147 g of a white solid was obtained according to the method of product V, yield 51.9%.
MS (ES+):m/e 285.13. MS (ES+): m/e 285.13.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.68 (s， 1H), 8.38 (t， 1H), 8.10 (s， 1H),7.94 (d， 2H, J=8.0Hz), 7.81 (dd, 1H, J=3.6,5.2Hz), 7.44 (d, 2H，Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.68 (s, 1H), 8.38 (t, 1H), 8.10 (s, 1H), 7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J=3.6, 5.2Hz), 7.44 (d, 2H,
J=4.8Hz)， 7.40 (d, 2H, J=8.4Hz), 5.13 (s, 2H), 4.34 (d， 2H, J=6.0Hz), 1.90 (s, 3H) 实施例 2 J = 4.8 Hz), 7.40 (d, 2H, J = 8.4 Hz), 5.13 (s, 2H), 4.34 (d, 2H, J = 6.0 Hz), 1.90 (s, 3H) Example 2
V -2 N-(2-氨基 -4-吡啶基 )- 4- (丙酰氨甲基） 苯甲酰胺 V -2 N-(2-Amino-4-pyridyl)-4-(propionylaminomethyl)benzamide
将丙酰氯（0.92g,10mmol)常温下缓慢加入到对氨甲基苯甲酸 (1.51g，10mmol)的氢氧化钠溶液（10ml，lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 （中间体 M-2) 1.87g, 收率 90.1%。 Propionyl chloride (0.92 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), 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-2) 1.87 g, yield 90.1%.
M-2(0.207g, l mmol)、 3,4-二氨基吡啶 (0.109g，l mmol)、 HBTU(0.379g, l mmol) N，N-二甲基甲酰胺（10ml)、 三乙胺（0.303g，3 mmol), 按通法产品 V的方法制备得白色固体 0.197g， 收率 66.2%。 MS(ES+):m/e 299.14. M-2 (0.207 g, l mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol) N,N-dimethylformamide (10 ml), triethylamine (0.303 g, 3 mmol), 0.197 g of a white solid was obtained by the method of product V, yield 66.2%. MS (ES+): m/e 299.14.
1H-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, 1H)， 8.30 (t， 1H, J=5.6Hz), 8.10 (s, 1H),7.91 (d, 2H, J=8.0Hz), 7.80 (d, 1H, J=5.2Hz), 7.43 (d, 2H, J=5.2Hz), 7.38 (d, 2H， J=8.0Hz), 5.13 (s, 2H), 4.31 (s, 2H), 2.16 (q; 2H, J=7.6Hz),1.02 (t, 3H, J=7.6Hz) 实施例 3 1H-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, 1H), 8.30 (t, 1H, J=5.6Hz), 8.10 (s, 1H), 7.91 (d, 2H, J=8.0Hz) , 7.80 (d, 1H, J=5.2Hz), 7.43 (d, 2H, J=5.2Hz), 7.38 (d, 2H, J=8.0Hz), 5.13 (s, 2H), 4.31 (s, 2H) , 2.16 (q ; 2H, J=7.6Hz), 1.02 (t, 3H, J=7.6Hz) Example 3
V -5 N-(2-氨基 -4-吡啶基 )- 4- (丁酰氨甲基） 苯甲酰胺 V -5 N-(2-Amino-4-pyridyl)-4-(butyrylaminomethyl)benzamide
将正丁酰氯 (0.106g，10mmol)常温下缓慢加入到对氨甲基苯甲酸 (1.51g，10mmol)的氢氧化钠溶液（10ml，lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白
色固体 （中伺体 M-3) 1.70g, 收率 76.7% 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%
M-3(0.221g,l mmol)、 3， 4-二氨基吡啶 (0.109g,l mmol)、 HBTU(0.379g,l mmol) , Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3 mmol), 按通法产品 V的方法制备得白色固体 0.206g， 收率 66.1%。 M-3 (0.221 g, 1 mmol), 3, 4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), triethyl The amine (0.303 g, 3 mmol) was obtained as a white solid (0.206 g).
MS(ES+):m/e 313.16. MS (ES+): m/e 313.16.
1H-NMR (400MHz, DMSO-d6) Sppm: 9.65 (s， 1H), 8.33(t， 1H), 8.09 (s， 1H),7.91 (d, 2H, J=8.4Hz), 7.80 (d, 1H, J=5.2Hz), 7.42 (d, 2H, J-5.2Hz), 7.38 (d, 2H， J=8.0Hz)， 4.31 (s, 2H), 2.14 (t, 2H, J=7.2Hz), 1.551H-NMR (400MHz, DMSO-d 6 ) Sppm: 9.65 (s, 1H), 8.33 (t, 1H), 8.09 (s, 1H), 7.91 (d, 2H, J = 8.4 Hz), 7.80 (d, 1H, J=5.2Hz), 7.42 (d, 2H, J-5.2Hz), 7.38 (d, 2H, J=8.0Hz), 4.31 (s, 2H), 2.14 (t, 2H, J=7.2Hz) , 1.55
(m, 2H)，0.88(t， 3H, J=7.2Hz) 实施例 4 (m, 2H), 0.88 (t, 3H, J = 7.2 Hz) Example 4
V -4 N-(2-氨基 -4-吡啶基 )- 4- (环己酰氨甲基） 苯甲酰胺 V -4 N-(2-Amino-4-pyridyl)-4-(cyclohexanoylaminomethyl)benzamide
环己基甲酸（1.28g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml溶 剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-4) 2.00g， 收率 76.7%。 将 3,4-二氨基吡啶（0.109g, l mmol)、 M-4 (0.208g,lmmol)、 HBTU (0.379g, l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol), 按通法产品 V的方法制备得白色固体 0.174g, 收率 49.5%。 Cyclohexylcarboxylic acid (1.28 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid (intermediate M-4) 2.00 g, yield 76.7%. 3,4-Diaminopyridine (0.109 g, l mmol), M-4 (0.208 g, 1 mmol), HBTU (0.379 g, l mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid.
MS(ES+):m/e 353.17. MS (ES+): m/e 353.17.
1H-NMR (400MHz, DMSO-d6) 6ppm: 9.74 (s, 1H), 8.26(t, 1H, J=6.0Hz)， 8.09 (s, 1H),7.91 (d， 2H， J=7.6Hz), 7.79 (d, 1H， J=5.6Hz)， 7.431H-NMR (400MHz, DMSO-d 6 ) 6ppm: 9.74 (s, 1H), 8.26(t, 1H, J=6.0Hz), 8.09 (s, 1H), 7.91 (d, 2H, J=7.6Hz) , 7.79 (d, 1H, J=5.6Hz), 7.43
(d, 2H, J=5.2Hz), 7.35 (d, 2H, J=7.2Hz), 6.94 (m， 1H，)， 5.15 (s， 2H), 4.31 (d， 2H, J=5.6Hz), 2.18 (m， 1H), 1.61- 1.72 (m, 4H), 1.14-1.41 (m, 5H) 实施例 5 (d, 2H, J=5.2Hz), 7.35 (d, 2H, J=7.2Hz), 6.94 (m, 1H,), 5.15 (s, 2H), 4.31 (d, 2H, J=5.6Hz), 2.18 (m, 1H), 1.61- 1.72 (m, 4H), 1.14-1.41 (m, 5H) Example 5
V -5 N-(2-氨基 -4-吡啶基 )- 4- (苯甲酰氨甲基） 苯甲酰胺
苯甲酸（1.22g,10 mmol)、 氯化亚砜 (4.72g，40 mmol)、 ΙΟπιΓ溶剂氯 化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-5) 2.00g， 收率 76.7%。 V -5 N-(2-Amino-4-pyridyl)-4-(benzoylaminomethyl)benzamide Benzoic acid (1.22g, 10mmol), thionyl chloride (4.72g, 40mmol), ΙΟπιΓ solvent, thionyl chloride, obtained as a white solid (intermediate M-5) 2.00g , the yield was 76.7%.
M-5(0.255g, lmmol)、 3,4-二氨基吡啶（0.109g，lmmol)、 HBTU (0.379g,l mmol)、 Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2mmol)， 按通法二产品 V的方法制备得白色固体 0.191g， 收率 55.3%。 M-5 (0.255 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), triethylamine 0.202 g, 2 mmol), 0.191 g of a white solid was obtained by the method of the product of the product of the second method, yield of 55.3%.
MS(ES+):m/e 347.17. MS (ES+): m/e 347.17.
Ή-NM (400MHz, DMSO-d6) Sppm: 9.71 (s， 1H), 9.09 (t, 1H, J=5.6Hz), 8.09 (s, 1H), 7.89-7.95 (m, 4H)， 7.79 (d, 2H, J=5.2Hz), 7.43-7.56 (m， 5H), 5.13 (s， 2H), 4.55 (d, 2H, J=5.6Hz) 实施例 6 Ή-NM (400MHz, DMSO-d 6 ) Sppm: 9.71 (s, 1H), 9.09 (t, 1H, J=5.6Hz), 8.09 (s, 1H), 7.89-7.95 (m, 4H), 7.79 ( d, 2H, J=5.2 Hz), 7.43-7.56 (m, 5H), 5.13 (s, 2H), 4.55 (d, 2H, J=5.6 Hz) Example 6
V -6 N-(2-氨基 -4-吡啶基) - 4-[ (4-甲氧基苯甲酰基） 氨甲基]苯甲 酰胺 V -6 N-(2-Amino-4-pyridyl)-4-[(4-methoxybenzoyl)aminomethyl]benzamide
4-甲氧基苯甲酸（1.52g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-6) 2.15g， 收率 75.6%。 将 3，4-二氨基吡啶（0.109g，l mmol)、 M-6 (0.285g, lmmol)、 HBTU (0.379g，l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.204g， 收率 54.3%。 4-methoxybenzoic acid (1.52 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent chlorosulfoxide, obtained as a white solid ( intermediate M) -6) 2.15 g, yield 75.6%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-6 (0.285 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid.
MS(ES+):m/e 377.12. MS (ES+): m/e 377.12.
Ή-NMR (400MHz, DMSO-d6) Sppm: 9.65 (s, 1H)， 8.91 (t， 1H), 8.09 (s, 1H),7.87-7.92 (m， 4H)， 7.80 (d, 1H， J=4.8Hz), 7.45 (d， 2H, J=8.0Hz),7.44-7.50 (m, 4H), 6.62 (dd, 1H， J=4.8,7.6Hz), 5.69 (s, 2H)， 4.56 (d, 2H, J=5.6Hz)
实施例 7 Ή-NMR (400MHz, DMSO-d 6 ) Sppm: 9.65 (s, 1H), 8.91 (t, 1H), 8.09 (s, 1H), 7.87-7.92 (m, 4H), 7.80 (d, 1H, J =4.8Hz), 7.45 (d, 2H, J=8.0Hz), 7.44-7.50 (m, 4H), 6.62 (dd, 1H, J=4.8, 7.6Hz), 5.69 (s, 2H), 4.56 (d , 2H, J=5.6Hz) Example 7
V -7 N-(2-氨基 -4-吡啶基 )- 4-[ ( 4-氟苯甲酰基） 氨甲基]苯甲酰胺 4-氟苯甲酸（1.40g，10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml溶 剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-7) 1.91g， 收率 70.1%。 将 3,4-二氨基吡啶 (0.109g，l mmol)、 M-7 (0.273g,lmmol)、 HBTU (0.379g，l mmol)、 N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol)， 按通法产品 V的方法制备得白色固体 0.195g， 收率 53.6%。 V -7 N-(2-Amino-4-pyridyl)- 4-[(4-fluorobenzoyl)aminomethyl]benzamide 4-fluorobenzoic acid (1.40 g, 10 mmol), Sulfone (4.72 g, 40 mmol), 10 ml of solvent chlorosulfoxide, was obtained as a white solid (intermediate M-7) 1.91 g, yield 70.1%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-7 (0.273 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid (0.195 g).
MS(ES+):m/e 365.12. MS (ES+): m/e 365.12.
Ή-NMR (400MHz, DMSO-d6) 6ppm: 10.44(s, 1H)， 9.63(s, IH), 8. 11 (s, IH), 8.06-8.10 (m， 2H), 8.00 (d, 2H， J=8.8Hz)， 7.93(d, 2H, J=8.8Hz)，7.81 (d, IH, J=5.2Hz), 7.45 (d, 1H， J=5.2Hz)， 7.36-7.41(m, 2H, J=5.2Hz),5.14 (s, 2H), 4.55 (d, 2H, J=6.0Hz) 实施例 8 Ή-NMR (400MHz, DMSO-d 6 ) 6ppm: 10.44(s, 1H), 9.63(s, IH), 8. 11 (s, IH), 8.06-8.10 (m, 2H), 8.00 (d, 2H , J=8.8Hz), 7.93(d, 2H, J=8.8Hz), 7.81 (d, IH, J=5.2Hz), 7.45 (d, 1H, J=5.2Hz), 7.36-7.41(m, 2H , J = 5.2 Hz), 5.14 (s, 2H), 4.55 (d, 2H, J = 6.0 Hz) Example 8
V -8 N-(2-氨基 -4-吡啶基) - 4-[ ( 3-甲氧基苯甲酰基） 氨甲基]苯甲 酰胺 V -8 N-(2-Amino-4-pyridyl)-4-[(3-methoxybenzoyl)aminomethyl]benzamide
3-甲氧基苯甲酸（1.52g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-8) 2.15g, 收率 75.6%。 将 3，4-二氨基吡啶 (0.109g，l mmol)、 M-8 (0.285g,lmmol)、 HBTU (0.379g,l mmol)、 N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol)， 按通法产品 V的方法制备得白色固体 0.204g， 收率 54.3%。 3-methoxybenzoic acid (1.52 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid ( intermediate M) -8) 2.15 g, yield 75.6%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-8 (0.285 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid.
MS(ES+):m/e 377.12. MS (ES+): m/e 377.12.
1H-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, IH), 9.06 (t, IH J=5.6Hz)， 8.10 (s， 1H)， 7.93 (d, 2H,J=8.4Hz), 7.80 (d， 2H，J=5.6Hz)
7.37-7.50 (m, 6H), 7.11 (m， 1H)， 5.12 (s， 2H), 4.55 (d, 2H, J=6.0Hz)， 3.80(s, 3H) 实施例 9 1H-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, IH), 9.06 (t, IH J=5.6Hz), 8.10 (s, 1H), 7.93 (d, 2H, J=8.4Hz), 7.80 (d, 2H, J=5.6Hz) 7.37-7.50 (m, 6H), 7.11 (m, 1H), 5.12 (s, 2H), 4.55 (d, 2H, J=6.0Hz), 3.80(s, 3H) Example 9
V-9 N-(2-氨基 -4-吡啶基 )- 4- (乙酰氨基） 苯甲酰胺 V-9 N-(2-Amino-4-pyridyl)-4-(acetylamino)benzamide
将乙酸酐（1.02g，10mmol)常温下缓慢加入到对氨基苯甲酸 (1.37g,10mmol)的氢氧化钠溶液 (10ml，lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 (中间体 M-9) 1.54g， 收率 86.2%。 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.
M-9(0.179g,l mmol)、 3,4-二氨基吡啶（0.109g,l mmol)、 HBTU(0.379g,l mmol) ^ N，N-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3 mmol), 按通法产品 V的方法制备得白色固体 0.141g， 收率 52.3%。 MS (ES+):m/e 271.13. M-9 (0.179 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol) ^ N,N-dimethylformamide (10 ml), triethyl Amine (0.303 g, 3 mmol) was obtained as a white solid. MS (ES+): m/e 271.13.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 10.24 (s, 1H), 9.84(s, 1H), 8.09(s， 1H),7.93 (d， 2H, J=8.8Hz), 7.80 (d, 2H, J=5.2Hz)， 7.71 (d, 2H, J=8.8Hz), 7.43 (d, 1H, J-5.2Hz), 5.14 (s, 2H), 2.09(s, 3H) 实施例 10 Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 10.24 (s, 1H), 9.84(s, 1H), 8.09(s, 1H), 7.93 (d, 2H, J=8.8Hz), 7.80 (d, 2H, J=5.2Hz), 7.71 (d, 2H, J=8.8Hz), 7.43 (d, 1H, J-5.2Hz), 5.14 (s, 2H), 2.09(s, 3H) Example 10
V -10 N-(2-氨基 -4-吡啶基 )- 4- (丙酰氨基） 苯甲酰胺 V -10 N-(2-Amino-4-pyridyl)-4-(propionylamino)benzamide
将丙酰氯（0.92g, 10mmol)常温下缓慢加入到对氨基苯甲酸 (1.37g，10mmol)的氢氧化钠溶液（10ml,lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 （中间体 M-10) 1.87g， 收率 84.1%。 Propionyl chloride (0.92 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-10) 1.87 g.
M-10(0.193g,l mmol)、 3,4-二氨基吡啶 (0.109g,l mmol)、 HBTU(0.379g, l mmol) Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3 mmol), 按通法产品 V的方法制备得白色固体 0.171g， 收率 60.4%。
MS(ES+):m/e 285.14. M-10 (0.193 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol) oxime, hydrazine-dimethylformamide (10 ml), triethylamine (0.303 g, 3 mmol) was obtained as a white solid (0.171 g). MS (ES+): m/e 285.14.
1H-NMR (400MHz, DMSO-d6) 5ppm: 10.09 (s, IH), 9.58(s, 1H)， 8.10(s, 1H),7.93 (d, 2H, J=8.8Hz), 7.80 (d, 2H, J=5.2Hz), 7.73 (d, 2H, J=8.8Hz), 7.43 (d, 1H， J=4.8Hz), 5.11 (s, 2H), 2.37(q, 2H, J=7.6Hz),2.09(t, 3H, J-7.6Hz) 实施例 11 1H-NMR (400MHz, DMSO-d 6 ) 5ppm: 10.09 (s, IH), 9.58 (s, 1H), 8.10 (s, 1H), 7.93 (d, 2H, J = 8.8 Hz), 7.80 (d, 2H, J=5.2Hz), 7.73 (d, 2H, J=8.8Hz), 7.43 (d, 1H, J=4.8Hz), 5.11 (s, 2H), 2.37(q, 2H, J=7.6Hz) , 2.09 (t, 3H, J-7.6Hz) Example 11
V -21 N-(2-氨基 -4-吡啶基 )- 4- (丁酰氨基） 苯甲酰胺 V -21 N-(2-Amino-4-pyridyl)-4-(butyrylamino)benzamide
将正丁酰氯（0.106g，10mmol)常温下缓慢加入到对氨基苯甲酸 (1.37g，10mmol)的氢氧化钠溶液（10ml，lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 (中间体 M-11) 1.70g， 收率 76.7%。 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%.
M-l l(0.207g,l mmol)、 3，4-二氨基卩比啶（0.109g，l mmol)、 HBTU(0.379g,l mmol)、 Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3 mmol), 按通法产品 V的方法制备得白色固体 0.182g, 收率 61.3%。 Ml l (0.207 g, 1 mmol), 3,4-diaminopyridinium (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), three Ethylamine (0.303 g, 3 mmol) was obtained as a white solid (yield: 61.3%).
MS(ES+):m/e 299.16. MS (ES+): m/e 299.16.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 10.09 (s, 1H)， 9.58(s, IH), 8.10(s, 1H),7.93 (d, 2H, J=8.8Hz), 7.80 (d, 2H， J=5.2Hz), 7.73 (d， 2H, J=8.8Hz)， 7.43 (d, IH, J=4.8Hz), 5.11 (s， 2H), 2.32(t, 2H, J=7.2Hz)， 1.63(m, 2H), 0.93(t, 3H, J=7.2Hz) 实施例 12 Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 10.09 (s, 1H), 9.58(s, IH), 8.10(s, 1H), 7.93 (d, 2H, J=8.8Hz), 7.80 (d, 2H, J=5.2Hz), 7.73 (d, 2H, J=8.8Hz), 7.43 (d, IH, J=4.8Hz), 5.11 (s, 2H), 2.32(t, 2H, J=7.2Hz) , 1.63 (m, 2H), 0.93 (t, 3H, J = 7.2 Hz) Example 12
V -12 N-(2-氨基 -4-吡啶基 )- 4- (环己酰氨基） 苯甲酰胺 V -12 N-(2-Amino-4-pyridyl)-4-(cyclohexanoylamino)benzamide
环己基甲酸（1.28g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml溶 剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-12) Cyclohexylcarboxylic acid (1.28 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, as a white solid ( intermediate M-12)
1.89g， 收率 76.7%。 将 3,4-二氨基吡啶（0.109g，l mmol)、 M-12(0.247g,lmmol)、 HBTU
(0.379g，l mmol)、 N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol), 按通法产品 V的方法制备得白色固体 0.189g， 收率 55.8%。 1.89 g, yield 76.7%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-12 (0.247 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol), obtained as a white solid, 0.189 g, yield 55.8%. .
MS(ES+):m/e 339.17. MS (ES+): m/e 339.17.
Ή-NMR (400MHz, DMSO-d6) 6ppm: 10.09 (s, IH), 9.58(s, IH),Ή-NMR (400MHz, DMSO-d 6 ) 6ppm: 10.09 (s, IH), 9.58(s, IH),
8.10(s， 1H),7.93 (d, 2H, J=8.8Hz), 7.80 (d, 2H, J=5.2Hz), 7.73 (d, 2H， J=8.8Hz), 7.43 (d, 1H， J=4.8Hz)， 5.11 (s， 2H), 2.36 (m, IH), 1.62-1.80 (m, 5H), 1.47-1.75(m, 5H) 实施例 13 8.10(s, 1H), 7.93 (d, 2H, J=8.8Hz), 7.80 (d, 2H, J=5.2Hz), 7.73 (d, 2H, J=8.8Hz), 7.43 (d, 1H, J = 4.8 Hz), 5.11 (s, 2H), 2.36 (m, IH), 1.62-1.80 (m, 5H), 1.47-1.75 (m, 5H) Example 13
V-13 N-(2-氨基 -4-吡啶基 )- 4- (苯甲酰氨基） 苯甲酰胺 V-13 N-(2-Amino-4-pyridyl)-4-(benzoylamino)benzamide
苯甲酸（1.22g，10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 Ι ΟΙΏΓ溶剂氯 化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-13) 1.85g, 收率 76.7%。 Benzoic acid (1.22g, 10mmol), thionyl chloride (4.72g, 40mmol), hydrazine sulfonate chloride, obtained as a white solid (intermediate M-13) 1.85 g, yield 76.7%.
M-13(0.241g g,lmmol)、 3,4-二氨基吡啶（0.109g,lmmol)、 HBTU (0.379g，lmmol)、 Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol), 按通法二产品 V的方法制备得白色固体 0.186g， 收率 55.8%。 MS(ES+):m/e 333.11. M-13 (0.241 gg, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), triethylamine (0.202) g, 2 mmol), 0.186 g of a white solid was obtained according to the method of the product of the second method of product V, yield 55.8%. MS (ES+): m/e 333.11.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 10.46(s， 1H)， 9.62(s, IH), 8. 10 (s, 1H)， 7.93-8.00 (m， 6H), 7.81 (d, IH, J=4.8Hz), 7.61(m, 1H),7.55 (m, 2H), 7.44 (d, 1H， J=4.8Hz),5.13 (s, 2H) 实施例 14 Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 10.46(s, 1H), 9.62(s, IH), 8. 10 (s, 1H), 7.93-8.00 (m, 6H), 7.81 (d, IH , J=4.8Hz), 7.61(m, 1H), 7.55 (m, 2H), 7.44 (d, 1H, J=4.8Hz), 5.13 (s, 2H) Example 14
V -14 N-(2-氨基 -4-吡啶基 )- 4-[ ( 4-甲氧基苯甲酰基） 氨基]苯甲酰 胺 V -14 N-(2-Amino-4-pyridyl)-4- [(4-methoxybenzoyl)amino]benzoylamine
4-甲氧基苯甲酸（1.52g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-14) 2.05g， 收率 75.6%。
将 3,4-二氨基吡啶 (0.109g，l mmol)、 M-14 (0.271g,lmmol) HBTU (0.379g，l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.224g， 收率 61.8%。 4-methoxybenzoic acid (1.52 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent chlorosulfoxide, obtained as a white solid ( intermediate M) -14) 2.05 g, yield 75.6%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-14 (0.271 g, 1 mmol) HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol), 0.224 g of a white solid was obtained by the method of product V, yield 61.8%.
MS(ES+):m/e 363.14. MS (ES+): m/e 363.14.
1H-NMR (400MHz, DMSO-d6) 6ppm: 10.30(s, IH), 9.61(s, IH), 8. 10 (s， IH), 7.92-8.01 (m, 6H)， 7.81 (d, IH, J=5.2Hz), 7.44(d， IH, J=5.2Hz),7.08 (d, 2H, J-8.8Hz), 5.12 (s, 2H), 3.86(s， 3H) 实施例 15 1H-NMR (400MHz, DMSO-d 6 ) 6ppm: 10.30(s, IH), 9.61(s, IH), 8. 10 (s, IH), 7.92-8.01 (m, 6H), 7.81 (d, IH , J = 5.2 Hz), 7.44 (d, IH, J = 5.2 Hz), 7.08 (d, 2H, J-8.8 Hz), 5.12 (s, 2H), 3.86 (s, 3H) Example 15
V-15 N-(2-氨基 -4-吡啶基 )- 4-[ ( 4-氟苯甲酰基） 氨基]苯甲酰胺 4-氟苯甲酸（1.40g，10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml溶 剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-15) 1.91g, 收率 70.1%。 将 3,4-二氨基吡啶 (0.109g,l mmol)、 M-15 (0.259g,lmmol)、 HBTU (0.379g,l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol), 按通法产品 V的方法制备得白色固体 0.205g， 收率 58.6%。 V-15 N-(2-Amino-4-pyridinyl)-4-[(4-fluorobenzoyl)amino]benzamide 4-fluorobenzoic acid (1.40 g, 10 mmol), chlorosulfoxide ( 4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid (intermediate M-15) 1.91 g, yield 70.1%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-15 (0.259 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid (0.25 g).
MS(ES+):m/e 351.12. MS (ES+): m/e 351.12.
1H-NMR (400MHz, DMSO-d6) 6ppm: 10.44(s, 1H)， 9.63(s, IH), 8. 11 (s， 1H)， 8.06-8.10 (m, 2H), 8.00 (d, 2H, J=8.8Hz), 7.93(d, 2H, J-8.8Hz),7.81 (d, 1H， J=5.2Hz), 7.45 (d, IH, J=5.2Hz), 7.36-7.41(m, 2H, J=5.2Hz)，5.14 (s, 2H) 实施例 16 1H-NMR (400MHz, DMSO-d 6 ) 6ppm: 10.44(s, 1H), 9.63(s, IH), 8. 11 (s, 1H), 8.06-8.10 (m, 2H), 8.00 (d, 2H , J=8.8Hz), 7.93(d, 2H, J-8.8Hz), 7.81 (d, 1H, J=5.2Hz), 7.45 (d, IH, J=5.2Hz), 7.36-7.41(m, 2H , J = 5.2 Hz), 5.14 (s, 2H) Example 16
V -16 N-(2-氨基 -4-吡啶基 )- 4-[ ( 3-甲氧基苯甲酰基） 氨基]苯甲酰 胺 V -16 N-(2-Amino-4-pyridyl)- 4-[(3-methoxybenzoyl)amino]benzoylamine
3-甲氧基苯甲酸（1.52g,10 mmol)、 氯化亚砜 (4.72g，40 mmol)、 10ml
溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-16) 2.05g， 收率 75.6%。 将 2，3-二氨基吡啶 (0.109g,l mmol)、 M-16(0.271g,lmmol)、 HBTU (0.379g，l mmol)、 N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mrnol), 按通法产品 V的方法制备得白色固体 0.227g， 收率 62.8%。 3-methoxybenzoic acid (1.52 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml Solvent chloride sulfoxide, white solid (intermediate M-16) 2.05 g, yield 75.6%. 2,3-Diaminopyridine (0.109 g, 1 mmol), M-16 (0.271 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mrnol) was obtained as a white solid (0.227 g, yield: 62.8%).
MS(ES+):m/e 363.12. MS (ES+): m/e 363.12.
Ή-NMR (400MHz, DMSO-d6) Sppm: 10.43(s, 1H)， 9.63(s, 1H), 8. 11 (s, 1H), 7.99 (d, 2H, J=8.8Hz), 7.94 (d， 2H, J=8.8Hz), 7.81 (d, 1H, J=4.8Hz), 7.44-7.59(m, 4H),7.19 (dd, 1H， J=2.4,8.0Hz)， 5.13 (s， 2H), 3.86(s, 3H) 实施例 17 Ή-NMR (400MHz, DMSO-d 6 ) Sppm: 10.43(s, 1H), 9.63(s, 1H), 8. 11 (s, 1H), 7.99 (d, 2H, J=8.8Hz), 7.94 ( d, 2H, J=8.8Hz), 7.81 (d, 1H, J=4.8Hz), 7.44-7.59(m, 4H), 7.19 (dd, 1H, J=2.4, 8.0Hz), 5.13 (s, 2H ), 3.86(s, 3H) Example 17
V -17 N-(2-氨基 -4-吡啶基 )- 4- (乙酰氨乙基） 苯甲酰胺 V -17 N-(2-Amino-4-pyridyl)-4-(acetylaminoethyl)benzamide
将乙酸酐（1.02g,10mmol)常温下缓慢加入到对氨乙基苯甲酸 (1.65g，10mmol)的氢氧化钠溶液（10ml,lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 （中间体 M-17) 1.78g， 收率 86%。 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%.
M-17(0.207g,l mmol)、 3,4-二氨基吡啶 (0.109g, l mmol)、 HBTU(0.379g,l mmol)、 Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g，3 mmol), 按通法产品 V的方法制备得白色固体 0.155g， 收率 51.9%。 M-17 (0.207 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), triethyl Amine (0.303 g, 3 mmol) was obtained as a white solid (yield: 51.
MS (ES+):m/e 299.13. MS (ES+): m/e 299.13.
^-NMR (400MHz, DMSO-d6) 5ppm: 9.68 (s, 1H), 8.38 (t, 1H), 8.10 (s, 1H),7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J-3.6,5.2Hz), 7.44 (d, 2H, J=4.8Hz)， 7.40 (d, 2H, J=8.4Hz), 5.13 (s， 2H), 3.53 (m, 2H), 2.74 (t， 2H), 1.90 (s, 3H)
实施例 18 ^-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.68 (s, 1H), 8.38 (t, 1H), 8.10 (s, 1H), 7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J-3.6, 5.2Hz), 7.44 (d, 2H, J=4.8Hz), 7.40 (d, 2H, J=8.4Hz), 5.13 (s, 2H), 3.53 (m, 2H), 2.74 ( t, 2H), 1.90 (s, 3H) Example 18
V-17 N-(2-氨基 -4-吡啶基 )- 4- (乙酰氨丙基） 苯甲酰胺 V-17 N-(2-Amino-4-pyridyl)-4-(acetylaminopropyl)benzamide
将乙酸酐（1.02g，10mmol)常温下缓慢加入到对氨丙基苯甲酸 (1.79g，10mmol)的氢氧化钠溶液（10ml,lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 （中间体 M-18) 1.83g， 收率 83%。 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%.
M-17(0.221g,l mmol)、 3,4-二氨基吡啶（0.109g，l mmol)、 HBTU(0.379g,l mmol) , Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3 mmol), 按通法产品 V的方法制备得白色固体 0.157g， 收率 50%。 M-17 (0.221 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol), hydrazine, hydrazine-dimethylformamide (10 ml), triethyl Amine (0.303 g, 3 mmol) was obtained as a white solid.
MS (ES+):m/e 313.13. MS (ES+): m/e 313.13.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.68 (s, 1H), 8.38 (t， 1H)， 8.10 (s, 1H)，7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J-3.6,5.2Hz), 7.44 (d, 2H, J=4.8Hz), 7.40 (d, 2H， J=8.4Hz), 5.13 (s, 2H), 3.20 (m， 2H), 2.55 (t, 2H),Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.68 (s, 1H), 8.38 (t, 1H), 8.10 (s, 1H), 7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J-3.6, 5.2Hz), 7.44 (d, 2H, J=4.8Hz), 7.40 (d, 2H, J=8.4Hz), 5.13 (s, 2H), 3.20 (m, 2H), 2.55 ( t, 2H),
1.88 (m, 2H), 1.90 (s， 3H) 实施例 19 1.88 (m, 2H), 1.90 (s, 3H) Example 19
V -19 N-(2-氨基 -4-吡啶基 )- 4- ( 1-乙酰氨基乙基） 苯甲酰胺 将乙酸酐 (1.02g，10mmol)常温下缓慢加入到 4-(1-氨基乙基)苯甲酸 V -19 N-(2-Amino-4-pyridyl)-4-(1-acetylaminoethyl)benzamide. Slowly add acetic anhydride (1.02 g, 10 mmol) to 4-(1-aminoethyl) at room temperature. Benzoic acid
(1.65g,10mmol)的氢氧化钠溶液（10ml，lmol/L)当中， 常温搅拌过夜。 停 止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白 色固体 （中间体 M-19) 1.61g， 收率 78%。 M- l(0.207g,l mmol)、 3,4-二氨基吡啶（0.109g，l mmol)、(1.65 g, 10 mmol) of a sodium hydroxide solution (10 ml, 1 mol/L) was 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-19) 1.61 g, yield 78%. M-l (0.207 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol),
HBTU(0.379g,l mmol) , N，N-二甲基甲酰胺（10ml)、 三乙胺（0.303g,3 mmol), 按通法产品 V的方法制备得白色固体 0.154g， 收率 51.7%。 HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethylamine (0.303 g, 3 mmol), obtained as a white solid 0.154 g, yield 51.7 %.
MS (ES+):m/e 299.13. MS (ES+): m/e 299.13.
1H-NMR (400MHz, DMSO-d6) 6ppm: 9.68 (s， 1H), 8.38 (t， 1H)， 8.10
(s, 1H),7.94 (d， 2H, J=8.0Hz), 7.81 (dd, 1H， J=3.6,5.2Hz), 7.44 (d, 2H, J=4.8Hz)， 7.40 (d， 2H, J=8.4Hz), 5.13 (s， 2H), 4.94 (m, 1H), 1.90 (s, 3H)， 1.44 (d, 3H) 实施例 20 1H-NMR (400MHz, DMSO-d 6 ) 6ppm: 9.68 (s, 1H), 8.38 (t, 1H), 8.10 (s, 1H), 7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J=3.6, 5.2Hz), 7.44 (d, 2H, J=4.8Hz), 7.40 (d, 2H, J=8.4 Hz), 5.13 (s, 2H), 4.94 (m, 1H), 1.90 (s, 3H), 1.44 (d, 3H) Example 20
V -20 N-(2-氨基 -4-吡啶基) - 4- ( 1-乙酰氨基 -2-苯基乙基） 苯甲酰 胺 V -20 N-(2-Amino-4-pyridyl)-4-(1-acetylamino-2-phenylethyl)benzamide
将乙酸酐（1.02g,10mmol)常温下缓慢加入到 4- ( 1-氨基 -2-苯基乙 基） 苯甲酸 (2.41g，10mmol)的氢氧化钠溶液（10ml,lmol/L)当中， 常温搅 拌过夜。 停止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得白色固体 （中间体 M-20) 2.09g， 收率 74%。 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%.
M-l(0.283g,l mmol)、 3,4-二氨基吡啶 (0.109g,l mmol)、 HBTU(0.379g, l mmol) Ν,Ν-二甲基甲酰胺（10ml)、 三乙胺（0.303g，3 mmol), 按通法产品 V的方法制备得白色固体 0.191g， 收率 51.0%。 Ml (0.283 g, 1 mmol), 3,4-diaminopyridine (0.109 g, 1 mmol), HBTU (0.379 g, 1 mmol) oxime, hydrazine-dimethylformamide (10 ml), triethylamine (0.303) g, 3 mmol), 0.191 g of a white solid was obtained by the method of product V, yield 51.0%.
MS (ES+):m/e 375.16. MS (ES+): m/e 375.16.
1H-NMR (400MHz, DMSO-d6) Sppm: 9.68 (s, 1H), 8.38 (t, 1H)， 8.10 (s, 1H),7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J=3.6,5.2Hz), 7.44 (d, 2H, J=4.8Hz), 7.40 (d, 2H, J=8.4Hz), 7.24 (s， 5H), 5.26 (m， 1H), 5.13 (s， 2H),1H-NMR (400MHz, DMSO-d 6 ) Sppm: 9.68 (s, 1H), 8.38 (t, 1H), 8.10 (s, 1H), 7.94 (d, 2H, J=8.0Hz), 7.81 (dd, 1H, J=3.6, 5.2Hz), 7.44 (d, 2H, J=4.8Hz), 7.40 (d, 2H, J=8.4Hz), 7.24 (s, 5H), 5.26 (m, 1H), 5.13 ( s, 2H),
2.97 (d, 2H), 1.90 (s， 3H) 实施例 21 2.97 (d, 2H), 1.90 (s, 3H) Example 21
V-21 N-(2-氨基 -4-吡啶基 )- 4- ( 2-乙酰氨基丙基） 苯甲酰胺 将乙酸酐（1.02g,10mmol)常温下缓慢加入到 4- ( 2-氨基丙基）苯甲 酸（1.79g,10mmol)的氢氧化钠溶液 (10ml，lmol/L)当中， 常温搅拌过夜。 停止反应， 5N盐酸调节 pH到 6左右， 析出大量固体。 过滤、 干燥得 白色固体 （中间体 M-21) 1.68g， 收率 76%。 V-21 N-(2-Amino-4-pyridinyl)-4-(2-acetylaminopropyl)benzamide. Acetic anhydride (1.02 g, 10 mmol) was slowly added to 4-(2-aminopropyl) at room temperature. The benzoic acid (1.79 g, 10 mmol) in sodium hydroxide solution (10 ml, 1 mol/L) was 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. Filtration and drying gave a white solid (intermediate M-21) 1.68 g, yield 76%.
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10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-23) 2.61g, 收率 75.6%。 将 3,4-二氨基吡啶 (0.109g,l mmol)、 M-23(0.345g,lmmol)、 HBTU (0.379g, l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.235g， 收率 54 %。 Zl.000/0T0ZN3/X3d 806SCl/0T0Z OAV 10 ml of the solvent chlorosulfoxide was obtained as a white solid (intermediate M-23) 2.61 g, yield: 75.6%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-23 (0.345 g, 1 mmol), HBTU (0.379 g, l mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid.
MS(ES+):m/e 437.12. MS (ES+): m/e 437.12.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, 1H)， 8.91 (t, IH), 8.09 (s, IH), 7.92 (m, IH), 7.80 (d, 2H, J=7.6Hz)，7.24 (d, 2H, J=7.6Hz), 6.83 (s，Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, 1H), 8.91 (t, IH), 8.09 (s, IH), 7.92 (m, IH), 7.80 (d, 2H, J=7.6 Hz), 7.24 (d, 2H, J=7.6Hz), 6.83 (s,
2H)， 6.62 (d, IH, J-7.6Hz), 5.69 (s, 2H), 4.56 (d, 2H, J=5.6Hz) 实施例 24 2H), 6.62 (d, IH, J-7.6Hz), 5.69 (s, 2H), 4.56 (d, 2H, J=5.6Hz) Example 24
V-24 N-(2-氨基 -4-吡啶基 )- 4-[ (4-吡啶甲酰基） 氨甲基]苯甲酰胺 4-吡啶甲酸（1.23g,10 mmol)、 氯化亚砜 (4.72g，40 mmol)、 10ml溶 剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-24) 1.97g， 收率 77%。 将 3,4-二氨基吡啶 (0.109g，l mmol)、 M-24(0.256g，lmmol)、 HBTU (0.379g,l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.205g， 收率 59 %。 V-24 N-(2-Amino-4-pyridyl)-4-[(4-pyridinecarbonyl)aminomethyl]benzamide 4-picolinic acid (1.23 g, 10 mmol), 4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid (intermediate M-24) 1.97 g, yield 77%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-24 (0.256 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid.
MS(ES+):m/e 348.12. MS (ES+): m/e 348.12.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, IH), 8.91 (t, IH), 8.38 (s, 1H),8.77 (d, 2H), 8.08 (d, 1H)，7.73 (d， 2H), 7.83 (d, 2H)， 7.37 (m, IH),Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, IH), 8.91 (t, IH), 8.38 (s, 1H), 8.77 (d, 2H), 8.08 (d, 1H), 7.73 ( d, 2H), 7.83 (d, 2H), 7.37 (m, IH),
7.24 (d, 2H), 6.66 (d, 1H),5.69 (s， 2H), 4.56 (d, 2H) 实施例 25 7.24 (d, 2H), 6.66 (d, 1H), 5.69 (s, 2H), 4.56 (d, 2H) Example 25
V -25 N-(2-氨基 -4-吡啶基 )- 4-[ (4-吗啉甲酰基） 氨甲基]苯甲酰胺 将 CDI (1.62g,10mmol)溶于 10ml无水四氢呋喃中， 冰浴控制温度
在 0-10°C。在 10分钟内分三次加入吗啉 (0.87g,10mmol)和 10ml无水四 氢呋喃混合液，保持 0-10Ό继续反应 1小时， 反应液变澄清。在 0-10°C 下将上述混合液滴加到对氨甲基苯甲酸 （1.51g，10mmol)和氢氧化钠的 水溶液 (10ml，lmol/L)中， 室温继续搅拌 4小时， 停止反应。 5N盐酸调 节 pH到 5左右， 反应液变澄清。 减压蒸出溶剂约 15ml，大量固体析出， 过滤、 真空干燥得白色固体 (中间体 M-25)2.28g， 收率 86.2%。 将 3，4-二氨基吡啶（0.109g，l mmol)、 M-24(0.264g，lmmol)、 HBTU (0.379g,l mmol) N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.209g， 收率 59 %。 V-25 N-(2-Amino-4-pyridinyl)-4-[(4-morpholinyl)aminomethyl]benzamide. CDI (1.62 g, 10 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Ice bath control temperature At 0-10 ° C. A mixture of morpholine (0.87 g, 10 mmol) and 10 ml of anhydrous tetrahydrofuran was added in three portions over 10 minutes, and the mixture was kept at 0-10 Torr for 1 hour, and the reaction mixture became clear. The above mixture was added dropwise to an aqueous solution (10 ml, 1 mol/L) of p-aminomethylbenzoic acid (1.51 g, 10 mmol) and sodium hydroxide at 0 to 10 ° C, and stirring was continued for 4 hours at room temperature to terminate the reaction. The pH of the 5N hydrochloric acid was adjusted to about 5, and the reaction solution became clear. The solvent was distilled off under reduced pressure to give a solvent (yield: 15%). 3,4-Diaminopyridine (0.109 g, 1 mmol), M-24 (0.264 g, 1 mmol), HBTU (0.379 g, 1 mmol) N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol) was obtained as a white solid (0.209 g, yield: 59%).
MS(ES+):m/e 356.12. MS (ES+): m/e 356.12.
1H-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, IH), 8.91 (t, 1H)， 8.38 (s, 1H)， 8.08 (d, IH), 7.83 (d, 2H), 7.24 (d, 2H), 6.66 (d, 1H),5.69 (s, 2H)， 4.56 (d, 2H),3.56(d, 2H),3.31(d, 2H) 实施例 26 1H-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, IH), 8.91 (t, 1H), 8.38 (s, 1H), 8.08 (d, IH), 7.83 (d, 2H), 7.24 ( d, 2H), 6.66 (d, 1H), 5.69 (s, 2H), 4.56 (d, 2H), 3.56 (d, 2H), 3.31 (d, 2H) Example 26
V -26 N-(2-氨基 -4-吡啶基 )- 4-[ ( 3-三氟甲基苯甲酰基） 氨甲基]苯 甲酰胺 V -26 N-(2-Amino-4-pyridyl)- 4-[(3-trifluoromethylbenzoyl)aminomethyl]benzenecarboxamide
3-三氟甲基苯甲酸（1.90g,10 mmol)、 氯化亚砜 (4.72g，40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 M-26) 2.51g, 收率 78%。 将 3，4-二氨基吡啶 (0.109g,l mmol)、 M-26(0.323g，lmmol)、 HBTU (0.379g,l mmol) N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.194g， 收率 47 %。 3-trifluoromethylbenzoic acid (1.90 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid ( intermediate) M-26) 2.51 g, yield 78%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-26 (0.323 g, 1 mmol), HBTU (0.379 g, 1 mmol) N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol) was obtained as a white solid (0.194 g, yield 47%).
MS(ES+):m/e 415.12. MS (ES+): m/e 415.12.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, IH), 8.91 (t, IH), 8.38 (s, 1H)，8.14 (s, 1H)， 8.08 (d, 1H),7.95 (d, IH), 7.92 (d， IH), 7.83 (d, 2H),
7.37 (m, IH), 7.24 (d, 2H), 6.66 (d, 1H),5.69 (s, 2H), 4.56 (d, 2H) 实施例 27 Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, IH), 8.91 (t, IH), 8.38 (s, 1H), 8.14 (s, 1H), 8.08 (d, 1H), 7.95 ( d, IH), 7.92 (d, IH), 7.83 (d, 2H), 7.37 (m, IH), 7.24 (d, 2H), 6.66 (d, 1H), 5.69 (s, 2H), 4.56 (d, 2H) Example 27
V -27 N-(2-氨基 -4-吡啶基 )- 4-[ ( 3-硝基苯甲酰基） 氨甲基]苯甲酰 胺 V -27 N-(2-Amino-4-pyridyl)- 4-[(3-nitrobenzoyl)aminomethyl]benzoylamine
3-硝基苯甲酸（1.67g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-27) 2.51g， 收率 81%。 将 3，4-二氨基吡啶 (0.109g, l mmol)、 M-27(0.300g，lmmol)、 HBTU (0.379g, l mmol) N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol), 按通法产品 V的方法制备得白色固体 0.215g， 收率 55 %。 3-nitrobenzoic acid (1.67 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid ( intermediate M- 27) 2.51 g, yield 81%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-27 (0.300 g, 1 mmol), HBTU (0.379 g, l mmol) N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol), 0.215 g of white solid was obtained by the method of product V, yield 55%.
MS(ES+):m/e 392.12. MS (ES+): m/e 392.12.
1H-NMR (400MHz, DMSO-d6) Sppm: 9.65 (s, IH), 8.91 (t, IH), 8.72 (s， IH), 8.51 (d, IH), 8.38 (s, IH), 8.34 (d, IH), 8.08 (d, 1H)， 5.69 (s, 2H), 7.85 (m, IH), 7.83 (d, 2H), 7.24 (d, 2H)， 6.66 (d, IH), 4.56 (d, 2H) 实施例 28 1H-NMR (400MHz, DMSO-d 6 ) Sppm: 9.65 (s, IH), 8.91 (t, IH), 8.72 (s, IH), 8.51 (d, IH), 8.38 (s, IH), 8.34 ( d, IH), 8.08 (d, 1H), 5.69 (s, 2H), 7.85 (m, IH), 7.83 (d, 2H), 7.24 (d, 2H), 6.66 (d, IH), 4.56 (d , 2H) Example 28
V -28 N-(2-氨基 -4-吡啶基 )- 4-[ ( 3-氨基苯甲酰基） 氨甲基]苯甲酰 胺 V -28 N-(2-Amino-4-pyridyl)-4- [( 3-aminobenzoyl)aminomethyl]benzoylamine
将 V -27(0,391g, lmmol)溶于甲醇中， 加入二水合氯化亚锡 (0.76g,4mmol) , 加热回流 3h， 反应完毕， 蒸干甲醇， 加水 100ml， 饱 和碳酸钾调 pH 到 10， 二氯甲垸提取， 无水硫酸镁干燥， 过滤， 减压 蒸除溶剂， 得产品 0.292g， 收率 81 %。 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.
MS(ES+):m/e 362.12. MS (ES+): m/e 362.12.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s， IH), 8.38(s, 1H)， 8.08 (d, IH), 7.83 (d, 2H)， 7.31 (d, IH), 7.24 (d, 2H), 7.19 (m, lH),7.15(s, 1H),6.71 (d, 2H), 6.66 (d， IH), 5.69 (s， 2H), 5.85 (s， 2H),4.56 (d, 2H)
实施例 29 Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, IH), 8.38 (s, 1H), 8.08 (d, IH), 7.83 (d, 2H), 7.31 (d, IH), 7.24 ( d, 2H), 7.19 (m, lH), 7.15 (s, 1H), 6.71 (d, 2H), 6.66 (d, IH), 5.69 (s, 2H), 5.85 (s, 2H), 4.56 (d , 2H) Example 29
V-29 N-(2-氨基 -4-吡啶基 )- 4-[ ( 3-氯苯甲酰基） 氨甲基]苯甲酰胺 3-氯苯甲酸（1.56g,10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml溶 剂氯化亚砜， 按通法中间体 ΙΠ的制备方法得白色固体（中间体 M-28) V-29 N-(2-Amino-4-pyridyl)-4-[(3-chlorobenzoyl)aminomethyl]benzamide 3-chlorobenzoic acid (1.56 g, 10 mmol), Sulfone (4.72g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid (intermediate M-28)
2.40g， 收率 83%。 将 3,4-二氨基吡啶 (0.109g, l mmol)、 M-28(0.289g，lmmol)、 HBTU (0.379g,l mmol)、 N,N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol)， 按通法产品 V的方法制备得白色固体 0.205g， 收率 54 %。 2.40g, yield 83%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-28 (0.289 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid.
MS(ES+):m/e 381.12. MS (ES+): m/e 381.12.
1H-NMR (400MHz, DMSO-d6) Sppm: 9.65 (s, IH), 8.38 (s, IH), 8.08 (d, IH), 7.87 (s， 1H),7.83 (d, 2H), 7.69 (d, IH), 7.67 (d, IH), 7.58 (m， IH), 7.24 (d， 2H), 6.66 (d, IH), 5.69 (s, 2H)， 4.56 (d, 2H) 实施例 30 1H-NMR (400MHz, DMSO-d 6 ) Sppm: 9.65 (s, IH), 8.38 (s, IH), 8.08 (d, IH), 7.87 (s, 1H), 7.83 (d, 2H), 7.69 ( d, IH), 7.67 (d, IH), 7.58 (m, IH), 7.24 (d, 2H), 6.66 (d, IH), 5.69 (s, 2H), 4.56 (d, 2H) Example 30
V -30 N-(2-氨基 -4-吡啶基) - 4-[ ( 2， 4-二氯苯甲酰基） 氨甲基]苯 甲酰胺 V -30 N-(2-Amino-4-pyridyl)-4-[(2,4-dichlorobenzoyl)aminomethyl]benzenecarboxamide
3-氯苯甲酸（1.89g,10 mmol)、 氯化亚砜 (4.72g，40 mmol)、 ΙΟπι 溶 剂氯化亚砜， 按通法中间体 III的制备方法得白色固体（中间体 Μ-29) 2.84g， 收率 88%。 将 3,4-二氨基吡啶 (0.109g,l mmol)、 M-29(0.323g, lmmol), HBTU (0.379g, l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.207g， 收率 50 %。 3-Chlorobenzoic acid (1.89 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), ΙΟπι solvent, thionyl chloride, obtained as a white solid ( intermediate Μ-29 ) 2.84 g, yield 88%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-29 (0.323 g, 1 mmol), HBTU (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethyl Amine (0.202 g, 2 mmol) was obtained as a white solid, 0.207 g, yield 50%.
MS(ES+):m/e 415.12. MS (ES+): m/e 415.12.
Ή-NMR (400MHz, DMSO-d6) Sppm: 9.65 (s， IH), 8.38(s, 1H)， 8.08 (d, IH), 7.83 (d, 2H), 7.61(s， IH), 7.49 (d, 1H),7.46 (d, IH), 7.24 (d, 2H),
6.66 (d, 1H)， 5.69 (s, 2H), 4.56 (d, 2H) 实施例 31 Ή-NMR (400MHz, DMSO-d 6 ) Sppm: 9.65 (s, IH), 8.38 (s, 1H), 8.08 (d, IH), 7.83 (d, 2H), 7.61 (s, IH), 7.49 ( d, 1H), 7.46 (d, IH), 7.24 (d, 2H), 6.66 (d, 1H), 5.69 (s, 2H), 4.56 (d, 2H) Example 31
V-31 N-(2-氨基 -4-吡啶基 )- 4-[ ( 4-苯基苯甲酰基） 氨甲基]苯甲酰 胺 V-31 N-(2-Amino-4-pyridyl)-4- [(4-phenylbenzoyl)aminomethyl]benzoylamine
4-苯基苯甲酸（1.98g,10 mmol)、 氯化亚砜 (4.72g，40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-30) 2.64g， 收率 80%。 将 3,4-二氨基吡啶 (0.109g，l mmol)、 M-30(0.331g, lmmol)、 HBTU 4-Phenylbenzoic acid (1.98 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent thionyl chloride, obtained as a white solid ( intermediate M- 30) 2.64 g, yield 80%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-30 (0.331 g, 1 mmol), HBTU
(0.379g,l mmol)、 N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g,2 mmol)， 按通法产品 V的方法制备得白色固体 0.231g， 收率 55 %。 (0.379 g, 1 mmol), N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol), obtained as a white solid, 0.231 g, yield 55%. .
MS(ES+):m/e 423.12. MS (ES+): m/e 423.12.
1H-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s， 1H)， 8.38 (s, 1H),1H-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, 1H), 8.38 (s, 1H),
8.08 (d, 1H), 7.83 (d, 2H), 7.82 (d, 2H), 7.75 (d, 2H), 7.48 (m, 1H), 7.46 (m， 2H)， 7.24 (d， 2H)， 7.09 (d, 2H), 6.66 (d, 1H), 5.69 (s, 2H), 4.56 (d, 2H) 实施例 32 8.08 (d, 1H), 7.83 (d, 2H), 7.82 (d, 2H), 7.75 (d, 2H), 7.48 (m, 1H), 7.46 (m, 2H), 7.24 (d, 2H), 7.09 (d, 2H), 6.66 (d, 1H), 5.69 (s, 2H), 4.56 (d, 2H) Example 32
V -31 N-(2-氨基 -4-吡啶基 )- 4-[ ( 3-苯基苯甲酰基） 氨甲基]苯甲酰 胺 V-31 N-(2-Amino-4-pyridyl)- 4-[(3-phenylbenzoyl)aminomethyl]benzoylamine
3-苯基苯甲酸（1.98g，10 mmol)、 氯化亚砜 (4.72g,40 mmol)、 10ml 溶剂氯化亚砜， 按通法中间体 III的制备方法得白色固体 (中间体 M-30) 2.64g， 收率 80%。 将 3,4-二氨基吡啶 (0.109g,l mmol)、 M-30(0.331g，lmmol)、 HBTU (0.379g,l mmol) N，N-二甲基甲酰胺（10ml)、 三乙胺 (0.202g，2 mmol)， 按通法产品 V的方法制备得白色固体 0.231g， 收率 55 %。 3-Phenylbenzoic acid (1.98 g, 10 mmol), thionyl chloride (4.72 g, 40 mmol), 10 ml of solvent chlorosulfoxide, obtained as a white solid ( intermediate M- 30) 2.64 g, yield 80%. 3,4-Diaminopyridine (0.109 g, 1 mmol), M-30 (0.331 g, 1 mmol), HBTU (0.379 g, 1 mmol) N,N-dimethylformamide (10 ml), triethylamine (0.202 g, 2 mmol), 0.231 g of white solid was obtained by the procedure of product of product V.
MS(ES+):m/e 423.12.
Ή-NMR (400MHz, DMSO-d6) 5ppm: 9.65 (s, 1H), 8.38 (s, 1H), 8.17 (s, 1H),8.08 (d, 1H)， 7.91 (d， 1H)， 7.83 (d, 2H),7.75 (d, 2H), 7.73 (d, 1H), 7.50(m, 1H), 7.48(m, lH),7.46(m, 2H),，7.24 (d， 2H), 6.66 (d， 1H), 5.69 (s, 2H), 4.46 (d, 2H) 实施例 33 MS (ES+): m/e 423.12. Ή-NMR (400MHz, DMSO-d 6 ) 5ppm: 9.65 (s, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 8.08 (d, 1H), 7.91 (d, 1H), 7.83 ( d, 2H), 7.75 (d, 2H), 7.73 (d, 1H), 7.50 (m, 1H), 7.48 (m, lH), 7.46 (m, 2H), 7.24 (d, 2H), 6.66 ( d, 1H), 5.69 (s, 2H), 4.46 (d, 2H) Example 33
化合物的组蛋白去乙酰化酶体外抑制活性测定参照 HDAC抑制剂 筛选试剂盒 （Biovision 公司 /Catalog #K340- 100) 说明书进行。 将待测 化合物分别配制成 200uM、 40uM的溶液， 检测化合物在该浓度下的抑 酶情况。 结果如下： 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:
num 化合物对 HDACs的抑制率 （％) Inhibition rate of num compound against HDACs (%)
200uM 40uM 200uM 40uM
V-1 62.3 0.6 V-1 62.3 0.6
V-2 69.9 1.7 V-2 69.9 1.7
V-3 69.0 8.7 V-3 69.0 8.7
V-4 71.6 9.5 V-4 71.6 9.5
V-5 80.1 21.7 V-5 80.1 21.7
V-6 81.5 28.7 V-6 81.5 28.7
V-7 64.6 5.2 V-7 64.6 5.2
V-8 83.8 27.2 V-8 83.8 27.2
V-9 70.5 20.2 V-9 70.5 20.2
V-10 70.3 12.3 V-10 70.3 12.3
V-11 50.3 3.0 V-11 50.3 3.0
V-12 58.5 15.8 V-12 58.5 15.8
V-13 55.6 13.4 V-13 55.6 13.4
V-14 52.7 10.8 V-14 52.7 10.8
V-15 57.9 19.7 V-15 57.9 19.7
V-16 57.9 16.2 V-16 57.9 16.2
CI-994 88.7 52.9
实施例 34 CI-994 88.7 52.9 Example 34
化合物的组蛋白去乙酰化酶体外抑制活性 IC5Q值的测定参照 HDAC抑制剂筛选试剂盒（Biovision 公司 /Catalog #K340- 100) 说明书 进行。 用 DMSO4倍倍比稀释化合物， 得到 10个稀释浓度， 依次为 200 Μ, 50μ Μ, 12.5 μΜ, 3.125 μ Μ, 0.78 μ Μ, 0.19 μΜ, 4.88Ε-02 Μ, 1.22E-02U Μ, 3.05Ε-03 Μ, 7.6Ε-04 μ Μ。 每个稀释度做一个 复孔。 8个化合物 IC5Q值的测定结果如下- 化合物 IC50值 （ μ Μ) 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 Μ, 50 μΜ, 12.5 μΜ, 3.125 μΜ, 0.78 μΜ, 0.19 μΜ, 4.88Ε-02 Μ, 1.22E-02U Μ, 3.05Ε -03 Μ, 7.6Ε-04 μ Μ. Make a duplicate hole for each dilution. The results of the 5 IC IC 5Q values are as follows - Compound IC 50 values ( μ Μ)
V-2 17.30 ± 1.34 V-2 17.30 ± 1.34
V-3 48.72 ± 1.12 V-3 48.72 ± 1.12
V-4 20.19 ± 1.17 V-4 20.19 ± 1.17
V-5 34.42 ± 1.14 V-5 34.42 ± 1.14
V-6 18.66 ± 1.32 V-6 18.66 ± 1.32
V-8 11.72± 1.20 V-8 11.72± 1.20
V-9 39.72 ± 1.15 V-9 39.72 ± 1.15
V-10 25.35 ± 1.17 V-10 25.35 ± 1.17
CI-994 36.72 ± 1.25 实施例 35 CI-994 36.72 ± 1.25 Example 35
化合物的肿瘤细胞体外抑制活性测定： In vitro inhibitory activity assay of compound tumor cells:
化合物在 100 μΜ和 10 μΜ下对 Hut78 T淋巴细胞白血病细胞、 Jurkat E6-1 人 T细胞淋巴瘤、 PANC-1 人胰腺癌细胞、 A549 人肺癌 细胞、 K562 人慢性髓原白血病细胞、 Hep3B2.1-7 人肝癌细胞、 MDA-MB-435S 人乳腺癌细胞、 Colo320 人直肠癌细胞系、 PC-3 人前 列腺癌、 HCT 116人结肠癌细胞、 HepG2人肝癌细胞株、 MDA-MB-435 人乳腺癌高转移细胞、 MKN-45胃癌细胞株抑制率通过 CCK-8法测得。 具体结果如下：
化合物对 Hut78、 Jurkat E6-K PANC-K A549、 HepG2细胞的抗 增殖作用 Compounds at 100 μΜ and 10 μΜ against Hut78 T lymphocytic leukemia cells, Jurkat E6-1 human T cell lymphoma, PANC-1 human pancreatic cancer cells, A549 human lung cancer cells, K562 human chronic myeloid leukemia cells, Hep3B2.1 -7 human liver cancer cells, MDA-MB-435S human breast cancer cells, Colo320 human rectal cancer cell lines, PC-3 human prostate cancer, HCT 116 human colon cancer cells, HepG2 human liver cancer cell lines, MDA-MB-435 human breast The inhibition rate of cancer metastatic cells and MKN-45 gastric cancer cell lines was measured by CCK-8 method. The specific results are as follows: Antiproliferative effects of compounds on Hut78, Jurkat E6-K PANC-K A549, HepG2 cells
Hut78 Jurkat E6-1 PANC-1 A549 HepG2 Hut78 Jurkat E6-1 PANC-1 A549 HepG2
100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ
V-1 -10 -7 22 10 -9 18 -1 5 4 3V-1 -10 -7 22 10 -9 18 -1 5 4 3
V-2 -1 -7 9 2 -10 -3 4 5 23 0V-2 -1 -7 9 2 -10 -3 4 5 23 0
V-3 2 -4 13 -1 -1 -4 10 5 25 6V-3 2 -4 13 -1 -1 -4 10 5 25 6
V -4 28 -3 20 9 -16 -7 -1 -3 49 3V -4 28 -3 20 9 -16 -7 -1 -3 49 3
V -5 108 0 51 9 8 -10 13 -1 60 5V -5 108 0 51 9 8 -10 13 -1 60 5
V -6 1 16 10 79 10 -15 -14 17 -3 71 27V -6 1 16 10 79 10 -15 -14 17 -3 71 27
V -7 67 6 83 16 1 -15 10 -4 48 12V -7 67 6 83 16 1 -15 10 -4 48 12
V -8 98 13 96 36 35 8 18 -2 80 13V -8 98 13 96 36 35 8 18 -2 80 13
V -9 5 2 87 6 3 -1 6 8 -4 1V -9 5 2 87 6 3 -1 6 8 -4 1
V-10 1 1 0 17 0 -5 -23 23 1 10 2V-10 1 1 0 17 0 -5 -23 23 1 10 2
V-1 1 4 3 36 20 9 28 0 -1 -7 15V-1 1 4 3 36 20 9 28 0 -1 -7 15
V -12 69 1 24 4 -14 -12 29 -5 67 30V -12 69 1 24 4 -14 -12 29 -5 67 30
V -13 87 19 42 0 33 4 64 31 64 42V -13 87 19 42 0 33 4 64 31 64 42
V -14 37 26 50 15 41 1 71 60 33 23V -14 37 26 50 15 41 1 71 60 33 23
V-15 65 22 38 15 51 34 70 70 73 58V-15 65 22 38 15 51 34 70 70 73 58
V-16 75 32 63 47 20 -1 58 59 73 52V-16 75 32 63 47 20 -1 58 59 73 52
CI-994 120 39 90 36 79 29 32 -7 81 14 化合物对 Κ562、 Hep3B2.1-7 > MDA-MB-435S、 Colo320 PC-3 细胞的抗增殖作用CI-994 120 39 90 36 79 29 32 -7 81 14 Anti-proliferative effect of compound on Κ562, Hep3B2.1-7 > MDA-MB-435S, Colo320 PC-3 cells
562 Hep3B2.1-7 MDA-MB-435S Colo320 PC-: 562 Hep3B2.1-7 MDA-MB-435S Colo320 PC-:
100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΝ100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΝ
V-1 33 7 -1 1 -1 -36 -25 -6 2 3 -10V-1 33 7 -1 1 -1 -36 -25 -6 2 3 -10
V -2 50 20 -12 -2 -13 -25 -2 2 -5 -16V -2 50 20 -12 -2 -13 -25 -2 2 -5 -16
V -3 69 29 -18 -6 -21 -19 -7 -6 6 0
V-4 74 56 -12 -4 -12 -56 -8 0 16 4V -3 69 29 -18 -6 -21 -19 -7 -6 6 0 V-4 74 56 -12 -4 -12 -56 -8 0 16 4
V-5 81 72 8 11 13 -16 4 3 13 -5V-5 81 72 8 11 13 -16 4 3 13 -5
V-6 76 51 -3 4 63 0 7 5 19 0V-6 76 51 -3 4 63 0 7 5 19 0
V-7 48 67 5 16 39 1 7 7 22 6V-7 48 67 5 16 39 1 7 7 22 6
V-8 90 63 4 10 57 -5 16 5 19 -8V-8 90 63 4 10 57 -5 16 5 19 -8
V-9 25 9 4 5 -37 -15 9 2 4 -9V-9 25 9 4 5 -37 -15 9 2 4 -9
V-10 31 9 16 3 13 -20 42 11 14 -12V-10 31 9 16 3 13 -20 42 11 14 -12
V-ll 30 14 -6 4 10 -19 2 1 12 -20V-ll 30 14 -6 4 10 -19 2 1 12 -20
V-12 86 84 15 3 45 -31 4 -1 5 17V-12 86 84 15 3 45 -31 4 -1 5 17
V-13 83 81 -1 8 90 8 11 7 8 -8V-13 83 81 -1 8 90 8 11 7 8 -8
V-14 63 59 -4 2 63 9 10 3 5 10V-14 63 59 -4 2 63 9 10 3 5 10
V-15 73 78 -20 -15 83 20 4 -3 31 1V-15 73 78 -20 -15 83 20 4 -3 31 1
V-16 86 85 -38 -22 86 -9 16 2 -6 -21V-16 86 85 -38 -22 86 -9 16 2 -6 -21
CI-994 81 41 -23 -25 36 -6 -4 -4 -7 -14 化合物对 MKN-45、 MDA-MB-435^ HCTl 16细胞的抗增殖作用 CI-994 81 41 -23 -25 36 -6 -4 -4 -7 -14 Anti-proliferative effect of compound on MKN-45, MDA-MB-435^ HCTl 16 cells
MKN-45 MDA-MB-435 HCTl 16 MKN-45 MDA-MB-435 HCTl 16
100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ 100 μΜ 10 μΜ
V-1 15 1 6 2 -6 3 V-1 15 1 6 2 -6 3
V-2 18 3 12 -5 9 -3V-2 18 3 12 -5 9 -3
V-3 18 8 31 0 26 6V-3 18 8 31 0 26 6
V-4 12 16 53 -3 37 5V-4 12 16 53 -3 37 5
V-5 22 36 79 -4 49 -6V-5 22 36 79 -4 49 -6
V-6 14 40 71 11 54 6V-6 14 40 71 11 54 6
V-7 8 6 51 20 29 5V-7 8 6 51 20 29 5
V-8 80 8 86 11 68 -1V-8 80 8 86 11 68 -1
V-9 -5 4 13 9 -6 7V-9 -5 4 13 9 -6 7
V-10 1 22 25 4 31 8V-10 1 22 25 4 31 8
V-11 12 -10 9 12 -6 8V-11 12 -10 9 12 -6 8
V-12 25 32 42 29 42 11
V-13 70 22 28 43 62 15 V-12 25 32 42 29 42 11 V-13 70 22 28 43 62 15
V-14 30 6 18 21 19 9 V-14 30 6 18 21 19 9
V-15 69 43 46 31 63 11 V-15 69 43 46 31 63 11
V-16 68 35 47 39 66 7 V-16 68 35 47 39 66 7
CI-994 64 31 88 -3 75 9 实施例 36 CI-994 64 31 88 -3 75 9 Example 36
化合物对肿瘤细胞体外抑制 IC5Q值的测定： Determination of IC 5Q values of compounds inhibiting tumor cells in vitro:
所有化合物和阳性对照均用 DMSO溶解至 25 mM， 使用时各取 7 μΐ 用完全培养基稀释至 140 μ1， 即化合物浓度为 1.25 mM, 含 5% DMSO, 以此为最高浓度， 用含 5% DMSO的完全培养基做 3倍梯度稀 释， SP: 从高浓度孔吸出 45 μΐ到 90 μΐ 稀释液， 依次类推。 化合物处 理细胞时， 吸取 25μ1稀释好的化合物到 100 μΐ细胞培养孔里， 使化合 物终浓度为 250 μΜ、 83.3 μΜ、 27.8 μΜ 0.038μΜ, 并含有 1% All compounds and positive control were dissolved in DMSO to 25 mM, 7 μΐ each, diluted to 140 μl with complete medium, ie 1.25 mM compound concentration, containing 5% DMSO, the highest concentration, 5% The DMSO complete medium was diluted 3-fold, SP: Aspirate 45 μΐ to 90 μΐ of the dilution from the high concentration well, and so on. When the compound is treated, absorb 25 μl of the diluted compound into a 100 μM cell culture well to give a final concentration of 250 μΜ, 83.3 μΜ, 27.8 μΜ 0.038 μΜ, and 1%.
DMSO。 通过 CCK-8法测得 IC50值结果如下： DMSO. The IC50 values obtained by the CCK-8 method are as follows:
化合物对 7个肿瘤细胞体外抑制 IC5Q值 （ μ Μ) Inhibition of IC 5Q values ( μ Μ) by compounds against 7 tumor cells in vitro
化合物 Hut78 Jurkat E6-1 A549 HepG2 562 M N-45 MDA-MB-435 Compound Hut78 Jurkat E6-1 A549 HepG2 562 M N-45 MDA-MB-435
V-1 83.3 150.9 102.1 89.04 220.4 129.0 199.4V-1 83.3 150.9 102.1 89.04 220.4 129.0 199.4
V-2 123.0 98.70 177.4 100.8 225.1 103.2 243.8V-2 123.0 98.70 177.4 100.8 225.1 103.2 243.8
V-3 220.4 112.4 312.0 231.0 100.4 332.0 131.4V-3 220.4 112.4 312.0 231.0 100.4 332.0 131.4
V-4 102.8 90.06 444.9 187.6 231.9 157.6 237.6V-4 102.8 90.06 444.9 187.6 231.9 157.6 237.6
V-5 44.32 23.15 65.73 54.31 31.08 24.01 104.3V-5 44.32 23.15 65.73 54.31 31.08 24.01 104.3
V-6 97.01 44.31 110.6 77.65 90.07 79.66 89.15V-6 97.01 44.31 110.6 77.65 90.07 79.66 89.15
V-7 81.03 60.41 137.8 80.01 56.09 90.06 55.32V-7 81.03 60.41 137.8 80.01 56.09 90.06 55.32
V-8 66.92 50.07 44.17 95.81 77.31 65.82 66.09V-8 66.92 50.07 44.17 95.81 77.31 65.82 66.09
V-9 99.08 68.11 200.5 119.4 168.2 157.4 99.54V-9 99.08 68.11 200.5 119.4 168.2 157.4 99.54
V-10 132.5 66.81 387.6 231.7 177.4 91.77 331.2V-10 132.5 66.81 387.6 231.7 177.4 91.77 331.2
V-11 231.3 108.6 549.2 149.8 120.8 249.9 240.1V-11 231.3 108.6 549.2 149.8 120.8 249.9 240.1
V-12 33.09 55.10 107.9 110.6 100.9 70.16 70.16V-12 33.09 55.10 107.9 110.6 100.9 70.16 70.16
V-13 67.14 34.27 53.29 99.08 66.07 109.8 98.24
V -14 55.61 99.03 97.08 42.17 76.13 40.07 79.10V-13 67.14 34.27 53.29 99.08 66.07 109.8 98.24 V -14 55.61 99.03 97.08 42.17 76.13 40.07 79.10
V -15 105.3 190.8 1 18.2 89.09 224.1 99.09 189.27V -15 105.3 190.8 1 18.2 89.09 224.1 99.09 189.27
V - 16 88.12 134.2 349.8 349.7 298.7 140.7 1 1 1.7V - 16 88.12 134.2 349.8 349.7 298.7 140.7 1 1 1.7
CI-994 74.02 54.27 170.2 77.92 89.75 70.67 97.23 实施例 37 CI-994 74.02 54.27 170.2 77.92 89.75 70.67 97.23 Example 37
对实施例中 5、 6、 7、 8、 12、 13、 14的化合物进行小鼠 LD50测 试， 灌胃给药， 实验方法参照北京医科大学中国协和医科大学联合出 版社出版的 《现代药理实验方法》 第一版， LD5Q值均大于 2g/kg。 部分化合物急性毒性实验结果 The compounds of 5, 6, 7, 8, 12, 13, and 14 in the examples 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
剂量 浓度 给药 Dosage concentration
化合物 动物数 观察情况 结论 Compound number of animals observation situation conclusion
(mg/kg) (mg/ml) 次数 (mg/kg) (mg/ml) times
均活动正常，无明显 All activities are normal, no obvious
V-5 5000 125 1 3 LD50>5000mg/kg V-5 5000 125 1 3 LD 50 >5000mg/kg
异常表现 Abnormal performance
均活动正常， 无明显 All activities are normal, no obvious
V-6 5000 125 1 3 LD50>5000mg/kg V-6 5000 125 1 3 LD 50 >5000mg/kg
异常表现 Abnormal performance
给药后第 2天拉稀， Dilute on the second day after administration,
5000 50 1 3 5000 50 1 3
第三天全部死亡 5000mg/kg>LD50>200All died on the third day 5000mg/kg>LD 50 >200
V-7 V-7
均活动正常，无明显 Omg/kg All activities are normal, no obvious Omg/kg
2000 25 1 3 2000 25 1 3
异常表现 Abnormal performance
给药后约 2h发现死 About 2 hours after administration, it was found dead.
5000 125 1 2 亡，解剖无明显异常 5000 125 1 2 dead, no obvious abnormalities in anatomy
V-8 发现 LD50>2000mg/kg V-8 found LD 50 >2000mg/kg
均活动正常， 无明显 All activities are normal, no obvious
2000 50 1 3 2000 50 1 3
异常表现 Abnormal performance
均活动正常， 无明显 All activities are normal, no obvious
V-12 5000 125 1 3 LD50>5000mg/kg V-12 5000 125 1 3 LD 50 >5000mg/kg
异常表现 Abnormal performance
均活动正常，无明显 All activities are normal, no obvious
V-13 5000 62.5 2 3 LD50>5000mg/kg V-13 5000 62.5 2 3 LD 50 >5000mg/kg
异常表现 Abnormal performance
给药后第 2天拉稀， Dilute on the second day after administration,
5000 62.5 2 3 5000 62.5 2 3
第三天全部死亡 5000mg/kg>LD50>200All died on the third day 5000mg/kg>LD 50 >200
V-14 V-14
均活动正常， 无明显 Omg/kg All activities are normal, no obvious Omg/kg
2000 50 1 3 2000 50 1 3
异常表现
实施例 38 Abnormal performance Example 38
片剂： 实施例 1-32的化合物 10mg Tablets: Compounds of Examples 1-32 10 mg
蔗糖 150mg Sucrose 150mg
玉米淀粉 38mg Corn Starch 38mg
硬脂酸钙 2mg 制备方法: 将活性成分与蔗糖、 玉米淀粉混合， 加水湿润， 搅拌 均匀， 干燥， 粉碎过筛， 加入硬脂酸钙， 混合均匀， 压片。 每片重 200 mg， 活性成分含量为 10mg。 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.
实施例 39 Example 39
针剂： 实施例 1-32的化合物 20mg Injection: Compound of Example 1-32 20mg
注射用水 80mg Water for injection 80mg
制备方法： 将活性成分溶解与注射用水， 混合均匀， 过滤， 将所 获得的溶液在无菌条件下分装与安瓿瓶中， 每瓶 10mg， 活性成分含量 为 2mg/瓶。
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.
Claims
1. N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于， 为具有如 下化学结构通式的化合物或其盐：
An N-(2-amino-4-pyridyl)benzamide derivative which is a compound having the following chemical structural formula or a salt thereof:
其中 R为氢、 1至 5个碳原子的垸基、 C5或 C6的脂肪环、 芳环或 杂环， 为氢、 （^〜(：5的烷基、 c5或 c6的脂肪环， 苯基或取代苯基; n = 0, 1 ,2,3。 Wherein 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 is hydrogen, (^~(: 5 alkyl, c 5 or c 6 fat) Ring, phenyl or substituted phenyl; n = 0, 1 , 2, 3.
2. 根据权利要求 1所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于， 芳环或杂环含有 1 至 4个取代基， 其取代基为卤素、 氨 基、 羟基、 硝基、 氰基、 1至 4个碳原子的垸基、 1至 4个碳原子的院 氧基、 1至 4个碳原子的氨垸基、 1至 4个碳原子的垸氨基、 2至 4个 碳原子的酰基、 2至 4个碳原子的酰氨基、 1至 4 个碳原子的硫代垸基、 三氟甲基、 1至 4个碳原子的羧基、 1至 4个碳原子的垸氧基羰基、 苯 基或杂环取代基。 The N-(2-amino-4-pyridyl)benzamide derivative according to claim 1, wherein the aromatic ring or the heterocyclic ring has 1 to 4 substituents, and the substituent is halogen. Amino group, hydroxyl group, nitro group, cyano group, fluorenyl group of 1 to 4 carbon atoms, oxime group of 1 to 4 carbon atoms, amino fluorenyl group of 1 to 4 carbon atoms, fluorene of 1 to 4 carbon atoms Amino group, acyl group of 2 to 4 carbon atoms, acylamino group of 2 to 4 carbon atoms, thioindenyl group of 1 to 4 carbon atoms, trifluoromethyl group, carboxyl group of 1 to 4 carbon atoms, 1 to 4 a decyloxycarbonyl group of a carbon atom, a phenyl or a heterocyclic substituent.
3. 根据权利要求 1所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于， 所述的取代苯基为苯环上含有 1 至 4个取代基， 其取代 基为卤素、 羟基、 硝基、 氰基、 1至 4个碳原子的烷氧基、 1至 4个碳 原子的垸基或氨基基团。 The N-(2-amino-4-pyridyl)benzamide derivative according to claim 1, wherein the substituted phenyl group has 1 to 4 substituents on the benzene ring, The substituent is a halogen, a hydroxyl group, a nitro group, a cyano group, an alkoxy group of 1 to 4 carbon atoms, a mercapto group or an amino group of 1 to 4 carbon atoms.
4. 根据权利要求 1所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于， 所述杂环为四氢吡咯、 二氢吡唑、 哌啶、 吗啉、 咪唑或 吡啶。 The N-(2-amino-4-pyridyl)benzamide derivative according to claim 1, wherein the heterocyclic ring is tetrahydropyrrole, dihydropyrazole, piperidine, morpholine. , imidazole or pyridine.
5. 根据权利要求 2或 3所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生
物， 其特征在于， 所述的卤素为氟、 氯、 溴或碘。 5. Derivatization of N-(2-amino-4-pyridyl)benzamide according to claim 2 or 3. And characterized in that the halogen is fluorine, chlorine, bromine or iodine.
6. 根据权利要求 2所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于： 所述的 1 至 4个碳原子的烷基为甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基或特丁基； The N-(2-amino-4-pyridyl)benzamide derivative according to claim 2, wherein the alkyl group having 1 to 4 carbon atoms is a methyl group or an ethyl group. N-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
所述的 1至 4个碳原子的垸氧基为甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁氧基或异丁氧基； The methoxy group of 1 to 4 carbon atoms is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group;
所述的 1至 4个碳原子的氨基垸基为氨基乙基、 1-氨基丙基或 2- 氨基丙基； The amino group of 1 to 4 carbon atoms is aminoethyl, 1-aminopropyl or 2-aminopropyl;
所述的 1 至 4个碳原子的垸基氨基为 N-甲氨基、 N-乙氨基或 N- 异丙氨基； The mercaptoamino group of 1 to 4 carbon atoms is N-methylamino, N-ethylamino or N-isopropylamino;
所述的 2至 4个碳原子的酰基为乙酰基、 丙酰基或异丁酰基； 所述的 2至 4个碳原子的酰氨基为乙酰氨基、 丙酰氨基、 丁酰氨 基或异丁酰氨基； The acyl group of 2 to 4 carbon atoms is acetyl, propionyl or isobutyryl; the acylamino group of 2 to 4 carbon atoms is acetylamino, propionylamino, butyrylamino or isobutyrylamino ;
所述的 2至 4个碳原子的硫代烷基为甲硫基、 乙硫基或丙硫基。 The thioalkyl group of 2 to 4 carbon atoms is a methylthio group, an ethylthio group or a propylthio group.
7. 根据权利要求 3所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于： The N-(2-amino-4-pyridyl)benzamide derivative according to claim 3, which is characterized in that:
所述的 1至 4个碳原子的垸氧基为甲氧基、 乙氧基、 正丙氧基、 异丙氧基、正丁氧基或异丁氧基， 1至 4个碳原子的垸基为甲基、乙基、 正丙基、 异丙基、 正丁基、 异丁基或特丁基。 The methoxy group of 1 to 4 carbon atoms is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group, and a fluorene of 1 to 4 carbon atoms. The group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
8. 根据权利要求 1所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于： 所述的盐为盐酸盐、 溴氢酸盐、 硫酸盐、 三氟醋酸盐或 甲磺酸盐。 The N-(2-amino-4-pyridyl)benzamide derivative according to claim 1, wherein the salt is a hydrochloride, a hydrobromide, a sulfate, or a trifluorocarbon. Acetate or methanesulfonate.
9. 根据权利要求 8所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物， 其特征在于： 所说的盐含 0.5〜3分子的结晶水。 The N-(2-amino-4-pyridyl)benzamide derivative according to claim 8, wherein the salt contains 0.5 to 3 molecules of water of crystallization.
10. 根据权利要求 1所述的 N-(2-氨基 -4-吡啶基)苯甲酰胺衍生物，
其特征在于： 所述的化合物包括： 10. The N-(2-amino-4-pyridyl)benzamide derivative according to claim 1, It is characterized in that: the compound comprises:
V-l N-(2-氨基 -4-吡啶基 )-4- (乙酰氨甲基） 苯甲酰胺、 V-l N-(2-amino-4-pyridyl)-4-(acetylaminomethyl)benzamide,
V-2N-(2-氨基 -4-吡啶基 )-4- (丙酰氨甲基） 苯甲酰胺、 V-2N-(2-amino-4-pyridyl)-4-(propionylaminomethyl)benzamide,
V-3N-(2-氨基 -4-吡啶基 )-4- (丁酰氨甲基） 苯甲酰胺、 V-3N-(2-amino-4-pyridyl)-4-(butyrylaminomethyl)benzamide,
V-4N-(2-氨基 -4-吡啶基 )-4- (环己酰氨甲基） 苯甲酰胺、 V-4N-(2-amino-4-pyridyl)-4-(cyclohexanoylaminomethyl)benzamide,
V-5N-(2-氨基 -4-吡啶基 )-4- (苯甲酰氨甲基） 苯甲酰胺、 V-5N-(2-amino-4-pyridyl)-4-(benzoylaminomethyl)benzamide,
V-6 N-(2-氨基 -4-吡啶基) - 4-[ (4-甲氧基苯甲酰基） 氨甲基]苯甲 酰胺、 V-6 N-(2-amino-4-pyridyl)-4-[(4-methoxybenzoyl)aminomethyl]benzamide,
V-7N-(2-氨基 -4-吡啶基 )-4-[ (4-氟苯甲酰基） 氨甲基]苯甲酰胺、 V-8 N-(2-氨基 -4-吡啶基) - 4-[ (3-甲氧基苯甲酰基） 氨甲基]苯甲 酰胺、 V-7N-(2-Amino-4-pyridyl)-4-[(4-fluorobenzoyl)aminomethyl]benzamide, V-8 N-(2-amino-4-pyridyl)- 4-[(3-methoxybenzoyl)aminomethyl]benzamide,
V· -9N-(2-氨基 -4-吡啶基 )-4- (乙酰氨基） 笨甲酰胺、 V· -9N-(2-amino-4-pyridyl)-4-(acetylamino)benzamide,
V· -10 (2-氨基-4-吡啶基)- 4- (丙酰氨基） 苯甲酰胺、 V· -10 (2-amino-4-pyridyl)-4-(propionylamino)benzamide,
V. -11 N-(2-氨基 -4-吡啶基) - 4- (丁酰氨基） 笨甲酰胺、 V. -11 N-(2-Amino-4-pyridyl)-4- 4-(butyrylamino)benzamide,
V. -121^-(2-氨基-4 比啶基)- 4- (环己酰氨基） 苯甲酰胺、 V. -121^-(2-amino-4-pyridyl)- 4-(cyclohexanoylamino)benzamide,
V· -13>^-(2-氨基-4-吡啶基)- 4- (苯甲酰氨基） 苯甲酰胺、 V· -13>^-(2-amino-4-pyridyl)-4-(benzoylamino)benzamide,
V- -14 (2-氨基-4-吡啶基)- 4-[ (4-甲氧基苯甲酰基） 氨基]苯甲酰 V- -14 (2-amino-4-pyridinyl)-4-[(4-methoxybenzoyl)amino]benzoyl
V· -15 1-(2-氨基-4-吡啶基)- 4-[ (4-氟苯甲酰基） 氨基]苯甲酰胺、V· -15 1-(2-Amino-4-pyridyl)- 4-[(4-fluorobenzoyl)amino]benzamide,
V- -16!^-(2-氨基-4-[1比啶基)- 4-[ (3-甲氧基苯甲酰基） 氨基]苯甲酰 V- -16!^-(2-Amino-4-[1-pyridyl)- 4-[(3-methoxybenzoyl)amino]benzoyl
V· -17 (2-氨基-4-吡啶基)- 4- (乙酰氨乙基） 苯甲酰胺、 V· -17 (2-amino-4-pyridyl)-4-(acetylaminoethyl)benzamide,
V- -18^(2-氨基-4 匕啶基)- 4- (1-乙酰氨丙基） 苯甲酰胺、 V- -18^(2-amino-4-acridinyl)-4-(1-acetylaminopropyl)benzamide,
V- -19N-(2-氨基 -4-P比啶基) - 4- (1-乙酰氨基乙基） 苯甲酰胺、V- -19N-(2-amino-4-Ppyridyl)-4-(1-acetylaminoethyl)benzamide,
V- ■20 N-(2-氨基 -4-吡啶基) - ■ 4- (1-乙酰氨基 2-苯基乙基） 苯甲酰 胺、 V- ■20 N-(2-amino-4-pyridyl)- ■ 4-(1-acetylamino 2-phenylethyl)benzamide,
V-21 N-(2-氨基 -4-吡啶基 )-4- (2-乙酰氨基丙基） 苯甲酰胺、 V-22N-(2-氨基 -4-吡啶基 )-4-[ (3,4-二甲氧基苯甲酰基） 氨甲基] 苯甲酰胺、 V-21 N-(2-Amino-4-pyridyl)-4-(2-acetamidopropyl)benzamide, V-22N-(2-amino-4-pyridyl)-4-[ (3 , 4-dimethoxybenzoyl)aminomethyl]benzamide,
V -23 N-(2-氨基 -4-吡啶基) - 4-[ ( 3,4,5-三甲氧基苯甲酰基）氨甲基]
苯甲酰胺、 V -23 N-(2-Amino-4-pyridyl)-4-[(3,4,5-trimethoxybenzoyl)aminomethyl] Benzoylamide,
V -24 N-(2-氨基 -4-吡啶基) - 4-[ ( 4-吡啶甲酰基）氨甲基]苯甲酰胺、 V-25 N-(2-氨基 -4-吡啶基) - 4-[ (4-吗啉甲酰基）氨甲基]苯甲酰胺、 V-26N-(2-氨基 -4-吡啶基 )-4-[ (3-三氟甲基苯甲酰基） 氨甲基]苯 甲酰胺、 V-24 N-(2-Amino-4-pyridyl)-4-[(4-pyridinecarbonyl)aminomethyl]benzamide, V-25 N-(2-amino-4-pyridyl)- 4-[(4-morpholinyl)aminomethyl]benzamide, V-26N-(2-amino-4-pyridyl)-4-[(3-trifluoromethylbenzoyl)carbamate Benzoylamide,
V-27N-(2-氨基 -4-吡啶基 )-4-[ (3-硝基苯甲酰基） 氨甲基]苯甲酰 胺、 V-27N-(2-amino-4-pyridyl)-4-[(3-nitrobenzoyl)aminomethyl]benzoylamine,
V-28N-(2-氨基 -4-吡啶基 )-4-[ (3-氨基苯甲酰基） 氨甲基]苯甲酰 胺、 V-28N-(2-amino-4-pyridyl)-4-[(3-aminobenzoyl)aminomethyl]benzoylamine,
V -29 N-(2-氨基 -4-吡啶基) - 4-[ ( 3-氯苯甲酰基）氨甲基]苯甲酰胺、 V-30 N-(2-氨基 -4-吡啶基) - 4-[ (2, 4-二氯苯甲酰基） 氨甲基]苯 甲酰胺、 V -29 N-(2-Amino-4-pyridyl)-4-[(3-chlorobenzoyl)aminomethyl]benzamide, V-30 N-(2-amino-4-pyridyl) - 4-[ (2, 4-dichlorobenzoyl)aminomethyl]benzamide,
V-31 N-(2-氨基 -4-吡啶基 )-4-[ (4-苯基苯甲酰基） 氨甲基]苯甲酰 胺或 V-31 N-(2-Amino-4-pyridyl)-4-[(4-phenylbenzoyl)aminomethyl]benzoylamine or
V-32N-(2-氨基 -4-吡啶基 )-4-[ (3-苯基苯甲酰基） 氨甲基]苯甲酰 胺。 V-32N-(2-Amino-4-pyridyl)-4-[(3-phenylbenzoyl)aminomethyl]benzoylamine.
11. 权利要求 1〜10任一项所述的化合物或其盐在制备治疗癌症 及与分化和增殖相关的疾病药物中的应用。 The use of the compound according to any one of claims 1 to 10 or a salt thereof for the preparation of a medicament for treating cancer and diseases associated with differentiation and proliferation.
12. 一种组合物， 包括治疗有效量的权利要求 1〜10任一项所述 的化合物或其盐和医药学上可接受的载体。
12. A composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 10, or a salt thereof, and a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100519366A CN101899001A (en) | 2009-05-25 | 2009-05-25 | N-(2-amino-4-pyridyl)-benzamide derivatives and their application |
| CN200910051936.6 | 2009-05-25 |
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| Publication Number | Publication Date |
|---|---|
| WO2010135908A1 true WO2010135908A1 (en) | 2010-12-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2010/000712 WO2010135908A1 (en) | 2009-05-25 | 2010-05-20 | N-(2-amino-4-pyridyl) benzamide derivatives and uses thereof |
Country Status (2)
| Country | Link |
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| CN (1) | CN101899001A (en) |
| WO (1) | WO2010135908A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850236B (en) | 2011-06-27 | 2016-05-18 | 国药一心制药有限公司 | New benzamides histone deacetylases inhibitor and application thereof |
| CN103420917B (en) * | 2012-05-18 | 2015-08-19 | 国药一心制药有限公司 | Containing the benzamide compound of condensed cyclic structure and apply as antitumor drug |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11335375A (en) * | 1998-05-20 | 1999-12-07 | Mitsui Chem Inc | Benzamide derivative having histone deacetylase inhibiting action |
| CN1513839A (en) * | 2003-07-04 | 2004-07-21 | 深圳微芯生物科技有限责任公司 | Benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activities and medicinal preparation thereof |
| WO2007017728A2 (en) * | 2005-08-05 | 2007-02-15 | Orchid Research Laboratories Limited | Novel heterocyclic compounds |
| WO2009152735A1 (en) * | 2008-06-20 | 2009-12-23 | 江苏国华投资有限公司 | Histone deacetylase inhibitors and uses thereof |
-
2009
- 2009-05-25 CN CN2009100519366A patent/CN101899001A/en active Pending
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2010
- 2010-05-20 WO PCT/CN2010/000712 patent/WO2010135908A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11335375A (en) * | 1998-05-20 | 1999-12-07 | Mitsui Chem Inc | Benzamide derivative having histone deacetylase inhibiting action |
| CN1513839A (en) * | 2003-07-04 | 2004-07-21 | 深圳微芯生物科技有限责任公司 | Benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activities and medicinal preparation thereof |
| WO2007017728A2 (en) * | 2005-08-05 | 2007-02-15 | Orchid Research Laboratories Limited | Novel heterocyclic compounds |
| WO2009152735A1 (en) * | 2008-06-20 | 2009-12-23 | 江苏国华投资有限公司 | Histone deacetylase inhibitors and uses thereof |
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| CN101899001A (en) | 2010-12-01 |
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