CN102002063B - 一类羧酸与β氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途 - Google Patents
一类羧酸与β氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途 Download PDFInfo
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- CN102002063B CN102002063B CN200910034130.6A CN200910034130A CN102002063B CN 102002063 B CN102002063 B CN 102002063B CN 200910034130 A CN200910034130 A CN 200910034130A CN 102002063 B CN102002063 B CN 102002063B
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- Prior art keywords
- beta
- boronic acid
- formyl
- compound
- phenyl
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- -1 ester compound Chemical class 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 title claims description 8
- 150000001576 beta-amino acids Chemical group 0.000 title abstract description 6
- 150000001735 carboxylic acids Chemical class 0.000 title abstract 2
- 108010016626 Dipeptides Proteins 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 229940079156 Proteasome inhibitor Drugs 0.000 claims abstract description 7
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- 239000003207 proteasome inhibitor Substances 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 155
- 238000006243 chemical reaction Methods 0.000 claims description 102
- 239000002253 acid Substances 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 230000009471 action Effects 0.000 claims description 8
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- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- 229910052757 nitrogen Inorganic materials 0.000 abstract description 29
- 125000000217 alkyl group Chemical group 0.000 abstract description 9
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- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
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- 125000004415 heterocyclylalkyl group Chemical group 0.000 abstract 2
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 abstract 1
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- 230000002194 synthesizing effect Effects 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 70
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 68
- 239000007787 solid Substances 0.000 description 67
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 22
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 22
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
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- 239000003814 drug Substances 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 20
- 239000011777 magnesium Substances 0.000 description 20
- 229910052749 magnesium Inorganic materials 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
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- 235000010233 benzoic acid Nutrition 0.000 description 17
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 14
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 14
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
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- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
化合物编号 | IC50(nM) | 化合物编号 | IC50(nM) | 化合物编号 | IC50(nM) |
VI-1 | 39.8 | VI-26 | 35.4 | VI-65 | 3.01 |
VI-2 | 38.9 | VI-27 | 457 | VI-66 | 117 |
VI-3 | 89.1 | VI-28 | 1100 | VI-69 | 1.02 |
VI-4 | 1250 | VI-32 | 1250 | VI-70 | 4000 |
VI-5 | 224 | VI-34 | 87 | VI-71 | 21.8 |
VI-7 | 19.0 | VI-41 | 22.9 | VI-72 | 195 |
VI-8 | 1250 | VI-43 | 50.1 | VI-73 | 28.1 |
VI-9 | 1200 | VI-44 | 21.3 | VI-74 | 21.8 |
VI-10 | 501 | VI-47 | 1480 | VI-75 | 164 |
VI-11 | 75.8 | VI-48 | 1090 | VI-76 | 78 |
VI-12 | 120 | VI-49 | 930 | VI-77 | 4500 |
VI-13 | 131 | VI-50 | 63 | VI-78 | 426 |
VI-15 | 301 | VI-51 | 1770 | VI-80 | 33.1 |
VI-16 | 16.5 | VI-52 | 89.1 | VI-81 | 4000 |
VI-17 | 316 | VI-53 | 602 | VI-84 | 870 |
VI-18 | 1620 | VI-54 | 26.9 | VI-85 | 41.6 |
VI-19 | 1150 | VI-55 | 590 | VI-86 | 691 |
VI-20 | 194 | VI-57 | 7300 | VI-87 | 158 |
VI-24 | 371 | VI-58 | 269 | VI-88 | 190 |
VI-25 | 50.1 | VI-59 | 97.7 | VI-90 | 3.89 |
VI-29 | 20.8 | VI-60 | 46.7 | VI-92 | 158 |
VI-30 | 26.3 | VI-61 | 42.6 | VI-93 | 831 |
VI-31 | 32.8 | VI-62 | 34.6 | VI-94 | 161 |
Velcade | 1.90 | VI-63 | 131 |
Claims (5)
Priority Applications (2)
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CN200910034130.6A CN102002063B (zh) | 2009-09-01 | 2009-09-01 | 一类羧酸与β氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途 |
PCT/CN2010/073063 WO2011026349A1 (zh) | 2009-09-01 | 2010-05-21 | 一类羧酸与β氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途 |
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CN200910034130.6A CN102002063B (zh) | 2009-09-01 | 2009-09-01 | 一类羧酸与β氨基酸组成的二肽硼酸及其酯类化合物、制备方法及其用途 |
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CN102002063A CN102002063A (zh) | 2011-04-06 |
CN102002063B true CN102002063B (zh) | 2015-07-29 |
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Country Status (2)
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CN (1) | CN102002063B (zh) |
WO (1) | WO2011026349A1 (zh) |
Families Citing this family (4)
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CN103030656B (zh) * | 2011-09-30 | 2015-08-26 | 北京大学 | 蛋白酶体抑制剂硼替佐米及其类似物的合成方法 |
CN102512407B (zh) * | 2011-11-23 | 2014-05-21 | 中山大学 | 一种β-苯丙氨酸类化合物作为醛糖还原酶抑制剂的应用 |
UY38291A (es) | 2018-07-05 | 2020-06-30 | Servier Lab | Nuevos derivados de amino-pirimidonilo un proceso para su preparación y composiciones farmacéuticas |
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