CN111171114B - Phosphonate dipeptide compound and application thereof - Google Patents
Phosphonate dipeptide compound and application thereof Download PDFInfo
- Publication number
- CN111171114B CN111171114B CN202010055295.8A CN202010055295A CN111171114B CN 111171114 B CN111171114 B CN 111171114B CN 202010055295 A CN202010055295 A CN 202010055295A CN 111171114 B CN111171114 B CN 111171114B
- Authority
- CN
- China
- Prior art keywords
- iii
- diethyl
- methylphosphonate
- phenylalanyl
- fluorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 61
- 108010016626 Dipeptides Proteins 0.000 title claims abstract description 22
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 11
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 claims description 52
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 17
- -1 L-phenylalanyl-oxy Chemical group 0.000 claims description 12
- 241000191967 Staphylococcus aureus Species 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 5
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims 5
- 238000004519 manufacturing process Methods 0.000 claims 4
- 238000011321 prophylaxis Methods 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 238000004809 thin layer chromatography Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 229960003767 alanine Drugs 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 4
- 229960001180 norfloxacin Drugs 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- NJZAZAXYWGUKEX-QKBJIULESA-N (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[1-[(2S)-pyrrolidine-2-carbonyl]cyclohexa-2,4-dien-1-yl]propanoic acid Chemical compound C(C)(C)(C)OC(=O)N[C@@H](CC1(CC=CC=C1)C([C@H]1NCCC1)=O)C(=O)O NJZAZAXYWGUKEX-QKBJIULESA-N 0.000 description 2
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 2
- QWDIKYPUYHLCPI-FAGLKTCQSA-N C[C@@H](C(C1(C[C@@H](C(O)=O)NC(OC(C)(C)C)=O)C=CC=CC1)=O)N Chemical compound C[C@@H](C(C1(C[C@@H](C(O)=O)NC(OC(C)(C)C)=O)C=CC=CC1)=O)N QWDIKYPUYHLCPI-FAGLKTCQSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000013475 authorization Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 2
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
Abstract
The invention discloses a phosphonate dipeptide compound in the technical field of organic chemistry, which has a structural general formula as follows:
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a phosphonate dipeptide compound and application thereof.
Background
The world health organization statistics show that: although the medical level is continuously improved, the global tumor morbidity and mortality are still high, which is particularly prominent in developing countries, and the tumor is becoming the first killer threatening the health of human in the new century. Therefore, the search for anti-tumor candidate compounds with novel structural types is of great significance.
In the early stage, a series of phosphonate derivatives containing an amino acid fragment are designed and synthesized by a subject group for research on antitumor activity (application publication No. CN 105503947A; authorization publication No. CN105503947B), and the results show that the derivatives have potential antitumor activity, and partial compounds have good proliferation inhibition effect on tumor cells A-549, SGC-7901 and EC-109. Wherein, the natural L-configuration amino acid derivative has better proliferation inhibition effect on the tested tumor cells than the D-configuration amino acid derivative; the compounds having a high antitumor activity mostly contain fluorine atoms. Is worthy of further structural modification, optimization and anti-tumor research.
Disclosure of Invention
On the basis of earlier research work (application publication number: CN 105503947A; authorization publication number: CN105503947B), the invention designs and synthesizes a phosphonate dipeptide compound for antitumor activity test according to modern drug design concept and organic synthesis technology. The results show that: although the antitumor activity of part of compounds is obviously better than that of the previous compounds, the antitumor activity expected by the inventor is not achieved; in order to expand the research and application range, antibacterial activity screening of the compounds is further attempted, and part of the compounds are found to have potential antibacterial activity.
The invention mainly aims to provide a phosphonate dipeptide compound, which is shown as a general formula III:
wherein R is 1-3 substituents independently selected from F, Cl, Br, I, NO 2 OH, C1-C3 alkyl, C1-C3 alkoxy;
R 1 and R 2 Identical or different, R 1 Is H or C1-C5 alkyl or phenyl or 5-10 membered heterocyclic group containing N, O, S; r 2 Is H or C1-C5 alkyl or phenyl or 5-10 membered heterocyclic group containing N, O, S.
And R 1 And R 2 If the directly attached carbon atom is chiral, then R 1 And R 2 In the R or S configuration.
"alkyl" in the present invention means a straight chain or branched alkyl group; "phenyl" means unsubstituted or substituted phenyl; "Heterocyclyl" refers to aromatic mono-or fused heterocycles and non-aromatic mono-or fused heterocycles.
The phosphonate dipeptide compound shown in the general formula III can be used for treating and/or preventing lung cancer, esophageal cancer and gastric cancer.
The phosphonate dipeptides compound of the general formula III can be used for treating and/or preventing staphylococcus aureus (S.
The phosphonate dipeptides compound of the general formula III can be used for treating and/or preventing quinolone-resistant staphylococcus aureus (QRSA).
The active phosphonate dipeptide compound shown in the general formula III can be combined with clinical antitumor drugs or antitumor active ingredients for use.
The active phosphonate dipeptide compound shown in the general formula III can be combined with clinical antibacterial drugs or antibacterial active ingredients for use.
The following synthetic schemes describe the preparation of compounds of general formula III of the present invention, which are conventional and well known in the art of organic chemistry.
The names of some phosphonate dipeptides in formula III are as follows:
compound III-1: o, O' -diethyl (α -phenyl- α - (L-alanyl-L-phenylalanyl-oxy)) methylphosphonate;
compound III-2: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-alanyl-L-phenylalanyl oxy)) methylphosphonate;
compound III-3: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-alanyl-L-phenylalanyl oxy)) methylphosphonate;
compound III-4: o, O' -diethyl (α -phenyl- α - (L-phenylalanyl-oxy)) methylphosphonate;
compound iii-5: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-phenylalanyl-L-phenylalanyl oxy)) methylphosphonate;
compound III-6: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-phenylalanyl-L-phenylalanyl oxy)) methylphosphonate;
compound III-7: o, O' -diethyl (α -phenyl- α - (L-prolyl-L-phenylalanyl oxy)) methylphosphonate;
compound III-8: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-prolyl-L-phenylalanyl)) methylphosphonate;
compound III-9: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-prolyl-L-phenylalanyl)) methylphosphonate;
compound iii-10: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-prolyl-glycinyloxy)) methylphosphonate;
compound III-11: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-prolyl-glycinyloxy)) methylphosphonate;
compound III-12: o, O' -diethyl (α -phenyl- α - (L-phenylalanyl-glycinyloxy)) methylphosphonate;
compound III-13: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-phenylalanyl-glycinyloxy)) methylphosphonate;
compound III-14: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-phenylalanyl-glycinyloxy)) methylphosphonate;
compound III-15: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-alanyl-L-alanyloxy)) methylphosphonate;
compound III-16: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-alanyl-L-alanyloxy)) methylphosphonate;
compound III-17: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-prolyl-L-alanyloxy)) methylphosphonate;
compound III-18: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-prolyl-L-alanyloxy)) methylphosphonate;
compound III-19: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-phenylalanyl-L-alanyloxy)) methylphosphonate;
compound iii-20: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-phenylalanyl-L-alanyloxy)) methylphosphonate.
Detailed Description
The present invention is further described with reference to the following examples, but the present invention is not limited to the following examples, and it is anticipated that one skilled in the art may make various modifications in combination with the prior art.
Preparation of the compounds of the general formula III of the invention:
example 1
Preparation of O, O' -diethyl (. alpha. -phenyl-. alpha. - (L-alanyl-L-phenylalanyl-oxy)) methylphosphonate (III-1)
And slowly dripping 0.5mol of triethylamine into the mixed solution of 0.5mol of diethyl phosphite and 0.5mol of benzaldehyde under the stirring at room temperature, slowly heating to 60 ℃, continuing the reaction, and tracking by TLC. Triethylamine was evaporated under reduced pressure and recrystallized from petroleum ether 2 times to give intermediate i-1 (R ═ H).
Taking 2.0mmol of phenylalanine methyl ester hydrochloride and 20mL of anhydrous tetrahydrofuran, stirring and reacting for 15min at room temperature, then adding 2.0mmol of NMM into the reaction bottle, and reacting for 30min at the temperature of-5-0 ℃; adding 2.0mmol of Boc-L-alanine, 2.0mmol of 1-hydroxybenzotriazole and 20mL of anhydrous tetrahydrofuran into another reaction bottle, stirring at room temperature for reaction for 15min, adding 2.0mmol of EDCI, and reacting at-5-0 ℃ for 45 min; combining the two reaction solutions, reacting at 0-5 ℃, performing TLC (thin layer chromatography) tracking, filtering to remove insoluble substances, adding 80mL of ethyl acetate into filtrate, sequentially washing with 25mL of 5% sodium bicarbonate solution, 25mL of 10% citric acid solution, 25mL of 5% sodium bicarbonate solution and saturated saline (25mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain a white solid; then, dissolving the white solid in a proper amount of methanol, controlling the reaction temperature to be about 0 ℃, slowly dripping 10% sodium hydroxide solution while stirring, tracking and detecting by TLC until the reaction is complete, and then using 2mol.L -1 Adjusting the pH value of the solution to be 7-8 by HCl, concentrating the solvent, adding a proper amount of distilled water, extracting the product by ethyl acetate, combining the extract liquor, drying by anhydrous magnesium sulfate, and concentrating to obtain white solid Boc-L-alanyl phenylalanine (II-1).
Adding 0.50mmol of Boc-L-alanyl phenylalanine (II-1), 0.50mmol of DMAP and 10mL of anhydrous dichloromethane into a 50mL reaction bottle, stirring at-5-0 ℃ for reaction, slowly adding 0.50mmol of EDCI, reacting for 15min, adding 0.50mmol of intermediate I-1, reacting at room temperature, and tracking by TLCAfter that, the solvent is concentrated and separated and purified by column chromatography (V) Ethyl acetate ：V Petroleum ether 1: 2) and then standby. Finally, taking a reaction bottle, adding 4mL of ethyl acetate, sequentially adding 0.03mmol of methanol and 0.03mmol of acetyl chloride, and stirring at-5-0 ℃ for reaction for 2.5 h; adding 0.02mmol of the above purified product (dissolved in 2mL ethyl acetate) into the reaction flask slowly, tracking by TLC, concentrating under reduced pressure, and purifying by column chromatography (V) Chloroform ：V Methanol When the ratio is 8: 1) and vacuum drying to obtain the target compound III-1.
Example 2
Preparation of O, O' -diethyl (. alpha. - (4-fluorophenyl) -alpha- (-L-prolyl-L-phenylalanyl)) methylphosphonate (III-9)
And slowly dripping 0.5mol of triethylamine into the mixed solution of 0.5mol of diethyl phosphite and 0.5mol of p-fluorobenzaldehyde under stirring at room temperature, slowly heating to 65 ℃, continuing the reaction, and tracking by TLC. Triethylamine was evaporated under reduced pressure and recrystallized 3 times from petroleum ether to give intermediate i-9 (R ═ 4-F).
Taking 2.0mmol of phenylalanine methyl ester hydrochloride and 20mL of anhydrous tetrahydrofuran, stirring and reacting for 20min at room temperature, then adding 2.0mmol of NMM into the reaction bottle, and reacting for 30min at the temperature of-5-0 ℃; adding 2.0mmol of Boc-L-proline, 2.0mmol of 1-hydroxybenzotriazole and 20mL of anhydrous tetrahydrofuran into another reaction bottle, stirring at room temperature for reaction for 15min, adding 2.0mmol of EDCI, and reacting at-5-0 ℃ for 45 min; combining the two reaction solutions, reacting at 0-5 ℃, performing TLC (thin layer chromatography) tracking, filtering to remove insoluble substances, adding 80mL of ethyl acetate into filtrate, sequentially washing with 25mL of 5% sodium bicarbonate solution, 25mL of 10% citric acid solution, 25mL of 5% sodium bicarbonate solution and saturated saline (25mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain a white solid; then, dissolving the white solid in a proper amount of methanol, controlling the reaction temperature to be about 0 ℃, slowly dripping 10% sodium hydroxide solution while stirring, tracking and detecting by TLC until the reaction is complete, and then using 2mol.L -1 Adjusting the pH value of the solution to 7-8 by HCl, concentrating the solvent, adding a proper amount of distilled water, extracting the product by ethyl acetate, combining the extract, drying by anhydrous magnesium sulfate,concentrating to obtain white solid Boc-L-prolyl phenylalanine (II-9).
Adding 0.50mmol of Boc-L-prolyl phenylalanine, 0.50mmol of DMAP and 10mL of anhydrous dichloromethane into a 50mL reaction bottle, stirring at the temperature of-5-0 ℃ for reaction, slowly adding 0.50mmol of EDCI, reacting for 15min, adding 0.50mmol of intermediate I-9, reacting at room temperature, tracking by TLC, concentrating the solvent, and purifying by column chromatography (V) Ethyl acetate ：V Petroleum ether 1: 1) and then standby. Adding 5mL of ethyl acetate into a reaction bottle, sequentially adding 0.03mmol of methanol and 0.03mmol of acetyl chloride, and stirring at-5-0 ℃ for reaction for 2.5 h; adding 0.02mmol of the above purified product (dissolved in 2mL ethyl acetate) into the reaction flask slowly, tracking by TLC, concentrating under reduced pressure, and purifying by column chromatography (V) Chloroform ：V Methanol 6: 1) and drying in vacuum to obtain the target compound III-9.
Example 3
Preparation of O, O' -diethyl (. alpha. - (2-fluorophenyl) -alpha- (-L-alanyl-L-alanyloxy)) methylphosphonate (III-15)
And slowly dripping 0.5mol of triethylamine into the mixed solution of 0.5mol of diethyl phosphite and 0.5mol of o-fluorobenzaldehyde under the stirring at room temperature, then slowly heating to 70 ℃, continuing the reaction, and tracking by TLC (thin layer chromatography) to finish. Triethylamine was evaporated under reduced pressure and recrystallized 3 times from petroleum ether to give intermediate i-15 (R ═ 2-F).
Taking 2.0mmol of alanine methyl ester hydrochloride and 20mL of anhydrous tetrahydrofuran, stirring and reacting for 20min at room temperature, then adding 2.0mmol of NMM into the reaction bottle, and controlling the temperature to be-5-0 ℃ for reacting for 30 min; adding 2.0mmol of Boc-L-alanine, 2.0mmol of 1-hydroxybenzotriazole and 20mL of anhydrous tetrahydrofuran into another reaction bottle, stirring at room temperature for reaction for 15min, adding 2.0mmol of EDCI, and reacting at-5-0 ℃ for 45 min; combining the two reaction solutions, reacting at 0-5 ℃, performing TLC (thin layer chromatography) tracking, filtering to remove insoluble substances, adding 100mL of ethyl acetate into filtrate, washing with 25mL of 5% sodium bicarbonate solution, 25mL of 10% citric acid solution, 25mL of 5% sodium bicarbonate solution and saturated saline (25mL multiplied by 3) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain a white solid;then, dissolving the white solid in a proper amount of methanol, controlling the reaction temperature to be about 0 ℃, slowly dripping 10% sodium hydroxide solution while stirring, tracking and detecting by TLC until the reaction is complete, and then using 2mol.L -1 Adjusting the pH value of the solution to be 7-8 by HCl, concentrating the solvent, adding a proper amount of distilled water, extracting the product by ethyl acetate, combining the extract liquor, drying by anhydrous magnesium sulfate, and concentrating to obtain white solid Boc-L-alanyl alanine (II-15).
Adding 0.50mmol of Boc-L-alanyl alanine, 0.50mmol of DMAP and 10mL of anhydrous dichloromethane into a 50mL reaction bottle, stirring at the temperature of-5-0 ℃ for reaction, slowly adding 0.50mmol of EDCI, reacting for 15min, adding 0.50mmol of intermediate I-15, reacting at room temperature, tracking by TLC, concentrating the solvent, and purifying by column chromatography (V) Ethyl acetate ：V Petroleum ether 2: 1) and then standby. Adding 6mL of ethyl acetate into a reaction bottle, sequentially adding 0.03mmol of methanol and 0.03mmol of acetyl chloride, and stirring at-5-0 ℃ for reaction for 2.5 h; adding 0.02mmol of the above purified product (dissolved in 2mL ethyl acetate) into the reaction flask slowly, tracking by TLC, concentrating under reduced pressure, and purifying by column chromatography (V) Chloroform ：V Methanol 7: 1) and vacuum drying to obtain the target compound III-15.
Example 4
Preparation of O, O' -diethyl (. alpha. - (2-fluorophenyl) -alpha- (-L-phenylalanyl-L-alanyloxy)) methylphosphonate (III-19)
And slowly dripping 0.5mol of triethylamine into the mixed solution of 0.5mol of diethyl phosphite and 0.5mol of o-fluorobenzaldehyde under stirring at room temperature, slowly heating to 70 ℃, continuing the reaction, and tracking by TLC. Triethylamine was evaporated under reduced pressure and recrystallized 3 times from petroleum ether to give intermediate i-19 (R ═ 2-F).
Taking 2.0mmol of alanine methyl ester hydrochloride and 20mL of anhydrous tetrahydrofuran, stirring and reacting for 15min at room temperature, then adding 2.0mmol of NMM into the reaction bottle, and controlling the temperature to be-5-0 ℃ for reacting for 30 min; adding 2.0mmol of Boc-L-phenylalanine, 2.0mmol of 1-hydroxybenzotriazole and 20mL of anhydrous tetrahydrofuran into another reaction bottle, stirring at room temperature for reaction for 20min, adding 2.0mmol of EDCI, and reacting at-5-0 ℃ for 45 min;combining the two reaction solutions, reacting at 0-5 ℃, performing TLC (thin layer chromatography) tracking, filtering to remove insoluble substances, adding 90mL of ethyl acetate into filtrate, washing with 25mL of 5% sodium bicarbonate solution, 25mL of 10% citric acid solution, 25mL of 5% sodium bicarbonate solution and saturated saline (25mL multiplied by 3) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating the solvent to obtain a white solid; then, dissolving the white solid in a proper amount of methanol, controlling the reaction temperature to be about 0 ℃, slowly dripping 10% sodium hydroxide solution while stirring, tracking and detecting by TLC until the reaction is complete, and then using 2mol.L -1 Adjusting the pH value of the solution to be 7-8 by HCl, concentrating the solvent, adding a proper amount of distilled water, extracting the product by ethyl acetate, combining the extract liquor, drying by anhydrous magnesium sulfate, and concentrating to obtain white solid Boc-L-phenylalanyl alanine (II-19).
Adding 0.50mmol of Boc-L-phenylalanyl alanine, 0.50mmol of DMAP and 15mL of anhydrous dichloromethane into a 50mL reaction bottle, stirring at the temperature of-5-0 ℃ for reaction, slowly adding 0.50mmol of EDCI, reacting for 15min, adding 0.50mmol of intermediate I-19, reacting at room temperature, tracking by TLC, concentrating the solvent, and purifying by column chromatography (V) Ethyl acetate ：V Petroleum ether 1: 2) and then standby. Adding 5mL of ethyl acetate into a reaction bottle, sequentially adding 0.03mmol of methanol and 0.03mmol of acetyl chloride, and stirring at-5-0 ℃ for reaction for 3 hours; adding 0.02mmol of the above purified product (dissolved in 2mL ethyl acetate) into the reaction flask slowly, tracking by TLC, concentrating under reduced pressure, and purifying by column chromatography (V) Chloroform ：V Methanol 5: 1) and vacuum drying to obtain the target compound III-19.
The relevant data for target compound iii are shown in table 1:
TABLE 1
The antitumor activity test of the invention: the MTT method is adopted, cisplatin is used as a contrast, the proliferation inhibition effect of the phosphonate dipeptide compound with the general formula III on tumor cells A-549 (human lung cancer cells), SGC-7901 (human gastric cancer cells) and EC-109 (human esophageal cancer cells) is measured, and the IC of the phosphonate dipeptide compound with the general formula III is calculated by a two-point method (Reed and Muench method) 50 The values, data are shown in table 2.
TABLE 2
From the experimental results, it is clear that the compounds of the general formula III to be protected have certain in vitro anti-tumor activity, and part of the compounds have obvious proliferation inhibition activity on tumor cells A-549, SGC-7901 and EC-109, are equivalent to that of a contrast medicament cisplatin, and are obviously superior to that of the previous patent (application publication No. CN 105503947A; grant publication No. CN 105503947B).
The antibacterial activity test of the invention: the Minimum Inhibitory Concentrations (MIC) of the phosphonate dipeptides of general formula iii against staphylococcus aureus (s. aureus) and quinolone-resistant staphylococcus aureus (QRSA) were determined by microdilution with norfloxacin (norfloxacin) as a control drug, and the data are shown in table 3.
TABLE 3
From the above experimental results, it is clear that some of the compounds of formula iii to be protected by the present invention have certain in vitro antibacterial activity. Wherein, the MIC of the compounds III-7, III-13, III-16 and III-19 to staphylococcus aureus (S.aureus) is close to that of a contrast drug norfloxacin; the MIC of the compounds III-7, III-9, III-16 and III-19 to quinolone-resistant staphylococcus aureus (QRSA) is far superior to that of a control drug norfloxacin, and the compounds show obvious antibacterial activity.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (6)
1. A phosphonate dipeptide compound having the chemical structure shown in formula iii:
III-1: o, O' -diethyl (α -phenyl- α - (L-alanyl-L-phenylalanyl-oxy)) methylphosphonate;
III-2: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-alanyl-L-phenylalanyl oxy)) methylphosphonate;
III-3: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-alanyl-L-phenylalanyl oxy)) methylphosphonate;
III-4: o, O' -diethyl (α -phenyl- α - (L-phenylalanyl-oxy)) methylphosphonate;
III-5: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-phenylalanyl-L-phenylalanyl oxy)) methylphosphonate;
III-6: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-phenylalanyl-L-phenylalanyl oxy)) methylphosphonate;
III-7: o, O' -diethyl (α -phenyl- α - (L-prolyl-L-phenylalanyl oxy)) methylphosphonate;
III-8: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-prolyl-L-phenylalanyl)) methylphosphonate;
III-9: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-prolyl-L-phenylalanyl)) methylphosphonate;
III-10: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-prolyl-glycinyloxy)) methylphosphonate;
III-11: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-prolyl-glycinyloxy)) methylphosphonate;
III-12: o, O' -diethyl (α -phenyl- α - (L-phenylalanyl-glycinyloxy)) methylphosphonate;
III-13: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-phenylalanyl-glycinyloxy)) methylphosphonate;
III-14: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-phenylalanyl-glycinyloxy)) methylphosphonate;
III-15: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-alanyl-L-alanyloxy)) methylphosphonate;
III-16: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-alanyl-L-alanyloxy)) methylphosphonate;
III-17: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-prolyl-L-alanyloxy)) methylphosphonate;
III-18: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-prolyl-L-alanyloxy)) methylphosphonate;
III-19: o, O' -diethyl (α - (2-fluorophenyl) - α - (L-phenylalanyl-L-alanyloxy)) methylphosphonate;
III-20: o, O' -diethyl (α - (4-fluorophenyl) - α - (L-phenylalanyl-L-alanyloxy)) methylphosphonate.
2. Use of the phosphonate dipeptide compound of claim 1, wherein iii-1, iii-2, iii-3, iii-5, iii-6, iii-7, iii-8, iii-9, iii-10, iii-11, iii-12, iii-13, iii-14, iii-15, iii-17, iii-18, iii-19, iii-20 is in the manufacture of a medicament for the treatment and/or prophylaxis of lung cancer.
3. Use of the phosphonate dipeptide compound of claim 1, wherein iii-1, iii-3, iii-4, iii-5, iii-6, iii-7, iii-8, iii-9, iii-10, iii-11, iii-12, iii-13, iii-15, iii-16, iii-17, iii-18, iii-19, iii-20 is in the manufacture of a medicament for the treatment and/or prophylaxis of gastric cancer.
4. Use of the phosphonate dipeptide compound of claim 1, wherein iii-1, iii-2, iii-3, iii-4, iii-6, iii-7, iii-8, iii-9, iii-10, iii-11, iii-12, iii-13, iii-14, iii-16, iii-17, iii-18, iii-19, iii-20 is in the manufacture of a medicament for the treatment and/or prevention of esophageal cancer.
5. Use of the phosphonate dipeptide compound of claim 1 in the manufacture of a medicament for the treatment and/or prevention of staphylococcus aureus.
6. Use of the phosphonate dipeptide compound according to claim 1 for the preparation of a medicament for the treatment and/or prophylaxis of quinolone-resistant staphylococcus aureus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010055295.8A CN111171114B (en) | 2020-01-17 | 2020-01-17 | Phosphonate dipeptide compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010055295.8A CN111171114B (en) | 2020-01-17 | 2020-01-17 | Phosphonate dipeptide compound and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111171114A CN111171114A (en) | 2020-05-19 |
| CN111171114B true CN111171114B (en) | 2022-08-12 |
Family
ID=70625047
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010055295.8A Expired - Fee Related CN111171114B (en) | 2020-01-17 | 2020-01-17 | Phosphonate dipeptide compound and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111171114B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111747917B (en) * | 2020-07-28 | 2022-09-13 | 遵义医科大学 | Osthole amide compound and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002045708A2 (en) * | 2000-12-05 | 2002-06-13 | The Brigham And Women's Hospital, Inc. | Use of zwitterionic polysaccharides for the specific modulation of immune processes |
| CN1780643A (en) * | 2003-04-25 | 2006-05-31 | 吉里德科学公司 | Antiviral phosphonate analogs |
| CN101563359A (en) * | 2006-11-08 | 2009-10-21 | 哉迪拉股份有限公司 | Michael systems as transglutaminase inhibitors |
| CN105503947A (en) * | 2015-12-31 | 2016-04-20 | 遵义医学院 | Preparation method of phosphonate derivative containing amino acid fragments and antineoplastic application |
| CN105601703A (en) * | 2016-01-04 | 2016-05-25 | 贵州医科大学 | Chirality oliopeptide phosphonate thiourea derivatives and application and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7777030B2 (en) * | 2005-12-29 | 2010-08-17 | Centre National de la Recherge Scientifique (CNRS) | Compositions and methods for the treatment and prevention of disease |
-
2020
- 2020-01-17 CN CN202010055295.8A patent/CN111171114B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002045708A2 (en) * | 2000-12-05 | 2002-06-13 | The Brigham And Women's Hospital, Inc. | Use of zwitterionic polysaccharides for the specific modulation of immune processes |
| CN1780643A (en) * | 2003-04-25 | 2006-05-31 | 吉里德科学公司 | Antiviral phosphonate analogs |
| CN101563359A (en) * | 2006-11-08 | 2009-10-21 | 哉迪拉股份有限公司 | Michael systems as transglutaminase inhibitors |
| CN105503947A (en) * | 2015-12-31 | 2016-04-20 | 遵义医学院 | Preparation method of phosphonate derivative containing amino acid fragments and antineoplastic application |
| CN105601703A (en) * | 2016-01-04 | 2016-05-25 | 贵州医科大学 | Chirality oliopeptide phosphonate thiourea derivatives and application and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases;Marta Maślanka等;《Pharmaceuticals》;mdpi;20190610;第12卷(第2期);第86页 * |
| 二肽类膦酸酯衍生物的合成与抗肿瘤活性;吴学姣等;《应用化学》;CNKI;20210131;第38卷(第1期);第36-43页 * |
| 双醋瑞因氨基膦酸酯类衍生物的合成及抗肿瘤活性研究;覃坚妹等;《江西师范大学学报（自然科学版）》;万方;20131224;第37卷(第5期);第510-514页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111171114A (en) | 2020-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2444411B1 (en) | Tripeptide boronic acid or boronic ester, preparative method and use thereof | |
| ES2233928T3 (en) | DOLASTATIN DERIVATIVES | |
| CN100383138C (en) | Novel n-monoacylated o-phenylenediamines, their condensed heterocyclic derivatives and their use as pharmaceutical agents | |
| KR100408909B1 (en) | Novel peptide derivatives | |
| JP6034802B2 (en) | Methods and intermediates for the preparation of macrocyclic lactams | |
| PT88992B (en) | PROCESS FOR THE PREPARATION OF COMPOUNDS CONTAINING UTEIS PHOSPHORUS AS COLLAGENASE INHIBITORS | |
| CN107118249B (en) | 18 beta-glycyrrhetinic acid derivative and application thereof | |
| JPH07507275A (en) | Dipeptidylquinazolones as anticancer agents | |
| KR20010014215A (en) | Bis-indole derivatives having antimetastatic activity, a process for their preparation and pharmaceutical compositions containing them | |
| CN111171114B (en) | Phosphonate dipeptide compound and application thereof | |
| CN102659630B (en) | A kind of hydroxamic acid compound and its production and use | |
| EP3487859B1 (en) | Antimetastatic 2h-selenopheno[3,2-h]chromenes, synthesis thereof, and methods of using same agents | |
| CN110461836B (en) | Selective kinase inhibition compound and application thereof | |
| Weber et al. | Highly potent, orally active diester macrocyclic human renin inhibitors | |
| JPH05505820A (en) | new compound | |
| CA2994377C (en) | Novel catechol derivative and pharmaceutical composition comprising the same | |
| EA013158B1 (en) | Novel betulinic acid derivatives | |
| EP2233467A1 (en) | Alpha-amino-n-substituted amides, pharmaceutical composition containing them and uses thereof | |
| CN111808062B (en) | Osthole sulfonate compound and application thereof | |
| CN104974221B (en) | Dipeptide and tripeptide proteasome inhibitors and preparation method and pharmaceutical application thereof | |
| EP2138507A1 (en) | Method for producing intermediates for the production of novel macrocycles that are inhibitors of the proteasomic degradation of p27, such as argyrin and derivatives thereof, and uses of said macrocycles | |
| JP3163391B2 (en) | Stilbene derivatives and anticancer agents containing the same | |
| CN109796519A (en) | A kind of steroidal compounds and its application | |
| EP1278502A2 (en) | Protease inhibitors | |
| CN115175913B (en) | Substituted bistricycles and pharmaceutical compositions and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220812 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |