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WO2016065525A1 - Utilisation de composés d'amide oxopipérazinyle - Google Patents

Utilisation de composés d'amide oxopipérazinyle Download PDF

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Publication number
WO2016065525A1
WO2016065525A1 PCT/CN2014/089631 CN2014089631W WO2016065525A1 WO 2016065525 A1 WO2016065525 A1 WO 2016065525A1 CN 2014089631 W CN2014089631 W CN 2014089631W WO 2016065525 A1 WO2016065525 A1 WO 2016065525A1
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Prior art keywords
formula
group
use according
compound
oxopiperazine
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PCT/CN2014/089631
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English (en)
Chinese (zh)
Inventor
孙明杰
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Xiangbei Welman Pharmaceutical Co Ltd
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Xiangbei Welman Pharmaceutical Co Ltd
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Priority to CN201480082678.7A priority Critical patent/CN106999499A/zh
Priority to PCT/CN2014/089631 priority patent/WO2016065525A1/fr
Publication of WO2016065525A1 publication Critical patent/WO2016065525A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/32—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an araliphatic carboxylic acid, which is substituted on the aliphatic radical by hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings

Definitions

  • the present invention relates to the use of an oxopiperazine amide compound, and in particular to a novel use of the compound for inhibiting PLK1 activity.
  • the oxopiperazine amide compounds of formula I are a class of known antibacterial agents. It has a good antibacterial effect on a variety of Gram-negative bacteria, and also has antibacterial effects on many anaerobic bacteria.
  • antibacterial drugs have long been used as anti-tumor drugs.
  • CN1911236A also reports that tetracycline antibacterial drugs (such as doxycycline) have anti-tumor, anti-inflammatory and cell survival effects in addition to antibacterial.
  • antibacterial drugs and anti-tumor drugs are essentially different. Antibacterial and anticancer are different indications. From the point of view of the object of action, bacteria have cell walls and belong to foreign pathogenic organisms; while tumors have no cell wall and are abnormal proliferation or lesions produced by the body itself, which determines the essential difference between the two drugs in terms of mechanism of action.
  • the oxopiperazine amide compounds of formula I are also used clinically for anti-infective treatment, including anti-infective treatment in patients with malignant tumors, but it still exerts an antibacterial effect. And it's with the various antibacterial or antineoplastic agents above.
  • the substance is different, and its mechanism of action is to bind to the PBPs protein on the bacterial cell membrane, inhibit the synthesis of bacterial cell walls, and promote bacterial cell apoptosis.
  • Polo like kinase is a serine/threonine kinase
  • PLK1 is a subtype of Polo-like kinase. Its structure has an N-terminus and a C-terminus, and its activity is exerted by phosphorylating a substrate.
  • Existing studies have shown that PLK1 is involved in the precise regulation of different stages of cell growth and is a key substance for maintaining the normal operation of the cell cycle.
  • PLK1 can regulate various downstream substrates such as Cdc25, cyclin B, Wee1 and Myt1 during cell G2/M phase transition; PLK1 plays an important role in cell centrosome maturation and isolation, affecting ninein like protein (Nlp) and Kizuna and other centrosome-associated protein activities; PLK1 acts on Mad3, Bub1, PICH and other spindle structure monitoring point related proteins to ensure the normal progression of cell mitosis.
  • Nlp ninein like protein
  • Kizuna ninein like protein
  • PLK1 acts on Mad3, Bub1, PICH and other spindle structure monitoring point related proteins to ensure the normal progression of cell mitosis.
  • CN103435608A discloses a pyridinopyrimidine PLK1 inhibitor
  • CN103435594A discloses an aminoquinazoline PLK1 inhibitor
  • CN103408546A discloses an amino group.
  • a PLK1 inhibitor of steroids CN102174035A discloses a PLK1 inhibitor of an aromatic dihydrazide
  • CN101636399A discloses a PLK1 inhibitor of pyrimidodiazepines
  • CN101568539A discloses an imidazolinoneaminopyrimidine PLK1 inhibitors
  • CN101541800A discloses a PLK1 inhibitor of pteridine derivatives, but these drugs are in the research and development stage, requiring new synthesis, raw materials are not easy to obtain, quality control of raw materials is not mature, and their structures are different. There is no obvious regularity, which makes it difficult to predict new PLK1 inhibitors by the structure of existing compounds.
  • One of the objects of the present invention is to provide a novel use of an oxopiperazine amide compound, and the second object is to find a new option for an anticancer drug in the clinic.
  • an oxopiperazine amide compound in the preparation of a drug for inhibiting PLK1 activity is selected from the group consisting of a compound of formula I, an isomer, hydrate or salt thereof,
  • R 1 is a C 1 -C 6 alkyl group
  • R 2 is selected from a substituted or unsubstituted C 1 -C 6 alkyl group, or a substituted or unsubstituted phenyl group;
  • R 3 is a -CONH-R 4 group, wherein R 4 is selected from Formula Ia or Formula Ib;
  • Y is oxygen or sulfur
  • R 5 is selected from the group consisting of acetyl, 1-methyl-tetrazolyl, or 5-methyl-[1.3.4]thiadiazolyl;
  • R 6 is selected from the group consisting of hydrogen, methoxy or -NH-CHO groups.
  • R 1 of formula I is ethyl
  • R 2 is hydroxyethyl, phenyl or hydroxy substituted phenyl.
  • the compound of formula I is selected from any of the following compounds of formula II to formula VIII:
  • the drug contains an oxopiperazine amide compound.
  • the drug further comprises a beta-lactamase inhibitor.
  • the weight ratio of the oxopiperazine amide compound to the ⁇ -lactamase inhibitor in the drug is 1:10 to 10:1; more preferably, the weight ratio is 1:1 to 8:1; further preferably The weight ratio is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1.
  • the beta-lactamase inhibitor is clavulanic acid, sulbactam, or an isomer, hydrate or salt of clavulanic acid, or an isomer, hydrate or salt of sulbactam. More preferably, the beta-lactamase inhibitor is potassium clavulanate or sulbactam sodium.
  • the medicament comprises: a sodium salt of a compound of formula II and sodium sulbactam, sodium of a compound of formula III Salt and sulbactam sodium, the sodium salt of the compound of formula IV and sulbactam sodium, or the sodium salt of the compound of formula V and sulbactam sodium.
  • the medicament comprises: a sodium salt of a compound of the formula II in a weight ratio of 1:1, 2:1, 4:1 or 8:1 and sulbactam sodium in a weight ratio of 1:1, 3:1 a sodium salt of a compound of the formula III of 6:1 or 8:1 and a sulbactam sodium, a sodium salt of the compound of the formula IV in a weight ratio of 2:1 or 10:1 and sodium sulbactam, or a weight ratio of 1:1 , 2:1, 5:1 or 10:1 compound sodium salt of formula V and sulbactam sodium.
  • the drug may contain no excipients or a pharmaceutically acceptable excipient depending on the dosage form.
  • the lyophilized powder for injection may contain no excipients, and the injection may contain sodium chloride or the like, and the tablet may contain fillers, binders, disintegrators, lubricants commonly used in the pharmaceutical field. Wait.
  • the filler may be selected from the group consisting of starch, pregelatinized starch, dextrin, glucose, sucrose, lactose, lactitol, microcrystalline cellulose, mannitol, sorbitol or xylitol;
  • the binder may be selected from the group consisting of carboxy Methylcellulose sodium, hydroxypropylmethylcellulose, ethylcellulose, povidone, starch syrup, sucrose, powdered sugar, syrup, gelatin, polyethylene glycol;
  • the disintegrant may be selected from cross-linking Sodium carboxymethylcellulose, crospovidone, low substituted hydroxypropylcellulose, sodium carboxymethyl starch or starch;
  • the lubricant may be selected from magnesium stearate,
  • the ratios referred to in the present invention are all weight ratios, and refer to the ratio of free or anhydrate, excluding salt ions or water of crystallization.
  • the sodium salt of the compound of formula III + sulbactam sodium (4:1) means that the weight ratio of the compound of formula III to sulbactam is 4:1; and the compound of formula II monohydrate + sulbactam Sodium (2:1) means that the weight ratio of the compound of formula II to sulbactam is 2:1.
  • the drug for inhibiting PLK1 activity in the present invention may also be referred to as a PLK1 inhibitor.
  • the effect of inhibiting PLK1 activity is to treat a cell proliferative disorder.
  • the cell proliferative disorder is selected from the group consisting of cancer, an autoimmune disease, or an inflammatory disease.
  • the cell proliferative disorder is selected from the group consisting of prostate cancer, ovarian cancer, genitourinary tract cancer, laryngeal cancer, leukemia or cystic fibrosis.
  • PLK1 is a subtype kinase of Polo like kinase (PLK) having an N-terminus in its structure. At the C-terminus, the activity of regulating cell growth and the like is exerted by phosphorylating the substrate.
  • PLK1 inhibitor is a substance that selectively binds to PLK1 kinase and blocks the activity of PLK1 kinase.
  • oxopiperazine amides of formula I can significantly inhibit PLK1 kinase, but penicillin has no similar effect, which may be due to the structure of 2,3-dioxo-piperazinecarboxamide. Specific binding of the PLK1 kinase results in the inactivation of the kinase. This is in contrast to the traditional indications of the oxopiperazine amides of the formula I and The mechanism of action is essentially different.
  • oxoperiperazine amide compounds can effectively reduce cell proliferation by inhibiting PLK1 activity, and can be used for treating cell proliferative diseases such as various cancers, autoimmune diseases, and inflammatory diseases. Expanded indications for existing drugs and provided new options for clinical use.
  • the inventors have unexpectedly discovered that some specific oxopiperazine amide compounds having a specific structure and stereo configuration can effectively inhibit PLK1 activity at a concentration of 150 ng/ml, and can control the tumor cell proliferation rate to about 60. % or less than 70%.
  • the combination of the oxopiperazine amide compound and the ⁇ -lactamase inhibitor shows a better effect than the oxopiperazine amide compound alone, and the combination which is particularly preferred in terms of ratio shows more excellent. Effect.
  • the oxopiperazine amide compound of the present invention has the advantages of less toxic side effects and good safety in inhibiting PLK1 activity, particularly anti-tumor.
  • the oxopiperazine amide compounds of the present invention are known and used as compounds, the raw materials are readily available, the synthesis process is mature, the impurities are well studied, and the quality control is mature. Therefore, it has the advantages of being more convenient and easy to obtain.
  • oxopiperazine amide compounds compounds having the structure of formula I
  • compounds having the structure of formula I are known compounds which can be obtained by commercial or literature methods.
  • the CAS numbers of some specific oxopiperazine amides are shown in Table 1:
  • test substance PLK1 kinase, substrate polypeptide, tumor cell strain, and each reagent, material, and instrument in the following Examples 1 or 2 were purchased from commercial sources, such as Sigma, PerkinElmer, American Custom Chemicals, and Shanghai Jingjing. Pure Biotechnology Co., Ltd., Shanghai Institute of Cell Biology, Chinese Academy of Sciences, etc.
  • Test substance a compound represented by the formula II to formula VIII of the present invention, amoxicillin, cefuroxime, penicillin, sulbactam, clavulanic acid, hydrates and salts thereof, and related compositions and the like.
  • each group of test solution DMSO was dissolved in a 20 nM aqueous solution of HEPES to form a DMSO/HEPES solution having a concentration of 20%.
  • the analytes were grouped (multiple control groups, separate groups, combined groups), and each group of the test substances was taken and dissolved in 20% DMSO/HEPES to obtain the test solution of each group, and used.
  • the grouping situation and the highest concentration of the analyte in each group of analytes obtained for the combined group, the concentration of the compound of formula II to formula VIII in the composition; the concentration is calculated as the free or anhydrous substance of the compound , unit ⁇ g / ml
  • Each group of test solution was diluted with a 20% concentration gradient with 20% DMSO/HEPES solution and diluted to 8 concentration gradients.
  • PLK1 kinase solution 0.07653 g of disodium diglyceride phosphate, 0.025 g of Chaps and 0.012 g of L-cysteine were dissolved in 50 ml of a 20 mM aqueous solution of HEPES to obtain a buffer I. PLK1 kinase was diluted with buffer I to obtain 10 nM of PLK1 kinase solution, which was used.
  • PLK1 substrate polypeptide solution 133 ⁇ l of an aqueous MgCl 2 solution (1 M), 1 ⁇ l of an aqueous MnCl 2 solution (1 M), and 9.867 ml of the buffer I in the step 2) were mixed to obtain a buffer solution II.
  • the substrate polypeptide and ATP were diluted together with buffer II to obtain a PLK1 substrate polypeptide solution containing 300 nM substrate polypeptide and 10 ⁇ M ATP, and used.
  • the inhibitory activity of PLK1 is expressed as the concentration of the test substance (IC 50 ) when 50% of PLK1 kinase is inhibited, and the smaller the IC 50 value, the stronger the inhibitory effect on PLK1 kinase.
  • IC 50 values (ng/ml) fall into the following five ranges:
  • Table 2 lists the IC 50 value levels of each group of analytes (for the combination group, the IC 50 value level of the compounds of formula II to formula VIII in the composition).
  • the results of the test in Table 2 indicate that the oxopiperazine amide compounds of the present invention can effectively inhibit PLK1 kinase activity compared with antibiotics such as penicillin, amoxicillin, cefuroxime, sulbactam and the like having no oxopiperazine amide structure. .
  • antibiotics such as penicillin, amoxicillin, cefuroxime, sulbactam and the like having no oxopiperazine amide structure.
  • the combination of the oxopiperazine amide compound and the ⁇ -lactamase inhibitor showed a better effect than the oxopiperazine amide compound alone.
  • prostate cancer and ovarian cancer will be exemplified, and the therapeutic effect of the oxopiperazine amide compound of the present invention on cell proliferative diseases, particularly tumors, will be further described.
  • Test substance a compound represented by the formula II to formula VIII of the present invention, amoxicillin, paclitaxel, sulbactam, salts and hydrates thereof, and related compositions and the like.
  • Solution preparation The test substances were grouped (multiple control group, single group, combined group), and the test substances in each group were taken separately. First, 1.23 ml of castor oil was added, shaken and dissolved, and then 1.23 ml of absolute ethanol was added. Shake well and dissolve to prepare the mother liquor of each group.
  • the grouping condition and the concentration of the analyte in the obtained group of test substances in the obtained group (for the combined group, the concentration of the compound represented by the formula II to the formula VIII in the composition; the concentration is based on the free or anhydrous substance of the compound, The unit is mg/ml), and the specific grouping and administration are shown in Tables 3 and 4.
  • mice Female BALB/cA nude mice, aged 35-40 days, weighing 18-22 g. Prostate cancer models and ovarian cancer models were established, respectively.
  • Prostate cancer model A human prostate cancer PC-3 cell strain was inoculated subcutaneously in nude mice. The amount of cells inoculated was 3 ⁇ 10 6 , and the cells were inoculated to form transplanted tumors and then used in nude mice for 3 generations.
  • Ovarian cancer model A human ovarian cancer HO-8910 cell strain was inoculated subcutaneously into nude mice. The amount of cells inoculated was 3 ⁇ 10 6 , and the cells were inoculated to form transplanted tumors and then used in nude mice for 3 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the nude mice xenografts were measured with vernier calipers to measure the diameter of the transplanted tumors.
  • the animals were randomly divided into groups of 8 animals. Except for the blank group, the situation of each group is consistent with the grouping of the objects to be tested. See Tables 3 and 4 for details.
  • the prostate cancer model animals were independently operated with the ovarian cancer model animals.
  • Intravenous administration castor oil was administered to the blank group, and each group and each treatment group were given a dilution of the test substance.
  • the drug was administered once a week for a total of 3 weeks.
  • the dose to be administered was adjusted in accordance with the body weight of each animal based on 20 ml of the administration substance (20 ml/kg) per kg of animal body weight. See Tables 3 and 4 for specific administration.
  • the number of animals was counted, the body weight of the animals was weighed, the tumor diameter was measured, and the tumor volume was calculated.
  • the relative tumor growth rate (RT) was used as an evaluation index for antitumor activity, and the smaller the RT value, the stronger the antitumor activity.
  • the animal survival rate (RN) and animal body weight change rate (RW) before and after the test were used as indicators for evaluating safety.
  • the high RN value and the difference between the RW value and the value of the blank group indicate that the safety is good.
  • the specific calculation formula is:
  • RW (W t / W 0 ) ⁇ 100%.
  • N 0 the number of animals before treatment (when initially grouped for 0 days),
  • the oxopiperazine amide compound of the present invention is effective for inhibiting tumor cell proliferation (RT value less than 60% or 70%) as compared with an antibiotic having no oxopiperazine amide structure such as amoxicillin.
  • RT value less than 60% or 70%
  • an antibiotic having no oxopiperazine amide structure such as amoxicillin.
  • the combination of the oxopiperazine amide compound and the ⁇ -lactamase inhibitor showed a better effect than the oxopiperazine amide compound alone.
  • the oxopiperazine amide compound of the present invention shows good safety (except for RN value higher than paclitaxel, reaching 100% in addition to the effect); the RW values of each individual group and the combined group are similar to those of the blank group, indicating Has little effect on body weight).
  • the present invention discloses a second use of an oxopiperazine amide compound, that is, for inhibiting PLK1 activity, and further for treating cell proliferative diseases, especially for treating prostate cancer, ovarian cancer, genitourinary tract cancer, laryngeal cancer, leukemia or sac Sexual fibrosis has a definite effect. Expanded indications for existing drugs and provided new options for clinical use.

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Abstract

L'invention concerne l'utilisation de composés d'amide oxopipérazinyle, tels que représentés par la formule I, et des isomères, des hydrates ou des sels de ceux-ci dans la préparation de médicaments d'inhibition de l'activité de PLK1.
PCT/CN2014/089631 2014-10-28 2014-10-28 Utilisation de composés d'amide oxopipérazinyle Ceased WO2016065525A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201480082678.7A CN106999499A (zh) 2014-10-28 2014-10-28 一种氧代哌嗪酰胺类化合物的用途
PCT/CN2014/089631 WO2016065525A1 (fr) 2014-10-28 2014-10-28 Utilisation de composés d'amide oxopipérazinyle

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PCT/CN2014/089631 WO2016065525A1 (fr) 2014-10-28 2014-10-28 Utilisation de composés d'amide oxopipérazinyle

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Citations (2)

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JPS6041681A (ja) * 1984-05-02 1985-03-05 Toyama Chem Co Ltd セフアロスポリンの新規製造方法

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KR100785601B1 (ko) * 2003-11-21 2007-12-14 화이자 프로덕츠 인크. 백신 아쥬반트로서의 항생제의 용도
WO2009149149A1 (fr) * 2008-06-04 2009-12-10 Trustees Of Dartmouth College Prévention ou traitement d'une maladie immunitaire par modification de populations microflorales

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Publication number Priority date Publication date Assignee Title
JPS5325589A (en) * 1976-08-03 1978-03-09 Toyama Chem Co Ltd Novel process for preparation of penicillins and cephalosporins
JPS6041681A (ja) * 1984-05-02 1985-03-05 Toyama Chem Co Ltd セフアロスポリンの新規製造方法

Non-Patent Citations (2)

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Title
DAVID, T. D. ET AL.: "Synthesis and Biological Activity of a Series of Piperazine-2, 3-Dione Containing Penicillins and 6- A Formamidopenicillins I. Derivatives Substituted At C(5) or C(6) of the Piperazine Ring", THE JOURNAL OF ANTIBIOTICS, vol. 42, no. 3, 31 March 1989 (1989-03-31), pages 367 - 373, XP055277913 *
FRANK, P.H. ET AL.: "Structure-Activity Relationships in a Series of Piperazine-2, 3-Dione Containing Penicillins and Cephalosporins II. Derivatives Substituted at N (4) of the Piperazine Ring", THE JOURNAL OF ANTIBIOTICS, vol. 42, no. 8, 31 August 1989 (1989-08-31), pages 1241 - 1247, XP055277908 *

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