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WO1996020179A1 - Derives de la piperazine-2,5-dione utilises comme modulateurs de la resistance multiple aux medicaments - Google Patents

Derives de la piperazine-2,5-dione utilises comme modulateurs de la resistance multiple aux medicaments Download PDF

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Publication number
WO1996020179A1
WO1996020179A1 PCT/GB1995/003028 GB9503028W WO9620179A1 WO 1996020179 A1 WO1996020179 A1 WO 1996020179A1 GB 9503028 W GB9503028 W GB 9503028W WO 9620179 A1 WO9620179 A1 WO 9620179A1
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WO
WIPO (PCT)
Prior art keywords
group
dioxo
methyl
dibenzylidene
piperazinyl
Prior art date
Application number
PCT/GB1995/003028
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English (en)
Inventor
Philip Anthony Ashworth
Sukhjit Hunjan
Ian Andrew Pretswell
Hamish Ryder
Original Assignee
Xenova Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Xenova Limited filed Critical Xenova Limited
Priority to GB9711211A priority Critical patent/GB2310854B/en
Priority to AU43101/96A priority patent/AU4310196A/en
Publication of WO1996020179A1 publication Critical patent/WO1996020179A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds useful as modulators of multi-drug resistance (MDR), to their
  • compositions containing them are provided.
  • tumours The resistance of tumours to treatment with certain cytotoxic agents is an obstacle to the successful
  • a tumour may acquire resistance to a cytotoxic agent used in a previous treatment.
  • a tumour may also manifest intrinsic resistance, or cross-resistance, to a cytotoxic agent to which it has not previously been exposed, that agent being unrelated by structure or mechanism of action to any agent used in previous treatments of the tumour.
  • pathogens may acquire resistance to pharmaceutical agents used in previous treatments of the diseases or disorders to which those pathogens give rise.
  • Pathogens may also manifest intrinsic resistance, or cross resistance, to pharmaceutical agents to which they have not previously been exposed. Examples of this effect include multi-drug resistant forms of malaria, tuberculosis, leishmaniasis and amoebic dysentery.
  • MDR multi-drug resistance
  • P-gp plasma membrane glycoprotein
  • Certain agents which have the capacity to modulate MDR may therefore also be useful in facilitating the delivery of drugs across the blood brain barrier, and in treating AIDS and AIDS-related complex.
  • RMAs resistance modifying agents
  • the present invention therefore provides a
  • R 1 and R 2 are H and the other is a group -COR 3 wherein R 3 is selected from:
  • n is 0 or 1 and m is 0, 1, 2, 3 or 4, at least one of n and m being other than 0, and either (a) R 4 is H or C 1 -C 6 alkyl and R 5 is C 1 -C 6 alkyl optionally substituted by one or two phenyl groups, or
  • R 6 and R 7 which are the same or different, are each hydrogen or C 1 -C 6 alkoxy, or R 6 and R 7 form together a methylenedioxy group;
  • R B is C 1 -C 6 alkyl optionally substituted by hydroxy, C 2 -C 6 alkenyl, or a phenyl group optionally substituted by C 1 -C 6 alkoxy;
  • An alkyl group may be linear or branched.
  • a C-.-C 6 alkyl group is typically a C 1 -C 4 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group.
  • a C 1 -C 6 alkyl group substituted by hydroxy may be substituted by 1, 2 or 3 hydroxy groups, for instance a C 2 -C 6 alkyl group substituted by 1, 2 or 3 hydroxy groups.
  • Preferably it is substituted by one hydroxy group. It is typically substituted on the terminal carbon atom.
  • a C 1 -C 6 alkyl group substituted by hydroxy is a 2-hydroxyethyl group.
  • a C 1 -C 6 alkoxy group is typically a C 1 -C 4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.
  • R 3 is a group of formula (A)
  • n is typically 1 and m is 0 or 2, or n is 0 and m is 2.
  • R 4 and R 5 may be as defined under (a), in which case R 4 is preferably C 1 -C 6 alkyl, for instance methyl.
  • R 5 is preferably C 1 -C 6 alkyl, for instance methyl or ethyl, either unsubstituted or
  • R 5 may be a diphenylmethyl or 2,2-diphenylethyl group.
  • R 4 and R 5 may be as defined under (b).
  • R 6 and R 7 are typically the same, and are preferably hydrogen or methoxy, or together form a methylenedioxy group.
  • R 8 is typically selected from methyl and ethyl optionally substituted by hydroxy, for instance 2-hydroxyethyl; prop-1-enyl and prop- 2-enyl; and phenyl monosubstituted at position 2, 3 or 4 by C 1 -C 6 alkoxy, for instance methoxy, preferably a 4- methoxyphenyl group.
  • R 3 is a group of formula (D)
  • p is preferably 2.
  • R 9 is typically ethenyl, prop-1-enyl or prop-2-enyl, or phenyl substituted by 1 or 2 C 1 -C 6 alkoxy groups, for instance methoxy groups.
  • R 9 is a 3,4-dimethoxyphenyl group.
  • R 1 is H
  • R 2 is a group -COR 3 wherein R 3 is a group of formula (A) wherein n is 0 or 1 and m is 2, and R 4 and R 5 form together with the nitrogen to which they are attached a heterocyclic ring (B) as defined above wherein R 6 and R 7 are as defined above.
  • R 6 and R 7 are both a C 1 -C 6 alkoxy group, which may be the same or different. More preferably R 6 and R 7 are both methoxy groups.
  • R 2 is H
  • R 1 is a group -COR 3 wherein R 3 is a group of formula (A) in which n is 0 and m is 2, or n is 1 and m is 2 , or n is 1 and m is 0, and either
  • R 4 is C 1 -C 6 alkyl and R 5 is unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted on the terminal C atom by 2 phenyl rings, or
  • R 4 and R 5 form together with the nitrogen atom to which they are attached a morpholino group or a
  • C 1 -C 6 alkyl is preferably methyl
  • C 1 -C 6 alkyl substituted by two phenyl rings is preferably diphenylmethyl or 2,2-diphenylethyl
  • C 1 -C 6 alkoxy is preferably methoxy
  • R 2 is H
  • R 1 is a group -COR 3 wherein R 3 is a group of formula (C) as defined above in which R 8 is unsubstituted C 1 -C 6 alkyl, or is a 2- hydroxyethyl, ethenyl, prop-1-enyl, prop-2-enyl or 4- methoxyphenyl group.
  • R 2 is H
  • R 1 is a group -COR 3 wherein R 3 is a group of formula (D) as defined above in which p is 1 or 2 and R 9 is ethenyl, prop-1-enyl, prop-2-enyl or phenyl substituted by one or two C 1 -C 6 alkoxy, typically methoxy, groups, for instance 3,4-dimethoxyphenyl.
  • Examples of preferred compounds of formula (I) are as follows: ⁇ (3Z,6Z)-3,6-Dibenzylidene-4-methyl-2,5-dioxo-1-piperazinyl)acetic acid (9005)
  • R 11 and R 21 are hydrogen and the other is -COOH, -COX wherein X is a halogen, or -CO(OCOR') wherein R' is C 1 -C 6 alkyl.
  • X may be F, Cl, Br or I, preferably Cl.
  • R' may be any of the examples quoted above for C 1 -C 6 alkyl, or may be isobutyl.
  • the process for producing a compound of formula (I) accordingly comprises treating a compound of formula (II) as defined above with an amine of formula:
  • R 3 is as defined above for formula (I) excluding hydroxy, in an organic solvent, the reaction being conducted in the presence of a coupling agent when R 11 or R 21 is -COOH; and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof.
  • Suitable solvents include dichloromethane at a
  • reaction may optionally be performed in the presence of a base.
  • Suitable bases include trialkylamines such as Et 3 N, and pyridine.
  • R 11 br R 21 is -COOH any suitable coupling agent may be used, for instance 1,3-dicyclohexylcarbodiimide, 1-cyclohexyl-3-(2- morpholinoethyl)carbodiimide, or 1,1'-carbonyldiimidazole.
  • the preparation of the starting compounds of formula (II) wherein either R 11 or R 21 , as appropriate, is -COOH is described in Reference Example 2 which follows.
  • the optional conversion of either of these compounds to the corresponding acid halide or mixed anhydride derivative is performed by conventional methods which are routine in organic synthesis.
  • an acid halide derivative may be prepared by treatment of the carboxylic acid with a halogenating agent, for instance a chlorinating agent such as SOCl 2 , PCl 3 , oxalyl chloride or PCl 5 .
  • a halogenating agent for instance a chlorinating agent such as SOCl 2 , PCl 3 , oxalyl chloride or PCl 5 .
  • anhydride derivative may be prepared by treatment of the carboxylic acid with a C 1 -C 6 alkyl haloformate, for instance iBuOCOCl or EtOCOCl, in the presence of a base such as a tertiary amme.
  • a C 1 -C 6 alkyl haloformate for instance iBuOCOCl or EtOCOCl
  • the amines H-R 3 are commercially available products or can be prepared from known starting materials by
  • Suitable salts include salts with pharmaceutically
  • inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid.
  • organic acids include p-toluenesulphonic acid, methanesulphonic acid, mucic acid and succmic acid.
  • P-gp plasma membrane glycoprotem
  • P-gp A major function of P-gp in normal tissues is to export mtracellular toxins from the cell. There is evidence to suggest that overexpression of P-gp may play a clinical role m multi-drug resistance. Increased levels of P-gp mRNA or protein have been detected in many forms of human cancers - leukaemias, lymphomas, sarcomas and carcinomas. Indeed, in some cases P-gp levels have been found to be increased in tumour biopsies obtained after relapse from chemotherapy.
  • the present compounds have been found in biological tests to have activity m modulating multi-drug resistance. The results are set out m Example 5 which follows.
  • the present compounds may therefore be used as multi-drug resistance modifying agents, also termed resistance-modifying agents, or RMAs .
  • the present compounds can modulate, e.g. reduce, or eliminate multi-drug resistance.
  • the present compounds can therefore be used in a method of potentiating the cytotoxicity of an agent which is cytotoxic to a tumour cell.
  • a method of potentiating the cytotoxicity of an agent which is cytotoxic to a tumour cell comprises, for instance, administering one of the present compounds to the tumour cell whilst the tumour cell is exposed to the
  • cytotoxic agent in question in question.
  • the therapeutic effect of a chemotherapeutic, or antineoplastic, agent may thus be enhanced.
  • the multi-drug resistance of a tumour cell to a cytotoxic agent during chemotherapy may be reduced or eliminated.
  • the present compounds can also be used in a method of treating a disease in which the pathogen concerned exhibits multi-drug resistance, for instance multi-drug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery.
  • a disease in which the pathogen concerned exhibits multi-drug resistance for instance multi-drug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery.
  • a human or animal patient harbouring a tumour may be treated for resistance to a chemotherapeutic agent by a method comprising the administration thereto of one of the present compounds.
  • the present compound is administered in an amount effective to potentiate the cytotoxicity of the said chemotherapeutic agent.
  • chemotherapeutic or antineoplastic agents which are preferred in the context of the present invention include Vinca alkaloids such as vincristine and vinblastine; anthracycline antibiotics such as daunorubicm and doxorubicm; mitoxantrone; actinomycin D; taxanes e.g. taxol; epipodophyllotoxms e.g. etoposide, and plicamycm.
  • a human or animal patient suffering from a disease in which the responsible pathogen exhibits multi-drug resistance may be treated for resistance to a
  • therapeutic agent by a method comprising the administration thereto of one of the present compounds.
  • Examples of such disease include multi-drug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery
  • MDR modulators also have utility m the delivery of drugs across the blood-brain barrier, and in the treatment of AIDS and AIDS-related complex.
  • the present compounds can therefore be used in a method of facilitating the delivery of drugs across the blood brain barrier, and in the
  • a human or animal patient in need of such treatment may be treated by a method comprising the administration thereto of one of the present compounds.
  • the present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously.
  • the present compounds may therefore be given by injection or infusion.
  • the dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 0.001 to 50 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration.
  • a piperazinedione derivative of formula (I) or a pharmaceutically acceptable salt thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent.
  • the compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form.
  • the solid oral forms may contain, together with the active compound, diluents such as lactose,
  • dextrose, saccharose, cellulose, corn starch or potato starch lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols
  • binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone
  • disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulphates.
  • preparations may be manufactured in known manners, for example by means of mixing, granulating, tabletting, sugar coating, or film-coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol.
  • a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
  • Suspensions or solutions for intramuscular injections may contain, together with the active compound, a
  • lidocaine such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine
  • hydrochloride Some of the present compounds are insoluble in water. Such compounds may be encapsulated within liposomes.
  • Example 2 was treated with amine 3.2, prepared according to Reference Example 3, in the presence of 1-hydroxybenzotriazole and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulphonate at room temperature for 18 hours to give N-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1,4-dimethyl-2,5-dioxo-3-p-perazinylidene)methylbenzamide.
  • Example 2 was treated with amine 3.1, prepared according to Reference Example 3, in the presence of 1,1'- carbonyldiimidazole and 4 -dimethylaminopyridine (catalytic amount) at a temperature of 0°C and the resultant mixture allowed to warm to room temperature to give compound 9019.
  • Tablets each weighing 0.15 g and containing 25 mg of a compound of the invention can be manufactured as follows: Composition for 10,000 tablets
  • the compound of the invention, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to
  • the granulate is dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
  • the EMT6 mouse mammary carcinoma cell line and the MDR resistant subline AR 1.0 were cultured in RPMI 1640 medium containing 10% foetal calf serum and 2mM glutamine at 37°C in 5% CO 2 .
  • Cells were passaged between 1 in 200 and 1 in 2000 in the case of the parental cell line and between 1 in 20 and 1 in 200 in the case of the MDR resistant subline, after trypsinisation (0.25% trypsin, 0.2gl -1 , EDTA).
  • AR 1.0 cells were seeded into 96 well opaque culture plates (Canberra Packard).
  • the assay medium contained a mixture of tritiated Daunorubicin (DNR), a cytotoxic agent, and unlabelled DNR (0.3 ⁇ Ci/ml; 2 ⁇ M).
  • DNR tritiated Daunorubicin
  • cytotoxic agent a cytotoxic agent
  • unlabelled DNR 0.3 ⁇ Ci/ml
  • results are expressed as % maximum accumulation where 100% accumulation is that observed in the presence of the known RMA verapamil at a concentration of 100 ⁇ m or as an IC 50 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé de la pipérazinedione de la formule (I). Dans cette formule, l'un des symboles R1 et R2 est H, l'autre étant un groupe -COR?3, où R3¿ est (i) un groupe hydroxy; (ii) un groupe de la formule (A) dans laquelle n est égal à 0 ou 1 et m est égal à 0, 1, 2, 3 ou 4, n et/ou m sont différents de 0 et soit (a) R4 est H ou C¿1?-C6 alkyle et R?5¿ est C¿1?-C6 alkyle, éventuellement substitué par un ou deux groupes phényle, soit (b) R?4 et R5¿ forment ensemble avec l'atome d'azote auquel ils sont rattachés un groupe hétéroxyclique ayant la formule (B1) ou (B2) dans laquelle R6 et R7, qui sont identiques ou différents, sont chacun un hydrogène ou un groupe C¿1?-C6 alcoxy, ou R?6 et R7¿ forment ensemble un groupe méthylènedioxy; (iii) un groupe de la formule (C) dans laquelle R8 est un C¿1?-C6 alkyle, éventuellement substitué par un hydroxy, un C2-C6 alcényle ou un groupe phényle éventuellement substitué par un groupe C1-C6 alcoxy; ou (iv) un groupe de la formule (D) dans laquelle p est égal à 1, 2 ou 3 et R?9¿ est un C¿2?-C6 alcényle ou un noyau phényle éventuellement substitué par un C1-C6 alcoxy. L'invention concerne également les sels de ces composés acceptables sur le plan pharmaceutique. Ces composés et leurs sels ont une activité de modulateurs de la résistance multiple aux médicaments.
PCT/GB1995/003028 1994-12-23 1995-12-22 Derives de la piperazine-2,5-dione utilises comme modulateurs de la resistance multiple aux medicaments WO1996020179A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9711211A GB2310854B (en) 1994-12-23 1995-12-22 Piperazine-2,5-dione derivatives as modulators of multi-drug resistance
AU43101/96A AU4310196A (en) 1994-12-23 1995-12-22 Piperazine-2,5-dione derivatives as modulators of multi-drug resistance

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9426071.8A GB9426071D0 (en) 1994-12-23 1994-12-23 Pharmaceutical compounds
GB9426071.8 1994-12-23

Publications (1)

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WO1996020179A1 true WO1996020179A1 (fr) 1996-07-04

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AU (1) AU4310196A (fr)
GB (1) GB9426071D0 (fr)
IL (1) IL116522A0 (fr)
WO (1) WO1996020179A1 (fr)
ZA (1) ZA9510903B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US7476680B2 (en) 2000-10-17 2009-01-13 H. Lee Moffitt Cancer Center & Research Institute, Inc. Substituted heterocyclic compounds for treating multidrug resistance
WO2012125447A3 (fr) * 2011-03-11 2012-12-06 Taipei Medical University Composés pipérazinedione
CN103396372A (zh) * 2013-08-09 2013-11-20 中国科学院南海海洋研究所 一类2,5-二酮哌嗪衍生物及其制备方法和在制备抗海洋污损生物防除剂中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001408A1 (fr) * 1992-07-10 1994-01-20 Laboratoires Glaxo S.A. Derives d'anilide
WO1994004512A1 (fr) * 1992-08-14 1994-03-03 Xenova Limited Dicetopiperazines pharmaceutiquement actives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001408A1 (fr) * 1992-07-10 1994-01-20 Laboratoires Glaxo S.A. Derives d'anilide
WO1994004512A1 (fr) * 1992-08-14 1994-03-03 Xenova Limited Dicetopiperazines pharmaceutiquement actives
WO1994004513A1 (fr) * 1992-08-14 1994-03-03 Xenova Limited Dicetopiperazines pharmaceutiquement actives

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US7304053B2 (en) 2000-10-17 2007-12-04 H. Lee Moffitt Cancer Center & Research Institute, Inc. Substituted heterocyclic compounds for treating multidrug resistance
US7476680B2 (en) 2000-10-17 2009-01-13 H. Lee Moffitt Cancer Center & Research Institute, Inc. Substituted heterocyclic compounds for treating multidrug resistance
WO2012125447A3 (fr) * 2011-03-11 2012-12-06 Taipei Medical University Composés pipérazinedione
CN103429586A (zh) * 2011-03-11 2013-12-04 台北医学大学 哌嗪二酮化合物
US8710062B2 (en) 2011-03-11 2014-04-29 Taipei Medical University Piperazinedione compounds
CN103396372A (zh) * 2013-08-09 2013-11-20 中国科学院南海海洋研究所 一类2,5-二酮哌嗪衍生物及其制备方法和在制备抗海洋污损生物防除剂中的应用
CN103396372B (zh) * 2013-08-09 2015-05-20 中国科学院南海海洋研究所 一类2,5-二酮哌嗪衍生物及其制备方法和在制备抗海洋污损生物防除剂中的应用

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AU4310196A (en) 1996-07-19
GB9426071D0 (en) 1995-02-22
IL116522A0 (en) 1996-03-31

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