EP0799222A1 - Piperazine 2,5 dione derivatives as modulators of multi-drug resistance - Google Patents

Piperazine 2,5 dione derivatives as modulators of multi-drug resistance

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Publication number
EP0799222A1
EP0799222A1 EP95941797A EP95941797A EP0799222A1 EP 0799222 A1 EP0799222 A1 EP 0799222A1 EP 95941797 A EP95941797 A EP 95941797A EP 95941797 A EP95941797 A EP 95941797A EP 0799222 A1 EP0799222 A1 EP 0799222A1
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EP
European Patent Office
Prior art keywords
dimethoxy
tetrahydro
isoquinolyl
dioxo
methylbenzamide
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.)
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Application number
EP95941797A
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German (de)
French (fr)
Inventor
Philip Anthony Ashworth
Sukhjit Hunjan
Ian Andrew Pretswell
Hamish Ryder
Stephen James Brocchini
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Xenova Ltd
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Xenova Ltd
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Publication of EP0799222A1 publication Critical patent/EP0799222A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds useful as modulators of multi-drug resistance (MDR) , to their preparation and to pharmaceutical and veterinary compositions containing them.
  • MDR multi-drug resistance
  • tumours to treatment with certain cytotoxic agents is an obstacle to the successful chemotherapeutic treatment of cancer patients.
  • 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.
  • certain 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
  • R x is (i) a group
  • each of Ra to Re which may be the same or different, is independently selected from hydrogen, Ci-Cg alkyl unsubstituted or substituted by one or more halogen atoms, C 1 -C 8 alkenyl, C x -Cg alkoxy, C x -C 6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH 2 OH, -CH 2 COOH,
  • n is 0 or is an integer of from 1 to 6, each of R 11 and R 12 is independently H or Cj-Cg alkyl and R 13 is C x -C 6 alkyl; or any of Ra and Rb, Rb and Re, Re and Rd or Rd and Re together form a methylenedioxy group, or form together with the carbon atoms to which they are attached a benzene ring which is optionally substituted; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S, which group may be fused to a benzene ring;
  • R 2 is H, C- L -Cg alkyl optionally substituted by a group -N(R 11 R 12 ) as defined above, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, -COOR 11 wherein R 11 is as defined above or a phenyl group as defined under (i) above, but is other than H when R 1 is unsubstituted phenyl; and one of R 3 and R 4 is hydrogen and the other is a group of formula (A) :
  • R 5 and R 6 which may be the same or different, are each H or Cj-Cg alkoxy, or R 5 and R 6 together form a methylenedioxy group; and is a double bond or, when R ⁇ is as defined under
  • a Ci-Cg alkyl group may be linear or branched.
  • a Cj-Cg alkyl group is typically a C ⁇ C ⁇ alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert- butyl group.
  • a C 3 -C 6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • a halogen is, for example, fluorine, chlorine, bromine or iodine.
  • a C j -C 8 alkoxy group is typically a C ⁇ C, alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.
  • a C 2 -C 6 alkenyl group is, for example, C 2 -C 4 alkenyl, for example ethenyl, prop-1-enyl or prop-2-enyl.
  • a heterocyclic group may be, for example, a pyridine, pyrrole, furan or thiophene group which is linked via any one of its constituent ring atoms. It may be, for instance, a 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2- thienyl or 3-thienyl group.
  • the integer q is from 1 to 4, and is preferably 1 or 2.
  • R 5 and R 6 are preferably the same and are preferably C 1 - C 4 alkyl, for instance methyl.
  • the phenyl group is unsubstituted or is substituted at one or more of positions 2 to 6. When it is mono-substituted it may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4.
  • one of Ra to Re is other than hydrogen, preferably Rb or Re, especially Re.
  • the substituent Ra to Re is preferably selected from a halogen, for instance chlorine, bromine or fluorine; a C j -Cg alkoxy group, for instance OMe; and an acetamido group -NHAc in which Ac denotes acetyl .
  • the phenyl group may instead be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- disubstituted, or 2,3,4-, 2,3,5-, 2,3,6- or
  • Ra to Re When it is disubstituted, three of Ra to Re are hydrogen and two are other than hydrogen.
  • Ra and Rb, or Ra and Re, or Ra and Rd, or Ra and Re, or Rb and Re, or Rb and Rd are other than hydrogen whilst, in each case, the other three of Ra to Re are hydrogen.
  • Ra to Re When the phenyl group is trisubstituted, two of Ra to Re are hydrogen and three are other than hydrogen.
  • Ra, Rb and Re, or Ra, Rb and Rd, or Ra, Rb and Re, or Rb, Re and Rd are other than hydrogen whilst, in each case, the other two of Ra to Re are hydrogen.
  • each of Ra to Re is hydrogen.
  • one of Ra to Re is selected from hydroxy, alkoxy, NHCOR 11 , -COjR 11 , -N(R 11 R 12 ) , -O(CH 2 ) n N(R X1 R 12 ) , -S0 2 R 13 , -CON R ⁇ R 12 ) , N0 2 , -SO ⁇ R ⁇ R 12 ) , -SOR 13 , -N(R 11 ) COR 12 and halogen and the other four of Ra to Re are H.
  • Alkoxy may be, for instance, OMe or OBu n .
  • NHCOR 11 is typically -NHAc.
  • C0 2 R 1X is typically -COOH or -COOMe.
  • NlR ⁇ R 12 ) is typically NMe 2 .
  • -CON(R xl R 12 ) may be -CONH 2 .
  • S0 2 R 13 is typically S0 2 Me, S0 2 N(R 11 R 12 ) is for example -S0 2 NMe 2 .
  • SOR 13 may be SOMe and -N(R lx )COR 12 may be -NMeCOBuX Halogen is typically F or Cl.
  • Re is alkoxy, especially OMe or OBu n ; NHCOR 11 , especially -NHAc; -CO-jR 11 , especially -C0 2 H or -C0 2 Me; -CO IR ⁇ R 12 ) especially -CONH 2 ; N0 2 ; N(R"R 12 ) especially NMe 2 ; -SOR 13 especially -SOMe; -S0 2 N(R R 12 ) especially -S0 2 NMe 2 or halogen, especially F or Cl; and each of Ra, Rb, Rd and Re is H.
  • Ra to Re are all hydrogen, or one or two of Ra to Re are other than hydrogen whilst the others are hydrogen.
  • one of Ra, Rb and Re is other than hydrogen.
  • Ra and Re, or Rb and Re are other than hydrogen.
  • Preferred values for the one or two of Ra to Re which is or are other than hydrogen include alkoxy such as OMe or OBu n , halogen such as Cl or F, hydroxy, -N(R R 12 ), -C0 2 R n , -CH 2 SCOR 13 , -CH- j SR 11 , -NHCOR 11 , -O(CH 2 ) n N(R X1 R 12 ) , -0(CH 2 ) ⁇ C0 2 R 11 , -CH 2 NHCO(CH 2 ) n C0 2 R n , -NHCOC ⁇ OR 11 , -NHCOCH 2 OCOR 13 , -CH 2 NHCOOR 13 and CF 3 .
  • Particularly preferred compounds are those wherein Ra,
  • ⁇ n i WESHEErmua, Rb, Rd and Re are each H, and Re is selected from H, OMe -NHAc, -C0 2 H, -C0 2 Me, -CONH 2 , N0 2 , -NMe 2 , S0 2 Me, -SOMe and -S0 2 NMe 2 .
  • Ra to Re are preferably each independently selected from H, halogen, hydroxy, alkoxy, nitro, -CH 2 SCOR 13 , -CH-jSR 11 , -C0 2 R 1X , -OCOR 13 , CF 3 , -0(CH 2 ) n N(R 11 R 12 ) , -O(CH 2 ) n C0 2 R 11 , -CH 2 NHCO(CH 2 ) n C0 2 R 11 , -NHCO(CH 2 ) n OR", -N(R 11 R 12 ) , -NHCOtCH- n OCOR 11 , -NHCO(CH 2 ) n C0 2 R 11 and -CH 2 NHC0 2 R 13 or Ra and Rb, Rb and Re, Re and Rd, or Rd and Re, form a methylenedioxy group or form, with the carbon atoms to which they are attached, an optionally substituted benzene ring.
  • Ra and Rb are independently H, nitro or halogen
  • Re is H, hydroxy, -O(CH 2 ) n N(R X1 R 12 ) , -OCOR 13 , -0 ( CR 2 ) n C0 2 R 11 , -CH 2 NHCO(CH 2 ) n C0 2 R 11 , alkoxy, -NHCO(CH 2 ) n OR 11 , -NHCO(CH 2 ) n OCOR 11 , -N(R 11 R 12 ) ,
  • Rd is H, halogen, alkoxy, -CH 2 SCOR 13 , -CHzSR 11 or -COjR 11 ; and Re is H, nitro or halogen.
  • R 1 is a phenyl group as defined above which is unsubstituted or mono-substituted at position 2, 3 or 4 by Cl or MeO, or is a pyridyl, furyl or
  • R 1 is unsubstituted phenyl
  • R 2 is 0* ⁇ 0 4 alkyl, preferably methyl, or is phenyl or cyclopropyl
  • R 3 is H
  • R" is a group of formula (A) wherein q is 2 and each of R 5 and R 6 is MeO.
  • R 1 is substituted phenyl as defined above or a furyl, thienyl or pyridyl group
  • R 2 is H
  • R 3 is H
  • R 4 is a group of formula (A) wherein q is 2 and each of R 5 and R 6 is MeO.
  • R 1 is substituted phenyl as defined above or a furyl, thienyl or pyridyl group
  • R 2 is H
  • R 3 is a group of formula (A) wherein q is 2 and each of R 5 and R 6 is MeO
  • R 4 is H.
  • R 1 is unsubstituted phenyl
  • R 2 is alkyl, preferably methyl, phenyl or cyclopropyl
  • R 3 is a group of formula (A) wherein q is 2 and each of R 5 and R 6 is MeO
  • R 4 is H.
  • R 1 is a furyl, thienyl or pyridyl group it is preferably a 3-furyl, 2-thienyl, 3- thienyl or 4-pyridyl group.
  • Examples of preferred compounds of the invention are as follows. The compound numbering is adhered to in the rest of the specification.
  • R 7 and R 8 is hydrogen and the other is -CHO, and q, r, R 5 and R 6 are as defined above; in the presence of a base in an organic solvent; and, if desired, converting the resulting compound into a pharmaceutically acceptable salt
  • Suitable bases include caesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium t- butoxide and triethylamine.
  • Suitable organic solvents include dimethylformamide
  • DMF tetrahydrofuran
  • THF tetrahydrofuran
  • the temperature is typically between 0°C and reflux temperature, for example from 80°C-95°C when caesium carbonate is used as base.
  • the reaction mixture is typically warmed from 0°C to room temperature, or to 40°C.
  • the reaction may be performed for a period of 1 to 4 hours, for example 2 or 3 hours.
  • the compounds of formula (II) wherein is a double bond are prepared by a process which comprises treating a compound of formula (IV) :
  • R 1 is as defined above, with an alkylating agent, in an organic solvent in the presence of a base.
  • the alkylating agent is typically an alkyl halide R 2 -CH 2 X, a methanesulphonate or p-toluenesulphonate ester R 2 CH 2 OS0 2 Me or R 2 CH 2 OS0 2 C 6 H 4 Me, respectively, or a dialkyl sulphate (R 2 CH 2 0) 2 S0 2 , wherein R 2 is as defined above and X is a halogen, for instance Cl Br or I.
  • Suitable bases and solvents include sodium hydride in THF or DMF or mixtures thereof, and potassium t-butoxide in t-butanol or THF or DMF or mixtures thereof.
  • the reaction mixture is typically warmed from 0°C to room temperature.
  • R 1 is as defined under (i) above and R 2 is as defined above with acetic anhydride.
  • the reaction is typically performed under reflux, for instance for 1 to 6 hours, typically 3 hours.
  • the compound of formula (X) may be prepared by treating a compound of formula (XI) :
  • the compounds of formula (XI) may be prepared by treating a compound of formula (XII) :
  • Compounds of formula (IV) may be prepared by a process which comprises treating 1,4-diacetyl-2, 5-piperazinedione of formula (V) :
  • R 1 is as defined above, in the presence of a base in an organic solvent .
  • Suitable bases and solvents include triethylamine, caesium carbonate, sodium carbonate, potassium carbonate and sodium hydride in DMF or THF or mixtures thereof, and potassium t-butoxide in t-butanol or DMF or THF or mixtures
  • the temperature of the reaction is typically from 100-140°C, for instance 120- 130°C.
  • potassium t-butoxide is used as base the reaction mixture is typically warmed from 0°C to room temperature.
  • the reaction is conducted in an organic solvent either with an excess of the amine of formula (IX) , or in the presence of a base such as a tertiary amine, e.g. Et 3 N, or pyridine.
  • the organic solvent is an inert organic solvent such as CH 2 C1 2 .
  • the coupling agent used in (a) or (b) with the 3- or 4- formylbenzoic acid, respectively, may be, for instance, 1- cyclohexyl-3- (2-morpholinoethyl) carbodiimide metho-p- toluenesulphonate or 2-chloro-l-methylpyridinium iodide.
  • the activated acid halide or mixed anhydride derivative of 3- or 4-formylbenzoic acid may be produced by conventional methods.
  • the 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 , PC1 3 , oxalyl chloride or PC1 5 .
  • a halogenating agent for instance a chlorinating agent such as SOCl 2 , PC1 3 , oxalyl chloride or PC1 5 .
  • the mixed anhydride derivative may be prepared by treatment of the carboxylic acid with a Cj-Cg alkyl haloformate such as iBuOCOCl or EtOCOCl , in the presence of a base such as Et 3 N.
  • the reduction step (ii) is typically performed using iron powder and concentrated hydrochloric acid in methanol, usually at a temperature of about 80°C and for a period of 1 to 4 hours, for instance 3 hours. Alternatively it may be carried out by catalytic hydrogenation over a palladium on carbon catalyst in methanolic HCl, isopropanol or acetic acid.
  • Suitable salts include salts with pharmaceutically acceptable inorganic or organic acids.
  • inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid.
  • organic acids include -toluenesulphonic acid, methanesulphonic acid, mucic acid and succinic acid.
  • MDR cells which exhibit multi-drug resistance
  • MDR cells display a reduction in intracellular drug accumulation compared with the corresponding drug-sensitive cells.
  • Studies using jLn vitro derived MDR cell lines have shown that MDR is often associated with increased expression of a plasma membrane glycoprotein (P-gp) which has drug binding properties.
  • P-gp plasma membrane glycoprotein
  • P-gp is thought to function as an efflux pump for many hydrophobic compounds
  • transfection studies using cloned P-gp have shown that its overexpression can confer the MDR phenotype on cells: see, for example, Ann. Rev. Biochem . 58 . 137-171 (1989) .
  • P-gp A major function of P-gp in normal tissues is to export intracellular toxins from the cell.
  • overexpression of P-gp may play a clinical role in 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.
  • Inhibition of P-gp function in P-gp mediated MDR has been shown to lead to a net accumulation of anti-cancer agent in the cells.
  • Verapamil a known calcium channel blocker was shown to sensitise MDR cells to Vinca alkaloids .in vitro and jLn vivo: Cancer Res. , 4.1, 1967-1972 (1981) .
  • the proposed mechanism of action involves competition with the anti-cancer agent for binding to the P- gp.
  • a range of structurally unrelated resistance-modifying agents acting by this mechanism have been described such as tamoxifen (Nolvadex: ICI) and related compounds, and cyclosporin A and derivatives.
  • the present compounds have been found in biological tests to have activity in modulating multi-drug resistance. The results are set out in 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. Such a method comprises, for
  • 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 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.
  • Such a method comprises, for instance, administering one of the present compounds with (separately, simultaneously or sequentially) the drug to which the pathogen concerned exhibits multi-drug resistance.
  • the therapeutic effect of the drug may thus be enhanced.
  • 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 daunorubicin and doxorubicin; mitoxantrone; actinomycin
  • 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.
  • Posmodium falciparum multi-drug resistant forms of malaria
  • tuberculosis tuberculosis
  • leishmaniasis amoebic dysentery.
  • MDR modulators also have utility in 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 treatment of AIDS or AIDS related complex.
  • 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.
  • An agent for use as a modulator of multi-drug resistance comprising any one of the present compounds is therefore provided.
  • 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.
  • 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
  • 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 pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride .
  • a pharmaceutically acceptable carrier 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 .
  • Method B 4-diacetyl-2, 5-piperazinedione was treated with a series of benzaldehydes R ⁇ CHO, where R 1 is as listed in table IB, in the presence of potassium t-butoxide in t- butanol-THF (1:1) at 0°C.
  • the reaction mixture was allowed to warm to room temperature for the time indicated in the table. Recrystallisation, which was optional, was conducted using the indicated solvent.
  • Method E Compound 1.1, described in Reference Example 1, was treated in DMF with sodium hydride and 2-dimethylaminoethyl chloride hydrochloride at 0°C. The reaction mixture was warmed to 20°C, and then further warmed to 80°C, over a period of 5 hours. The product was purified by recrystallisation from 1% MeOH in EtOAc to give 2.41 in 32% yield, which is a compound of formula (II) wherein R 2 is -CH 2 NMe 2 .
  • Method F Compound 1.1, described in Reference Example 1, was treated in acetonitrile with Cs 2 C0 3 and ethyl bromoacetate at -20°C. The reaction mixture was warmed to 20°C for 2 hours. The product was purified by flash chromatography using EtOAc-hexane (1:2) to give 2.42 in 35% yield, which is a compound of formula (II) wherein R 2 is -C0 2 Et.
  • 4-formylbenzoyl chloride was prepared by treating 4- formylbenzoic acid with thionyl chloride in toluene under reflux. It was then treated with compound 3.4, prepared according to Reference Example 5, in CH 2 C1 2 in the presence of Et 3 N at a temperature of about 0°C and allowed to warm to room temperature, to afford the following compound 4.2 in 53% yield:
  • Example 2 The compounds prepared in Example 2 were converted to the corresponding hydrochloride salts by treatment with gaseous HCI in THF.
  • Example 4 Selected compounds prepared in Example 4 were converted to the corresponding hydrochloride salts by treatment with gaseous HCI in CH,Cl 2 .
  • the hydrochloride denoted in Table 5 below by the suffix ".HCI” was in some cases then recrystallised as shown in the table.
  • Example 7 Pharmaceutical Composition Tablets, each weighing 0.15 g and containing 25 mg of a compound of formula (I) or salt thereof can be manufactured as follows:
  • the compound of formula (I) or salt thereof, 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 granulate the powder. 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.
  • Example 8 Testing of compounds of formula (I) and their salts as modulators of MDR
  • 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% C0 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 " ⁇ EDTA) .
  • Drug accumulation assay 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
  • Compounds of formula I were serially diluted in assay medium over a range of concentrations from 5 nM to 100 ⁇ M. The cells were incubated at 37°C for 1 hr before washing and determination of cell associated radioactivity. 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 E0 .

Abstract

A piperazinedione derivative of formula (I), wherein R1 is: (i) a group α, wherein p is 0 or 2; (ii) a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from O, N and S, which group may be fused to a benzene ring; R2 is H, C¿1?-C6 alkyl optionally substituted by a group -N(R?11R12¿) as defined above, C¿3?-C6 cycloalkyl, C2-C6 alkenyl, -COOR?11¿ wherein R11 is as defined above or a phenyl ring as defined under (i) above, but is other than H when R1 is unsubstituted phenyl; and one of R?3 and R4¿ is hydrogen and the other is a group of formula (A), wherein q is an integer of 1 to 4, r is 0 or 1 and R?5 and R6¿, which may be the same or different, are each H or C¿1?-C6 alkoxy, or R?5 and R6¿ together form a methylenedioxy group; ----- is a double bond or, when R1 is as defined under (i) above, is a double bond or a single bond; and pharmaceutically acceptable salts thereof have activity as modulators of multi-drug resistance.

Description

PIPERAZINE 2,5 DIONE DERIVATIVES AS MODULATORS OF MULTI-DRUG RESISTANCE
The present invention relates to compounds useful as modulators of multi-drug resistance (MDR) , to their preparation and to pharmaceutical and veterinary compositions containing them.
The resistance of tumours to treatment with certain cytotoxic agents is an obstacle to the successful chemotherapeutic treatment of cancer patients. 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. Analogously, certain 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.
The above phenomena are referred to collectively as multi-drug resistance (MDR) . As discussed more fully later on, a plasma membrane glycoprotein (P-gp) is implicated in the mechanism which underlies MDR. P-gp has drug binding properties. 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.
Disadvantages of drugs which have so far been used to modulate MDR, termed resistance modifying agents or RMAs, are that they frequently possess a poor pharmacokinetic profile and/or are toxic at the concentrations required for MDR modulation.
It has now been found that a series of piperazinedione derivatives have activity as modulators of multi-drug resistance. The present invention therefore provides a piperazinedione derivative of formula (I) :
wherein CD
Rx is (i) a group
wherein p is 0 or 2; each of Ra to Re, which may be the same or different, is independently selected from hydrogen, Ci-Cg alkyl unsubstituted or substituted by one or more halogen atoms, C1-C8 alkenyl, Cx-Cg alkoxy, Cx-C6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH2OH, -CH2COOH,
-COj-R11, -NHCOR11, -NHS02R13, -S02R13, -CON(R^R12) , -SOR13, -S02N(RuR12) , -N(RnR12), -O(CH2)nN(R"R12) , -O(CH2)nC02R11, -OCOR11, -C^OCOR11, -C^NHCOR11, -CH2NHCOOR13, -CHjSR11, -C^SCOR11, -CH2S(0)mR13 wherein m is 1 or 2,
-CΗ2IffiCO{CH2)nC02R11 -NCR^COR12, -NHCOCF3, -NHCO(CH2)nC02R11, -NHCOtCH-^OCOR11 and -NHCO (CH2)nC02R ; wherein n is 0 or is an integer of from 1 to 6, each of R11 and R12 is independently H or Cj-Cg alkyl and R13 is Cx-C6 alkyl; or any of Ra and Rb, Rb and Re, Re and Rd or Rd and Re together form a methylenedioxy group, or form together with the carbon atoms to which they are attached a benzene ring which is optionally substituted; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S, which group may be fused to a benzene ring;
(iii) a Cj-Cg alkyl or C5-C7 cycloalkyl group; or
(iv) a C5-C7 cycloalkenyl group which is unsubstituted or substituted by C2-C6 alkenyl;
R2 is H, C-L-Cg alkyl optionally substituted by a group -N(R11R12) as defined above, C3-C6 cycloalkyl, C2- C6 alkenyl, -COOR11 wherein R11 is as defined above or a phenyl group as defined under (i) above, but is other than H when R1 is unsubstituted phenyl; and one of R3 and R4 is hydrogen and the other is a group of formula (A) :
SUBSTITUTE SHEET (RULE 2&)
wherein q is an integer of 1 to 4, r is 0 or 1 and R5 and R6, which may be the same or different, are each H or Cj-Cg alkoxy, or R5 and R6 together form a methylenedioxy group; and is a double bond or, when Rλ is as defined under
(i) above, is a double bond or a single bond; or a pharmaceutically acceptable salt thereof.
A Ci-Cg alkyl group may be linear or branched. A Cj-Cg alkyl group is typically a C^C^ alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert- butyl group. A C3-C6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl . A halogen is, for example, fluorine, chlorine, bromine or iodine.
A Cj-C8 alkoxy group is typically a C^C, alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. A C2-C6 alkenyl group is, for example, C2-C4 alkenyl, for example ethenyl, prop-1-enyl or prop-2-enyl.
A heterocyclic group may be, for example, a pyridine, pyrrole, furan or thiophene group which is linked via any one of its constituent ring atoms. It may be, for instance, a 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2- thienyl or 3-thienyl group.
The integer q is from 1 to 4, and is preferably 1 or 2. R5 and R6 are preferably the same and are preferably C1- C4 alkyl, for instance methyl.
When R1 is as defined under (i) above, the phenyl group is unsubstituted or is substituted at one or more of positions 2 to 6. When it is mono-substituted it may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4. Thus for instance, one of Ra to Re is other than hydrogen, preferably Rb or Re, especially Re. When the phenyl group is mono-substituted the substituent Ra to Re is preferably selected from a halogen, for instance chlorine, bromine or fluorine; a Cj-Cg alkoxy group, for instance OMe; and an acetamido group -NHAc in which Ac denotes acetyl .
The phenyl group may instead be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- disubstituted, or 2,3,4-, 2,3,5-, 2,3,6- or
3 , 4 , 5-trisubstituted. When it is disubstituted, three of Ra to Re are hydrogen and two are other than hydrogen. For example Ra and Rb, or Ra and Re, or Ra and Rd, or Ra and Re, or Rb and Re, or Rb and Rd are other than hydrogen whilst, in each case, the other three of Ra to Re are hydrogen.
When the phenyl group is trisubstituted, two of Ra to Re are hydrogen and three are other than hydrogen. For example, Ra, Rb and Re, or Ra, Rb and Rd, or Ra, Rb and Re, or Rb, Re and Rd are other than hydrogen whilst, in each case, the other two of Ra to Re are hydrogen.
In a preferred series of compounds of formula (I) each of Ra to Re is hydrogen. In another preferred series of compounds, one of Ra to Re is selected from hydroxy, alkoxy, NHCOR11, -COjR11, -N(R11R12) , -O(CH2)nN(RX1R12) , -S02R13, -CON R^R12) , N02, -SO^R^R12) , -SOR13, -N(R11) COR12 and halogen and the other four of Ra to Re are H. Alkoxy may be, for instance, OMe or OBun. NHCOR11 is typically -NHAc. C02R1X is typically -COOH or -COOMe. NlR^R12) is typically NMe2. -CON(RxlR12) may be -CONH2. S02R13 is typically S02Me, S02N(R11R12) is for example -S02NMe2. SOR13 may be SOMe and -N(Rlx)COR12 may be -NMeCOBuX Halogen is typically F or Cl. Preferably Re is alkoxy, especially OMe or OBun; NHCOR11, especially -NHAc; -CO-jR11, especially -C02H or -C02Me; -CO IR^R12) especially -CONH2; N02; N(R"R12) especially NMe2; -SOR13 especially -SOMe; -S02N(R R12) especially -S02NMe2 or halogen, especially F or Cl; and each of Ra, Rb, Rd and Re is H.
In the above-mentioned series of preferred compounds Ra to Re are all hydrogen, or one or two of Ra to Re are other than hydrogen whilst the others are hydrogen. For instance one of Ra, Rb and Re is other than hydrogen. Alternatively Ra and Re, or Rb and Re, are other than hydrogen. Preferred values for the one or two of Ra to Re which is or are other than hydrogen include alkoxy such as OMe or OBun, halogen such as Cl or F, hydroxy, -N(R R12), -C02Rn, -CH2SCOR13, -CH-jSR11, -NHCOR11, -O(CH2)nN(RX1R12) , -0(CH2)πC02R11, -CH2NHCO(CH2)nC02Rn, -NHCOC^OR11, -NHCOCH2OCOR13, -CH2NHCOOR13 and CF3.
Particularly preferred compounds are those wherein Ra,
"βniWESHEErmua, Rb, Rd and Re are each H, and Re is selected from H, OMe -NHAc, -C02H, -C02Me, -CONH2, N02, -NMe2, S02Me, -SOMe and -S02NMe2. Also preferred are compounds wherein Ra to Re are preferably each independently selected from H, halogen, hydroxy, alkoxy, nitro, -CH2SCOR13, -CH-jSR11, -C02R1X, -OCOR13, CF3, -0(CH2)nN(R11R12) , -O(CH2)nC02R11, -CH2NHCO(CH2)nC02R11, -NHCO(CH2) nOR", -N(R11R12) , -NHCOtCH- nOCOR11, -NHCO(CH2)nC02R11 and -CH2NHC02R13 or Ra and Rb, Rb and Re, Re and Rd, or Rd and Re, form a methylenedioxy group or form, with the carbon atoms to which they are attached, an optionally substituted benzene ring. Still more preferably, Ra and Rb are independently H, nitro or halogen, Re is H, hydroxy, -O(CH2)nN(RX1R12) , -OCOR13, -0 ( CR2 ) nC02R11 , -CH2NHCO(CH2)nC02R11, alkoxy, -NHCO(CH2)nOR11, -NHCO(CH2) nOCOR11, -N(R11R12) ,
-CH2NHC02R13, -CH2SR1L or -NHCOR11; Rd is H, halogen, alkoxy, -CH2SCOR13, -CHzSR11 or -COjR11; and Re is H, nitro or halogen.
When any two adjacent groups of Ra to Re form, together with the carbon atom to which they are attached, a benzene ring, that ring is either unsubstituted or it may be substituted by any of the options specified above for Ra to Re. The benzene ring forms, together with the phenyl group, an optionally substituted naphthalene ring structure. In one embodiment of formula (I) R1 is a phenyl group as defined above which is unsubstituted or mono-substituted at position 2, 3 or 4 by Cl or MeO, or is a pyridyl, furyl or
SUBSTITUTE SHEET ( I 26) thienyl group, R2 is H, CH3, cyclopropyl or phenyl, and one of R3 and R4 is H and the other is a group of formula (A) wherein q is 2 and each of R5 and R6 is a methoxy group.
In a second embodiment, R1 is unsubstituted phenyl, R2 is 0*^04 alkyl, preferably methyl, or is phenyl or cyclopropyl, R3 is H and R" is a group of formula (A) wherein q is 2 and each of R5 and R6 is MeO.
In a third embodiment R1 is substituted phenyl as defined above or a furyl, thienyl or pyridyl group, R2 is H, R3 is H and R4 is a group of formula (A) wherein q is 2 and each of R5 and R6 is MeO.
In a fourth embodiment R1 is substituted phenyl as defined above or a furyl, thienyl or pyridyl group, R2 is H, R3 is a group of formula (A) wherein q is 2 and each of R5 and R6 is MeO, and R4 is H.
In a fifth embodiment R1 is unsubstituted phenyl, R2 is alkyl, preferably methyl, phenyl or cyclopropyl, R3 is a group of formula (A) wherein q is 2 and each of R5 and R6 is MeO, and R4 is H. When in the above embodiments R1 is a furyl, thienyl or pyridyl group it is preferably a 3-furyl, 2-thienyl, 3- thienyl or 4-pyridyl group.
Examples of preferred compounds of the invention are as follows. The compound numbering is adhered to in the rest of the specification.
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2-
SUBS TUTE SHEET (R I 26) isoquinolyl) ethyl)phenyl) -4- ( (3Z, 6Z) -6-benzylidene-1-ethyl- 2, 5-dioxo-3-piperazinylidene) methylbenzamide, hydrochloride (9112)
N- (4- (2- (6 , 7-Dimethoxy-l, 2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -4- ( (3Z, 6Z) -1-benzyl-6-benzylidene- 2, 5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride
(9113)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -4- ( (3Z, 6Z) -6-benzylidene-l- cyclopropylmethyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9114)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl) phenyl) -4- ( (3Z,6Z) -6- (3-furylmethylene) -1- methyl-2, 5-dioxo-3-piperazinylidene) methylbenzamide, hydrochloride (9108)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -4-{(3Z,6Z)-6-(4- methoxybenzylidene) -1-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9109)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -4- ( (3Z, 6Z) -6- (4- chlorobenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9091)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl)ethyl)phenyl) -4-((3Z,6Z)-6-(2- chlorobenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9092)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3 ,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -4- ( (3Z, 6Z) -6- (3- chlorobenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9093)
N- (4- (2- (6,7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -4- { (3Z,6Z) -l-methyl-2, 5-dioxo-6- (3-pyridylmethylene) -3-piperazinylidene)methylbenzamide, hydrochloride (9110)
N- (4- (2- (6 , 7-Dimethoxy-l, 2, 3,4-tetrahydro-2- isoquinolyl) ethyl) henyl) -4- ( (3Z, 6Z) -l-methyl-2, 5-dioxo-6- (3-thenylidene) -3-piperazinylidene)methylbenzamide, hydrochloride (9111)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3- ( (3Z, 6Z) -l-methyl-2, 5-dioxo-6- (2-thenylidene) -3-piperazinylidene) ethylbenzamide (9155)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3- ( (3Z, 6Z) -l-methyl-2, 5-dioxo-6- (3-thenylidene) -3-piperazinylidene) ethylbenzamide (9160)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3- ( (3Z, 6Z) -6- (3- chlorobenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9157)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3- ( (3Z, 6Z)-6-(2- chlorobenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9158)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3- ( (3Z,6Z) -6- (3-furylmethylene) -1* methyl-2 , 5-dioxo-3-piperazinylidene)methylbenzamide (9159)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3-( (3Z,6Z)-6-(3- methoxybenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene) methylbenzamide (9156)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -3- ( (3Z, 6Z) -6-benzylidene-1-ethyl- 2 , 5-dioxo-3-piperazinylidene)methylbenzamide (9139)
N- ( 4 - ( 2 - ( 6 , 7 -Dimethoxy- l , 2 , 3 , 4 - tetrahydro- 2 -
SUBSrrrUTE SHEET (RI JLE 26) isoquinolyl) ethyl)phenyl) -3- ( (3Z, 6Z) -6-benzylidene-l- cyclopropylmethyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9141)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z, 6Z) -1-allyl-6-benzylidene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9178)
N- (4- (2- (6,7-Dimethoxy-l,2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z, 6Z) -1-allyl-6-benzylidene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9179)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z, 6Z) -l-methyl-6- (2-naphthyl)methylene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9193)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z, 6Z) -l-methyl-6- (1-naphthyl) methylene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9194)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) - 3- ( (3Z, 6Z) -l-methyl-6- (1-naphthyl) ethylene-2, 5-dioxo-3-
suss : : η ι- ,
'■ ■ ■ SJ I L OΠ LX (r t ? ?PJ piperazinylidene)methylbenzamide (9195)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 4-( (3Z,6Z)-6- (2-furyl)methylene-1-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9196)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3- ( (3Z, 6Z) -6- (2-furyl)methylene-l-methyl-2, 5-dioxo-3- piperazinylidene) ethylbenzamide (9197)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 4-((3Z,6Z) -l-methyl-6- (l-methyl-3-pyrrolyl)methylene-2, 5- dioxo-3-piperazinylidene)methylbenzamide (9198)
N- (4- (2- (6, 7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3-((3Z,6Z) -l-methyl-6- (l-methyl-3-pyrrolyl) methylene-2, 5- dioxo-3-piperazinylidene)methylbenzamide (9199)
N- (4- (2- (6, 7-Dimethoxy-l, 2,3, 4-tetrahydro-2- isoquinolyl) ethyl) phenyl) - 3- ((3Z,6Z) -l-methyl-6- (2-naphthyl) methylene-2 , 5-dioxo-3- piperazinylidene)methylbenzamide (9209) N- (4- (2- (6, 7-Dimethoxy-l, 2,3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z, 6Z) -l-methyl-6- (1-methyl-3-indolyl)methylene-2, 5- dioxo-3-piperazinylidene)methylbenzamide (9210)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z, 6Z) -l-methyl-6- (3-methylbenzo(b) thien-2-yl)methylene-
2, 5-dioxo-3-piperazinylidene)methylbenzamide (9211)
N- (4- (2- (6, 7-Dimethoxy-l,2,3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z, 6Z) -l-methyl-6- (l-methyl-3-indolyl)methylene-2, 5- dioxo-3-piperazinylidene)methylbenzamide (9214)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl) henyl) -
4- ( (3Z, 6Z) -l-methyl-6- (3-methylbenzo(b) thien-2-yl)methylene*
2 , 5-dioxo-3-piperazinylidene)methylbenzamide (9215)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z, 6Z) -6-benzylidene-l-methoxycarbonylmethyl-2, 5-dioxo-
3-piperazinylidene)methylbenzamide (9217)
N- (4- (2- (6, 7-Dimethoxy-l,2,3 , 4-tetrahydro-2- isoquinolyl) ethyl) phenyl) - 4- ( (3Z, 6Z) -l-methyl-6- (2-methylpropylidene) -2, 5-dioxo-3- piperazinylidene)methylbenzamide (9228)
N- (4- (2- (6, 7-Dimethoxy-l, 2,3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z, 6Z) -l-methyl-6-cyclohexylmethylene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9229)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 ,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z, 6Z) -1-methyl-6-cyclohexylmethylene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9230)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z, 6Z) -l-methyl-2, 5-dioxo-6-pentylidene-3- piperazinylidene)methylbenzamide (9231)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
-3- ( (3Z, 6Z) -l-methyl-2, 5-dioxo-6-pentylidene-3- piperazinylidene) ethylbenzamide (9232)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl) phenyl) -
3- ( (3Z, 6Z) -l-methyl-6- (2-methylpropylidene) -2, 5-dioxo-3- piperazinylidene)methylbenzamide (9233)
SUBSTITUTE SHEET ^ u N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 ,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4-((3Z,6Z)-6-(3, 3-dimethylbutylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene) ethylbenzamide (9234)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3 ,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3-((3Z,6Z)-6-(3, 3-dimethylbutylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9235)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
4- ( (3Z,6Z) -6- ( (4S) -4-isopropenyl-1-cyclohexenyl)methylene-1- methyl-2, 5-dioxo-3-piperazinylidene)methylbenzamide (9236)
N- (4- (2- (6, 7-Dimethoxy-l, 2, 3, 4-tetrahydro-2- isoquinolyl) ethyl) henyl) -
3- ( (3Z, 6Z) -6-benzylidene-1-carboxymethyl-2 , 5-dioxo-3- piperazinylidene)methylbenzamide (9241)
N- (4- (2- (6, 7-Dimethoxy-l,2, 3 ,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z,6Z) -6- ( (4S) -4-isopropenyl-l-cyclohexenyl)methylene-1* methyl-2 , 5-dioxo-3-piperazinylidene)methylbenzamide (9250)
N- (2- (6, 7-Dimethoxy-l, 2,3, 4-tetrahydro-2-isoquinolyl) ethyl) 3- ( (3Z, 6Z) -l-methyl-6- (2-naphthyl)methylene-2, 5-dioxo-3-
'SUBSΠTIΓTE SHΓΓ P* ■■:: p? piperazinylidene)methylbenzamide (9260)
N- (2- (6, 7-Dimethoxy-l,2, 3,4-tetrahydro-2-isoquinolyl) ethyl) 4- ( (3Z, 6Z) -l-methyl-6- (2-naphthyl)methylene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9261)
N- (2- (6, 7-Dimethoxy-l, 2, 3 ,4-tetrahydro-2-isoquinolyl) ethyl) 3- ( (3Z, 6Z) -l-methyl-2, 5-dioxo-6- (3-phenylpropylidene) -3- piperazinylidene)methylbenzamide (9266)
N- (2- (6, 7-Dimethoxy-l, 2, 3,4-tetrahydro-2-isoquinolyl) ethyl) 4- { (3Z, 6Z) -l-methyl-2, 5-dioxo-6- (3-phenylpropylidene) -3- piperazinylidene)methylbenzamide (9267)
N- (4- (2- (6, 7-Dimethoxy-1,2, 3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3-((3Z,6Z)-6- (4-acetoxybenzylidene) -l-methyl-2 , 5-dioxo-3- piperazinylidene)methylbenzamide (9272)
N- (4- (2- (6, 7-Dimethoxy-1,2, 3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z,6Z) -6- (3-acetoxybenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene) ethylbenzamide (9273)
N- (4- (2- (6, 7-Dimethoxy-1,2, 3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3- ( (3Z,6Z) -6- (2-acetoxybenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9274)
N- (4- (2- (6, 7-Dimethoxy-1, 2,3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3- ( (3Z, 6Z) -6-benzylidene-1- (2-dimethylaminoethyl) -2, 5-dioxo- 3-piperazinylidene)methylbenzamide (9275)
N- (4- (2- (6, 7-Dimethoxy-1,2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3-((3Z,6Z)-6- (4-hydroxybenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9276)
N- (4- (2- (6, 7-Dimethoxy-1, 2,3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3- ( (3Z, 6Z) -6-benzylidene-l-ethoxycarbonylmethyl-2, 5-dioxo-3 piperazinylidene)methylbenzamide (9299)
N- (4- (2- (6, 7-Dimethoxy-1,2, 3 , 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3-((3Z,6Z)-6- (2-hydroxybenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene) methylbenzamide (9300)
N- (4- (2- (6, 7-Dimethoxy-1, 2,3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3- ( (3Z, 6Z) -6- (3-hydroxybenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9301) N- (4- (2- (6, 7-Dimethoxy-1,2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) -
3- ( (3Z, 6E) -l-methyl-6-pentylidene-2, 5-dioxo-3* piperazinylidene)methylbenzamide (9306)
N- (4- (2- (6, 7-Dimethoxy-1,2, 3, 4-tetrahydro-2- isoquinolyl) ethyl)phenyl) - 3- ( (3Z) -l-methyl-6-benzyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9308)
Compounds of formula (I) may be prepared by a process which comprises treating a compound of formula (II) :
wherein R1, R2 and are as defined above, with a compound of formula (III) :
wherein one of R7 and R8 is hydrogen and the other is -CHO, and q, r, R5 and R6 are as defined above; in the presence of a base in an organic solvent; and, if desired, converting the resulting compound into a pharmaceutically acceptable salt
SUBSTITUTESHEET S P2S) thereof .
Suitable bases include caesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium t- butoxide and triethylamine. Suitable organic solvents include dimethylformamide
(DMF) , tetrahydrofuran (THF) and, in the case of potassium t-butoxide, t-butanol and mixtures thereof.
When DMF is used as solvent the temperature is typically between 0°C and reflux temperature, for example from 80°C-95°C when caesium carbonate is used as base.
When sodium hydride or potassium t-butoxide is used as the base the reaction mixture is typically warmed from 0°C to room temperature, or to 40°C. The reaction may be performed for a period of 1 to 4 hours, for example 2 or 3 hours. The compounds of formula (II) wherein is a double bond are prepared by a process which comprises treating a compound of formula (IV) :
wherein R1 is as defined above, with an alkylating agent, in an organic solvent in the presence of a base. The alkylating agent is typically an alkyl halide R2-CH2X, a methanesulphonate or p-toluenesulphonate ester R2CH2OS02Me or R2CH2OS02C6H4Me, respectively, or a dialkyl sulphate (R2CH20) 2S02, wherein R2 is as defined above and X is a halogen, for instance Cl Br or I. Suitable bases and solvents include sodium hydride in THF or DMF or mixtures thereof, and potassium t-butoxide in t-butanol or THF or DMF or mixtures thereof. The reaction mixture is typically warmed from 0°C to room temperature.
Compounds of formula (II) wherein is a single bond may be prepared by treating a compound of formula (X) :
wherein R1 is as defined under (i) above and R2 is as defined above with acetic anhydride. The reaction is typically performed under reflux, for instance for 1 to 6 hours, typically 3 hours. The compound of formula (X) may be prepared by treating a compound of formula (XI) :
with glycine methyl ester hydrochloride and triethylamine in a solvent, typically CHC13, at a low temperature, typically -50°C to -70°C, preferably -65°C, for 1 to 6 hours. This is followed by warming to room temperature overnight. The reaction mixture is then refluxed in a solvent such as toluene for 12-18 hours, typically 16 hours, to give the desired compound of formula (X) .
The compounds of formula (XI) may be prepared by treating a compound of formula (XII) :
with phosgene in THF at 0°C, followed by warming to room temperature overnight. Compounds of formula (IV) may be prepared by a process which comprises treating 1,4-diacetyl-2, 5-piperazinedione of formula (V) :
with an aldehyde of formula:
R'-CHO
wherein R1 is as defined above, in the presence of a base in an organic solvent .
Suitable bases and solvents include triethylamine, caesium carbonate, sodium carbonate, potassium carbonate and sodium hydride in DMF or THF or mixtures thereof, and potassium t-butoxide in t-butanol or DMF or THF or mixtures
SUBSTITUTE 3HEET fR! ^F 2 thereof .
When triethylamine in DMF is used the temperature of the reaction is typically from 100-140°C, for instance 120- 130°C. When potassium t-butoxide is used as base the reaction mixture is typically warmed from 0°C to room temperature.
1, 4-Diacetyl-2, 5-piperazinedione may be prepared by the published procedure (S.M. Marcuccio and J.A. Elix, Aust. J. Chem. , 1984, 37, 1791) .
Compounds of formula (III) may be prepared by a process which comprises
(i) reacting together compounds of the following formulae (VI) and (VII) :
wherein q, R5 and R6 are as defined above and X is a halogen, in the presence of a base in an organic solvent;
(ii) reducing the resulting compound of formula (VIII) :
SUBSTITUTE ShLEτ (R ϊ 26) wherein q, R£ and R6 are as defined above; and
(iii) treating the resulting compound of formula (IX) :
wherein q, R5 and R6 are as defined above, and r is 1, with
(a) either 3-formylbenzoic acid in the presence of a coupling agent, or a derivative of 3-formylbenzoic acid in which the -COOH group has been activated by conversion to the acid halide group -COX in which X is a halogen, for instance F, Cl, Br or I, preferably Cl, or the mixed anhydride group -CO(OCOR') in which R' is alkyl; in both cases to give a compound of formula (III) wherein R7 is hydrogen and Re is -CHO; or
(b) 4-formylbenzoic acid in the presence of a coupling agent, or a derivative of 4-formylbenzoic acid in which the -COOH group has been activated by conversion to the acid halide group -COX in which X is a halogen, for instance F, Cl, Br or I, preferably Cl, or the mixed anhydride group
-CO(OCOR') in which R' is alkyl; in both cases to give a compound of formula (III) wherein R7 is -CHO and R8 is hydrogen.
When the 3- or 4-formylbenzoic acid has been activated by conversion of -COOH to -COX, the reaction is conducted in an organic solvent either with an excess of the amine of formula (IX) , or in the presence of a base such as a tertiary amine, e.g. Et3N, or pyridine. The organic solvent is an inert organic solvent such as CH2C12.
When the 3- or 4-formylbenzoic acid has been activated by conversion of -COOH to -CO(OCOR') , the reaction with the compound of formula (IX) is conducted in an inert organic solvent such as CH2C12 or THF.
The coupling agent used in (a) or (b) with the 3- or 4- formylbenzoic acid, respectively, may be, for instance, 1- cyclohexyl-3- (2-morpholinoethyl) carbodiimide metho-p- toluenesulphonate or 2-chloro-l-methylpyridinium iodide.
The activated acid halide or mixed anhydride derivative of 3- or 4-formylbenzoic acid may be produced by conventional methods. For instance, the acid halide derivative may be prepared by treatment of the carboxylic acid with a halogenating agent, for instance a chlorinating agent such as SOCl2, PC13, oxalyl chloride or PC15. The mixed anhydride derivative may be prepared by treatment of the carboxylic acid with a Cj-Cg alkyl haloformate such as iBuOCOCl or EtOCOCl , in the presence of a base such as Et3N. The reduction step (ii) is typically performed using iron powder and concentrated hydrochloric acid in methanol, usually at a temperature of about 80°C and for a period of 1 to 4 hours, for instance 3 hours. Alternatively it may be carried out by catalytic hydrogenation over a palladium on carbon catalyst in methanolic HCl, isopropanol or acetic acid.
Other starting compounds are known compounds or can be readily synthesised from known compounds using conventional methods .
Compounds of formula (I) may be converted into pharmaceutically acceptable salts, and salts may' be converted into the free compound, by conventional methods. Suitable salts include salts with pharmaceutically acceptable inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid. Examples of organic acids include -toluenesulphonic acid, methanesulphonic acid, mucic acid and succinic acid.
Cancer cells which exhibit multi-drug resistance, referred to as MDR cells, display a reduction in intracellular drug accumulation compared with the corresponding drug-sensitive cells. Studies using jLn vitro derived MDR cell lines have shown that MDR is often associated with increased expression of a plasma membrane glycoprotein (P-gp) which has drug binding properties. P-gp is thought to function as an efflux pump for many hydrophobic compounds, and transfection studies using cloned P-gp have shown that its overexpression can confer the MDR phenotype on cells: see, for example, Ann. Rev. Biochem .58. 137-171 (1989) .
A major function of P-gp in normal tissues is to export intracellular toxins from the cell. There is evidence to suggest that overexpression of P-gp may play a clinical role in 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. Inhibition of P-gp function in P-gp mediated MDR has been shown to lead to a net accumulation of anti-cancer agent in the cells. For example, Verapamil a known calcium channel blocker was shown to sensitise MDR cells to Vinca alkaloids .in vitro and jLn vivo: Cancer Res. , 4.1, 1967-1972 (1981) . The proposed mechanism of action involves competition with the anti-cancer agent for binding to the P- gp. A range of structurally unrelated resistance-modifying agents acting by this mechanism have been described such as tamoxifen (Nolvadex: ICI) and related compounds, and cyclosporin A and derivatives.
Compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as "the present compounds") have been found in biological tests to have activity in modulating multi-drug resistance. The results are set out in 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. Such a method comprises, for
SUBSTITUTE ShLEτ (Ft^i. S} instance, administering one of the present compounds to the tumour cell whilst the tumour cell is exposed to the cytotoxic agent 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. Such a method comprises, for instance, administering one of the present compounds with (separately, simultaneously or sequentially) the drug to which the pathogen concerned exhibits multi-drug resistance. The therapeutic effect of the drug may thus be enhanced.
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. Examples of 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 daunorubicin and doxorubicin; mitoxantrone; actinomycin
l*3S7T>.τE 5H ' -. ' :>f\ D; taxanes e.g. taxol; epipodophyllotoxins e.g. etoposide and plicamycin.
In addition, 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 in 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 treatment of AIDS or AIDS related complex. 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. An agent for use as a modulator of multi-drug resistance comprising any one of the present compounds is therefore provided.
For example, 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. Such 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. In particular, 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 pharmaceutically acceptable carrier 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 .
The invention will be further illustrated in the Examples which follow. Reference Example 1; Preparation of starting compounds of formula (IV) .
Method A
1, 4-Diacetyl-2, 5-piperazinedione (25.0g, 126 mmol) (S.M. Marcuccio and J.A. Elix, loc. cit. ) was heated at 120- 130°C in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol) . After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml) , and washed three times with brine. Any solid formed at this stage was filtered off. The filtrate was dried (MgS04) and the solvent removed in vacuo. The residue was recrystallised from EtOAc:Hexane to give 11.78 g (38%) of l-acetyl-3-benzylidene-2, 5-piperazinedione. This compound of formula (IV) is listed as 1.1 in Table 1 below.
Following the same procedure, but replacing benzaldehyde by the appropriately substituted benzaldehyde Rx-CHO, where R1 is as listed in Table 1A, the further starting compounds 1.2 to 1.10 were prepared:
TABLE 1A: Compounds of formula IV
SUBSTITUTE SHEET (RULE 25\
Method B 1, 4-diacetyl-2, 5-piperazinedione was treated with a series of benzaldehydes R^CHO, where R1 is as listed in table IB, in the presence of potassium t-butoxide in t- butanol-THF (1:1) at 0°C. The reaction mixture was allowed to warm to room temperature for the time indicated in the table. Recrystallisation, which was optional, was conducted using the indicated solvent.
TABLE IB: Compounds of formula (IV)
SUBST'TI E SH" T .T" '■ ' e«
ςjcv -'r; p". ■;,, ,r'rτ <τ» Reference Example 2 ; Preparation of starting compounds of formula (II) wherein is a double bond
Method A l-Acetyl-3-benzylidene-2, 5-piperazinedione, compound
1.1 prepared in Reference Example 1, was treated with ethyl bromide and KOtBu/t-BuOH in DMF at a temperature of about 0°C and allowed to warm to room temperature to give l-acetyl-3- benzylidene-4-ethyl-2 , 5-piperazinedione . This compound of formula (II) is listed as 2.1 in Table 2A below.
Further compounds of formula II were prepared by alkylating compounds 1.2 to 1.10, prepared in Reference Example 1, under the conditions set out in Table 2A:
" ?* Table 2A: Compounds of formula II
Method B
Compound 1.11 described in Reference Example 1 was treated, in THF-DMF (5:1) , with sodium hydride and Mel at 0°C. The reaction mixture was allowed to warm to room temperature for 18 hours. The product was purified by recrystallisation from EtOAc to give the corresponding compound of formula (II) in 40% yield. Following this procedure, but replacing compound 1:11 by other compounds of formula IV described in Reference Example 1, and modifying the reaction time if necessary, the compounds listed in table 2B were prepared. Where indicated, purification was performed by flash chromatography or by recrystallisation as shown in the footnote.
TABLE 2B: Compounds of formula II
:i«
Footnote a = recrystallisation from EtOAc b = flash chromatography with EtOAc-hexane (1:1) c = flash chromatography with CH2C12 d = flash chromatography with Et20-hexane (1:1) e = recrystallisation from EtOAc-hexane
Method C
Compound 1.1, described in Reference Example 1, was treated with Cs2C03 (2eq.) , Me3SiCl (1 eq.) and allyl bromide (1 eq.) in acetonitrile at 0°C. The reaction mixture was allowed to warm to room temperature for 5 hours. Flash chromatography of the product using 20% EtOAc in hexane gave 2.39 in 50% yield, which is a compound of formula (II) in which R2 is -CH=CH2.
Method D
Compound 1.1, described in Reference Example 1, was treated in THF-DMF (5:1) with sodium hydride and methyl bromoacetate at 0°C. The reaction mixture was allowed to warm to room temperature for 3 hours . The product was purified by recrystallisation from EtOAc-hexane to give 2.40 in 35% yield, which is a compound of formula (II) in which R2 is -C02Me.
Method E Compound 1.1, described in Reference Example 1, was treated in DMF with sodium hydride and 2-dimethylaminoethyl chloride hydrochloride at 0°C. The reaction mixture was warmed to 20°C, and then further warmed to 80°C, over a period of 5 hours. The product was purified by recrystallisation from 1% MeOH in EtOAc to give 2.41 in 32% yield, which is a compound of formula (II) wherein R2 is -CH2NMe2.
Method F Compound 1.1, described in Reference Example 1, was treated in acetonitrile with Cs2C03 and ethyl bromoacetate at -20°C. The reaction mixture was warmed to 20°C for 2 hours. The product was purified by flash chromatography using EtOAc-hexane (1:2) to give 2.42 in 35% yield, which is a compound of formula (II) wherein R2 is -C02Et.
Reference Example 3 ; Preparation of a compound of formula (II) wherein is a single bond l-methyl-6-benzyl-2, 5-piperazinedione was treated with acetic anhydride under reflux for 3 hours to give compound 2.43 in 98% yield, which is a compound of formula (II) wherein is a single bond, R1 is Ph and R2 is H.
Reference Example 4: Preparation of 1-methyl-6-benzyl
-2, 5-piperazinedione
Compound (i) was treated with phosgene in THF at 0°C for 15 minutes. The reaction mixture was then warmed to room temperature overnight. The resulting compound (ii) was treated with glycine methyl ester hydrochloride and triethylamine in CHC13 at -65°C for 3 hours. The reaction mixture was allowed to warm to room temperature overnight and was then refluxed for 16 hours in toluene to give the desired product in 53% yield.
Reference Example 5: Preparation of 4- (2- (6,7-
Dimethoxy-1.2.3,4-tetrahydro -2-isoguinolyl) ethyl) aniline (a) The title compound, which is a compound of formula (IX) , was prepared according to the following scheme:
3.4
SUBSTITUTE Snc " ' (RU E 2 255') Compound 3.1 was treated with 3.2 in the presence of K2C03 in DMF, at a temperature of 100°C for 12 hours, to give 3.3 in 78% yield. 3.3 was then reduced with Fe powder in concentrated HCI and MeOH at 80°C for 3 hours to give 3.4 in 51% yield. Alternatively 3.3 was reduced by catalytic hydrogenation at 30psi over a palladium on carbon catalyst in methanolic HCI for 3 hours to give 3.4 in quantitative yield.
(b) Following the synthetic route described under (a) , but replacing compound 3.1 by 4-bromomethylbenzoic acid and 4-'
(3-bromopropyl)benzoic acid, respectively, the following two further compounds of formula (IX) were prepared:
(c) Following the synthetic route described under (a) , but replacing compound 3.2 by 1, 2, 3,4-tetrahydroisoquinoline hydrochloride, the following further compound of formula (IX) was prepared:
SUBSTTIΓΓF SHI v* •; r °^
(d) An amine of formula (IX) in which r is 0, compound 3.10, was prepared as follows:
3.8 3.9
3.10
6, 7-Dimethoxy-1,2,3, 4-tetrahydroisoquinoline hydrochloride (3.8) was treated with chloroacetonitrile in the presence of K2C03 in acetonitrile under reflux for 24 hours. Compound 3.9 was obtained in 92% yield. 3.9 was then treated with LiAlH4 in ethylene glycol dimethyl ether at room temperature overnight. The temperature was then raised to 40°C and the reaction continued for 30 minutes. The desired amine 3.10 was obtained in 98% yield.
SSST'T;."- •; , -*-τ ,,* Example 1: Preparation of compounds of formula
III Method 1
Compound 3.4 prepared according to Reference Example 5 was treated with 2-chloro-l-methylpyridinium iodide and 3- formylbenzoic acid in CH2C12 in the presence of Et3N at a temperature of about 0°C and allowed to warm to room temperature overnight to afford the following compound of formula III in 43% yield:
4.1
Following the same procedure, but replacing compound 3.4 by compounds 3.5 and 3.6, respectively, the following two further compounds of formula III were prepared:
4.3
4.4
*"*.,.f-i^,*»,-- Method 2
4-formylbenzoyl chloride was prepared by treating 4- formylbenzoic acid with thionyl chloride in toluene under reflux. It was then treated with compound 3.4, prepared according to Reference Example 5, in CH2C12 in the presence of Et3N at a temperature of about 0°C and allowed to warm to room temperature, to afford the following compound 4.2 in 53% yield:
4.2
Following the same procedure, but replacing compound 3.4 by compounds 3.5 and 3.7, respectively, the following two further compounds of formula III were prepared:
4.6
VX∞MTE SHEET (RULE 2 Method 3
4-formylbenzoyl chloride, as described in Method 2 above, was treated with Et3N in CH2C12 at a temperature of -20°C. Compound 3.10 prepared according to Reference Example 5 was then added. Following aqueous work-up and purification by flash chromatography, the following compound 4.7 was obtained in 43% yield:
4.7
Following the same procedure, but replacing 4- formylbenzoyl chloride by 3-formylbenzoyl chloride, the following compound 4.8 was obtained in 48% yield:
4.8 Example 2: Preparation of compounds of formula (I)
By reacting together a compound of formula (II) , prepared in Reference Example 2 , and a compound of formula (III) , prepared in Example 1, the following compounds of the invention were prepared under the conditions set out in Table 3A:
Table 3A: Compounds of formula (I)
SUBSTITUTE SHE .' U E
Example 3 : Preparation of salts
The compounds prepared in Example 2 were converted to the corresponding hydrochloride salts by treatment with gaseous HCI in THF.
Example 4: Preparation of compounds of formula (I)
By reacting together a compound of formula (II) , prepared in Reference Example 2 or 3 , and a compound of formula (III) , prepared in Example 1, in DMF at 80°C in the presence of Cs2C03 for the time specified in Table 4, the compounds of formula (I) listed in the Table were prepared. Some of the compounds were purified by recrystallisation or flash chromatography, also as indicated in Table 4. TABLE 4: Compounds of formula (I)
SUSSTITir^ SHEE 'jL- ς,
MβmWE SHEET (RULE 26)
Footnote (a) Recrystallisation solvent
(b) Flash chromatography eluent
Example 5 : Preparation of Salts
Selected compounds prepared in Example 4 were converted to the corresponding hydrochloride salts by treatment with gaseous HCI in CH,Cl2. The hydrochloride, denoted in Table 5 below by the suffix ".HCI" was in some cases then recrystallised as shown in the table.
TABLE 5 : Hydrochloride salts
WTE SHEET (RULE Example 6 : Interconversions of compounds of formula 11
Compounds of formula (I) were prepared by treating selected compounds of formula (I) prepared in Example 4 with appropriate reagents using conventional synthetic techniques, as follows:
1. 9217 was treated with LiOH in aqueous THF at room temperature for 2 hours to give compound 9241.
2. 9272 was treated with NaBH4 in MeOH at 0°C for 2 hours to give compound 9276 in 73% yield.
3. 9274 was treated with NaBH3CN in MeOH and THF at 0°C. The reaction mixture was then warmed to 50°C over 5 hours, and the product recrystallised from 20% EtOH in EtOAc to give compound 9300 in 58% yield.
4. 9273 was treated with NaBH3CN in MeOH and THF at reflux for 7 hours. The product was recrystallised from EtOAc- hexane (1:5) to give compound 9301 in 18% yield.
Example 7 ; Pharmaceutical Composition Tablets, each weighing 0.15 g and containing 25 mg of a compound of formula (I) or salt thereof can be manufactured as follows:
SUBSTITUTE SHEET(RULF26) Composition for 10,000 tablets compound of formula (I) or salt thereof (250 g) lactose (800 g) corn starch (415 g) talc powder (30 g) magnesium stearate (5 g)
The compound of formula (I) or salt thereof, 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 granulate the powder. 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.
Example 8: Testing of compounds of formula (I) and their salts as modulators of MDR
Materials and Methods 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% C02. 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"\ EDTA) . 1. Drug accumulation assay 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 μ Ci/ml; 2μM) . Compounds of formula I were serially diluted in assay medium over a range of concentrations from 5 nM to 100 μM. The cells were incubated at 37°C for 1 hr before washing and determination of cell associated radioactivity. 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 μM or as an ICE0.
The results are set out in the following Table 6.
TABLE 6
2_^_ Potentiation of Doxorubicin toxicity
Compounds of formula (I) were examined for their ability to potentiate the toxicity of doxorubicin in AR 1.0 cells. In initial proliferation assays compounds were titrated against a fixed concentration of doxorubicin
(0.86μM) which alone is non-toxic to AR 1.0 cells. After a four day incubation with doxorubicin proliferation was measured using the colorimetric sulphorhodamine B assay (Skehan et al; J.Natl. Cancer Inst . H pp 1107-1112 (1990)) . The results are shown in Table 7.
Compounds which were shown to be able to sensitise AR 1.0 cells to 0.86μM doxorubicin without high innate toxicity were selected for further study. Cells were cultured for four days with concentrations of doxorubicin over the range of 0.01 nM-50 μM in the presence of fixed concentrations of compounds of formula (I) . Proliferation was quantified as
SLi I ' r SH<- T Ϊ described by Skehan et. al., loc cit. The IC50 (concentration required to reduce proliferation to 50% of the untreated controls) for doxorubicin alone and for the compounds of formula (I) were derived and used to calculate the potentiation index (PI) :
IC50 for Doxorubicin alone
PI=
IC50 for Doxorubicin plus RMA The results are shown in Table 8 :
TABLE 7
■'i £S'.i.:o*X
' X • .α--~*.- -< TABLE 8
^■ rrη rτ i" "f
r*, -r. ** -,
Example 6: Characterisation of the present compounds
The compounds and salts prepared in Examples 1 and 2 were characterised by mass spectroscopic and proton nmr techniques. The results are set out in Tables 9 and 10: TABLE 9
σ-*
H
O
cr> ω
σ* σ
-
<
C
TABLE 10

Claims

A piperazinedione derivative of the formula (I):
wherein
R1 is (i) a group
wherein p is 0 or 2;
each of Ra to Re, which may be the same or different, is independently selected from hydrogen, C1-C6 alkyl
unsubstituted or substituted by one or more halogen atoms, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH2OH,
-CH2COOH, -CO2R11, -NHCOR11, -NHSO2R13, -SO2R13, -CON(R11R12), -SOR13, -SO2N(R11R12) , -N(R11R12), -O (CH2)nN(R11R12), -O (CH2)nCO2R11, -OCOR11, -CH2OCOR11, -CH2NHCOR11, -CH2NHCOOR13, -CH2SR11,
-CH2SCOR11, -CH2S(O)mR13 wherein m is 1 or 2,
-CH2NHCO(CH2)nCO2R11, -N(R11)COR12, -NHCOCF3,
-NHCO(CH2)nCO2R11, -NHCO(CH2)nOCOR11 and -NHCO(CH2)nCO2R11;
wherein n is 0 or is an integer of from 1 to 6, each of R11 and R12 is independently H or C1-C6 alkyl and R13 is C1-C6 alkyl; or any of Ra and Rb, Rb and Re, Re and Rd or Rd and Re together form a methylenedioxy group, or form together with the carbon atoms to which they are attached a benzene ring which is optionally substituted;
(ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S, which group may be fused to a benzene ring;
(iii) a C1-C6 alkyl or C5-C7 cycloalkyl group; or
(iv) a C5-C7 cycloalkenyl group which is unsubstituted or substituted by C2-C6 alkenyl;
R2 is H, C1-C6 alkyl optionally substituted by a group
-N(R11R12) as defined above, C3-C6 cycloalkyl, C2-C6 alkenyl, -COOR11 wherein R11 is as defined above or a phenyl group as defined under (i) above, but is other than H when R1 is unsubstituted phenyl;
one of R3 and R4 is hydrogen and the other is a group of formula (A):
wherein q is an integer of 1 to 4, r is 0 or 1 and R5 and R6, which may be the same or different, are each H or C1-C6 alkoxy, or R5 and R6 together form a methylenedioxy group; and - - - - - - is a double bond or, when R1 is as defined under
(i) above, is a double bond or a single bond; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R1 is a phenyl group as defined under (i) in which one of Ra to Re is selected from hydroxy, C1-C6 alkoxy, NHCOR11, -CO2R11,
-N(R11R12), -O(CH2)nN(R11R12), -SO2R13, -CON(R11R12), NO2,
-SO2N(R1XR12) , -SOR13, -N(R11)COR12 and halogen, and the other four of Ra to Re are H.
3. A compound according to claim 1 or 2 wherein
R1 is a phenyl group as defined under (i) in which each of Ra to Re is hydrogen, or one of Ra, Rb and Re is halogen or C1-
C6 alkoxy and the rest of Ra to Re are hydrogen; or is a pyridyl, furyl or thienyl group;
R2 is H, CH3, cyclopropyl or phenyl; and
one of R3 and R4 is H and the other is a group of formula (A) wherein q is 2 and each of R5 and R6 is a methoxy group.
4. A compound according to claim 1, 2 or 3 wherein R1 is a 4-pyridyl, 3-furyl, 2-thienyl or 3-thienyl group.
5. A compound selected from:
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-ethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9112)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-benzyl-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride
(9113) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-cyclopropylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9114)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3-furylmethylene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,
hydrochloride (9108)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(4-methoxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9109)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(4-chlorobenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9091)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(2- chlorobenzylidene)-1-methyl-2,5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9092)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3- chlorobenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9093)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2,5-dioxo-6-(3-pyridylmethylene)-3-piperazinylidene)methylbenzamide, hydrochloride (9110)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2,5-dioxo-6-(3-1henylidene)-3-piperazinylidene)methylbenzamide, hydrochloride (9111)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5-dioxo-6- (2-thenylidene)-3-piperazinylidene)methylbenzamide (9155)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5-dioxo-6- (3-thenylidene)-3-piperazinylidene)methylbenzamide (9160)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-chlorobenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9157)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-chlorobenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9158) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyDphenyl)-3-((3Z,6Z)-6-(3-furylmethylene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide ( 9159)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyDphenyl)-3-((3Z,6Z)-6-(3-methoxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9156)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-ethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9139)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-cyclopropylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9141)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyDphenyl)- 4-((3Z,6Z)-1-allyl-6-benzylidene-2,5-dioxo-3- piperazinylidene)methylbenzamide (9178) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-1-allyl-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9179)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyDphenyl)- 4-{(3Z,6Z)-1-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9193)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-6-(1-naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9194)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-1-methyl-6-(1-naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide ( 9195 )
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-6-(2-furyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide ( 9196 )
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(2-furyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9197)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-6-(1-methyl-3-pyrrolyl)methylene-2,5-dioxo- 3 -piperazinylidene) methylbenzamide ( 9198)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyDphenyl)- 3-((3Z,6Z)-1-methyl-6-(1-methyl-3-pyrrolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9199)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9209)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-6-(1-methyl-3-indolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9210)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyDphenyl)- 3-((3Z,6Z)-1-methyl-6-(3-methylbenzo(b)thien-2-yl)methylene- 2,5-dioxo-3-piperazinylidene)methylbenzamide (9211) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-1-methyl-6-(1-methyl-3-indolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9214)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-6-(3-methylbenzo(b)thien-2-yl)methylene- 2,5-dioxo-3-piperazinylidene)methylbenzamide (9215)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-{(3Z,6Z)-6-benzylidene-1-methoxycarbonylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9217)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-6-(2-methylpropylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9228)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-6-cyclohexylmethylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9229)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-1-methyl-6-cyclohexylmethylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9230)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-1-methyl-2,5-dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9231)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- -3-((3Z,6Z)-1-methyl-2,5-dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9232)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-{(3Z,6Z)-1-methyl-6-(2-methylpropylidene)- 2 ,5-dioxo-3-piperazinylidene)methylbenzamide (9233)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-6-(3,3-dimethylbutylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9234)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(3,3-dimethylbutylidene)-1-methyl-2,5-dioxo-3 piperazinylidene)methylbenzamide (9235) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-6-((4S)-4-isopropenyl-1-cyclohexenyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9236)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-benzylidene-1-carboxymethyl-2 ,5-dioxo-3-piperazinylidene)methylbenzamide (9241)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-((4S)-4-isopropenyl-1-cyclohexenyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9250)
N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)3-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9260) N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)4-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9261)
N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)3-((3Z,6Z)-1-methyl-2,5-dioxo-6-(3-phenylpropylidene)-3-piperazinylidene)methylbenzamide (9266) N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-1-methyl-2,5-dioxo-6-(3-phenylpropylidene)-3-piperazinylidene)methylbenzamide (9267) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyDphenyl)- 3-((3Z,6Z)-6-(4-acetoxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9272) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(3-acetoxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9273) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(2-acetoxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9274) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-benzylidene-1-(2-dimethylaminoethyl)-2,5-dioxo- 3-piperazinylidene)methylbenzamide (9275) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(4-hydroxybenzylidene)-1-methyl-2,5-dioxo-3- piperazinylidene)methylbenzamide (9276)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-ethoxycarbonylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9299)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-hydroxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9300)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-hydroxybenzylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9301)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6E)-1-methyl-6-pentylidene-2,5-dioxo-3-ppperazinylidene)methylbenzamide (9306)
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z)-1-methyl-6-benzyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9308)
6. A pharmaceutical or veterinary composition comprising a pharmaceutically acceptable carrier or diluent and, as an active principle, a compound as claimed in any one of the preceding claims .
7. A process for producing a compound as defined in claim 1, which process comprises treating a compound of formula (II)
wherein R1, R2 and - - - - - are as defined in claim 1, with a compound of formula (III):
wherein one of R7 and R8 is hydrogen and the other is -CHO, and q, r, R5 and R6 are as defined in claim 1; in the presence of a base in an organic solvent; and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof.
8. A compound as defined in any of claims 1 to 5 for use as a modulator of multi-drug resistance.
9. Use of a compound as defined in any one of claims 1 to 5 in the manufacture of a medicament for use as a modulator of multi-drug resistance.
10. A compound of formula III:
wherein q, r , R5 and R6 are as def ined in claim 1 , one of R7 and R8 is hydrogen and the other of R7 and R8 is -CHO .
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SK83697A3 (en) 1998-05-06
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FI972660A0 (en) 1997-06-19
BR9510410A (en) 1999-09-08
WO1996020190A1 (en) 1996-07-04
CA2207500A1 (en) 1996-07-04
JPH10511384A (en) 1998-11-04
NZ297847A (en) 1999-04-29
PL320916A1 (en) 1997-11-10
GB9426224D0 (en) 1995-02-22
HUT77943A (en) 1998-12-28
NO972937L (en) 1997-06-23
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AU698828B2 (en) 1998-11-05
FI972660A (en) 1997-08-22

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