NZ297847A - Piperazine-2,5-dione derivatives and their use as medicaments - Google Patents

Piperazine-2,5-dione derivatives and their use as medicaments

Info

Publication number
NZ297847A
NZ297847A NZ297847A NZ29784795A NZ297847A NZ 297847 A NZ297847 A NZ 297847A NZ 297847 A NZ297847 A NZ 297847A NZ 29784795 A NZ29784795 A NZ 29784795A NZ 297847 A NZ297847 A NZ 297847A
Authority
NZ
New Zealand
Prior art keywords
phenyl
ethyl
dimethoxy
tetrahydro
methylbenzamide
Prior art date
Application number
NZ297847A
Inventor
Philip Anthony Ashworth
Sukhjit Hunjan
Ian Andrew Pretswell
Hamish Ryder
Stephen James Brocchini
Original Assignee
Xenova Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xenova Ltd filed Critical Xenova Ltd
Publication of NZ297847A publication Critical patent/NZ297847A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number £97847 New Zealand No 297847 International No PCT/GB95/03027 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 23 12 1994, Complete Specification Filed 22 12 1995 Classification (6) C07D401/12.14, C07D217/04, C07D405/14, C07D409/14, C07D241/02, A61K31/495 Publication date 29 Apnl 1999 Journal No 1439 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention Piperazine 2,5 dione derivatives as modulators of multi-drug resistance Name, address and nationality of applicant(s) as in international application form XENOVA LIMITED, a British body corporate of 240 Bath Road, Slough, Berkshire SL1 4EF, United Kingdom O 96/20190 PCT/GB95/03027 297 8 4 PIPERAZINE 2,5 DIONE DERIVATIVES AS MODULATORS OF MULTI-DRUG RESISTANCE The present invention relates to compounds useful as modulators of multl-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 m 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 m previous treatments of the tumour Analogously, certain pathogens may acquire resistance to pharmaceutical agents used m 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 m the mechanism which underlies MDR P-gp has drug binding properties Certain agents which have the capacity to SUBSTITUTE SHtET (RULE 26) O 96/20190 modulate MDR may therefore also be useful m facilitating the delivery of drugs across the blood brain barrier, and m 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 mult1-drug resistance The present invention therefore provides a piperazinedione derivative of formula (I): wherein O Rj is (1) a group (I) -(CHdp—^ Rc \ 6 5/ Re Rd wherein p is 0 or 2, each of Ra to Re, which may be the same or different, is independently selected from hydrogen, Cl-C6 alkyl unsubstituted or substituted by one or more halogen atoms, Cj-Cs alkenyl, Cj-Cg alkoxy, C,-C6 alkylthio, halogen, hydroxy, SUBSTITUTE SHEET (RULE 26) 0 96/20190 PCT/GB95/03Q27 mtro, optionally substituted phenyl, cyano, -CH20H, -CH.COOH, - COjR11, -NHCOR11, -NHS02R13, -S02R13, - CON (R1XR12) , -SOR13, -SOrN(R11R12) , -N (RnR12) , -0 (CH2) nN (RX1R12 ) , -O (CH2) nC02Rn, -OCOR11, - CH20C0R1:i , -CHjNHCOR11, -CH2NHCOOR13, -CH2SR", -CH:SCORla, -CH2S (O) mR13 wherein m is 1 or 2, - CH2NHC0 (CH2) hCC^R11 , -N (R11) COR12 , -NHCOCF3, -NHCO (CH2) nCC^R11, -NHCO (CH2) nOCOR11 and -NHCO (CH2) nC02R:L1, 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 Cj-Cg alkyl, or any of Ra and Rb, Rb and Rc, Rc 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, (n) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from 0, N and S, which group may be fused to a benzene ring; (in) a Cx-C6 alkyl or C5-C7 cycloalkyl group, or (iv) a C5-C7 cycloalkenyl group which is unsubstituted or substituted by C2-Cf alkenyl, R2 is H, C1-C6 alkyl optionally substituted by a group -N(R11R12) as defined above, C3-C6 cycloalkyl, C2-C6 alkenyl, -C00R11 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 R" is hydrogen and the other is a group of formula (A) SUBSTITUTE SHEET (RULE 26) O 96/20190 4 —C-NH O II R5 R6 (A) wherein q is an integer of 1 to 4, r is 0 or 1 and R5 and Rfc, which may be the same or different, are each H or Ca-C6 alkoxy, or R5 and R6 together form a methylenedioxy group, (a) above, is a double bond or a single bond, or a pharmaceutically acceptable salt thereof A Cj-C6 alkyl group may be linear or branched A C^-Cg alkyl group is typically a Cj-C^ alkyl group, for example a methyl, ethyl, propyl, l-propyl, n-butyl, sec-butyl or tert-butyl group A C,-C6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl A halogen is, for example, fluorine, chlorine, bromine or iodine A Cj-Cj alkoxy group is typically a C^-Q, alkoxy group, for example a methoxy, ethoxy, propoxy, l-propoxy, n-butoxy, sec-butoxy or tert-butoxy group A C2-C6 alkenyl group is, for example, C2-C4 alkenyl, for example ethenyl, prop-l-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 and is a double bond or, when is as defined under SUBSTITUTE SHEET (RULE 26) •v O 96/20190 PCT/GB95/03Q27 R5 and Rfc are preferably the same and are preferably Cx-C4 alkyl, for instance methyl When R1 is as defined under (1) above, the phenyl group is unsubstituted or is substituted at one or more of 5 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 Rc, especially Rc When the phenyl group is mono-substituted 10 the substituent Ra to Re is preferably selected from a halogen, for instance chlorine, bromine or fluorine, a C^-Cg alkoxy group, for instance OMe, and an acetamido group -NHAc m which Ac denotes acetyl The phenyl group may instead be 2,3-, 2,4-, 2,5-, 2,6-, 15 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 Rc, or Ra and Rd, or Ra and Re, or Rb and Rc, or Rb and Rd are other than hydrogen whilst, 20 m each case, the other three of Ra to Re are hydrogen When the phenyl group is trisubstituted, two of Ra to Rc are hydrogen and three are other than hydrogen For example, Ra, Rb and Rc, or Ra, Rb and Rd, or Ra, Rb and Re, or Rb, Rc and Rd are other than hydrogen whilst, m each 25 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 SUBSTITUTE SHEET (RULE 26) O 96/20190 compounds, one of Ra to Re is selected from hydroxy, Ca-C6( alkoxy, NHCOR11, -CO^R11, -N(RUR12), -0 (CH2) nN (R11R1~) , -SO.R13, -CON (R11R12) , N02, -S02N(R11R12) , -SOR13, -NfR^JCOR1- and halogen and the other four of Ra to Re are H Alkoxy may be, for instance, OMe or OBun. NHCOR11 is typically -NHAc CO^R11 is typically -C00H or -COOMe. NtR^R12) is typically NMe2 -CON (RnR12) may be -CONH2 S02R13 is typically S02Me, S02N (R11Ri2) is for example -S02NMe2 SOR13 may be SOMe and -N (R11) COR12 may be -NMeCOBuc Halogen is typically F or CI Preferably Rc is alkoxy, especially OMe or OBun, NHCOR11, especially -NHAc, -CO^11, especially -C02H or -C02Me, - CON (R11Rx2) especially -C0NH2, N02/ N(RX1R12) especially NMe2, -SOR13 especially -SOMe, -S02N (R11R12) 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 Rc is other than hydrogen Alcernatively Ra and Rc, or Rb and Rc, are other than hydrogen Preferred values for the one or two of Ra to Re which is or are other than hydrogen include Cj-Cg alkoxy such as OMe or OBun, halogen such as Cl or F, hydroxy, -N(R11R12), - C02R1x , -CH.SCOR13, -CH2SRn, -NHCOR11, -0 (CH2) nN (RX1R12) , -OfCHj^COaR11, -CH2NHC0 (CH2) jjCOjR11 , -NHC0CH20RU , -NHC0CH20C0R13, -CH2NHC00R13 and CF3 Particularly preferred compounds are those wherein Ra, ^TIME SHEET (RULE 26) O 96/20190 Rb, Rd and Re are each H, and Rc is selected from H, OMe -NHAc, -CO,H, -C02Me, -CONH2, N02, -NMe2, S02Me, -SOMe and -S02NMe;, Also preferred are compounds wherein Ra to Re are preferably each independently selected from H, halogen, hydroxy, C1-Ct alkoxy, nitro, -CH2SC0R13, -CH2SR11, -COjR11, -OCOR13, CF3, -0(CH,)nN(RnR12) , -O (CH2) nCOjR11, -CHjNHCOtCHjJnCOjR1', -NHCO (CH2) nORxl, -N (R11R12) , -NHCO (CH2) nOCORi:, -NHCO (CH2)nC02R" and -CH2NHC02R13 or Ra and Rb, Rb and Rc, Rc 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, Rc is H, hydroxy, -0 (CH2) nN (RX1R12) , -OCOR13, -0(CH2)_C02R1\ -CH2NKC0(CH2) nC02R", Ci-Cg alkoxy, -NHCO(CH2)nOR", -NHCOtCH^nOCOR11, -N (R11R12) , -CH2NHC02R13, -CH2SR-- or -NHCOR11, Rd is H, halogen, Cj-C6 alkoxy, -CH2SC0Ri:, -CH^R11 or -C02Rxl; and Re is H, nitio 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 oi 4 by Cl or MeO, or is a pyridyl, furyl or Substitute sheet 2si O 96/20190 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 C1~Cii alkyl, preferably methyl, or is phenyl or cyclopropyl, 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 third embodiment R1 is substituted phenyl as defined above or a furyl, thienyl or pyrxdyl 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, thienyD 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 Cj-C, 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 m 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-Dimethox>-1,2,3,4-tetrahydro-2- SUBSTJTUTc SHE£T *} WO 96/20 'C PCT/GB9S/03027 isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-l-ethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9112) N- (4- (2 - (6,7-Dimethory-l,2,3,4-tetrahydro-2- lsoqumolyl) ethyl) phenyl) -4- ( (3Z, 6Z) - 1-benzyl-6-benzylidene 2,5-dioxo-3-piperazmylidene)methylbenzamide, hydrochloride (9113) N- (4 - (2 - ( 6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)-4-((3Z,6Z)- 6-benzylidene-1-cyclopropylmethyl-2,5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9114) N- (4- (2-(6,7-Dimethoxy-l,2,3,4-tetrahvdro-2-lsoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3-furylmethylene)-1 methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (910 8) N- (4- (2 - (6,7-Dimethoxy-l,2,3,4-tetrahydro-2-isoqumolyl) ethyl) phenyl) -4- ( (3Z, 6Z) -6- (4-methoxybenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene)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- SUBSTITUTE SHEET (RULE 26) O 96/20190 pxperazinylxdere)methylbenzamide, hydrochloride (9091) N-(4-(2 - (6, 7-Dir.ethoxy-l ,2,3, 4-tetrahydro-2-isoquinolyl)etayl)phenyl)-4-((3Z,6Z)-6-(2-chlorobenzylu dene)-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-pipev mylidene)methylbenzamide, hydrochloride (9093) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) 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-isoqumolyl) ethyl) phenyl) - 4- ( (3Z, 6Z) - l-methyl-2 , 5-dioxo-6 (3 -1henylidene) - 3 -piperazmylidene) methylbenzamide, hydrochloride (9111) N-(4-(2-(6,7-Dimethoxy-l,2,3, 4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-l-methyl-2,5-dioxo-6 (2-thenylidene)- 3-piperazinylidene)methylbenzamide (9155) N-(4- (2 -(6,7-Dimethoxy-l,2,3, 4-tetrahydro-2- SUBSTITUTE SHEET (RULE 26) O 96/20190 isoquinolyl)ethyl)phenyl)-3 - ((3Z,6Z)-l-methyl-2,5-dioxo-6-(3-thenylidene)-3-piperazinylidene)methylbenzamide (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-lsoquinolyl)ethyl)phenyl)-3 -((3Z, 6Z)-6-(2-chlorobenzylldene) -l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9158) N- (4-(2-(6 7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) -3- ( (3Z, 6Z) -6- (3-furylmethylene) -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-l-ethyl 2,5-dioxo-3-piperazinylidene)methylbenzamide (9139) N-(4 -(2 -(6,7-Dimethoxy-l,2,3,4-tetrahydro-2- SUBSnnJTE SHEET rRIHE 26) O 96/20190 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-lsoquinolyl)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)-l-allyl-6-benzylidene-2,5-dioxo-3-piperazmylidene) methylbenzamide (917 9) N- (4- (2- (6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 4-((3Z,6Z)-l-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9193) N- (4- (2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 4-((3Z,6Z)-l-methyl-6-(1-naphthyl)methylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9194) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoqumolyl) ethyl)phenyl) - 3-((3Z,6Z)-l-methyl-6-(1-naphthyl)methylene-2,5-dioxo-3- 7iji l hnLi7 (RVr ,¥•) O 96/20190 piperazinylidene)methylbenzamide (9195) N- (4- (2 - (6 , 7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 4-((3Z,6Z)-6-(2-furyl)methylene-l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9196) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3-((32,6Z)-6-(2-furyl)methylene-1-mathyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9197) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-l-methyl-6-(1-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-(1-methyl-3-pyrrolyl)methylene-2,5-dioxo-3-piperazmylidene)methylbenzamide (9199) N-(4 -(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3 -((3Z,6Z)-l-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazmylidene)methylbenzamide (9209) SUBSTITUTE SHEET (RULE 26) N-(4-(2 - (6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 4-( (3 Z,6Z)-l-methyl-6-(1-methyl-3-mdolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9210) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3-((3Z,62)-l-methyl-6-(3-methylbenzo(b)thien-2-yl)methylene 2 , 5-dioxo-3-piperazmylidene) methylbenzamide (9211) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3 - ( (3Z, 62) - l-methyl-6 - (1-methyl-3-mdolyl) methylene-2, 5-dioxo-3-piperazinylidene)methylbenzamide (9214) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)- 4-( (3Z,6Z)-l-methyl-6- (3-methylbenzo(b)thien-2- yl)methylene 2,B-dioxo-3-piperazinylidene)methylbenzamide (9215) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)- 3 -((3Z,6Z)-6-benzylidene-1-methoxycarbonylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9217) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- SUBSTITUTE SHEET (RULE 26) O 96/20190 4-( (3 Z,6Z)-l-methyl-6-(2-methylpropylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9228) N- (4- (2 - (6,7-Dimethoxy-l,2,3,4-tetrahydro-2-5 isoquinolyl)ethyl)phenyl)- 4 -((3Z,6Z)-1-methyl-6-cyclohexylmethylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9229) N- (4 - (2 - (6 ,7-Dimethoxy-1,2,3,4-tetrahydro-2-10 isoquinolyl)ethyl)phenyl)- 3 -((3Z,6Z)-l-methyl-6-cyclohexylmethylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9230) N- (4- (2- (6,7-Dimethoxy-l,2,3,4-tetrahydro-2-15 isoquinolyl)ethyl)phenyl)- 4 - ( (3Z,6Z)-l-methyl-2,5-dioxo-6-pentylidene-3 ■ piperazinylidene)methylbenzamide ( 3231) N- (4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-20 isoquinolyl)ethyl)phenyl)- -3 -( (3Z,6Z)-l-methyl-2,5-dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9232) N- (4 - (2 - (6,7-Dimethoxy-l,2,3,4-tetrahydro-2-2 5 isoquinolyl)ethyl)phenyl)- 3-(<3Z,6Z)-l-methyl-6-(2-methylpropylidene)-2,5-dioxo-3-piperazmylidene) methylbenzamide (9233 ) SUBSTtTdTE SnEEr (Wil? 2F) N-(4 -(2-(6,7-Dimethoxy-l,2,3,^-tetrahydro-2-isoquxnolyl)ethyl)phenyl)- 4 - ( (3Z,6Z)-6-(3,3-dimethylbutylidene)-l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide ( 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 (923 5) N-(4 -(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-isoqumolyl) ethyl) phenyl) - 4- ( (3Z, 6Z) -6- ( (AS) -4-isopropenyl-l-cyclohexenyl) tnethylene-1 methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9236) N-(4 -(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-benzylidene-1-carboxymethyl-2,5-dioxo-3-piperazmylidene) 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)methy]ene-1 methyl-2,5-dioxo-3-piperazmylidene)methylbenzamide (9250) N-(2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 3-( (3Z,6Z)-l-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3- SUBSTmfTE SHEP O 96/20190 PCT/GB9S/03027 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-piperazmylidene)methylbenzamide (9261) N-(2-(6, 7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 3-((3 Z,6Z)-l-methyl-2,5-dioxo-6-(3-phenylpropylidene)-3-piperazmylidene) methylbenzamide (9266) N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 4-((3 Z,6Z)-l-methyl-2,5-dioxo-6-(3-phenylpropylidene)-3-piperazmyl idene) methylbenzamide (9267) N-(4 - (2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoquinolyl)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-lsoquinolyl)ethyl)phenyl)- 3-((3Z, 6Z)-6-(3-acetoxybenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (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- SUBST1TUTE SHEET (RULE 26) O 96/20190 piperazinylidene)methylbenzamide (9274) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4 -tetrahydro-2-isoqumolyl) ethyl) phenyl) - 3- ( (3Z, 6Z) -6-benzylidene-l- (2-dimethylammoethyl) -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-lsoquinolyl)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-lsoqumolyl) ethyl) phenyl) - 3- ( (3Z,6Z) -6- (2-hydroxybenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene) mechylbenzamide (9300) N-(4- (2- (6,7-Dimethoxy-1, 2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3-( (3Z,6Z)-6-(3-hydroxybenzylidene)-l-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9301) SUBSTITUTE SHEET (RULE 26) O 96/20190 N-(4 -(2 -(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoqumolyl) ethyl)phenyl) - 3-((3Z,6E)-1-methyl-6-pentylidene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9306) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)-3-((3Z)-1-methyl-6-benzyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (93 08) Compounds of formula (I) may be prepared by a process which comprises treating a compound of formula (II) O ,Ac (ii) wherein R1, R2 and are as defined above, with a compound of formula (III) (CH2)q (m) wherein one of R1 and R8 is hydrogen and the other is -CHO, and q, r, R5 and R6 are as defined above, m tiie presence of base m an organic solvent, and, if desired, converting the resulting compound into a pharmaceutically acceptable salt sussmre sheet (im 26) •w O 96/20190 PCT/GB9S/03027 t thereof Suitable bases include caesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium t-butoxide and tnethylamme 5 Suitable organic solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and, m 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 10 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 4 0°C The reaction may be performed for a period of 1 tc 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) O ^ *NAc nr. J ( IV ) wherein R1 is as defined above, with an alkylating agent, m an organic solvent m the presence of a base The 25 alkylating agent is typically an alkyl halide R2-CH2X, a methanesulphonate or p-toluenesulphonate ester R2CH20S02Me or R2CH20S02C6H4Me, respectively, or a dialkyl sulphate SUBSTITUTE SHEET (RULE 26) O 96/20190 (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 m 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) O (X) o wherein R1 is as defined under (l) 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) O r2 i o (xi) r o with glycine methyl ester hydrochloride and triethylamine m a solvent, typically CHC13, at a low temperature, typically -50°C to -70°C, preferably -65°C, for 1 to 6 hours This is 25 followed by warming to room temperature overnight The reaction mixture is then refluxed m a solvent such as toluene for 12-18 hours, typically 16 hours, to give the SUBSTITUTE SHEET (RULE 26) O 96/20190 PCT/GB95/03027 desired compound of formula (X) The compounds of formula (XI) may be prepared by treating a compound of formula (XII) R1/ ^co2H r2. j|h (x» ) with phosgene m 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) O o with an aldehyde of formula R^CHO wherein R1 is as defined above, m 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 ffRF 2ft O 96/20190 23 thereof When triethylamine in DMF is used the temperature of the reaction is typically from 100-140°C, for instance 120-13 0°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 (l) reacting together compounds of the following formulae wherein q, R5 and R6 are as defined above and X is a halogen, m the presence of a base m an organic solvent; (n) reducing the resulting compound of formula (VIII): (VI) and (VII) (VI) (CHsOq-f (VIII) NOg SlSSTITI'TE ShLtT (RLi_Z 26) •t O 96/20190 PCT/GB95/03027 wherein q, R5 and R6 are as defined above, and (111) treating the resulting compound of formula (IX) R5 (IX) H2N' wherein q, R5 and R6 are as defined above, and r is 1, with (a) either 3-formylbenzoic acid m the presence of a coupling agent, or a derivative of 3-formylbenzoic acid m which the -COOH group has been activated by conversion to the acid halide group -COX m which X is a halogen, for instance F, Cl, Br or I, preferably Cl, or the mixed anhydride group -CO(OCOR') m which R' is Cj-Cg alkyl, in both cases to give a compound of formula (III) wherein R7 is 15 hydrogen and Re is -CHO; or (b) 4-formylbenzoic acid m the presence of a couplmq agent, or a derivative of 4-formylbenzoic acid in which the -COOH group has been activated by conversion to the acid halide group -COX m which X is a nalogen, for instance F, Cl, Br or I, preferably Cl, or the mixed anhydride group -CO(OCOR') m which R' is C^-C^ alkyl, m both cases to gave a compound of formula (III) wherein R7 is -CHO and R8 is hydrogen.
When the 3- or 4-formylbenzoic acid has been activated 2 5 by conversion of -COOH to -COX, the reaction is conducted m an organic solvent either with an excess of the amine of formula (IX), or m the presence of a base such as a SUBSTITUTE SHEET (RULE 26) 0 96/20190 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 m an inert organic solvent such as CH2Cl2 or THF The coupling agent used m (a) or (b) with the 3- or 4-formylbenzoic acid, respectively, may be, for instance, 1-cyclohexyl-3- (2-morpholmoethyl) carbodnmide metho-p-toluenesulphonate or 2-chloro-l-methylpyndinium 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 halogenatmg agent, for instance a chlorinating agent such as S0C1_,, 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 (n) 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 m methanolic HCl, isopropanol or acetic acid Other starting compound's are known compounds or can be SUBSTITUTE SHFET (RULE 26) O 96/20390 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 E"toluenesulphonic acid, methanesulphonic acid, mucic acid and succinic acid Cancer cells wh_ch exhibit mult1-drug resistance, referred to as MDR cells, display a reduction in intracellular drug accumulation compared with the corresponding drug-sensitive cells Studies using in 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 overexpressio1- can confer the MDR phenotype on cells see, for example, Ann Rev Biochem 5.8 137-171 (1989) A major function of P-gp m 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 m multi-drug resistance Increased levels of P-gp mRNA or SUBSTITUTE ShEET (RULE 26) O 96/20190 protein have been detected m many forms of human cancers -leukaemias, lymphomas, sarcomas and carcinomas Indeed, m some cases P-gp levels have been found to be increased m tumour biopsies obtained after relapse from chemotherapy Inhibition of P-gp function m 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 Vmca alkaloids in vitro and in vivo Cancer Res , 41, 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 m Example 5 which follows The present compounds may therefore be used as multi-drug resistance modifying agents, also termed resistance-modifying agents, or RMAs. The present compounds can modulate, e g reduce, or eliminate multi-drug resistance.
The present compounds can therefore be used m a method of potentiating the cytotoxicity of an agent which is cytotoxic to a tumour cell Such a method comprises, for SiSSTJTiiTc ShLZ7 O 96/20190 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 m a method of treating a disease m 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 presenc 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 m the context of the present invention include Vmca alkaloids such as vincristine and vinblastine, anthracycline antibiotics such as daunorubicin and doxorubicin; mitoxantrone, actinomycin 9 5^7^ Qf-ir77 /rv - O 96/20190 D, taxanes e g taxol, epxpodophyllotoxms e g etoposide and plicamycm In addition, a human or animal patient suffering from a disease m which the responsible pathogen exhibits multidrug resistance may be treated for resistance to a therapeutic agent by a method comprising the administration thereto of one of the present compounds Examples of such disease include multi-drug resistant forms of malaria (Plasmodium falciparum) , tuberculosis, leishmaniasis and amoebic dysentery MDR modulators also have utility m the delivery of drugs across the blood-bram barrier, and m the treatment of AIDS and AIDS-related complex The present compounds can therefore be used m 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 m 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 m 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 0 96/20190 PCT/GB95/03027 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 m 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, lub-ricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols, binding agents such as starches, arable gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone, disintegrating agents such as starch, algmic acid, alginates or sodium starch glycolate, effervescing mixtures, dyestuffs, sweeteners, wetting agents such as SUBSTITUTE SHEET (RULE 26) O 96/20190 PCT/GB95/03027 lecithin, polysorbates, lauryl sulphates Such preparations may be manufactured in known manners, for example by means of mixing, granulating, tablettmg, 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 m water Such compounds may be encapsulated within liposomes The invention will be further illustrated m the Examples which follow SUBSTITUTE SHEET (RULE 26) O 96/20190 32 Reference Eyatripl <* i; Preparation of starting compounds Method A l,4-Diacetyl-2, 5-piperazinedione (25. Og, 126 mrnol) (S.M Marcuccio and J A Elix, loc. cit ) was heated at 120-130°C m DMF (200 ml) with triethylamine (17 6 ml, 126 mrnol) and benzaldehyde (13 0 ml, 126 mmol) After 4 h the mixture was cooled to room temperature and poured into EtOAc (10 00 ml), and washed three times with brine Any solid formed at this stage was filtered off The filtrate was dried (MgSO„) and the solvent removed in vacuo The residue was recrystallised from EtOAcrHexane to give 11 78 g (38%) of l-acetyl-3-benzylidene-2,5-piperazinedione This compound of formula (IV) is listed as 1 1 m Table 1 below Following the same procedure, but replacing benzaldehyde by the appropriately substituted benzaldehyde R1-CHO, where RJ is as listed m Table 1A, the further starting compounds l 2 to 1 10 were prepared of formula (IV).
TABLE 1A Compounds of formula IV O NAc (IV) O SUBSTITUTE SHEET (RULE 25} •u O 96/20190 PCT/GB95/03027 Compound Number R1 1.1 phenyl 1 2 4-chlorophenyl 1.3 2-chloropheny1 1.4 3 -chlorophenyl 1.5 3-furyl 1 6 4-methoxyphenyl 1 7 3-pyridyl 1 8 3 -tnienyl 1 9 3-methoxyphenyl 1.10 2-thienyl Method B 1,4-diacetyl-2,5-piperazinedione was treated with a series of benzaldehydes R^CHO, where R1 is as listed m table IB, m the presence of potassium t-butoxide m t-butanol-THF (1.1) at 0°C The reaction mixture was allowed to warm to room temperature for the time indicated m the 20 table. Recrystallisation, which was optional, was conducted using the indicated solvent TABLE IB Compounds of formula (IV) o (IV) SUSSTITi r* Sh!IET th O 96/20190 Compound Number R1 Reaction time (hours) Recryst solvent (if used) Yield (%) 1 11 2-naphthyl 18 98 1 12 1-naphthyl 18 67 1 13 1-naphthyl 18 67 1.14 2-furyl 12 74 1 15 2-furyl 12 74 1.16 1-methyl-2-pyrrolyl 52 EtOAc 80 1 17 l-methvl - 2 -pyrroly"1 52 EtOAc 80 1 18 2-naphthyl 18 98 1 19 1 - methyl - 3 - mdolyl 14 33 1 20 3- methylbenzo[b]thien -2-yl 18 72 1 21 1 - methyl - 3 - mdolyl 14 33 1 22 3- methylben^o[b]thien -2-yl 18 72 1 23 Me,CH 12 EtOAc 48 1 24 Cyclohexyl 2 80 1 25 Cyclohexyl 2 80 1 26 n-Butvl 14 EtOAc 60 1 27 n-Butyl 14 EtOAc 60 1 28 Me,CH 12 EtOAc 48 1 29 Me,CCH, 18 EtOAc 62 1 30 Me,CCH-, 18 EtOAc 62 1 31 (4S)-4-isopropeny1-1-cyclohexenyl 18 1 32 (4S)-4-isopropenyl-1-cyclohexenyl 18 1 33 4 -AcOC6H4 3 86 1.34 3 - AcOCfH4 3 EtOAc-hexane 42 1 35 2 -AcOCtH4 3 EtOAc-hexane 31 1 36 n-Butyl 14 EtOAc 60 1 37 Ph- ( CHn) r 16 60 SbrP p1 _ --C\ 0 96/20190 PCT/GB95/03027 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 m Reference Example 1, was treated with ethyl bromide and KOtBu/t-BuOH m 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 m Reference Example 1, under the conditions set out m Table 2A Ttsp—,T .. •w O 96/20190 36 - Table 2A Compounds of formula II (II) Compound Number R- Starting Compound (IV) Alkylation conditions 2 1 Me 1 1 (a) KOtBu/tBuOH, DMF, EtBr, 0°C to rt, or (b) 1 1 eq NaH, DMF-THF (1 5), 2 eq EtI, 0°C to rt, then column chromatography 2 2 Ph 1 1 KOtBu/tBuOH, DMF, PhCH2Cl, 2 3 cyclopropyl 1.1 (a) KOtBu/tBuOH, DMF, C3H5CH,Br, 0°C to rt, or (b) 1 1 eq NaH, DMF THF (1 5), 1 3 eq C3H5CH2Br, 0°C to rt, reflux 6h, column chromatography to H 1 2 NaH, Mel, THF, DMF 0°C to rt 2 5 H 1 3 II II 2.6 H 1 4 II tl 2 7 H 1 5 II II 2.8 H 1 6 It II 2.9 H 1 7 II II 2 10 H 1 8 I! II to H H H 1 9 tl II 2 12 H 1 10 If N Method B Compound 1 11 described m Reference Example 1 was treated, m THF-DMF (5 1), with sodium hydride and Mel at r\t i — — ;7 . J?- O 96/20190 PCT/GB95/03027 37 - 0°C The reaction mixture was allowed to warm to room temperature for 18 hours The product was purified by recrvstallisation from EtOAc to give the corresponding compound of formula (II) m 4 0% yield Following this 5 procedure, but replacing compound 1 11 by otner compounds of formula IV described m Reference Example 1, and modifying the reaction time if necessary, the conpounds listed m table 2B were prepared Where indicated, purification was performed by flash chromatography or by recrystallisation as 10 shown in the footnote.
TABLE 2B Compounds of formula II (II) Compound Number R2 Starting Compound (IV) Reaction time Purification method (see footnote) Yield (%) 2 13 H 1 11 18 a 40 2 14 H 1 12 18 b 8 2 15 H 1 13 18 b 8 2 16 H 1.14 18 a 50 2 17 H 1.15 18 a 50 2 18 H 1 16 b 26 2.19 H 1 17 b 26 2.20 H 1.18 18 a 40 2.21 H 1.19 72 b 18 2 22 H 1.20 16 c r> t— — t , s ■' 96/20190 PCT/GB95/03027 2 23 H 1 21 72 b 18 2 24 H 1 22 16 c 2 25 H 1. 23 18 d 73 2 26 H 1. 24 14 d 86 2 27 H 1. 25 14 d 86 2 28 H 1.26 d 75 2 29 H 1. 27 d 75 2 30 H 1.28 18 d 73 2 31 H 1.29 18 d 70 2.32 H 1.30 18 d 70 2.33 H 1.31 d 46 2 34 H 1.32 d 46 2 35 H 1.33 3 b 33 2.36 H 1.34 72 b 2 37 H 1.35 3 b 45 2 .38 H 1.36 d 75 2 44 H 1 37 16 e 37 Footnote a = recrystallisation from EtOAc b = flash chromatography with EtOAc-hexane (1 1) c = flash chromatograpny 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 created with Cs2C02 (2eq ) , Me3SiCl (1 eq ) and allyl bromide (1 eq ) m acetonitrile at 0°C The reaction mixture was 3 0 allowed to warm to room temperature for 5 hours Flash o 96/20190 pct/gb95/03027 chromatograpny of the product using 2 0% EtOAc m hexane gave 2 39 m 50% yield, which is a compound of formula (II) in which R2 is — CH~CHn Method D Compound 1 1, described m 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 m 35% yield, whicn is a compound of formula (II) m which R2 is -C02Me Method E Compound 1 1, described m Reference Example 1, was treated in DMF with sodium hydride and 2-dimethylammoethyl chloride hydrochloride at 0°C The reaction mixture was warmed to 2 0°C, and then further warmed to 8 0°C, over a period of 5 hours The product was purified by recrystallisation from ]% 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 m acetonitrile with Cs2CO, and ethyl bromoacetate at -20°C The reaction mixture was warmed to 20°C for 2 hours SUBSTITUTE SHEET (RULE 26) •t O 96/20190 PCT/GB95/03027 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 1-methyl-6-benzyl-2,5-piperazinedione was treated with acetic anhydride under reflux for 3 hours to give compound 2 43 m 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-piperazmedione Ph' ,co2h MeNH (') Ph MeN i o («i) SUBSTITUTE SHEET (RULE 26) 41 Compound (1) was treated with phosgene m THF at 0°C for 15 minutes The reaction mixture was then warmed ro room temperature overnight The resulting compound (n) was treated with glycine methyl ester hydrochloride and triethylamine m CHC13 at -6 5°C for 3 hours The reaction mixture was allowed to warm to room temperature overnaght and was then refluxed for 16 hours nn toluene to give the desired product m 53% yield Reference Example 5. Preparation of 4-(2-(6.7- (a) The title compound, which is a compound of formula (IX), was prepared according to the following scheme.
Dimethoxv-1.2.3.4-tetrahydro -2-isocrainolvl) ethyl) aniline OMe + 3 1 32 o2n OMe OMe 34 SU3SfiTdTc Shut! (R'JlE 25} O 96/20190 PCT/GB95/03027 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 3m 78% yield 3 3 was then reduced with Fe powder m concentrated HCI and MeOH at 80°C for 3 hours to give 3 4m 51% yield Alternatively 3.3 wss reduced by catalytic hydrogenation at 3 0psi over a palladium on carbon catalyst m methanolic HCl 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.
H,N (3.5) HoN OMe OMe (3.6) (c) Following the synthetic route described under (a), but replacing compound 3 2 by 1, 2, 3 , 4-tetrahydroisoqumoline hydrochloride, the following further compound of formula (IX) was prepared O 96/20190 (3.7) (d) An amine of formula (IX) in which r is 0, compound 3 10, was prepared as follows HCI.HN OMe OMe 3.8 3.9 3.10 6, 7-Dimethoxy-1, 2,3, 4 - tetrahydroisoqumolme 20 hydrochloride (3 8) was treated with chloroacetonitrile in the presence of K:C03 m acetonitrile under reflux for 24 hours Compound 3 9 was obtained m 92% yield 3.9 was then treated with LiA1H4 m ethylene glycol dimethyl ether at room temperature overnight The temperature was then raised 25 to 40°C and the reaction continued for 30 minutes The desired amine 3 10 was obtained in 98% yield <ocr>T; >-r~ . p i - ^ ■"If*! 96/20190 PCT/GB95/03027 Ex^mpi* i? Preparation of compounds of formula III Method 1 Compound 3 4 prepared according to Reference Example 5 was treated with 2-chloro-l-methylpyndinium iodide and 3-5 formylbenzoic acid in CH2C12 m 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 m 43% yield v OMe 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 OHC 4.3 OHC 44 $cvo 96/20190 pct/gb95/03027 Method 2 4-formylbenzoyl chloride was prepared by treating 4-formylbenzoic acid witn thionyl chloride m toluene under reflux It was then treated with compound 3 4, prepared 5 according to Reference Example 5, in CH,C12 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 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 OMe OHC OHC OMe 4.6 SUBSTITUTE SHEET (RULE 26) O 96/20190 46 Method 3 4-formylbenzoyl chloride, as described in Method 2 above, was treated with Et3N m CH^Cl;, 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 Following the same procedure, but replacing 4-formylbenzoyl chloride by 3-formylbenzoyl chloride, the following compound 4 8 was obtained m 4 8% yield.
OMe OMe OHC 4.7 H N OMe OHC OMe 4.8 SUBSTITUTE SHEET (RULE 26) % O 96/20190 BvaTnpl p 2; Preparation of compounds of formula (I) By reacting together a compound of formula (II), prepared m Reference Example 2, and a compound of formula 5 (III), prepared m Example l, the following compounds of the invention were prepared under the conditions set out in Table 3A Table 3A Compounds of formula (I) Compound (I) N° Compound II Compound III Conditions 9112 2 1 4 2 KOtBu, tBuOH, THF, 0°C to rt 9113 2 2 4 2 rt 9114 2 3 4 2 it 9091 2 4 4 2 Cs2C03, DMF, 90°C, 2-3 hours 9092 2 5 4 2 11 9093 2 6 4 2 11 9108 2 7 4 2 11 9109 2 8 4 2 II 9110 2.9 4 2 11 9111 2 10 4 2 11 9155 2 12 4 1 Cs.C03, DMF, 90°C, 2-3 hours 9156 2 11 4 1 11 9157 2 6 4 1 11 9158 2 5 4 1 II 9159 2.7 4 1 II substitute SHEF" 'rTj O 96/20190 PCT/GB95/03C27 9160 o H 4 1 II 9139 2 .1 4 1 CsnCOi, DMF, 8 0°C, 2-3 hours 9141 2 3 4 1 II Example 3: Preparation of salts The compounds prepared in Example 2 were converted to the corresponding hydrochloride salts by treatment with gaseous HC1 m THF •pvaTnpl 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, m DMF at 80°C m the presence of Cs^COj for the time specified m 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 m Table 4 TABLE 4 Compounds of formula (I) Compound (I) Compound (II) Compound (III) Reaction time (h) Purification solvent or eluent (see footnote) 9178 2 39 4 2 3 % H20 in PrOH (a) 9179 2 39 4 1 3 % H,0 in PrOH (a) 9193 2 13 4.2 16 EtOAc (a) 9194 2 14 4 2 EtOAc (a) 9195 2 15 4 1 EtOAc (a) 9196 2 16 4 . 2 16 9197 2 17 4 .1 16 9198 2 18 4.2 14 nPrOH (a) Q;«XJ7'Prr~ „ . _ O 96/20190 9199 2 19 4 1 lPrOH (a) 9209 2 20 4 1 EtOAc (a) 9210 2 21 4 2 12 EtOAc-MeOH (a) 9211 2 22 4 1 14 MeOH, EtOAc, Et20 (a) 9214 2 23 4 1 18 CH2C1?-Et20 (a) 9215 2 24 4 2 4 EtOAc -Et20 (a) 9217 2 40 4 1 2 EtOAc-hexane (a) 9228 2 25 4 2 8 % MeOH in Et-,0 (b) 9229 2 26 4 2 14 % MeOH in Et-,0 (b) 9230 2 27 4 1 18 % MeOH in Et-,0 (b) 9231 2 28 4 2 14 9232 2 29 4 1 14 % MeOH in Et-,0 (b) 9233 2 30 4 1 % MeOH in Et-,0 (b) 9234 2 31 4 2 18 % MeOH m Et-,0 (b) 9235 2 32 4 1 14 % MeOH m Et-,0 (b) 9236 2 33 4 2 14 % MeOH in Et-,0 (b) 9250 2 34 4 1 14 % MeOH m Et^O (b) 9260 2 13 4 7 4 9261 2 13 4 8 4 EtOAc-heptane (a) 9266 2 44 4 . 8 16 EtOAc-hexane (a) 9267 2 44 4 7 16 9272 2 35 4 .1 3 EtOAc-hexane (a) 9273 ? 36 4 .1 2 EtOAc-hexane (a) 9274 2 37 4.1 3 EtOAc-hexane (a) 9275 2 41 4.1 3 EtOAc-hexane (a) 9299 2 42 4.1 3 substirute sheet (rule 26) ®u O 96/20190 PCT/GB95/03027 9306 2 38 4 1 14 % MeOH m Et-,0 (b) 9308 2 43 4 1 16 % MeOH m EtOAc (b) Footnote (a) Recrystallisation solvent (b) Flash chromatography eluent Example 5 Preparation of Salts Selected compounds prepared m Example 4 were converted 10 to the corresponding hydrochloride salts by treatment with gaseous HC1 m CH.Cl, The hydrochloride, denoted m Table 5 below by the suffix " HCl" was m some cases then recrystalllsed as shown in the table TABLE 5 Hydrochloride salts Salt Recrystallisation Yield solvent (%) 9193 HCl 9144 HCl EtOAc 21 9195 HCl EtOAc 22 9196 HCl 9197 HCl EtOAc 9232.HCl 9306.HCl SUBSTITUTE sheet (RULE 26) O 96/20190 PCT/GB9S/03027 Example 6. Interconversions of compounds of formula 111 Compounds of formula (I) were prepared by treating selected compounds of formula (I) prepared m Example 4 with appropriate reagents using conventional synthetic techniques, as follows 1 9217 was treated with LiOH m aqueous THF at room temperature for 2 hours to give compound 9241 2 9272 was treated with NaBH„ m MeOH at 0°C for 2 hours to give compound 9276 m 73% yield 3 9274 was treated witn 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 m 58% yield 4 9273 was treated with NaBH3CN m MeOH and THF at reflux for 7 hours The product was recrystallised from EtOAc-hexane (1.5) to give compound 9301 m 18% yield 'ffyample 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 ,'R»'Lf 2® O 96/20190 PCT/GB95/03027 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 m 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 (X) 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 m RPMI 1640 medium containing 10% foetal calf serum and 2mM glutamme at 37°C m 5% C02 Cells were passaged between 1 in 200 and 1 in 2000 in the case of the parental cell line and between 1 m 2 0 and 1 m 200 m the case of tne MDR resistant subline, after trypsinisation (0 25% trypsin, 0 2gl 1, EDTA) 1 Drug accumulation assay SUBSTITUTE sheet (rule 26) O 96/20190 PCT/GB95/03027 AR 1 0 cells were seeded into 96 well opaque culture plates (Canberra Packard) The assay medium contained a mixture of tritiated Daunorubicm (DNR), a cytotoxic agent, and unlabelled DNR (0 3 ft Ci/ml, 2^M) Compounds of formula 5 I were serially diluted m assay medium over a range of concentrations from 5 nM to 100 /iM 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 10 observed in the presence of the known RMA verapamil at a concentration of 100 fj.M or as an ICc0 The results are set out m the following Table 6 TABLE 6 Compound No ic50 (mm) Accumulation Maximum (%) Accumulation 9091 2.0 9092 1 2 9093 3 0 9108 0 7 9109 2 0 9110 2 0 9111 1 0 9112 0 2 9113 0 9114 0 6 9139 0 2 9141 0 S 9155 O O 9156 0 1 SUBSTITUTE sheet (rule 26) * 096/20190 9157 0 2 9158 0 6 9159 0.4 9160 % 9178 0 080 9179 0 170 9193 HCl 7 0 9194 HCl 1 800 9195 HCl 0 210 919f> HCl 0 140 9197 HCl 0 025 9198 0 200 9199 0 14 0 9209 0 600 9210 0 220 9211 1 400 9214 0 070 9215 1.100 9217 0 700 9228 0.350 9229 0 .200 9230 0 .130 9231 2 . 000 9232 0 020 9233 0 . 600 9234 0 500 9235 0 600 9236 2 000 9250 0 800 9260 0 800 9261 1 200 9266 1 200 substitute sheet (r'jle 26) 096/20190 9267 000 9272 0 400 9273 0 070 9274 0 800 9275 0 600 9276 1 900 9276 HCl 0 700 9299 0 500 9300 0 200 9301 0 200 9308 3 000 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 86/xM) which alone is non-toxic to AR 1 0 cells After a four day incubation with doxorubicin proliferation was measured using the colorimetric sulphorhodamme B assay (Skehan et al, J Natl Cancer Inst 82. 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 86piM 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 nM m the presence of fixed concentrations of compounds of formula (I) Proliferation was quantified as % 0 96/20190 PCT/GB95/03027 described by Skehan et al, loc cit The IC5D (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 5 potentiation index (PI) IC50 for Doxorubicin alone PI= IC50 for Doxorubicin plus RMA The results are shown m Table 8 10 TABLE 7 Compound No Compound toxicity Toxicity with (IC50 iM) cytotoxic agent <IC50 fM) 9091 1 8 0.15 9092 0 7 0.07 9093 2 0 0.09 9108 4 0 0.10 9109 4 0 0 30 9110 6 0 1.00 9111 2 5 0.15 9112 2.0 0. 015 9113 0.4 0 1 9114 1 0 0 06 9139 4 0 3 9141 2 0 3 9178 1.50 0.008 9179 0.50 0 . 0 8 0 9193.HCl 2 00 0 .200 9194.HCl 6 00 0 050 k£or;jr- s :r 9195 HCl 1 . 00 0. 010 9196 HCl 7 00 0 060 9197 HCl o o CO (N 1 0 010 9198 8 .00 0.020 9199 o o o 0 . 050 9209 45 00 0.070 9210 40.00 0.080 9211 O o o LO 0.080 9214 100.00 0.008 9215 o o o 0.030 9228 0 60 0 .100 9229 0.50 0.070 9330 0 45 0 .100 9231 2 00 0 .120 9232 3. 00 0 .060 9233 8. 00 0 400 9234 1.00 0 080 9235 0. 50 0.100 9236 0 . 80 0.13 0 9250 2.00 0 080 9260 3 . 00 0 350 9261 .00 0 400 9272 9.00 0 200 9273 00 0 02 0 9274 o o o 0 050 9275 1 80 0 700 9276 00 0 500 | ' O "i * O 96/20190 - 58 -TABLE 8 Compound No Potentiation index PI determined at (uM) 9108 1000 1 9109 250 1 9111 500 1 9112 1000 1 9139 500 0.5 9141 285 0.5 9155 67 0 2 9156 0.2 9157 40 0 2 9158 75 0 2 9159 50 0 2 9178 7.1 0 .01 27 3 0 .03 69 8 0 .10 250. 0 0.30 9193.HCl 0 0.30 2 0 0.10 9194.HCl 50 0 0.30 7 5 0 10 1 5 0 03 1 2 0 01 9195 HCl 454 .0 0 30 50. 0 0 10 2 5 0.03 1 2 0 .01 9196 HCl 37.5 0.30 0 0 10 1 5 0 .03 1 0 0.10 9197 HCl 65.0 0.30 4 3 0.10 1 3 0 03 1 3 0 10 9198 32.5 0 30 3.3 0 10 1.3 0 03 1.3 0 01 Kv-p - , - r —> .
O 96/20190 PCT/GB9S/03027 9199 65 . 0 0.30 2.2 0 10 1 3 0 03 1.3 0 01 9209 125. 0 0.30 .0 0 10 1 2 0. 03 1.2 0. 01 9210 75 0 0.30 8 3 0.10 1 5 0. 03 1.3 0 01 9211 1538.0 1 00 1000.0 0 50 9214 200.0 0.30 150.0 0.10 .0 0. 03 2.0 0. 01 9215 66 7 0.30 .0 0.10 3 0 0. 03 1 5 0. 01 9217 11 0 0 30 1.0 0 10 0 9 0 03 0.8 0. 01 9231 .0 0.30 3 0 0. 10 0.9 0 03 1.1 0. 01 9232 80.0 0 30 0 0 10 3.0 0. 03 1 0 0 01 9234 O O If) 0.30 0 0.10 9235 37.5 0.30 2 3 0.10 9236 16.7 0.30 2 1 0. 10 9250 286 0 0. 50 9260 3 3 0.30 2 0 0.10 fas, ;• 0 96/20190 9261 2 2 0.30 1 7 0 10 9272 175 0 1 00 6 0 30 1 4 0.10 9273 100 0 3 .00 96 .1 1.00 83 .3 0.30 29.4 0.10 9274 100 0 3 .00 90 9 1.00 71.4 0.30 .0 0.10 9275 .0 1 00 6.9 0.30 0.7 0 .10 9276 166 . 6 3 .00 .0 1 00 0 . 8 0 30 0.8 0.10 9299 16 .0 0.30 1.8 0.10 9300 133 .3 1. 00 61.5 0 30 .0 0.10 9301 HCl 133 3 1. 00 88.9 0.30 28 .6 0 10 Kxanvpl p fi * Characterisation of the present compoxinda The compounds and salts prepared in Examples 1 and 2 were characterised by mass spectroscopic and proton nmr techniques The results are set out m Tables 9 and 10 SUBSTITUTE SHEET (RULE 26) • 0 TABLE 9 No Mol Formula mass spec data JH nmr data mass (intensity) mode solvent/field 6 9091 C39H37C1N405 HCl 679(10). 677(10) 208(100) CI dj-DMSO/300MHz 2 5-4 7 (lOH.m) 2 95 (3H.s) 3 83 (6H s) 6 88 (IH s) 6 92 (IH s) 6 98 (IH s) 7 15 (IH s) 7 40 (2H d) 7 51 (2H d) 7 59 (2H d) 7 83 (2H d) 7 90 (2H d) & 12 (2H d) 10 45 (IH s) 10 8 (111 s) 11 1 (IH bs) 9092 C39H3,C1N405 HCl 679(10) 677(10) 208(100) CI d6-DM50/300MHz 2 5-3 7 (8H.ni), 2 88 (3H 5). 3 84 (6H s). 4 5 (2H m). 6 89 (IH s) 6 93 (IH s) 7 01 (IH.s). 7 15 (IH.s). 7 40 (2H d) 7 50 (3H m) 7 65 (IH m) 7 82 (2H d) 7 90 (2H d). 8 14 (2H d) 47 (IH s). 10 90 (IH s) 11 37 (IH bs) 9093 C39H5?C1N405 HCl 679(10) 677(5) 208(100) 190(100) CI d6-DMS0/300MHz 2 3-4 7 (10H m) 2 94 (3H s) 3 84 (6H.s) 6 89 (IH s) 6 93 (IH s) 6 99 (IH s) 7 16 (IH s) 7 40 (ZH.d) 7 42-7 60 (411 m) 7 82 U'H d) 7 90 (2H d) 8 14 (2H d) 10 45 (IH s) 85 (IH s) 11 30 (IH bs) | • • • • No Hoi Formula mass spec data mass (intensity) mode 'H nmr data solvent/field 9108 9109 C3,H36N406 HCl 633(25) 439(40) 206(85) 91(100) CI d6-DMSO/300MHz 3 0-4 7 (10H m) 3 2 (3H s) 3 7 (2x3H s) 6 74 (IH s) 6 90 (IH s) 6 94 (2x]H s) 7 00 (IH s) 7 41 (2H d) 7 80 (2H d) 7 85 (IH s) 7 86 (2H d) 8 08 (IH s) 8 09 (ZH d). 10 43 (IH s) 673(2). 672U). 246(25). 206(100), 164(90). 91(60) CI d,-DM50/300MHz 2 9-4 0 (10H m) 3 00 (3H s) (3H,s) (IH s) (2H d). (2H d) (2x2H d) (IH s) 3 6 6 81 (2x3H s) 3 89 81 (IH.s) 6 83 95 (IH s) 7 09 7 13 (IH s) 7 37 7 41 (2H d) 7 81 8 09 (2H d) 10 40 9110 CmMSOS 2HC1 d6-DMSO/3GOMHz 2 96 (3H s) 3 0-4 7 (10H m) 3 84 (2x3H s) 6 90 (IH s) 6 93 (IH s) 7 01 'IH s) 7 19 (IH s) 7 42 (2H d) 7 83 (5H m) 8 12 (3H m) 8 73 (IH d) 8 85 (IH s) 10 45 (IH s) 9111 C37H36N405S HCl 649(30) 456(30) 337(50) 208(100) 164(60) CI 6c DMSO/300MHZ 3 0-4 0 (8H m) 3 07 (3H s) 3 84 (2x3H s) 4 41 (2H bs) 6 88 (IH s) 6 92 (IH s) 6 96 (IH s) 7 14 (IH s) 7 29 (IH d) 7 41 (2H d) 7 71 (111 dd) 7 77 (IH m) 7 81 (2H d). 7 85 (2H d) 8 10 (2H d) 10 45 (IH.s) cn N> O W to in o w o -J No Hoi. Formula mass spec data mass (intensity) mode 'H nmr data solvent/field 9112 C40H,0N?O5 HCl 657(7) 286 (60) 269 (100) CI d,-DMSO/3QOMHz 0 99 (3H t). 3 0-4 7 (lOH.m) (3H.s) (IH s) (IH.s) (2H d). (2H.d). (2H.d) (IH bs) 3 67 (2H q) 3 86 (3H s) 6 93 (IH s) 7 22 (IH.s) 7 52 (5H.m). 7 90 (2H.d). 10 45 (IH s) , 3 84 6 90 7 01 7 42 7 82 8 14 11 20 9113 C«MA HCl 719(25) 286(60) 269(100) CI d6-DMS07300MHz 3 0-4 7 (10H m) 3 85 (2x3H s) 4 85 (2H s) 6 92 (4H.m) 7 04 (IH.s). 7 20 (IH s) 7 33 (3H m) 7 40 (2H.d). 7 55 (5H.m) 7 85 (2H d) 7 91 (2H d) 8 14 (2H d) 10 45 (IH s) 10 83 (IH s) 11 25 (IH bs) 9114 c<?h,2n,o5 HCl 683(20) 206(40). 167(80) 149(100) 57(40) CI dfi-dm50/300mhz 0 0-1 1 (12H m) (IH.s) (IH s) (2H d) f2H d) (2H d) (IH s) (5H.m), 3 0 4 3 87 (2x3H s) 6 94 (IH s) 7 20 (IH s) 7 52 (5H m) 7 90 (2H d) 10 45 (IH s) 10 90 (IH bs) 6 90 7 01 7 40 7 85 8 13 10 80 9139 ^40^40^4^5 657(34) 431(57) 206(83) 190(100) CI CDCy 400MHz 0 96 (3H t) 2 72-2 94 (8H m) 3 63 (2H s) 3 67 3 84 (2H q) (IH s) 6 60 (IH s) 7 (IH s) 7 18 (IH s) 7 7 52 (8H m) 7 83 (IH d) 8 13 (IH s) (2x3H s) 6 55 09 20-7 55 (4H m) 7 99 (IH s) • m • • No MoT Formula mass spec data u !H nmr data mass (intensity) mode solvent/field 6 9141 w40s 683(8) 614(62) 190(100) CI CDCy400MH^ 0 05 (2H d) 0 35 (2H d) 0 97 (IH m). 2 70-2 90 (8H m) 3 53 (2H d) 3 63 (2H s) 3 83 (2x3H s) 6 55 (IH s) 6 60 (IH s). 7 05 (IH s). 7 11 (IH s) 7 20 7 65 (12H m) 7 82 (IH d) 8 00 (IH s) 8 13 (IH s) 9156 CDCy 400MHz 2 74-2 95 (8H m) 3 01 (3H s) 3 68 (2H si 3 82- 3 85 (9H m) 6 54 (IH s) 6 62 (IH s) 6 80 (IH.s). 6 82-6 90 (2H m) 7 10 (IH s) 7 20-7 33 (5H m) 7 54-7 60 (4H m) 7 83 (IH m) 7 97 (IH s) 8 08 (IH s) 9157 c39h37c1n405 CDC13/400MHz 2 73-2 94 (8H ra) 3 00 (3H s) 3 66 (2H s) 3 84 (2x3H s) 6 55 (IH s) 6 62 (IH s) 7 12 (IH s) 7 20 (IH s) 7 23-7 28 (3H m) 7 32 (d 2H) 7 53-7 60 (6H m) 7 82 (IH m) 7 92 (IH s) 7 97 (IH S) 9158 c39h37cin4o5 677(100) ESI cdci3/400hhz 2 73-2 93 (11H m) 3 64 (2H s) 3 84 (2x3H s) 6 56 (IH s) 6 61 (IH s) 7 12 (IH s) 7 19-7 31 (7H m) 7 45 (IH m). 7 54-7 59 (4H ro). 7 84 (IH m). 7 96 (IH s) 8 00 (IH s) No Hoi Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 6 9159 ^37^36^4^6 633(100) ESI CDC13/400MHZ 2 73-2 93 (8H m) 3 18 (3H s) 3 65 (2H s) 3 84 (2x3H S) 6 43 (IH s) 6 56 (IH s) 6 61 (IH S) 1 00 (IH s) 7 06 (IH s) 7 23 (2H d) 7 48 (IH m) 7 52-7 59 (4H m) 7 83 (IH m) 7 95 (IH s) 8 03 (IH s) 9160 WAS 649(100) ESI CDCy40OI1H2 2 72-2 92 (8H m) 3 09 (3H s) 3 68 (2H s) 3 84 (2x3H s) 6 57 (IH s) 6 01 (IH s) 7 06 (IH d) 7 08 (IH S) 7 12 (IH s) 7 22-7 29 (4H m) 7 3P (IH m) 7 55-7 59 (4H m) 7 82 (IH m) 7 97 (IH s) 8 04 (IH s) 9155 1 c3,h36n4o5s 649(100) ESI CDC13/400MHz 2 72-2 93 (8H m) 3 19 (3H S) 3 65 (2H s) 3 o5 (2x3H s) 6 54 (IH s) 6 60 (IH s) 7 04 (IH m) 7 08-7 10 (2H m) 7 22-7 29 (3H in) 7 45 (IH m) 7 52-7 60 (4H m) 7 81 (IH m). 7 95 (2H s) 8 38 (IH.s) | No Mol Formula mass spec data *H nmr data mass (intensity) mode sol vent/field 6 9178 CjiHio^Os CDC13/400IIHZ 2 70-2 95 (8H m) 3 50 (2H s) 3 70 (2x3H s) 4 20 (2H d) 4 65 (IH d) 4 90 (IH d) 5 45 (111 m) 6 45 (IH s) 6 55 (IH s) 6 95 (IH s) 7 10 (2H d) 7 15 (IH s) 7 15-7 25 (511 m) 7 40 (2H d) 7 55 (2H d) 7 90 (IH s) 7 95 (2H d) (8 85 (IH s) 9178 HCl C4|H40NA HCl 669(20) DCl CDCl3/400MHz 2 75-3 65 (8H,m). 3 70 (3H.S), 3 75 (2H s) 3 80 (3H.S). 4 25 (2H.d). 4 70 (IH.d) 5 00 (IH.d). 5 55 (1H m) 6 45 (IH s) 6 55 (111 s) 6 90 (111 s) 7 10 (2H d) 7 20-7 50 (8H m) 7 80 (2H d). 8 05 (2H d) 8 50 (IH s) 8 50 (IH s) 9 50 uH s) 9179 669(100) ESI CDC13/400MHZ 2 70-2 90 (8H m) 3 60 (2H s) 3 80 (2x3H s) 4 30 (2H d) 4 75 (IH o) 5 00 (IH d) 5 50 (IH m) 6 55 (IH s) 6 60 (IH s) 7 05 (IH s). 7 15 (IH s) 7 20-7 60 (llH.m), 7 70 (IH.d). 7 80 (IH s) 7 90 (IH s) 8 65 (IH brs) • m • • No Mol Formula mass spec data mass (intensity) mode 'H nmr data solvent/field 9193 caihionjoj CDC13/400MHz 2 80-2 90 (6H m) 3 (3H s) 3 68 (2H s) (2H d) (IH s) 7 7 78 (2H d), 7 95 (2H d) 05 3 82 (2x3H s) 6 55 (IH s) 6 6^ (IH s) 7 10 (IH s) 7 28 7 41 (IH d) 7 49 51-7 60 (6H m) 7 85 (3H m) 8 05 (IH s) 9193 HCl Ca3H40N4O5 HCl d6-DMSC)/400MHz 90 2 3 3 4 6 7 25 (IH s) 7 50 (lH.dd) 75 (4H.m), (2H d). 10 58 (IH bs) (3H s) 10 (4H m). 75 (2x3H s) (IH bs) (IH s) 49 80 7 8 02 2 95 (2H bs) 3 40 (2H.bs) 4 25 (IH s) 6 78 (IH s) 6 91 (IH s) 7 30 (2H d) 7 53 (2H m) 7 95 (4H m), 10 38 (IH.s) 68 (IH s) 9194 HCl C„H40N4O5 HCl 693(100) ESI d6-DMS0/400MHz 2 65 (3H s). 3 12 (4H m) 3 73 (2x3H.s) 4 50 (IH bd). 6 82 (IH s) 7 30 (2H d) 7 50 (IH s), (3H m) 7 76 8 02 (5H m) 10 50 (IH s) 2 95 (2H m) 3 42 (2H m) 4 26 (IH m) 6 79 (IH s) 6 93 (IH s) 7 48 (IH d) 7 51-7 62 (4H ra) 7 90-10 30 (IH s) 69 (IH s) No MoT Formula mass spec data mass (intensity) mode ]H nmr data solvent/field 9195 C4JHt0NA 693 esi CDC13/40011Hz 2 74-2 94 (8H m) 2 80 '3H s) 3 65 (2H s) 3 85 (2x3H s) 6 50 (IH s) 6 60 (IH s) (2H d) 7 12 (IH s) 7 30 (IH d) 7 25 7 48 (IH t) 7 54 (6H m) 7 68 (IH s) 7 80-7 94 (4H m) 8 0 (2H s) 8 52 (IH bs) 9195 HCl C43H40N,Os HCl d6-DMSO/400MHz 2 65 (3H 5) 12 73 4 50 (IH m) (2x3H.s) (IH bd) (IH s) (2H d) (IH s) (4H m) 7 78 8 00 (5H ni) 10 30 (IH.s) 10 68 (IH s) 80 30 51 2 94 (2H m) 3 42 (2H.m) 4 26 (lH.rn) 6 79 (IH.s), 6 95 (IH s) 7 49 (IH d) 7 52-7 64 (2H d) 7 85- 8 1? (IH s) 10 50 (IH s) CTl OO 9196 c3,h36h4o# 633(100) esi CDCl3/400MHz 2 72-2 90 (6H m) 2 92 (2H.m) 3 4 (3H s) 3 62 (2H s) 3 85 (6H s) 6 52 (IH m+lH s) 6 60 (2H s) 7 08 (2H d) 7 50 (2H d) 7 82 (IH s) 8 00 (IH s) 7 26 (2H m) 7 54 (3H m) 7 91 (2H d) 8 ve © © K> -4 • • No Hoi Formula mass spec data mass (intensity) mode 'H nmr data solvent/field 9196 HCl ^37^36^6 dfc-DMSO/400MH/ 2 98 (2H m) 3 19 (3H s) 3 75 (2x3H s) 4 50 (IH m). 6 79 (IH s) (IH m+lH s) 6 90 (IH s) 7 70 (2H d) 7 87 (IH d) 10 30 (IH s) 10 60 (IH s) 3 12 (4H m) 3 40 (2H m) 4 26 (lH.bs) 6 68 (IH m) 6 82 6 88 (IH s) 7 30 (2H d) 7 76 (2H d) 8 01 (2H d) 55 (IH bs) 9197 HCl WA HCl 633(100) ESI ds-DMS()/400MHz 2 98 (2H bd^ 3 15 (4H m) 3 21 (3H s) 3 42 (2H m) 3 75 (2x3H s) 4 28 (IH m) 4 50 (IH bd) 6 62 (IH in) 78 (IH s) 6 82 (IH d) 83 (IH s) 6 89 (2xlH s) 30 (2H d). 7 56 (IH t) 71-7 78 (3H m) 7 90 (2H m) 8 10 (IH s) 10 30 (IH s) (IH bs) 70 (IH s) 10 76 9198 646U00) ESI d6-DMSQ/400MHz 2 61 (6H m) 3 06 (3H s) 3 65 (3H,s) 6 18 (2H in) 6 82 (IH s) (IH s+lH m) 7 68 (4H m), 10 15 (IH s) 2 81 (2H t) 3 55 (2H.s) 3 70 (6H s) 6 65 (ZxlH s) 6 98 7 25 (2H d) 7 98 (2H d) 50 (IH s) No Mol Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 6 9199 ^38^3*^5 646(100) ESI d6-DM50/400MHz 2 70 (6H m) 2 81 (2H t) 3 06 (3H s) 3 55 (2H s) 3 65 (3H s) 3 70 (6H s) 6 16 (2H.m) 6 65 (2xlH s) 6 85 (IH s) 6 98 (IH s+lH m) 7 25 (2H d) 7 55 (IH t) 7 68 (2H d) 6 71 (IH d) 7 85 fIH d) 8 10 (IH s) 10 16 (IH s) 10 60 (IH bs) 9209 C4jH4CNJt05 693(100) ESI d6 DM50/400MHZ 2 60 (6H.m) 2 80 (2H t) 3 58 (3H s) 3 70 (6H s) 6 62 (IH s) 6 66 (IH s) 6 91 (IH s) 7 36 (3H m) 7 50 (IH d) 7 52-7 62 (3H m) 7 70 f2H d) 7 76 (IH d) 7 89 (IH.d) 7 90-799 (4H.ro). 8 14 (IH.s) 20 (IH.s) 10 73 (IH s) 9210 cjyiA 696(100) ESI d6-DMSC)/400MHz 2 69 (6H ip) 2 82 (2H t) 3 06 (3H s) 3 55 (2H s) 3 70 (2x3H s) 3 88 (3H s), 6 65 (2xlH.s) 6 85 (IH s) 7 16 (IH.t) 7 20-7 29 (4H m) 7 50 (IH d) 7 58 (IH d) 7 63 (IH s) 7 70 (2H d) 7 75 (2H d) 7 99 (2H d) 10 14 (IH s) 10 45 (IH bs) *0 fJ o -J o 3 s )o tjl 8 s vj ♦ $ • ® No Hoi Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 6 9211 C«H40NA 713 ESI d6 DMSO/400MHZ 2 3 (3H s) 2 7 (6H m) 2 82 (2H t) 2 98 (3H s) 3 57 (2H s) 3 7 (2x3H s) 6 65 (2xlH s) 6 93 (IH s) 7 12 (IH s) 7 26 (2H d) 7 38-7 48 (2H m) 7 56 (IH t) 7 69 (2H d) 7 78 (ih d) 7 80 (ih d) 7 88 (IH d) 1 95 (IH d), 8 15 (IH s) 10 17 (IH s) 10 79 (IH bs) 9214 c«h40n4o5 696(100) ESI d6-DHS0/400MHz 2 63-2 73 (6H m) 2 81 (2H t) 3 08 (3H s) 3 55 (2H s) 3 71 (2x3H s) 3 87 (3H s) 6 65 (2xlH s) 6 88 (IH S) 7 18 (IH t) 7 28 (4H m) 7 48-7 57 (3H m) 7 63 (IH s) 7 69 (2H d) 7 75 (IH d) 7 85 (IH d) 8 12 (IH s) 10 20 (IH s) 10 54 (IH.s) 9215 c4,h40n4o,s 713(100) ESI d5-DI ISO/400MHz 2 30 (3H s) 2 70 (6H m) 2 80 (2H t) 2 98 (3H s) 3 55 (2H s) 3 71 (6H s) 6 63 (2xlH s) 6 89 (IH s) 7 12 (IH s) 7 24 (2H d) 7 35-7 45 (2H m) 7 65 (2H d) 7 79 (3H m) 7 97 (IH d) 8 00 (2H d) 10 15 (IH s) 10 72 (IH bs) No Mol Formula mass spec data lH nmr data mass (intensity) mode solvent/field 6 9217 701(100) CI CDC13/400MHZ 2 70-2 95 (8H m) 3 65 (3H s) 3 70 (2H s) 3 80 (2x3H s). 4 30 (2H s) 6 50 (IH s) 6 60 (IH s) 7 10 (IH s) 7 20-7 55 (13H m) 7 85 (IH s) 7 90 (IH s) 8 10 (IH s) 9228 ^36^40^4^5 609(100) ESI d6-DM50/400MHz 1 08 (6H d) 2 69 (6H m) 2 80 (2H t) 2 88-2 99 (IH m) 3 34 (3H s) 3 55 (2H s) 3 70 (6H.s) 5 84 (IH d) 6 62 (2xlH s) 6 78 (IH s) 7 23 (2H d) 7 68 (4H m) 7 98 (2H d) 10 18 (IH s) 10 41 (IH bs) 9229 WA 649(100) ESI d6-DflSQ/400MHz 1 10-1 38 (5H m) 1 60-1 73 (5H m) 2 50-2 63 (IH m) 2 63-2 73 (6H m) 2 76-2 83 (2H t) 3 32 (3H s) 3 55 (2H s). 3 70 (2x3H s) 5 86 (IH d) 6 62 (2xlH s) 6 80 (IH s) 7 23 (2H d) 7 67 (4H m) 7 97 C2H d) 10 15 (IH s) 10 39 (IH bs) I to I O W VO cn o w o K» No Mol Formula mass spec data *H nmr data mass (intensity) mode solvent/field 6 9230 c39h„n4o5 649(100) ESI CDC1/400MHz 1 03-1 35 (5H m) 1 60-1 80 (5H m). 2 49-2 60 (IH m) 2 70-2 94 (8H,m) 3 35 (3H s). 3 63 (2H.s) 3 83 (2x3H s) 5 93 (1H d) 6 55 (IH s) 6 60 (IH s) 7 02 (IH s) 7 20 (2H d) 7 50- 7 60 (4H m) 7 86 (IH m) 7 92 CIH s) 8 50 (IH s) 8 98 (IH bs) 9231 c3,h«na 623(100) ESI CDC13/400MHZ 0 92 (3H t). 1 40 (2H m) 1 52 (2H r,.) 2 43 and 2 76 (2H two quartets) 2 71-2 92 (8H m) 3 31 and 3 46 (3H two singlets) 3 68 (2H s) 3 85 (6H s) 5 75 and 6 30 (IH.t), 6 55 (IH s), 6 60 (IH s) 7 00 IH two singlets), 7 28 (2H d) 7 50 (2H d) 7 60 (2H d) 7 80 (IH s) 7 85 (IH bs) 7 93 (2H d) -0 No Mol Formula mass spec data mass (intensity) mode 'H nmr data solvent/field 9232 C3 H,,N,0S 623 ESI CDC1 j/40011MZ 0 90 (3H.t). 1 29-1 50 (4H m) 2 36 and 2 68 (2M two quartets) 2 72-2 94 (8H m) 3 27 and 3 36 (3H two singlets) 3 65 (2H s) 3 83 (2x3H s) 5 68 and 6 12 (IH two triplets) 6 56 (IH s) 6 60 (IH s) 6 98 and 6 90 (IH two singlets),7 20 (2H m) 7 52 (2H.d) 7 58 (2H m). 7 85 (IH m) 7 94 (IH m) 8 35 and 8 40 (IH two singlets) 8 58 and 8 83 (IH two broad singlets) 9933 Cj6^4()N.A 609(100) ESI CDCl3/400MHz 1 08 (6H d) 2 71-2 92 (9H m) 3 35 (3H s) 3 65 (2H s) 3 83 (2x3H s) 5 93 (IH d) 6 55 (IH s) 6 60 (IH s) 7 02 (IH s) 7 22 (2H d) 7 54 (4H m) 7 32 (IH m) 7 81 (IH s) 8 37 (IH s) 8 82 (IH bs) 9234 ^•38^44^4^5 637(100) ESI CDC13/400MHz 1 01 (9H s) 2 38 (2H d) 2 74-2 98 (811 m) 3 47 (3H s) 3 67 (2H s) 3 84 (2x3H s) 6 42 (IH t) 6 55 (IH s) 6 62 (IH s) 7 28 (2H d) 7 52 (2H d) 7 58 (2H.d) 7 75 (IH s) 7 82 (IH s) 7 92 (2H d) ® 9 • m No Mol Formula mass spec data 'H nmr data mass (intensity) mode solvent/field S 9235 C39H4jNA 637(100) ESI CDCl3/400MHz 0 99 (9H s). 2 31 and 2 70 (2H, two doublets) 2 71-2 92 (8H m) 3 32 and 3 40 (3H two singlets) 3 6b (2H s) 3 85 (2x3H s) 5 79 and 6 32 (IH two triplets) 6 54 (IH s) 6 60 (IH s) 7 02 (IH two singlets) 7 25 (2H m) 7 56 (4H m) 7 80 (1H m) 7 88 (IH two singlets) 7 96 (IH s) 8 05 (IH bs) 8 22 (IH bs) 9236 c42h46n4o5 687(100) ESI d6-DMSO/400MHz 1 50 (IH m) 1 73 (3H s) 1 83-1 84 (IH m) 2 10 UH m) 2 19 (3H m) 2 30 (IH m) 2 70 (6H m) 2 80 (2H m) 3 08 (3H s) 3 55 (2H s) 3 70 (6H s) 4 72 (2H s) 5 67 (IH bs) 6 39 (1H bs) 6 62 (2xlH s) 6 80 (111 two singlets) 7 23 (2H d) 7 68 (4H d) Q 00 (2H d) 10 18 (IH s) 10 55 (IH bs) 9241 687(100) ESI CDC13/400f1Hz 2 65-2 90 (8H in) 3 55 (2H s) 3 70 (2x3H s) 4 00 (2H s) 6 60 (IH s) 6 65 (IH s) 6 85 (IH s) 7 10 (IH s) 7 25 (2H d) 7 35 7 45 (6H m) 7 55 (IH t) 7 65 (2H d) 7 70 (IH d) 7 85 (IH d) 8 10 (1H s) 10 10 (IH s) 10 70 (IH brs) 9 9 No MoT Formula mass spec data mass (intensity) mode *H nmr data solvent/field 9250 c42h<6na 687(100) ESI d6-DMSQ/400MHz 1 50-1 60 (IH m) 1 73 (3H s) 1 82 (IH in) 2 1 2 (3H m) 2 31 71 (6H m) 2 81 (IH ID) (IH m) (2H t) (2H s) (2H s) (IH s) 2 2 3 3 6 (3H s). 3 56 70 (2x3H S) 4 75 68 (IH bs) 6 38 65 (2xlH s) 6 85 (IH two singlets) 7 25 (2H d) 7 54 (IH t) 7 70 (3H ra) 7 85 (IH d) 8 07 (IH s) 10 18 (IH s) 10 55 (IH s) 9260 Ca^NA 617(100) CI CDCK/400HHz 2 70-2 80 (faH m) 3 05 (3H s) 3 60 (2H s> 3 65 (2H m) 3 75 (2x3H s) 6 50 (IH s) 6 60 (IH S) 7 0-8 1 (15H m) 9261 W-A 617(100) 615(60) CI CDCy400flllz 2 80 (6H m) 3 05 (311 s) 3 60 (2H s) 3 65 (211 ro) 3 80 (2a3H S) 6 50 (111 S) 6 52 (IH s) 7 0-8 10 (15H m) 9266 595 CI CDC13/400IIHZ 3 in (2H q) 3 60 (2H S) 3 80 (2x3H s) .. . 6 50 (IH s) 60 (IH s), 6 80 (lH.brs) 7 15-7 90 80 (8H m) 20 (3H s) 65 (2H t) 70 (IH t) 2 3 3 6 6 95 (IH s) (10H m) -j <T\ I * ft W SO o w o Kl -4 • • No Mol Formula 9267 ^35^33^4^5 mass spec data mass (intensity) 595 mode Cl 'H nmr data solvent/field CDC13/400MHz 2 80 (8H m) 3 20 (3H s) 3 70 (2H t) 70 (IH t) 6 60 (IH s) 7 0 (IH brs) (9H m) 3 10 (2H q) 3 65 (2H s) 3 80 (2x3H s) 6 52 (IH s) 6 95 (IH s) 7 10-8 10 9272 C «,W, 190(100) CI CDCl3/400flHz 2 30 (3H s) (8H in) 3 00 (2H s) 3 80 (IH s) 6 65 (IH s) (IH s) 7 10 (2H d) 7 30 (5H m) (4H in) 7 80 (IH s). 8 10 (IH s) (IH brs) 2 70-2 90 (3H s) 3 65 (2/3H s) 6 58 7 05 7 20-50-7 60 8 00 8 70 7 (IH d), 9273 CDC13/400MHz 2 30 (3H s) (8H in) 3 00 (2H s) 3 80 2 70-2 90 (3H s) 3 60 (2x3H s) 6 55 (IH s) 6 60 (IH s) 7 00 (IH s) 7 00- 7 85 (2H t) 8 10 (111 s) 7 60 (10H m) 8 05 (IH s) 8 75 (IH brs) 9274 CDCl3/400MHz 2 25 (3H s) 2 70-2 90 (8H m) 3 0 (3H s) 3 65 (2H s) 3 85 (2x3H s) 6 55 (IH s) 6 60 (IH s) 7 05 (IH s). 7 10 (IH s) 7 10- 7 60 (11H m) 7 80 (IH d) 8 00 (IH s) 8 45 (12H brs) P o \o o V© o • $ • • No Hoi Formula mass spec data !H nmr data mass (intensity) mode solvent/field 6 9275 700(100) ESI CDC y 400MHz 2 00 (6H.s) 2 20 (2H t) 2 75-2 95 (8H,m) 3 65 (2H s) 3 75 (2H t) 3 85 (2x3H s) 6 55 (IH s) 6 60 (IH s) 7 05 (IH s) / 20 (IH s) 7 20-7 60 (10H m) 7 90 (IH d) 7 95 (IH s) 8 00 (IH s) 8 20 (lh brs) 9276 c39hj8n406 659(100) CI CDC y 400MHz 2 75-2 95 (8H ra) 3 00 (3H s) 3 70 (2H s) 3 90 (2x3H s) 6 55 (IH s) 6 65 (IH s) 6 80 (2H d) 7 00-7 30 (6H m) 7 60 (4H m) 7 80 (IH d) 8 00 (IH s) 8 40 (IH s) 8 60 (IH s) 9299 c4?h4-n407 715(50) ESI CDC13/400MHz 1 20 (3H t) 2 70-2 90 (8H m) 3 65 (2H s) 3 80 (2x3H s) 3 90 (2H q) 4 30 (2H s) 6 55 (IH s) 6 60 (IH 5) 7 05 (IH s) 7 20 7 45 (9H m) 7 55 (4H m) 8 00 (IH s) 8 05 (IH s) 8 45 (IH brs) 9300 ds-DMSO/400MHz 2 65-2 85 (8H m) 2 85 (3H s) 3 55 (2H s) 3 70 (2x3H s) 6 65 (2/1H s) 6 85 (3H ra) 7 05 (IH s) 7 10 7 75 (8H id) 7 85 (IH d) 8 10 (IH s) 9 75 (IH s) 10 15 (IH s) 10 60 (IH brs) p § © v© e» cd ft td v© C£i S Ui o M -J • • • # .
Hoi Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 6 9300 HCl d6-DMS()/400MHz 2 85 (3H s) 2 90-3 30 (8H m) 3 35 (2H s) 3 70 (2x3H s) 6 80-6 95 (5H 7 05 (IH S) 7 10-7 35 (6H m) 7 60 (IH t) 7 75 (2H m) 7 85 (IH d) 8 10 (IH s) 9 90 (IH s) 10 25 (IH s) 9301 CDCl3/400MHz 2 70-2 85 (8H m) 2 90 (3H.s). 3 50 (2H s) 3 65 (2x3H s) 6 65 (2xlH s) 6 70-6 80 (3H n) 6 85 (IH s) 7 00 (IH s) 7 20- 7 85 (9H m) 8 10 (IH s) 9 50 (IH s) 10 20 (IH s) 9306 HCl C.,H42N40s HCl d6-DM50/400MHZ 0 90 (3H t) 1 30-1 52 (4H m) 2 68 (2H q) 2 90-3 00 (2H m) 3 10 (411 ro) 3 20 (3H s) 3 30 (2H m) 3 75 (2x3H s) 4 25 (IH dd) 4 50 (IH bd) 5 75 (IH t) 6 78 (IH s) 6 81 (IH s) 6 83 (IH S) 7 30 (2H d) 7 52 (IH t) 7 69 (IH d) 7 78 (2H d) 7 85 (IH d) 8 06 (IH s) 10 30 (IH s) 10 42 (IH s) 10 56 (JJI bs) 9308 Cl^HjgfJ^Oj 645 CI CDCl3/400MHz 2 60-2 95 (8H m) 3 15 (3H s) 3 20 (2H d) 3 /0 (2H d) 3 70 (2H s) 3 85 (2x3H s) 4 30 (IH t) 6 55 (IH s) 6 60 (IH s) 6 65 (IH s) 7 05-8 50 (15H w)

Claims (15)

• 9 • • TABLE 10 No Hoi Formula mass spec data 1 'H nmr data mass (intensity) mode solvent/field 6 4 1 CDCyiOOfiHz 2 70-2 94 (BH m) 3 64 (2H s) 3 83 (2x3H s) 6 53 (Iff s) 6 60 (IH s) 7 27 (2H d) 7 57 (2H d) 7 68 (IH t) 7 93 (IH s) 8 03 (IH d) 8 19 (IH d) 8 34 (IH s) 10 09 (IH s) 4 2 CDCl3/400MHz 2 72-2 96 (8H m) 3 65 (2H s) 3 82 (2x3H s) 6 54 (IH s) 6 61 (IH s) 7 28 (2H d) 7 56 (2H d) 7 82 (IH s) 7 97-8 04 (4H m) 10 11 (IH s) 4 3 431(80) CI CDC13/400HHz 2 92 (4H m) 3 70(2H s) 3 82- 3 87 (8H m) 6 50 (IH s) 6 61 (iH s) 7 47 (2H d) I 64 (2H d) 7 70 (IH t) 7 97 (IH s) 8 05 (IH m) 8 37 (IH m) 10 12 (111 s) 4 4 Cjs^jo^Oj 459(100) 445(60) CI CDCy 400MHz
1 93 (2H m). 2 47-2 85 (8H m) 3 57 (2H s) 3 83 (2x3H s) 6 53 (IH s) 6 60 (IH s) 7 24 (2H d) 7 59 (2H d) 7 68 (111 m) 8 04 (2H m) 8 20 (IH m) 8 37 (IH s) 10 09 (IH s) 4 5 C?6^?6^A 431(3) 19?(100) CI CDC1,/400MHz 2 86-3 04 (4H m) 3 72 (2H s) 3 84 (2x3H s) 3 88 (2H s) 6 48 (IH s) 6 61 (IH s) 7 40-8 10 (8H m) 10 11 (IH s) 4 6 ^2sH24N20? 385(10) 146(70) 130(100) CI CDC13/400HHz 2 76-3 04 (8H m) 3 79 (2H s) 7 00-8 10 (13H m) 10 10 (IH s) % O 96/20190 PCT/GB95/03027 - 81 -CLAIMS 2978 47 A piperazinedione «ierivati\e of the formula (I) O ,R3 (I) 10 15 20 25 wherein Rj is (i) a group Ra Rb -fCHsJp Re Rd wherein p is 0 or 2, each of Ra to Re, which may be the same or different, is independently selected from hydrogen, C,-C6 alkyl unsubstituted or substituted by one cr more halogen atoms, C3-C6 alkenyl, C^C,; alkoxy, C,-Cfi alkvlthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH:0H, -CH2COOH, -C02Ri:, -NHCOR11, -NHSO:R13, -S02R13, -CON (RUR12) , -SOR13, -S02N(RuR12) , -N(R11R12}, -0 (CH:; _N (R11R1?) , -0 (CH2) nC03Ru, -OCOR'1, -CH2OCORn, -CH.NHCOR1-, -CH2NnCOOR13, -CH,SRU, -CHiSCOR11, -CH-.S (O) mRn wherein m is 1 or 2, -CH2NHC0(CH2)rC02Ru, -N (R11) COR12, -NKCOCF,, -NHCO (CHj) nCO;Ru, -NHCO(CH2)nOCORu ana -NHCO (CH2) rC02Ru , wherein n is 0 or is an inteaer of from 1 to 6, each of R11 SUBSTITUTE Snt£T (fiUus O 96/20190 PCT/GB95/03027 2 9 7 8 4 7 and R12 is independently H or Cj-Ce alkyl and R13 is C^-Cj alkyl, or any of Ra and Rb, Rb and Rc, Rc 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, (11) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from 0, N and S, which group may be fused to a benzene ring, (in) a Cj-Cg alkyl or C5-C7 cycloalkyl group, or (iv) a Cs-C7 cycloalkenyl group which is unsubstituted or substituted by C2-C6 alkenyl, R2 is H, Cj-Cj alkyl optionally substituted by a qroup -N(RUR12) as defined above, C3-C6 cycloalkyl, C2-C6 alkenyl, -COOR11 wherein R11 is as defined above or a phenyl group as defined under (l) 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 Cj-Cs alkoxy, or R5 and R6 together form a methylenedioxy group, and 1S a double bond or, when Rj is as defined under (l) above, is a double bond or a single bond, substitute sheet (rule 26) O 96/20190 PCT/GB95/03027 2978 4 7 or a pharmaceutically acceptable salt thereof
2 A compound according to claim 1 wherein R1 is a phenyl group as defined under (l) in which one of Ra to Re is selected from hydroxy, C^-C,, alkoxy, NHCOR11, -COjR11, -N (RUR12) , -O (CHi) nN (RUR12) , -SO.R13, -CON (RllR12) , N02, -SO=N(R11R12) , -SOR13, -MR11)COR12 and halogen, and the other four of Ra to Re are H
3 A compound accox-dmg to claim 1 or 2 wherein R1 is a phenyl group as defined under (1) m which each of Ra to Re is hydrogen, or one of Ra, Rb and Rc is halogen or Cj-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 R-' 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-l,2,3,4-tetrahydro-2-isoqumolyl) ethyl)phenyl^ -4- ( (3Z, 6Z) -6-benzylidene-l-ethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9112) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoqumolyl) ethyl)phenyl) -4- ( (3Z, 6Z) -l-benzyl-6-benzylidene- 2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9113) SUBSTITUTE SHEET (RULE 26) K O 96/20190 PCT/GB9S/03027 - 84 - oQ78 a 7 N- (4 - (2- (6 , 7-Dimethoxy-1, 2 , 3 , 4 - tetrahydro-2 - Cm** ' v » / isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzyliaene-1-cyclopropylmethyl-2 , 5-dioxo-3- piperazmylidene)methylbenzamide, hydrochloride (9114) N-(4- (2 - (6 ,7-Dimethoxy-1,2,3,4-tetrahydro-2- lsoquinolyl)ethyl)phenyl)-4-((3Z,GZ)-6-(3-furylmethylene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide « hydrochloride (910 8) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoqumolyl) ethyl) phenyl) - 4- ( (3Z, 6Z) -6 - (4-methoxybenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene)methylbenzamide, hydrochloride (9109) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-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-1,2,3,4-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-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3- &jbstitute sheet (rule 26) O 96/20190 PCT/GB95/03027 2 9 7 8 4 7 chlorooenzylidene)-l-methyl-2,5-dioxo-3- *«- ' * piperazinylidene)methylbenzamide, hydrochloride (9093) N- (4 (2 - (S,7-Dimethoxy-1,2,3,4 -tetrahydro-2-isoqumolyl) ethyl) phenyl) -4- { (3Z, £Z) -l-methyl-2, "5 dioxo-6-(3-pyridylmethylene) - 3-piperazinylidene)methylbenzamide, hydrochloride (9110) N- (4 - (2 - (C,7-Dimethoxy-1,2,3,4-tetrahydro-2 -isoquinolyl)ethyl; phenyl)-4-({3Z,6Z)-l-methyl-2,5-dicxo-6-(3 -thenylidene)-3-pipers? my1idene)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)methylbenzamide (9155) N-(4 -(2-(S,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoquinolvl)ethyl)phenyl *-3 -( {3Z,6Z)-l-methyl-2,5-dioxo-6 -(3-tnenyiidene)-3-piperazinylidene)methylbenzamide (Q160) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-;(3Z,6Z)-6-(3-chlorobenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9157) N-(4 - (2 - (6,7-Dimethoxy-1,2 r 3,4-tetrahydro-2- sjbstitute sheet (rule 26) 'O 96/20190 PCT/GB95/03027 , 2 9 7 8 4 7 isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-{2-chlorobenzylidene)-l-methyl-2,5-dioxo-3-piperazmyl idene)methylbenzamide (9158) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2 - isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-furylmethylene)-1- methyl-2,5-dioxo-3-piperazinyiidene)methylbenzamide (9159) N-(4 - (2-(6,7-Dimethoxy-1,2,3,4-tetranydro-2-isoqumolyl) ethyl) phenyl) -3- ( (3Z, 6Z) -6- (3-methoxybenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene)methylbenzamide (9156) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- lsoqumolyl) ethyl) phenyl) -3- ( (3Z, 6Z) -6 -benzylidene-l-ethy] - 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-l-cyclopropylmethyl-2,5-dioxo-3 -piperazinylidene)methylbenzamide (9141) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4 -((3 Z r6Z)-l-allyl-6-benzylidene-2,5-dioxo-3-piperazmylidene)methylbenzairide (9178) substitute sheet (rule 26) 10 $ 20 25 29 7 8 4 O 96/20190 PCT/GB95/03027 - 87 - N-(4 -(2-(6,7 -Dimethoxy-1,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)- 3-((32,6Z) -l~allyl-6-benzylidene-2,S-dioxc-3-piperazmylidene)methylbenzamide (9179) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-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-1,2,3,4-tetrahydro-2-lsoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-l-methyl-6-(1-naphthyl)methylene-2,5-dioxo-3 -piperazinylidene)methylbenzamide (9194) 15 N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3-((3Z, 6Z) - l-methyl-6-(1-naphthyl)methylene-2,5-dioxo-3-piperaz my1idene)methylbenzamide (9195) N-(4-(2 -(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-6-(2-furyl)methylene-l-methyl-2,5-dioxo-3 piperazinylidene)methylbenzamide (9196) N- (4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- substitute sheet (rule 26) O 96/20190 PCT/GB95/03027 2 9 7 8 4 7 3-((3Z,62)-6-(2-furyl)methylene-1-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9197) N- (4 - (2- (6 ,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3Z,6Z)-l-methyl-6-(1-methyl-3-pyrrolyl)methylene-2,5-dioxo-3-piperazmylidene)methylbenzamide (9198) N- (4- (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-l-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-lsoqumolyl) ethyl) phenyl) - 3-((3Z,6Z)-l-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9209) N- (4- (2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4- ( (3Z, 6Z) - l-methyl-6 - (1-methyl-3-mdolyl) methylene-2 , 5-dioxo-3-piperazinylidene)methylbenzamide (9210) N- (4- (2-(6,7-Dimethoxy-1,2,3,4-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) SUBSTITUTE shtet (rule 26) •u 10 15 20 25 O 96/20190 PCT/GB95/03027 9 9 7 8 4 7 N- (4- (2 - (6 , 7-Dimethoxy-1, 2,3, 4-tetrahydro-2- L w w ' ' 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)phenyl)- 4-((3Z,6Z)-l-methyl-6-(3-methylbenzo(b)thi3n-2-yl)methylene-2 , 5-dioxo-3-piperazinylidene)methylbenzamide (9215) N-(4 -(2 -(6,7 -Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)pher yl)- 3- ( (3Z, 6Z) -6 -benzyl idene -1-met hoxycarbony lme thyl - 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)-l-methyl-6-(2-methylpropylidene) -2 , 5-d£oxo-3-piperazinylidene)methylbenzamide (9228) N-(4 -(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4- ((3Z,6Z)-1-methyl-6-cyclohexylmethylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9229) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl)phenyl) - substitute sheet (rule 26) 0 96/20190 PCT/GB95/03027 , 29 7 8 4 7 3-((3Z,6Z)-l-methyl-6-cyclohexylmethylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9230) N- (4- (2-(6,7-Dimethoxy-1,2,3,4-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-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- -3-( (3Z,6Z)-l-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)-l-methyl-S-(2-methylpropylidene)-2,5-dioxo-3-piperazmylidene) methylbenzamide (9233) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 4-((3 Z,6Z)-6-(3,3-dimethylbutylidene)-l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9234) N- (4- (2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(3, 3-dimethylbutylidene)-l-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9235) substitute shccmrule ot 0 96/20190 PCT/GB95/03027 - 91 - N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2- 29 7 8 47 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-lsoqumolyl)ethyl)phenyl) - 3-((3Z,6Z)- 6-benzylidene-1-carboxymethyl-2,5-dioxo-3-piperazmyl idene)methylbenzamide (9241) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-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-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-l-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)-l-methyl-6-(2-naphthyl)methylene-2,5-dioxo-3-piperazmylidene) methylbenzamide (9261) N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-l-methyl-2,5-dioxo-6-(3-phenylpropylidene)-3-piperazmylidene) methylbenzamide (926'6) SUBSTITUTE SHEET (RULE 26) WO 96/20190 PCT/GB95/03027 - 92 - N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isod 4-((3Z,6Z)-l-methyl-2,5-dioxo-6-(3-phenylpropylidene)-3-piperazinylidene)methylbenzamide (9267) o Q 7 8 4 7 jpiinoiyl) ethyl) - 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-piperazmylidene) methylbenzamide (9772) 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-piperazmylidene) methylbenzamide (9273) N-(4 -(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3-((3Z,6Z)-6-(2-acetoxybenzylidene)-1-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9274) N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-benzylidene-l-(2-dimethylaminoethyl)-2, 5-dioxo-3-piperazinylidene)methylbenzamide 19275) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-l soqumolyl) ethyl) phenyl) - 3-({3Z,6Z)-6-(4-hydroxybenzylidene)-l-methyl-2, 5-dioxo-3- SUBSTITUTE SHEET (RIH.E 26) WO 96/20190 - 93 - piperazinylidene)methylbenzamide (9276) pct/gb95/03027 297847 N-(4- (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-benzylidene-l~ethoxycr»rbonylmethyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9299) N-(4-(2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoguinolyl)ethyl)phenyl)- 3-((3Z,6Z)-6-(2-hydroxybenzylidene)-1-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9300) N-(4-(2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoqumolyl) ethyl) phenyl) - 3-((3Z,6Z)-6-(3-hydroxybenzylidene)-l-methyl-2,5-dioxo-3-piperazmylidene) methylbenzamide (9301) N-(4- (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-lsoqumolyl) 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-lsoqumolyl) etnyl) phenyl) -3-((3Z)-1-methyl-6-benzyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9308) substitute sheet (rule 26) 10 WO 96/20lyO lfCT/GB95/03027 / 2.9 7 8 4 7
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 m claim 1, which process comprises treating a compound of formula (II) (») wherein R1, R2 and are as defined m claim 1, with a 15 compound of formula (III) (CHsJq—N (IH) 20 wherein one of R7 and R8 is hydrogen and the other is -CHO, and q, r, R5 and R6 are as defined m claim 1, in the presence of a base m an organic solvent, and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof 25
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 SUBSTITUTE SHEET (RULE 26) 95 - 4 7 1 to 5 in. the manufacture of a medicament for use as a modulator of multi-drug resistance
10. A compound of formula III R7 r8^' C-NH il O (CHjj)q—* (m) wherein q, r, R5 and R6 are as defined m claim 1, one of R7 and Ra is hydrogen ana the other of R7 and R0 is -CHO
11. A piperazinedione derivative of the formula (I) as defined m claim 1 substantially as herein described with reference to any example thereof.
12. A pharmaceutical or veterinary composition as claimed in claim 7 substantially as herein described with reference to any example thereof.
13. A process as claimed in claim 7 substantially as herein described with reference to any example thereof.
14. A use as claimed in claim 9 substantially as herein described with reference to any example thereof.
15. A compound of formula (III) as defined in claim 10 substantially as herein described with reference to any example thereof. / 5 mar .339 p r - i i -
NZ297847A 1994-12-23 1995-12-22 Piperazine-2,5-dione derivatives and their use as medicaments NZ297847A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9426224.3A GB9426224D0 (en) 1994-12-23 1994-12-23 Pharmaceutical compounds
PCT/GB1995/003027 WO1996020190A1 (en) 1994-12-23 1995-12-22 Piperazine 2,5 dione derivatives as modulators of multi-drug resistance

Publications (1)

Publication Number Publication Date
NZ297847A true NZ297847A (en) 1999-04-29

Family

ID=10766589

Family Applications (1)

Application Number Title Priority Date Filing Date
NZ297847A NZ297847A (en) 1994-12-23 1995-12-22 Piperazine-2,5-dione derivatives and their use as medicaments

Country Status (19)

Country Link
EP (1) EP0799222A1 (en)
JP (1) JPH10511384A (en)
CN (1) CN1175253A (en)
AU (1) AU698828B2 (en)
BG (1) BG101602A (en)
BR (1) BR9510410A (en)
CA (1) CA2207500A1 (en)
CZ (1) CZ190097A3 (en)
FI (1) FI972660A (en)
GB (1) GB9426224D0 (en)
HU (1) HUT77943A (en)
IL (1) IL116525A0 (en)
NO (1) NO972937L (en)
NZ (1) NZ297847A (en)
PL (1) PL320916A1 (en)
SK (1) SK83697A3 (en)
TW (1) TW358094B (en)
WO (1) WO1996020190A1 (en)
ZA (1) ZA9510909B (en)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA979329B (en) * 1996-10-18 1999-04-19 Xenova Ltd Pharmaceutical compounds
GB9717576D0 (en) * 1997-08-19 1997-10-22 Xenova Ltd Pharmaceutical compounds
GB9708805D0 (en) 1997-05-01 1997-06-25 Smithkline Beecham Plc Compounds
GB9810876D0 (en) 1998-05-20 1998-07-22 Smithkline Beecham Plc Compounds
CA2346689A1 (en) 1998-10-08 2000-04-20 Gregor James Macdonald Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents)
IL150430A0 (en) * 2000-01-18 2002-12-01 Nereus Pharmaceuticals Inc Cell division inhibitors and process for producing the same
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US7919497B2 (en) 2002-08-02 2011-04-05 Nereus Pharmaceuticals, Inc. Analogs of dehydrophenylahistins and their therapeutic use
US7935704B2 (en) 2003-08-01 2011-05-03 Nereus Pharmaceuticals, Inc. Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
IL166628A0 (en) 2002-08-02 2006-01-15 Nereus Pharmaceuticals Inc Dehydrophenyl lahistins and analogs thereof and the synthesis of dehydrophenyllahistins and analogs thereof
US8129527B2 (en) 2006-11-03 2012-03-06 Nereus Pharmacuticals, Inc. Analogs of dehydrophenylahistins and their therapeutic use
CN103396372B (en) * 2013-08-09 2015-05-20 中国科学院南海海洋研究所 2,5-diketopiperazine derivative, as well as preparation method and application thereof in preparing control agent for resisting marine fouling organisms
US10076518B2 (en) 2015-03-06 2018-09-18 Beyondspring Pharmaceuticals, Inc. Method of treating a brain tumor
US10238650B2 (en) 2015-03-06 2019-03-26 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
MX2018000451A (en) 2015-07-13 2018-05-07 Beyondspring Pharmaceuticals Inc Plinabulin compositions.
RU2753543C1 (en) 2016-02-08 2021-08-17 Бейондспринг Фармасьютикалс, Инк. Compositions containing tucaresol or analogues thereof
WO2017214052A1 (en) 2016-06-06 2017-12-14 Beyondspring Pharmaceuticals, Inc. Composition and method for reducing neutropenia
WO2018129381A1 (en) 2017-01-06 2018-07-12 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
JP2020514412A (en) 2017-02-01 2020-05-21 ビヨンドスプリング ファーマシューティカルズ，インコーポレイテッド Methods for reducing neutropenia
KR20200112881A (en) 2018-01-24 2020-10-05 비욘드스프링 파마수티컬스, 인코포레이티드. Composition and method for reducing thrombocytopenia through administration of plinabulin

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0649410B1 (en) * 1992-07-10 1997-05-02 Laboratoires Glaxo Sa Anilide derivatives
GB9217331D0 (en) * 1992-08-14 1992-09-30 Xenova Ltd Pharmaceutical compounds

Also Published As

Publication number Publication date
IL116525A0 (en) 1996-03-31
WO1996020190A1 (en) 1996-07-04
BG101602A (en) 1998-02-27
ZA9510909B (en) 1996-08-30
AU4310096A (en) 1996-07-19
FI972660A0 (en) 1997-06-19
NO972937D0 (en) 1997-06-23
NO972937L (en) 1997-06-23
GB9426224D0 (en) 1995-02-22
TW358094B (en) 1999-05-11
AU698828B2 (en) 1998-11-05
EP0799222A1 (en) 1997-10-08
HUT77943A (en) 1998-12-28
CA2207500A1 (en) 1996-07-04
JPH10511384A (en) 1998-11-04
PL320916A1 (en) 1997-11-10
SK83697A3 (en) 1998-05-06
CZ190097A3 (en) 1998-01-14
BR9510410A (en) 1999-09-08
FI972660A (en) 1997-08-22
CN1175253A (en) 1998-03-04

Similar Documents

Publication Publication Date Title
NZ297847A (en) Piperazine-2,5-dione derivatives and their use as medicaments
EP1040103B1 (en) Anilide derivative, production and use thereof
US6218393B1 (en) Anthranilic acid derivatives as multi drug resistance modulators
AU2017312712B2 (en) Beta-amino-isoquinolinyl amide compounds
CA3133753A1 (en) Novel small molecule inhibitors of tead transcription factors
EP3154954B1 (en) Metabotropic glutamate receptor negative allosteric modulators (nams) and uses thereof
JP2010514689A (en) Heteroaryl-heteroaryl compounds as CDK inhibitors for the treatment of cancer, inflammation and viral infections
KR20190076031A (en) Pyrrolamide &amp;lt; / RTI &amp;gt; as an alpha V integrin inhibitor
JP2003529584A (en) Pharmaceutically active pyrrolidine derivatives as Bax inhibitors
JP2007520440A (en) Indan derivatives as muscarinic receptor agonists
JPWO2005080322A1 (en) Fluorene derivative
JP2023540661A (en) Methods and compositions for targeting Tregs using CCR8 inhibitors
AU1711999A (en) Acyl guanidine sodium/proton exchange inhibitors and method
JP2008542242A (en) Novel tetrahydropyridothiophene
AU700891B2 (en) Piperazine-2,5-dione derivatives as modulators of multidrug resistance
Awasthi et al. A three-component, general and practical route for diastereoselective synthesis of aza-spirocyclic pyrazolones via a decarboxylative annulation process
JP2004519486A (en) CHROMAN DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND USE AS ANTI-TUMOR AGENT
EP1683523A1 (en) 2-Phenylquinoxalines as inhibitors for MPP1
JPH11240832A (en) Amide or amine derivative
CA2700893A1 (en) Substituted tetrazole compounds and uses thereof
KR20230026487A (en) Compounds and Uses as MIF Inhibitors
US7053223B2 (en) Inhibitors of farnesyl protein transferase
JP2007502308A (en) Substituted thiophenes and their use
Varlamov et al. Intramolecular [4+ 2] cycloaddition of furfurylsubstituted homoallylamines to allylhalides, acryloyl chloride and maleic anhydride
KR101082227B1 (en) Methanesulfonic acid salt of pyrazolopyrimidine compound crystal thereof and process for producing the same