NO972937L - Pharmaceutical piperazine compounds - Google Patents

Description

Pharmaceutical piperazine compounds

The present invention relates to compounds which are useful as modulators of multidrug resistance (MDR), their preparation and pharmaceutical and veterinary compositions containing them.

The resistance of tumors to treatment with certain cytotoxic agents is an obstacle to successful chemotherapeutic treatment of cancer patients. A tumor can acquire resistance to cytotoxic agents used in a previous treatment. A tumor may also manifest intrinsic resistance, or cross-resistance, to a cytotoxic agent to which it has not been previously exposed, which agent is unrelated in terms of structure and mechanism of action to any agent used in previous treatments of the tumor.

Analogously, certain pathogens can acquire resistance to pharmaceutical agents used in previous treatments of diseases or disorders caused by these pathogens. Pathogens can also manifest intrinsic resistance, or cross-resistance, to pharmaceutical agents to which they have not previously been exposed. Examples of this effect include multidrug-resistant forms of malaria, tuberculosis, leishmaniasis and amoebic dysentery.

The above-mentioned phenomenon is collectively reserved for multidrug resistance (MDR). As discussed fully below, a plasma membrane glycoprotein (P-gp) is implicated in the mechanism underlying MDR. P-gp has drug-binding properties. Certain agents capable of modulating MDR can therefore also be useful in facilitating drug delivery across the blood-brain barrier and in the treatment of AIDS and AIDS-related complex.

Disadvantages of drugs that have been used to modulate MDR, called resistance modifying agents or RMA, are that they often have a poor pharmacokinetic profile and/or are toxic at the concentrations required for MDR modulation.

A number of piperazinedione derivatives have been found to have activity as modulators of multidrug resistance. Accordingly, the present invention provides a piperazinedione derivative of formula (I):

wherein Rx is (i) a group wherein p is 0 or 2; each of R a to R e , which are the same or different, is independently selected from hydrogen, C-L-Cj alkyl unsubstituted or substituted with one or more halogen atoms, C 1-C 8 alkenyl, C 1-C 6 alkoxy, C 1-C 8 -alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH2OH, -CH2COOH, -COjR<11>, -NHCOR<11>, -NHSO.R11, -SO2R<13>, -CON (R1XR12) , -SOR13, - SO2N(R11R12) , -N(R13R12), -0 (CH2) nN (R1XR12) , -0 (CH2) nCOjR11, -0C0R-<11>, -CH^COR11, C^NHCOR<11> , -CH2NHCOOR13, -CH2SRU, -CHjSCOR<11>, -CH2S(0)mR<1>3 where m is 1 and 2,

-CHjNHCOtCHjJnCOjR<11>, -N (R11)COR12, -NHCOCF3,

-NHCOCCH^nCOjR<11>, -NHCOfCH^OCOR11 and NHCO (CH2) nCC^R11, wherein n is 0 or an integer in the range 1-6, each of R<11> and R<12> is independently H or C-L- C8-alkyl and R<13> are C8-C8-alkyl (or any of Ra, Rb, Rb and Rc, Rc and Rd or Rd and Re together form a methylenedioxy group, or together with the carbon atoms to which they are attached form a benzene ring which is optionally substituted: (ii) 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;

(iii) a C 1 -C 8 alkyl or C 5 -C 7 cycloalkyl group, or

(iv) a C 5 -C 7 cycloalkenyl group which is unsubstituted or substituted with C 2 -C 6 alkenyl; R2 is H, C1-C6 alkyl optionally substituted with a group -N(RX1R<12>) as defined above, C3-C6 cycloalkyl, C2-C6alkenyl, -C00R<11>wherein R<11> is as defined above, or a phenyl group as defined under (i) above, but is something other than H when R<1>is unsubstituted phenyl, and one of R<3> and R<4> is hydrogen and the other is a group of formula (A);

wherein q is an integer in the range 1-4, r is 0 or 1 and R<5> and R<6>, which may be the same or different, are each H or C₁-C₆ alkoxy, or R<5>and R<6> together form methylenedioxy group; and ----- is a double bond or, when R<1> is as defined under (i) above, is a double bond or a single bond; or a pharmaceutically acceptable salt thereof.

A C 1 -C 8 alkyl group can be linear or branched. A C 1 -C 8 alkyl group is typically a C 1 -C 1 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group . A C3-C6 cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A halogen is, for example, fluorine, chlorine, bromine or iodine.

A C 1 -C 8 alkoxy group is typically a C 1 -C 6 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec.-butoxy or tert.-butoxy group. A C2-C6 alkenyl group is, for example, C2-C4 alkenyl, for example ethenyl, prop.-1-enyl or prop.-2-enyl.

A heterocyclic group can, for example, be a pyridine, pyrrole, furan or thiophene group which is attached via one of its constituent ring atoms. It can be, for example, a 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl group.

The integer q is in the range 1-4 and preferably 1 or 2.

R<5> and R<6> are preferably the same and preferably C1-C4 alkyl, for example methyl.

When R<1> is as defined under point (i), the phenyl group is unsubstituted or substituted at one or more of positions 2-6. When it is monosubstituted, it can be the substituent in any of positions 2-6, for example position 3 or 4, especially position 4. Thus, for example, one of Ra to Re is other than hydrogen, preferably Rb or Rc, especially Rc. When the phenyl group is monosubstituted, the substituent Ra to Re is preferably selected from a halogen, for example chlorine, bromine or fluorine; a C 1 -C 8 alkoxy group, for example OMe; and an acetamido group - NHAc where Ac denotes acetyl.

The phenyl group can instead be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-disubstituted, or 2,3,4-, 2,3,5-, 2,3,6- or 3 , 4 , 5 -trisubstituted.. When it is disubstituted, three of Ra to Re are hydrogen and two are something 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 something other than hydrogen while, in this case, the other three of Ra to Re are hydrogen .

When the phenyl group is trisubstituted, two of Ra to Rc (Re?) 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 while, in this case, the other two of Ra to Re are hydrogen.

In a preferred series of compounds of formula (I), each of Ra to Re is hydrogen. In another preferred series of compounds, one of R a to R e is selected from hydroxy, C 1 -C 8 alkoxy, NHCOR<11>, -COaR<11>, -N (R1XR12) , -O(CH2)nN (RX1R12) , -S02R13, CON(R11R12), N02, -S02N (R^R12) , -SOR13, -N(R<11>)COR<12> and halogen, and the other four of Ra to Re are H. Alkoxy can for example be OMe or OBu<n>. NHCOR<11> is typically -NHAc. Co2R<i:L>is typically -COOH or COOMe.

N(R<13>R<12>) is typically NMe2. -CON(R<u>R<12>) can be -CONH2. S02R<13> is typically S02Me, S02N(RX1R12) is for example -S02NMe2. SOR<13>can be SOMe and -N(R<11>)COR<12>can be -NMeCOBufc. Halogen is typically F or Cl. Preferably, Rc is alkoxy, especially OMe or OBu"; NHCOR13, especially -NHAc; -CO^<11>, especially -CO2H or -Co2Me; -CON(R11R12) especially -CONH2; N02; N(R<1X>R12) especially NMe2; -SOR<13>especially -SOMe; -SO2N (R<1X>R12) especially -SO2NMe2or 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 while the others are hydrogen. For example, one of Ra, Rb and Rc is something other than hydrogen. Alternatively, Ra and Rc, or Rb and Rc are something other than hydrogen. Preferred values for one or both of Ra to Re other than hydrogen include C 1 -C 8 alkoxy such as OMe or OBun, halogen such as Cl or F, hydroxy, -N(R11R12), -COjR<11>, - CH 2 SCOR 13 , -CH 2 SRX 1 , NHCOR<11>, -O (Ch 2 ) nN (RX 1 R 12 ), -O(CH 2 ).

nCO^1<1>, -Ch2NHC0(CH2)nC02R<11>, -NHCOO^OR11, -NHC0CH2

OCOR13, -CH2NHC00R<13>and CF3.

Particularly preferred compounds are those wherein Ra, Rb and Re are each H, and Rc is selected from H, OMe -NHAc, -CO 2 H,

-CO2Me, -CONH2, NO2, NMe2, SO2Me, -SOMe and -SO2NMe2. Also preferred are compounds in which Ra to Re are preferably each independently selected from H, halogen, hydroxy, C1-C6 alkoxy, nitro, -CH2SC0R<13>, -O^SR<11>, -CO2R<13>, -OCOR< 13>, CF3, - 0 (CH2) nN (RX1R12) , - 0 (CH2)nC02R<11>, -CH2NHC0(C<H>2)nC02R<11>, -N(R11R12), -NHCO (CH2) nOCOR11, -NHC0(-CH^a^R11 and -CH2NHC02R1<3>or Rb, Rb and Rc, Rc and Rd, or Rd and Re form a methylenedioxy group or together with carbon atoms to which they are attached form an alternatively substituted benzene ring Even more preferably, Ra and Rb are independently H, nitro or halogen, Rc is H, hydroxy, -0(CH2)nN(R11R12), -OCOR13, -0(CH2)nC02R1:L, -CHjNHOMCHj^COzR<11> . SR 11 or -NHCOR<11>, Rd is H, halogen, C 1 -C 4 alkoxy, -CH 2 SCOR<13>, CH 2 SR 1 :L or -COjR<11>, and Re is H, nitro or halogen.

When any two adjacent groups of Ra to Re together with the carbon atoms to which they are attached form a benzene ring, which ring is unsubstituted or it may be substituted with any of the alternatives specified above for Ra to Re. The benzene ring together with the phenyl group forms an alternatively substituted naphthalene ring structure. 1 an embodiment of formula (I) is R<1> a phenyl group as defined above, which group is unsubstituted or monosubstituted in position 2, 3 or 4 with Cl or MeO, or is a pyridyl, furyl or thienyl group, R<2> is H, CH3, cyclopropyl or phenyl, and one of R<3> and R<4> is H, and the other is a group of formula (A) wherein q is 2 each of R<5 >and R<6>is a methoxy group.

In another embodiment, R<1> is unsubstituted phenyl, R<2> is C1-C4 alkyl, preferably methyl, or phenyl or cyclopropyl, R<3> is H and R<4> is a group of formula (A) wherein q is 2 and each of R<5> and R6 is MeO. A third embodiment is R<1> substituted phenyl as defined above, or a furyl, thienyl or pyridyl group, R<2> is H, R<3> is H and R4 is a group of (A) wherein q is 2 and each of R<5> and R6 is MeO. 1 a fourth embodiment R<1> is substituted phenyl as defined above, or a furyl, thienyl or pyridyl group, R<2> is H, R<3> is a group of formula (A), wherein q is 2 and each of R<5> and R<6> is MeO, and R<4> is H.

In a fifth embodiment R<1> is unsubstituted phenyl, R<2> is C 1 -C 1 -alkyl, preferably methyl, phenyl or cyclopropyl, R<3> is a group of formula (A) wherein q is 2 and each of R<5> and R<6> is MeO, and R<4> is H.

When R<1> in the above embodiments 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 according to the invention are as follows: The compound numbering is observed in the rest of the description.

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-ethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9112).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-benzyl-6-benzylidene -2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9113). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro,2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-cyclopropylmethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9114).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3-furylmethylene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9108).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(4-methoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9109).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(4-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9091).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(2-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9092).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9093).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(3-pyridylmethylene)-3-piperazinylidene)methylbenzamide, hydrochloride (9110).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(3-thenylidene)-3-piperazinylidene)methylbenzamide, hydrochloride (9111) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(2-thenylidene)-3-piperazinylidene)methylbenzamide (9155).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(3-thenylidene)-3-piperazinylidene)methylbenzamide (9160).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9157).

N-(4 - (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9158).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-furylmethylene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9159).

j N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-methoxybenzylidene )-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9156).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-ethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide (9139).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-cyclopropylmethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide (9141) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-allyl-6-benzylidene -2,5-dioxo-3-piperazinylidene)methylbenzamide (9178).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-allyl-6-benzylidene -2,5-dioxo-3-piperazinylidene)methylbenzamide (9179). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6- (2-Naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9193).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6- (1-Naphthyl)-methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9194) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( 1-Naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9195).

N-(4-(2-6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-6-(2-furyl) methylene-1-methyl-2n5-dioxo-3-piperazinylidene)methylbenzamide (9196).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-(2-furyl )methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9197).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6- (1-Methyl-3-pyrrolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9198).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( (1-Methyl)-3-pyrrolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9199).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( 2-Naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9209).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-( 1-methyl-3-indolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9210). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6- (3-methylbenzo(b)thien-2-yl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide

(9211).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( 1-methyl-3-indolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9214).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-( 3-Methylbenzo(b)thien-2-yl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide

(9215) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1- methoxycarbonylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9217).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-( 2-Methylpropylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9228) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-cyclohexylmethylene -2,5-dioxo-3-piperazinylidene)methylbenzamide (9229).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6- cyclohexylmethylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9230) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2, 5-dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9231).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5 -dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9232). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6- (2-Methylpropylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9233) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-6-(3,3 -dimethylbutylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9234) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-(3,3 -dimethylbutylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9235) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-6-((4S) -4-isopropenyl-1-cyclohexenyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9236).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1- carboxymethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9241).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-((4S) -4-isopropenyl-1-cyclohexenyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9250).

N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene -2,5-dioxo-3-piperazinylidene) methylbenzamide (9260).

N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene -2,5-dioxo-3-piperazinylidene) methylbenzamide (9261).

N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-1-methyl-2,5-dioxo-6- (3-phenylpropylidene)-3-piperazinylidene)methylbenzamide (9266). N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-1-methyl-2,5-dioxo-6- (3-Phenylpropylidene)-3-piperazinylidene)methylbenzamide (9267) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-(4-acetoxybenzylidene) )-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9272).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9273).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9274).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-( 2-Dimethylaminoethyl)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9275).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-ethoxycarbonylmethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide (9299).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3^.( (3Z,6Z)-6-(2-hydroxybenzylidene ) - 1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9300) .

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl-3-((3Z,6Z)-6-(3-hydroxybenzylidene)- 1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9301).

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl-3-((3Z,6Z)-6-pentylidene-2,5- dioxo-3-piperazinylidene)methylbenzamide (9306).N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl-3-((3Z) -1-methyl-6-benzyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9308).

Compounds of formula (I) can be prepared by a method which comprises treating a compound of formula

(II) :

wherein R<1>, R<2> and ------ are as defined above with a compound of formula (III) :

wherein one of R<7> and R<8> is hydrogen, and the other -CHO, and q, r, R<5> and R6 are as defined above; in the presence of a base in an organic solvent, and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof.

Suitable bases include cesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium t-butoxide and triethylamine.

Suitable organic solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and, in the case of potassium t-butoxide, t-butanol and mixtures thereof.

When DMF is used as solvent, the temperature is typically between 0°C and reflux temperature, for example in the range 80°C-95°C when cesium carbonate is used as base.

When sodium hydride or potassium t-butoxide is used as the base, the reaction mixture is typically heated from 0°C to room temperature or to 40°C. The reaction can be carried out for a period of 1-4 h, for example 2-3 h.

The compound of (II) wherein ----- is a double bond, prepared by a process which comprises treating a compound of formula (IV):

wherein R<1> is as defined above, with an alkylating agent in an organic solvent in the presence of a base. The alkylating agent is typically an alkyl halide R<2->CH2X, a methanesulfonate or p-toluenesulfonate ester, respectively R<2>CH2OS02Me or R2CH2OS02C6H4Me, or a dialkylsulfonate (R2CH20)2S02, where R2 is as defined above, and X is a halogen, for example Cl, Br or I. Suitable bases and solvents include sodium hydride in THF or DMF or mixtures thereof and potassium t-butoxide in t-butanol or THF or DMF or mixtures thereof. The reaction mixture is typically heated from 0°C to room temperature.

Compounds of formula (II) in which ----- is a single bond can be prepared by treating a compound of formula (X):

wherein R<1> is as defined under (i) above, and R2 is as defined above with acetic anhydride. The reaction is typically carried out under reflux, for example for 1-6 h, typically 3 h. The compound of formula (X) can be prepared by treating a compound of (XI): with glycine methyl ester hydrochloride and triethylamine in a solvent, typically CHCl3, at a low temperature, typically -50°C to -70°C, preferably -65°C, for 1-6 hours. This is followed by heating to room temperature overnight. The reaction mixture is then refluxed in a solvent such as toluene for 12-18 h, typically 16 h, to give the desired compound of formula (X).

The compound of (XI) can be prepared by treating a compound of formula (XII):

with phosgene in THF at 0°C, followed by warming to room temperature overnight. The compound with (IV) can be prepared by a process which comprises treating 1,4-diacetyl-2,5-piperazinedione of formula (V): with an aldehyde of formula

wherein R<1> is as defined above, in the presence of a base in an organic solvent. Suitable bases and solvents include triethylamine, cesium carbonate, sodium, 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 thereof.

When triethylamine in DMF is used, the reaction temperature is typically in the range 100-140°C, for example 120-130°C. When potassium t-butoxide is used as a base, the reaction mixture is typically heated from 0°C to room temperature.

1,4-Diacetyl-2,5-piperazinedione can be prepared by the published method (S.M. Marcuccio and J.A. Elix, Aust. J. Chem., 1984, 37, 1791).

Compounds of formula (III) can be prepared by a method which comprises

(i) to react together compounds of the following formula

(VI) and (VII):

wherein, R<5> and R<6> are as defined above, and X is a halogen, in the presence of a base in an organic solvent; (ii) reducing the resulting compound with (VIII):

wherein q, R<5>and R<6> are as defined above, and

(iii) treating the resulting compound with formula

(IX) :

wherein q, R<5> and R<6> are as defined above, and r is 1, med

(a) either 3-formylbenzoic acid in the presence of a coupling agent or a derivative of 3-formylbenzoic acid in which -COOH groups are activated by conversion to the acid halide group - COX in which X is a halogen, for example F, Cl, Br or I, preferably Cl , or the mixed anhydride group

-CO(OCOR') wherein R<1> is C 1 -C 8 alkyl; in both cases to give a compound of formula (III) in which R<7> is hydrogen and R<8> is -CHO: or

(b) 4-formylbenzoic acid in the presence of a coupling agent or a derivative of 4-formylbenzoic acid in which the -COOH group has been activated by conversion to the acid halide group -COX in which X is a halogen, for example F, Cl, Br or I , preferably Cl, or the mixed anhydride group -CO(OCOR') wherein R' is C^Cg alkyl, in either case to give a compound of formula (III) wherein R<7> is -CHO and R<8> is hydrogen.

When the 3- or 4-formylbenzoic acid is activated by conversion of -COOH- to -COX, the reaction is carried out in an organic solvent either with an excess of amines of formula (IX), or in the presence of a base such as a tertiary amine, for example Et3N, or pyridine. The organic solvent is an inert organic solvent such as CH 2 Cl 2 .

When 3- or 4- formylbenzoic acid is activated by conversion of -COOH to -CO(OCOR'), the reaction is carried out with compound (IX) in an inert organic solvent such as CH2C12 or

THF.

The binding agent used in (a) or (b) with the 3- or 4-formylbenzoic acid, respectively, can be, for example, 1-cyclohexyl-3-(2-morpholineethyl)carbodiimide metho-p-toluenesulfonate or 2-chloro-1-methylpyridinium iodide .

The activated acid halide or mixed anhydride derivative of 3- or 4-formylbenzoic acid can be prepared by conventional methods. For example, the acid halide derivative can be prepared by treating the carboxylic acid with a halogenating agent, for example a chlorinating agent such as SOCl2, PC13, oxalyl chloride or PC15. The mixed anhydride derivative can be prepared by treating the carboxylic acid with a C1-C6 alkyl haloformate such as iBuOCOCl or EtOCOCl, in the presence of a base such as Et3N.

The reduction step (ii) is typically carried out using iron powder and concentrated hydrochloric acid in methanol, usually at a temperature of around 80°C and for a period of 1-4-p, for example 3 h. Alternatively, it can be carried out by catalytic hydrogenation over a palladium on carbon catalyst in methanolic HCl, isopropanol or acetic acid.

Other starting compounds are known compounds which can be easily synthesized from known compounds using conventional methods. Compounds of (I) can be converted to pharmaceutically acceptable salts, and salts can be converted to free compounds, by conventional methods. Suitable salts include salts with pharmaceutically acceptable inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, sulfuric acid and orthophosphoric acid. Examples of organic acids include p-toluenesulfonic acid, methanesulfonic acid, mucilaginous acid and succinic acid.

Cancer cells expressing multidrug resistance, referred to as MDR cells, exhibit a reduction in intra-cellular drug accumulation compared to 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 overexpression can add to the cells

MDR phenotype: see, for example, Ann. Fox. Biochem 58., 137-171

(1989).

An important function of P-gp in normal tissues is to export intracellular toxins from the cell. There is evidence indicating that overexpression of P-gp may play a clinical role in multidrug resistance. Increased levels of P-gp mRNA or protein have been detected in many forms of human cancer—leukemia, lymphoma, sarcoma, and carcinoma. In fact, P-gp levels have in some cases been found to be increased in tumor biopsies obtained after relapse after chemotherapy. Inhibition of P-gp function in P-gp-mediated MDR has been shown to lead to a net accumulation of anti-cancer agents in the cells. For example, Verapamil, a known calcium channel blocker, was shown to sensitize MDR cells to Vinca alkaloids in vitro and in vivo: Cancer Res., 41, 1967-1972 (1981). The proposed mechanism of action involves competition with anticancer agents for binding to P-gp. A number of structurally unrelated resistance modifiers acting by this mechanism have been described, for example tamoxifen (Nolvadex:ICI) and related compounds, and cyclosporine A and derivatives.

Compounds of formula I and their pharmaceutically acceptable salts thereof (hereinafter referred to as "the present compounds") have been found in biological studies to have activity in modulating multidrug resistance. The results are given in example 5 below. The present compounds can therefore be used as multidrug resistance modifying agents, also referred to as resistance modifying agents, or RMA. The present compounds can modulate, for example reduce, or eliminate multidrug resistance.

The present compounds can therefore be used in a method for potentiating the cytotoxicity of an agent which is cytotoxic to a tumor cell. Such a method comprises, for example, administration of one of the present compounds to the tumor cell, while the tumor cell is exposed to the relevant cytotoxic agent. The therapeutic effect of a chemotherapeutic or anti-neoplastic agent can thus be enhanced. A tumor cell's multidrug resistance to a cytotoxic agent during chemotherapy can be reduced or eliminated. The present compounds can also be used in a method for the treatment of disease in which the relevant pathogen exhibits multidrug resistance, for example multidrug resistant forms of malaria, (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery. Such procedures comprise, for example, the administration of one of the present compounds with (separately, simultaneously or sequentially) a drug to which the pathogen in question exhibits multidrug resistance. The therapeutic effect of the drug can thus be enhanced.

A human or animal patient with a tumor can be treated for resistance to a chemotherapeutic agent by a method comprising administering thereto one of the present compounds. The present invention is administered in an effective amount to potentiate cytotoxicity of the chemotherapeutic agent. Examples of chemotherapeutic or antineoplastic agents that are preferred in the context of the present invention include Vinca alkaloids such as vincristine and vinblastine; anthracycline antibiotics such as daunorubicin and doxorubicin; mitoxanaatron; actinomycin D; taxanes, for example taxol; epipodophyllotoxins, for example etoposide and plicamycin.

Moreover, a human or animal patient suffering from a disease in which the responsible pathogen expresses multidrug resistance can be treated for resistance to a therapeutic agent by a method comprising administering thereto one of the present compounds.

Examples of such disease include multidrug-resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery.

MDR modulators are also useful in the delivery of drugs across the blood-brain barrier and in the treatment of AIDS and AIDS-related complexes. The present compounds can therefore be used in a method that facilitates the delivery of drugs across the blood-brain barrier, and in the treatment of AIDS and AIDS-related complexes. A human or animal patient in need of such treatment can be treated by a method which comprises administration thereto of one of the present compounds.

The present inventions can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. Accordingly, the present compounds can be given by injection or injection.

The dose depends on a number of factors including age, weight and the patient's condition and route of administration. When a compound according to the invention is administered alone to adult humans, however, the typical dose adapted to each route of administration is in the range of 0.001-50 mg/kg, most commonly in the range of 0.01-5 mg/kg, body weight. Such a dose can be given, for example, 1-5 times a day 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 which also comprises a pharmaceutically or veterinary acceptable carrier or diluent. The compositions are typically prepared according to conventional methods and administered in a pharmaceutical or veterinary suitable form. An agent for use as a modulator of multidrug resistance comprising any of the present inventions is thus provided.

For example, these solid oral forms may contain, together with the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants such as silicon oxide, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; moisturizing agents such as lecithin, polysorbates, lauryl sulfates. Such compositions can be prepared in a known manner, for example by means of mixing, granulation, tableting, sugar coating or film coating process.

Liquid dispersions for oral administration can be syrups, emulsions and suspensions. The syrups can contain, for example, sucrose or sucrose with glyceros and/or mannitol and/or sorbitol as a carrier. For diabetic patients in particular, the syrup can contain as a carrier only products, for example sorbitol, which are not metabolized into glucose or which are only metabolized into glucose in small amounts. The suspensions and emulsions can contain, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as a carrier.

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, suitable amounts of lidocaine hydrochloride. Some of the present compounds are insoluble in water. Such compounds can be encapsulated into liposomes.

The invention will be further illustrated in the following examples.

Reference Example 1: Preparation of starting compounds of formula ( IV).

Procedure A

1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol) (S.M. Marcuccion and J.A. Elix, loe. eit.) was heated at 120-130°C in DMF (200 mL) with triethylamine (17, 6 mL, 126 mmol) and benzaldehyde (13.0 mL, 126 mmol). After 4 h, the mixture was cooled to room temperature and poured into EtOAc (1000 mL) and washed three times with brine. Any solid formed at this step was filtered off. The filtrate was dried (MgSO 4 ), and the solvent removed in vacuo. The residue was recrystallized from EtOAc:Hexane to give 11.78 g (38%) of 1-acetyl-3-benzylidene-2,5-piperazinedione. This compound with (IV) is listed as 1.1 in Table 1 below.

By following the same procedure, but replacing benzaldehyde with the appropriately substituted benzaldehyde R^CHO, where R<1>s are as listed in Table IA, the additional starting compounds 1.2 to 1.10 were prepared:

TABLE IA: Compounds of formula ( IV)

Procedure B

1,4-Diacetyl-2<5-piperazinedione was treated with a series of benzaldehydes R<3->CHO, where R<1> are as listed in Table IB, in the presence of potassium t-butoxide in t-butanol-THF (1:1) at 0°C. The reaction mixture was allowed to warm to room temperature in the time interval indicated in the table. Recrystallization, which was optional, was performed using the indicated solvent.

Reference example 2: Preparation of starting materials of formula (II) in which

is a double bond

Progress<g>small A

1-Acetyl-3-benzylidene-2,5-piperazinedione, compound 1.1 prepared according to Reference Example 1, was treated with ethyl bromide and KOtBu/t-BuOH in DMF at a temperature of about 0°C and allowed to warm to room temperature to give 1-acetyl-3-benzylidene-4-ethyl-2,5-piperazinedione. This compound of formula (II) is listed as 2.1 in Table 2A below.

Additional compounds of formula II were prepared by alkylation of compounds 1.2 to 1.10, prepared according to Reference Example 1, under the conditions given in Table 2A:

Procedure B

Compound 1.11 described in Reference Example 1 was treated, in THF-DMF (5:1) with sodium hydride and Mel at 0°C. The reaction mixture was allowed to warm to room temperature for 18 h. The product was purified by recrystallization from EtOAc to give the corresponding compound of formula (II) in 40% yield. By following this procedure, but replacing compound 1.11 with other compounds of formula IV described in Reference Example 1, and modifying the reaction time if necessary, the compounds listed in Table 2B were prepared. Where indicated, purification was performed by fresh water chromatography or by recrystallization as shown in the footnote.

Footnote

a = recrystallization from EtOAc b = fresh chromatography with EtOAc-hexane (1:1) c = fresh chromatography with CH2C12

d = fresh chromatography with Et2O-hexane (1:1) e = recrystallization from EtOAc-hexane Method C

Compound 1.1 described in Reference Example 1 was treated with Cs 2 CO 3 (2 eq.), Me 3 SiCl (1 eq.) and allyl bromide (1 eq.) in acetonitrile at 0°C. The reaction mixture was allowed to warm to room temperature for 5 h. Flash chromatography of products using 20% EtOAc in hexane gave 2.39 in 50% yield, which is a compound of formula (II) wherein R 2 is -CH=CH 2 .

Procedure D

Compound 1.1 described in Reference Example 1 was treated in THF-DMF (5:1) with sodium hydride and methyl bromoacetate at 0°C. The reaction mixture was allowed to warm to room temperature for 3 h. The product was purified by recrystallization from EtOAc-hexane to give 2.40 in 35% yield, which is a compound of formula (II) in which R2

is -CO 2 Me.

Procedure E

Compound 1.1, described in Reference Example 1 was treated in DMF with sodium hydride and 2-dimethylaminoethyl chloride hydrochloride at 0°C. The reaction mixture was heated to 20°C, and then further heated to 80°C, over a period of 5 h. The product was purified by recrystallization from 1% MeOH in EtOAc to give 2.41 in 32% yield, which is a- compound of formula (II) in which R<2> is - CH2NMe2.

Procedure F

Compound 1.1, described in Reference Example 1, was treated in acetonitrile with Cs 2 CO 3 and ethyl bromoacetate at

-20°C. The reaction mixture was warmed to 20°C for 2 h. The product was purified by flash chromatography using EtOAc-hexane (1:2) to give 2.42 in 35% yield, which is a compound of formula (II) wherein R 2 is - C02Et. Reference Example 3: Preparation of a compound with formula (II) wherein is a single binding 1-Methyl-6-benzyl-2,5-piperazinedione was treated with acetic anhydride under reflux for 3 h to give compound 2.43 in 98% yield, which is a compound of formula (II) in which ----- is a single bond , R<1> is Ph and R<2> is H. Reference example 4: Preparation of 1-methyl-6-benzyl-2,5-piperazinedione

Compound (i) was treated with phosgene in THF at 0°C for 15 min. The reaction mixture was then warmed to room temperature overnight. The resulting compound (ii) was treated with glycine methyl ester hydrochloride and triethylamine in CHCl3 at -65°C for 3 h. The reaction mixture was allowed to warm to room temperature overnight and was then refluxed for 16 h in toluene to give the desired product in 53% yield.

Reference Example 5: Preparation of 4-( 2-( 6, 7-

Dimethoxysv-1, 2, 3, 4-tetrahydro

- 2- isoquinolvl) ethylaniline

(a) The title compound, which is a compound of formula (IX), was prepared according to the following scheme:

Compound 3.1 was treated with 3.2 in the presence of K 2 CO 3 in DMF at a temperature of 100°C for 12 h to give 3.3 in 78% yield. 3.3 was then reduced with Fe powder in concentrated HCl and MeOH at 80°C for 3 h to give 3.4 in 51% yield. Alternatively, 3.3 was reduced by catalytic hydrogenation at 210 kPa over a palladium on carbon catalyst in methanolic HCl for 3 h to give 3.4 in quantitative yield.

(b) By following the synthesis route described in (a), but replacing compound 3.1 with 4-bromomethylbenzoic acid and 4-(3-bromopropyl)benzoic acid respectively, according to the two further compounds of formula (IX) were prepared: (c) By following the synthetic route described under (a), but replacing compound 3.2 with 1,2,3,4-tetrahydroisoquinoline hydrochloride, the following additional compound of formula (IX) was prepared: (d) An amine of formula (IX) in which r is 0, compound 3.10, was prepared as follows:

6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3,8) was treated with chloroacetonitrile in the presence of K 2 CO 3 in acetonitrile under reflux for 24 h. Compound 3.9 was obtained in 92% yield. 3.9 was then treated with LiAlH4i ethylene glycol dimethyl ether at room temperature overnight. The temperature was then increased to 40°C and the reaction continued for 30 min. The desired amine 3.10 was obtained in 98% yield.

Example 1: Preparation of compounds of formula

III

Procedure 1

Compound 3.4 prepared according to Reference Example 5 was treated with 2-chloro-1-methylpyridinium iodide and 3-formylbenzoic acid in CH2C12 in the presence of Et3N and a temperature of about 0°C and allowed to warm to room temperature overnight to form the following compound with formula III with 43% yield:

By following the same procedure, but replacing compound 3.4 with compounds 3.5 and 3.6 respectively, with the following two additional compounds of formula III were prepared:

Procedure 2

4-Formylbenzoyl chloride was prepared by treating 4-formylbenzoic acid with thionyl chloride in refluxing toluene. It was then treated with compound 3.4, prepared according to Reference Example 5, in Ch2Cl2 in the presence of Et3N at a temperature of about 0°C and allowed to warm to room temperature to form the following compound 4.2 in 53% yield:

By following the same procedure, but replacing compound 3.4 with compounds 3.5 and 3.5, respectively, the following two additional compounds of formula III were prepared:

Procedure 3 r,

4-Formylbenzoyl chloride, as described in Method 2 above, was treated with Et 3 N in CH 2 Cl 2 at a temperature of -20°C. Compound 3.10 was prepared according to Reference Example 5 and then added. After aqueous work-up and purification by fresh chromatography, the following compound 4.7 was obtained in 43% yield:

Following the same procedure, but replacing 4-formylbenzoyl chloride with 3-formylbenzoyl chloride, the following compound 4.8 was obtained in 48% yield:

Example 2: Preparation of the compounds of formula (I) By reacting together a compound of formula (II), prepared according to Reference Example 2, and a compound of formula (III), prepared according to Example 1, the following compounds according to the invention under the conditions given in Table 3A:

Example 3: Production of salts

The compounds prepared in Example 2 were converted to the corresponding hydrochloride salts by treatment with the gaseous forms of HCl in THF.

Example 4: Preparation of compounds of formula (I) By reacting together a compound of formula (II), prepared according to Reference Example 2 or 3, and a compound of formula (III), prepared according to Example 1, in DMF at 80°C in the presence of Cs 2 CO 3 at the time specified in Table 4, the compounds of formula (I) given in the table were prepared. Some of the compounds were purified by recrystallization or fresh chromatography, which is also indicated in Table 4.

Footnotes

(a) Recrystallization solvent

(b) Fresh chromatography eluent

Example 5: Production of salts

Selected compounds prepared in Example 4 were converted to the corresponding hydrochloride salts by treatment with the gaseous forms HC1 or CH2C12. The hydrochloride, denoted to Table 5 below with the suffix ".HCl" was in some cases then recrystallized as shown in the table.

Example 6: Interconventions of compounds with

formula (I)

Compounds of formula (I) were prepared by treating selected compounds of formula (I) prepared according to Example 4 with appropriate reagents using conventional synthetic techniques, as follows: 1. 9217 was treated with LiOH in aqueous THF at room temperature for 2 h to give compound 9241. 2. 9272 was treated with NaBH4 in MeOH at 0°C for 2 h to give compound 9276 in 73% yield. 3. 9274 was treated with NaBH3 in MeOH and THF at 0°C. The reaction mixture was then heated to 50°C for 5 h, and the product was recrystallized from 20% EtOH in EtOAc to give compound 9300 in 58% yield. 4. 9273 was treated with NaBH 3 CN in MeOH and THF at reflux for 7 h. The product was recrystallized from EtOAc-hexane (1:5) to give compound 9301 in 18% yield.

Example 7: Pharmaceutical composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of formula (I) or salt thereof, may be prepared as follows:

Composition for 10,000 tablets

Compound of formula (I) or salt thereof (250 g) lactose (800 g)

corn starch (415 g)

talcum 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 with a mesh size of 0.5 mm. Corn starch (10 g) is suspended in hot 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 with a mesh size of 1.4 mm. The remaining amount of starch, talc and magnesium stearate is added, mixed carefully and processed into tablets.

Example 8: Testing of compounds of formula (I) and

salts thereof as modulators of MDR

1. Drug Accumulation Assay

AR 1.0 cells were seeded in 96-well opaque culture plates (Canberra Packard). The assay medium contained a mixture of tritiated Daunorubicin (DNR), a cytotoxic agent, and unlabeled DNR (0.3 µCi/ml; 2( µM). Compounds of formula I were serially diluted in assay medium over a range of concentrations ranging from 5 nM to 100 /iM). The cells were incubated at 37°C in oxygen before washing and determination of cell-associated radioactivity. The results were given as percent maximum accumulation when 100% accumulation is that observed in the presence of the known RMA verapamil at 100/xM. When possible, the IC50 was determined.

The results are given in the following table 6.

2. Potentiation of Doxorubicin toxicity

Compounds of formula (I) were examined for their ability to potentiate toxicity of doxorubicin in AR 1.0 cells. In initial proliferation assays, compounds were titrated against a fixed concentration of doxorubicin (0.86 µM) which alone is non-toxic to AR 1.0 cells. After four days of incubation with doxorubicin, proliferation was measured using the colorimetric sulforhodamine B assay (Skehan et al; J. Nat. Cancer Inst. 82 pp 1107-1112 (1990). The results are shown in Table 7.

Compounds shown to sensitize AR 1.0 cells to 0.86/xM doxorubicin without high intrinsic toxicity were selected for further study. Cells were cultured for 4 days with a titration of doxorubicin (0.01/xM-50/xM) in the presence of a fixed concentration of each compound. Proliferation was quantified as described by Skehan

et al., loe one. The IC50 (concentration required to reduce proliferation 50% of untreated controls) for doxorubicin alone and with each compound was derived and used to calculate the potentiation index (PI):

The results are shown in table 8:

Example 6: Characterization<g>of the present

connections

The compounds and salts prepared according to examples 1 and 2 were characterized by mass spectroscopy and proton nmr techniques. The results are given in Tables 9 and 10:

Claims (10)

1. A piperazine derivative of formula (I) wherein Rx is (i) a group wherein p is 0 or 2; each of Ra to Re, which are the same or different, is independently selected from hydrogen, C-L-Cg-alkyl unsubstituted or substituted with one or more halogen atoms, C-L-Cg-alkenyl, C1-C8-alkoxy, C1-Cg- alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH2 OH, -CH2 COOH, - COj R <11> , -NHCOR <11> , -NHSOj R <11> , -SO2R13, -CON (R11R12) , -SOR13, - SO2N (RX1R12) , - N (R13R12) , - 0 (CH2)nN (R1XR12) , - 0 (CH2)n COj R <11> , - OCOR - <11> , -CHj OCOR <11 > , CH2NHCOR1:L, -CH2 NHCOOR <13> , -C^SR <11> , -CT^SCOR <11> , - CH2 S(0 )raR13 where m is 1 and 2, -CH2 NHCO(CH2 )nC02 R <11> , -N (R11) COR12 , -NHCOCF3, -NHaMCH^COj R <11> , -NHCOlCHjJn OCOR <11> and NHCO (CH2)nCO^11, wherein n is 0 or an integer in the range 1-6, each of R <11> and R <12> is independent H or Ci-Q-alkyl and R<13> is Ci-Cg-alkyl (or any of Ra, Rb, Rb and Rc, Rc and Rd or Rd and Re together form a methylenedioxy group, or together with the carbon atoms they are attached a benzene ring which is optionally substituted; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from 0, N and S, which group may be fused to a benzene ring; (iii) a C 1 -C 8 alkyl or C 5 -C 7 cycloalkyl group, or (iv) a C5 -C7 cycloalkenyl group which is unsubstituted or substituted with C2 -C6 alkenyl; R2 is H, Cx-C6 alkyl optionally substituted with a group -N (RU R <12> ) as defined above, C3 -C6 -s <y> chloroalkyl, C2 -C6 alkenyl, -C00R <11> wherein R <11 > is as defined above, or a phenyl group as defined under (i) above, but is something other than H when R <1> is unsubstituted phenyl, and one of R3 and R<4> is hydrogen and the other is a group of formula (A); wherein q is an integer in the range 1-4, r is 0 or 1 and R <5> and R <6> , which may be the same or different, are each H or C 1 -C 8 -alkoxy, or R <5> and R <6> together form methylenedioxy group; and ----- is a double bond or, when R <1> is as defined under (i) above, is a double bond or a single bond; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1 where R<1> is a phenyl group as defined under (i) in which one of Ra to Re is selected from hydroxy, C₁C₆-Alkoxy, NHCOR <11> , -CO^ <11> , - N(R11R12), -0(CH2)n-N (R11R12) , -S02R13, C0N(R1:LR12), N02 , -S02N (R1XR12) , -SOR13,-N (R <11> )C0R <12> and halogen , and the other four of Ra to Re are H. 3. Compound according to claim 1 or 2, in which R<1> is a phenyl group as defined under (i) in which each of Ra to Re is hydrogen, or one of Ra, Rb and Rc is halogen or Cx-C6 alkoxy and the remainder of Ra to Re is hydrogen, or a pyridyl, furyl or thienyl group, R2 is H, CH3 , cyclopropyl or phenyl, and one of R3 and R <4> is H, and the other is a group of formula (A) wherein q is 2 and each of R<5> and R<6> is a methoxy group. 4. Compound according to claim 1, 2 or 3 in which R<1> is a 4-pyridyl-, 3-furyl-, 2-thienyl- or 3-thienyl group. 5. Connection selected from: N-(4 - (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-ethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9112). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-benzyl-6-benzylidene -2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9113). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro,2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-cyclopropylmethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9114 ). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3-furylmethylene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (91 08). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(4-methoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9109) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(4-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9091). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(2-chlorobenzylidene) -1-methyl'-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9092). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-(3-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9093). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(3-pyridylmethylene)-3-piperazinylidene)methylbenzamide, hydrochloride (9110). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(3-thenylidene)-3-piperazinylidene)methylbenzamide, hydrochloride (9111). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(2-thenylidene)-3-piperazinylidene)methylbenzamide (9155). N-(4 - (2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5 -dioxo-6-(3-thenylidene)-3-piperazinylidene)methylbenzamide (9160). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9157). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9158). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-furylmethylene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9159) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-methoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9156). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-ethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide (9139) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-cyclopropylmethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide (9141). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-allyl-6-benzylidene -2,5-dioxo-3-piperazinylidene)methylbenzamide (9178). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-allyl-6-benzylidene -2,5-dioxo-3-piperazinylidene)methylbenzamide (9179). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6- (2-Naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9193). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6- (1-Naphthyl)-methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9194). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( 1-Naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9195). N-(4-(2-6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-6-(2-furyl) methylene-1-methyl-2n5-dioxo-3-piperazinylidene)methylbenzamide (9196) . N-(4 - (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-(2-furyl )methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9197). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6- (1-Methyl-3-pyrrolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9198). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( (1-Methyl)-3-pyrrolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9199). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( 2-Naphthyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9209). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-( 1-methyl-3-indolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9210). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6- (3-Methylbenzo(b)thien-2-yl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9211). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6-( 1-methyl-3-indolyl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9214). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-( 3-Methylbenzo(b)thien-2-yl)methylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9215) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1- methoxycarbonylmethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9217). N-(4 -(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-( 2-methylpropylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9228) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-1-methyl-6-cyclohexylmethylene -2,5-dioxo-3-piperazinylidene)methylbenzamide (9229) . N-(4 - (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6- cyclohexylmethylene-2,5-dioxo-3-piperazinylidene)methylbenzamide (9230) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-1-methyl-2, 5-dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9231). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-1-methyl-2,5 -dioxo-6-pentylidene-3-piperazinylidene)methylbenzamide (9232) . N-(4 - (2 - (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-1-methyl-6- (2-Methylpropylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9233). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-6-(3,3 -dimethylbutylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9234). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-(3,3 -dimethylbutylidene)-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9235). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-4-((3Z,6Z)-6-((4S) -4-isopropenyl-1-cyclohexenyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9236). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene- 1-carboxymethyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9241). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-((4S) -4-isopropenyl-1-cyclohexenyl)methylene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9250) . N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene -2,5-dioxo-3-piperazinylidene) methylbenzamide (9260). N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-1-methyl-6-(2-naphthyl)methylene -2,5-dioxo-3-piperazinylidene) methylbenzamide (9261). N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-1-methyl-2,5-dioxo-6- (3-phenylpropylidene)-3-piperazinylidene)methylbenzamide (9266). N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-1-methyl-2,5-dioxo-6- (3-Phenylpropylidene)-3-piperazinylidene)methylbenzamide (9267). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)-ethyl)phenyl)-3-((3Z,6Z)-6-(4-acetoxybenzylidene) )-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9272) . N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3-acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9273). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9274) . N-(4-(2-(6,7-Dimethoxy-1,2,3(4-tetrahydro-2-isoquinoyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-( 2-dimethylaminoethyl)-2,5-dioxo-3-piperazinylidene)methylbenzamide (9275 ). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-ethoxycarbonylmethyl -2,5-dioxo-3-piperazinylidene)methylbenzamide (9299). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(2-hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9300). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl-3-((3Z,6Z)-6-(3-hydroxybenzylidene)- 1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide (9301). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl-3-((3Z,6Z)-6-pentylidene-2,5- dioxo-3-piperazinylidene)methylbenzamide (9306). N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl-3-((3Z)-1-methyl-6-benzyl-2, 5-dioxo-3-piperazinylidene) methylbenzamide (9308). 6. Pharmaceutical or veterinary composition containing a pharmaceutical carrier or diluent and, as an active principle, a compound according to any of the preceding claims. 7. Method for the production of compounds as defined in claim 1, which method comprises treating a compound of formula (II): wherein R <1> , R <2> and are as defined in claim 1, with a compound of formula (III) : wherein one of R <7> and R <8> is hydrogen, and the other is -CHO, and q, R <5> and R <6> are as defined in claim 1, in the presence of a base in an organic solvent , and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof. 8. A compound as defined in any of claims 1-5 for use as a modulator of multidrug resistance. 9. Use of a compound as defined in one of claims 1-5 in the preparation of a drug for use as a modulator of multidrug resistance. 10. Compound of formula (III)-: wherein q, r, R <5> and R6 are as defined in claim 1, one of R <7> and R<8> is hydrogen and the other of R <7> and R<8> is -CHO.