SK83697A3 - Piperazine-2,5-dione derivatives as modulators of multi-drug resistance - Google Patents

Abstract

A piperazinedione derivative of formula (I), wherein R<1> is: (i) a group alpha , wherein p is 0 or 2; (ii) a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from O, N and S, which group may be fused to a benzene ring; R<2> is H, C1-C6 alkyl optionally substituted by a group -N(R<11>R<12>) as defined above, C3-C6 cycloalkyl, C2-C6 alkenyl, -COOR<11> wherein R<11> is as defined above or a phenyl ring as defined under (i) above, but is other than H when R<1> is unsubstituted phenyl; and one of R<3> and R<4> is hydrogen and the other is a group of formula (A), wherein q is an integer of 1 to 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 a methylenedioxy group; <u>-----</u> is a double bond or, when R<1> is as defined under (i) above, is a double bond or a single bond; and pharmaceutically acceptable salts thereof have activity as modulators of multi-drug resistance.

Description

Piperazine-2,5-dione derivatives as modulators of multidrug resistance

Technical field

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

BACKGROUND OF THE INVENTION

Tumor resistance to certain cytotoxic drugs is an obstacle to successful chemotherapy of cancer patients. The tumor may acquire resistance to the cytostatic used in previous treatment. The tumor may also exhibit intrinsic or cross-resistance to a cytostatic that has not been used to date and is not close to the previously used cytostatics in terms of structure or mechanism of action.

Similarly, some drugs have been used caused by these pathogens. intrinsic or cross resistance have not yet met some forms of dysentery.

pathogens can in treatment Pathogens against Examples of this phenomenon of malaria, tuberculosis, acquire disease can also manifest drugs, is multidrug leishmaniasis and resistance to or disorders with which the resistance of amoebic

These phenomena are collectively referred to as multidrug resistance (MDR). As will be described in more detail below, the plasma membrane glycoprotein (P-gp), which has the ability to bind the drug, is involved in the MDR mechanism. Therefore, some agents that have the ability to modulate MDR may also facilitate the passage of the drug through the blood-brain barrier and assist in the treatment of AIDS and related conditions.

The deficiency of drugs used to modulate MDR, so-called. resistance modifiers or RMA, there is a very frequent lack of pharmacokinetic profile and / or toxicity at concentrations necessary to modulate MDR.

SUMMARY OF THE INVENTION

It has now been found that a number of piperazinedione derivatives have the effects of multidrug resistance modulators. The present invention provides piperazinedione derivatives of formula I:

wherein R ¹ is (i) a group

wherein p = 0 or 2;

all R ^a to R ^e , the same or different, may be selected from H, C 1 -C 6 alkyl unsubstituted or substituted with one or more halogens, C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio , halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH 2 OH, -CH 2 COOH; -COOR ¹¹ , -NHCOR ¹¹ , -NHSO ² R ¹³ , -SO ² R ¹³ , -CON (R ^{1: L} R ¹² ), -SOR ¹³ , -SO 2 N (R ^{1: L} R ¹² ), -N (R ^{X 1} R ¹² ) , -O (CH 2) n n (R ^{X 1} R ^12), -O- (CH 2) _n COOR ^1X, -OCOR ^11, -CH2OCOR ^{1: L,} -ch2nhcor ^{i: l, 13} -ch2nhcoor, ^and -CH 2 ^{SR: l} - CH 2 SCOR ^{1: 1} , -CH 2 S (o) R 1 -R ¹³ where m = 1 or 2, -CH ₂ NHCO (CH ₂ ) n COOR ^{1: L} , -N (R ¹¹ ) COR ¹² , -NHCOCF 3, -NHCO (CH ₂₎ ) _n COOR ^{1: L} , -NHCO (CH 2) nOCOR ^{X 1} and -NHCO (CH 2 J 1 COR ¹¹ ; where η = 0 or an integer from 1 to 6, all R ¹¹ and R ¹² are independently H or C 1-4 - cg alkyl and R ¹³ is a C - ^ - cg alkyl; or any of R ^a and R ³ or R ³ and R ^c and R ^c and R ^ or R ^ and R ^e together form methylenedioxy, or together with the carbon atom to which they are attached, a benzene ring or an optionally substituted benzene ring;

(ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S, which heterocycle may be fused to the benzene ring;

(iii) C 1 -C 6 alkyl or C ₅ -C ₇ cycloalkyl; or (iv) C ₅ -C ₇ cycloalkenyl, unsubstituted or substituted with ^C 2 ^-C 6 alkenyl;

R ² is H, ^C 1 -C 8 alkyl optionally substituted with N (R ¹¹ R ¹² ), C ₃ -C 8 cycloalkyl, C ₂ -C 8 alkenyl, -COOR ¹¹ , wherein R ¹¹ is as defined above or represents phenyl as defined in (i) but not H when R ¹ is unsubstituted phenyl; and one of R ³ and R ⁴ is H and the other is of formula A:

(A) wherein q is an integer from 1 to 4, r = 0 or I and R 6 and R 6 are the same or different and are H or C 1 -C 6 alkoxy, or together R ⁵ and R ⁶ form a methylenedioxy group; and ----- is a double bond, or where the R ¹ is as defined under (i) ----- is a double or single bond; or a pharmaceutically acceptable salt thereof.

^{The C} 1 ^-C 6 alkyl group may be straight or branched.

^{_c c} L 6 ^and L ^to D ^e yl typically Ci ^- C ₄ alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. C ₃ -C 8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Halogen is, for example, fluorine, chlorine, bromine or iodine.

^{CL _c} 6 alkoxy group is typically a C ^- C ₄ alkoxy, e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy. C ₂ -C ₆ alkenyl is, for example, C ₂ -C ₄ alkenyl, for example ethenyl, prop-1-enyl or prop-2-enyl.

A heterocyclic group is, for example, a pyridine, pyrrole, furan or thiophene group attached by any constitutional atom, particularly 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl.

The number q is an integer of 1 to 4, preferably 1 or 2. R ⁵ and R ⁶ are I.

preferably identical and preferably C 1 -C ₄ alkyl, for example methyl. When R ^{1 is} defined as in (i), the phenyl group is unsubstituted or substituted in one or more of the 2 to 6 positions. When monosubstituted, the substituent may be at any of 2 to 6 positions, for example in the 3 or 4 position, in particular in the 4-position. For example, one of R ^a to R ^e is other than H, preferably R ^b or R ^c , preferably R ^c . When the phenyl group is monosubstituted, R ^a to R ^{e is} preferably selected from halogen, for example chlorine, bromine or fluorine; C 1 -C 8 alkoxy, for example OMe; and acetamido -NHAc (where Ac is an abbreviation for acetyl).

The phenyl group may also be disubstituted at the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position, or trisubstituted at the 2,3,4-, 2-position. , 3,5-, 2,3,6- or 3,4,5-. In the case of two substituents, three of R ^a to R ^e are H and two are different, for example R ^a and R a or R ^a and R ^c or R ^a and R 6 or R ^a and R ^e or R ^b and R ^c or R ^b and R ^d are other than H and the remaining three of R ^a to R ^e are H.

For the three substituents, two of R ^a to R ^e are H and three are different, for example R ^a , R ^b and R ^c or R ^a , R ^b and R ^d or R ^a , R 6 and R ^e or R 6, R ^c and R ^d are other than H and the other two of R ^a to R ^e are H.

In a preferred embodiment, a series of compounds of formula I, all R ^a to R ^e groups are H. In another preferred embodiment, a series of compounds of formula I one of the substituents R ^a to R ^{e is} selected from C 6 -C 6 alkoxy, -NHCOR ¹¹ , -COOR ¹¹ , -ΝΝΡ ¹ ( ¹² ), -O (CH 2) _n N (R ¹¹ R ¹² ), -SO ² R ¹³ , -CON (R ^{1; L} R ¹² ), NO 2, -SO ₂ N (R ^{1; L} R) ¹² ), -SOR ¹³ , -N (R ¹³ ) COR ¹² , halogen, and the other four of R ^a to R ^e are H. Alkoxy is, for example, OMe or OBu ⁿ . -NHCOR ¹¹ is typically -NHAc. -COOR ¹¹ is typically -COOH or COOMe. -N (R ¹ V ² ) is typically -NMe 2. -CON (R ¹¹ R ¹² ) can be -CHNH 2. -SOR ¹³ is typically SO ₂ Me, -SO ₂ N (R ¹¹ R ¹² ) is, for example, -SO ₂ NMe ₂ . -SOR ¹³ can be SOMe and -N (R ¹¹ ) COR ¹² can be -NMeCOBub. Halogen is typically F or Cl. Preferably R ^{c is} alkoxy, especially OMe or OBu ⁿ ; NHCOR ¹¹ , especially -NHAc;

J

-COOR ¹¹ , especially -COOH or -COOMe; -CON (R ^{1: L} R 1 · ² ), in particular CONH 2; NO2; -N (R ^1: R ¹² ), especially NMe 2; -SOR ¹³ , in particular SOMe; -SO ₂ N (R ^{1: L} R ¹² ), especially -SO ₂ NMe ₂ or halogen in particular F or Cl, and all R ^a , R ^b , R ^d and R ^e are H.

In said series of preferred compounds of formula I, all R ^a to R ^{e are} H, or one or two of R ^a to R ^e are other than H and the rest of R ^a to R ^e are H. For example, one of R a ^and R ^e is H. , R 6 and ^{c c} are other than H. Alternatively, R ^a and R ^c , or R b and R ^c are other than H. For one or two substituents R ^a to R ^e , which are not H, preferred C 6 -C 6 groups are alkoxy OMe or OBu ^11, halogen, Cl or F, hydroxy, N (R ¹¹ R ^12), -COOR ^11, -CH2SCOR ^13, -CH 2 SR ^{1: L,} -NHCOR ^11, -O (CH 2) _n N (R ^{and L} R ¹² ), -O (CH 2) n COOR ^{1: 1} , -NHCOCH 2 R ¹¹ , -NHCOCH 2 COR ¹¹ , -CH 2 NHCOOR ¹³ and CF ₃ .

Particularly preferred compounds of formula I are those wherein all the substituents R ^a , R b, R ^d and R ^e are H and R ^c is selected from H, OMe, -NHAc, -COOH, -COOMe, -CONH ₂ , -NO ₂ ,

-NMe ₂ , -SO ₂ Me, -SOMe and SO ₂ NMe ₂ are also preferred. Compounds of formula I are also preferred, wherein all substituents R ^a to R ^e are preferably independently of one another selected from H, halogen, hydroxy, C 1-6 -C 8 alkoxy, nitro, -CH ² SCOR ¹³ , -CH-gSR ¹¹ , -COOR ¹¹ , -OCOR ¹¹ , CF 3, -O (CH ₂ ) _n N (R ¹¹ R ¹² ), -O (CH 2) n COOR ^{1: L} , -CH ₂ NHCO (CH ₂ ) _n COOR ^{1: L} , -NHCO (CH 2) n OR ¹¹ , -N (R ^{1: L} R ¹² ), NHCO (CH 2) _n OCOR ^{1: L} , NHCO (CH 2) n COOR ^{1: L} and -CH ² NHCOOR ¹³ or R ^a and R ^b and R ^c , R ^c and R ^d or R ^d and R ^e together form a methylenedioxy group or together with the carbon atoms to which they are attached form a benzene ring or an optionally substituted benzene ring. Even more preferably, R ^a and R ^b independently of one another are H, nitro or halogen, R ^c is H, hydroxy, -O (CH 2) n N (R ^1; -R ¹² ), -OCOR ¹³ , -O (CH 2) _n C00R ^1] -, C 1 -C 8 alkoxy, -NHCO (CH 2) n OR ^{1: L} , -NHCO (CH 2) _n OCOR ^{1: L} , -N (R ^{1: L} R ¹² ), -CH 2 NHCOO R ¹³ , -CH 2 SR ¹¹ or -NHCOR ¹¹ ; R ^d is H, halogen, C 1 -C ₆ alkoxy, -CH ₂ SCOR ¹³ , -C 1 SR ¹¹ or -COOR ¹¹ ; and R ^e is H, nitro or halogen.

If any two adjacent substituents R ^a to R ^e together with the carbon atoms to which they are attached form a benzene ring, this ring may be unsubstituted or substituted by any group as specified for R ^a to R ^e . The benzene ring forms, with the phenyl group, a naphthalene cyclic structure, optionally substituted.

In one embodiment of Formula I, R ^{1 is} unsubstituted phenyl or phenyl monosubstituted in the 2, 3 or 4 position by Cl or MeO, or R ^{1 is} pyridyl, furyl or thienyl, R ² is H, CH ₃ , cyclopropyl or phenyl and one of the groups R ³ and R ⁴ is H and the other is a group of formula A wherein q = 2 and both R ⁵ and R ⁶ are MeO.

In a second embodiment, ^R1 is substituted phenyl, R ² is ^C l ^"c 4 ^Al ^ yl, preferably methyl, or phenyl or cyclopropyl, R ³ is H and R ⁴ is a group of formula A where q is 2 and both R ⁵ and R ⁶ are MeO.

In a third embodiment, R ^{1 is} substituted phenyl as defined above, or furyl, thienyl, or pyridyl, R ² is H,

R ³ is H and R ⁴ is a group of formula A wherein q = 2 and both R ⁵ and R ⁶ are MeO.

In a fourth embodiment, R ^{1 is} substituted phenyl as defined above, or furyl, thienyl or pyridyl, R ² is H, R ³ is a group of formula A wherein q = 2 and both R ⁵ and R ⁶ are MeO and R ⁴ is H.

In a fifth embodiment, R ¹ · unsubstituted phenyl, R ⁵ is ^{C l-C4 alk} yl / preferably methyl, or phenyl or cyclopropyl, R ³ is a group of formula A where q is 2 and both R ⁵ and R ⁶ is MeO and R ⁴ is H.

Ί

In the above embodiments, when R is furyl, thienyl or pyridyl, it is preferably 3-furyl, 2-thienyl, 3-thienyl or

4-pyridyl.

¹ · '. The following are examples of preferred compounds of Formula I. The numbering of the compounds is retained throughout 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-methoxybenz). ylidene) -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-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-methyl-2,5 -dioxo-6- (3-thienylidene) -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- (3-thienylidene) -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-thienylidene) -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-futylmethylene) -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-2,5-dioxo-3-piperazinylidene-methylbenzamide (9196)

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

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

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

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

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

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

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

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

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

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

N- (4- (2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6- (4-hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide (9276)

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

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

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

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

I can be prepared by reaction

Compounds of formula (II):

wherein R ¹ , R ² and are as defined above, with a compound of formula III:

(IU) wherein one of R ⁷ and R ⁸ is H a and the other is -CHO, aq, r, C ZR and R are as defined above; in the presence of a base, in an organic solvent; and, if desired, converting the resulting compound into an appropriate pharmaceutically acceptable salt.

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

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

When DMF is chosen as the solvent, the reaction temperature is typically in the range of 0 ° C and the boiling point, for example in the range of 80 to 95 ° C, when cesium carbonate is used as the base.

When sodium hydride or potassium t-butoxide is used as the base, the reaction mixture is typically warmed from 0 ° C to room temperature or to 40 ° C. The reaction time is in the range of 1 to hours, for example 2 to 3 hours.

Compounds of formula II wherein ---- is a double bond may be prepared by reacting a compound of formula IV

(IV) wherein R ¹ is as defined above, with an alkylating agent, in an organic solvent and in the presence of a base. A typical alkylating agent is an alkyl halide R ² -CH ² X, a methanesulfonic acid or p-toluenesulfonic ester R ² -CH ₂ OSO ₂ Me, respectively. R ² -CH ² OSO ² C 6 H ⁵ Me, or dialkyl sulfates (R ² CH ² O) ₂ SO ₂ , wherein R ² is as defined above and X is halogen such as Cl, Br or I. Suitable bases and solvents are sodium hydride in THF or DMF or mixtures thereof; potassium t-butoxide in t-butanol or THF or DMF or mixtures thereof. The temperature of the reaction mixture was allowed to rise from 0 ° C to room temperature overnight.

Compounds of formula II wherein ----- is a single bond may be prepared by reacting a compound of formula X:

wherein R ¹ is as defined in (i) and R ² is as defined above, with acetic anhydride. The reaction is typically carried out under reflux, for example 1 to 6 hours, typically 3 hours. A compound of formula X can be prepared by reacting a compound of formula XI:

(XI) with glycine methyl ester hydrochloride and triethylamine in a solvent, typically CHCl ₃ , at low temperature, typically -50 to -70 ° C, preferably

4-65 ° C, 1-6 h. The temperature of the reaction mixture was allowed to rise to room temperature overnight. The reaction mixture is then further heated under reflux in a solvent such as toluene for 12-18 hours, typically 16 hours, to give the desired compound of formula X.

Compounds of formula XI with compounds of formula XII:

can prepare by reaction

(XII) with phosgene in THF, at 0 ° C and the temperature of the reaction mixture was allowed to rise to room temperature overnight.

Compounds of formula IV may be prepared by reaction

1,4-diacetyl-2,5-piperazinedione of formula V:

(V) with an aldehyde of general formula

R ¹ -CHO wherein R ¹ is as defined above, in the presence of a base and in an organic solvent.

Suitable bases and solvents are triethylamine, cesium and potassium carbonate and sodium hydride in THF or DMF or mixtures thereof and potassium t-butoxide in t-butanol or THF or DMF or mixtures thereof.

When triethylamine is chosen in DMF, the reaction temperature is typically in the range 100 to 140 ° C, for example 120 to 130 ° C. If potassium t-butoxide is chosen, the reaction temperature is typically allowed to rise from 0 ° C to room temperature.

!

1,4-diacetyl-2,5-piperazinedione can also be prepared as described (Marcuccio S. M., Elix J A., Aust. J. Chem., 1984, 37, 1791).

Compounds of formula III may be prepared by a process comprising (i) reacting compounds of formulas VI and VII:

(VI) (VH) wherein q, R ⁵ and R ⁶ are as defined above and X is halogen, in the presence of a base in an organic solvent;

(ii) reducing the resulting compound of formula VIII

(VIII) wherein q, R ⁵ and R ⁶ are as defined above; and (iii) reacting the resulting compound of Formula IX:

(K) where q, R ⁵ and R ⁶ have the meanings defined above and ar = 1 s:

(a) 3-formylbenzoic acid in the presence of a condensing agent, or a carboxylic acid activated 3-formylbenzoic acid derivative, for example, converted to a -COX acid halide, wherein X is halogen, for example F, Cl, Br or I, preferably Cl, or mixed anhydride -COfOCOR ¹ ) wherein R ¹ is C 1 -C 6 alkyl; in both cases to form a compound of formula III wherein R ⁷ is H and R ⁸ is -CHO; or (b) 4-formylbenzoic acid in the presence of a condensing agent, or a carboxylic acid activated 4-formylbenzoic acid derivative, for example, converted to an -COX acid halide, wherein X is halogen, for example F, Cl, Br or I, preferably Cl, or mixed anhydride -CO (OCOR ¹ ) wherein R ¹ is C 1 -C 6 alkyl; in both cases to form a compound of formula III wherein R ⁷ is -CHO and R ⁸ is H.

Activation of the 3- or 4-formylbenzoic acid carboxylic acid to -COX is carried out in an organic solvent either with an excess of an amine of formula IX or in the presence of a base, for example a tertiary amine such as Et ₃ N or pyridine. A suitable organic solvent is inert CH ₂ Cl ₂ .

Activation of the 3- or 4-formylbenzoic acid carboxylic acid to -COCOOCOR ¹ ) is carried out by reaction with a compound of formula IX in an inert organic solvent such as CH ₂ Cl ₂ or THF. '''

For example, 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide meto-p-toluenesulfonate or 2-chloro-1- can be used as condensing agent in steps (a) and (b) for reaction with 3- or 4-formylbenzoic acid. methylpyridinium iodide.

Activated acyl halide or mixed acid anhydride

3- or

4-formylbenzoic procedures.

Acyl halide with a carboxylic acid chlorinating agent such as

PC1 ₅ . The mixed anhydride may be prepared in general, for example by reaction with a halogenating agent, for example

SOCl ₂ , PCl 3, oxalyl chloride or may be prepared by reacting a carboxylic acid with a C 1 -C 8 alkyl haloformate, for example iBuOCOCl or EtOCOCl, in the presence of a base, for example Et ₃ N.

The reduction (ii) is usually carried out with iron powder in concentrated hydrochloric acid and methanol, at a temperature of 1 to 4 h, for example 3 h. Alternatively, hydrogenation can be carried out under catalysis with palladium on carbon, in methanolic HCl, isopropanol or acetic acid.

Other starting materials are known compounds or readily prepared by conventional synthetic procedures.

The compounds of formula (I) may be converted into pharmaceutically acceptable salts and conversely the salts may be converted into the free compounds by conventional methods. Salts of pharmaceutically acceptable inorganic and organic acids are suitable. Suitable inorganic acids are hydrochloric, sulfuric and orthophosphoric acid. Suitable organic acids are p-toluenesulfonic acid, methanesulfonic acid, mucic acid and succinic acid.

In cancer cells that exhibit multidrug resistance, the so-called &quot; MDR cells, there is a decrease in intracellular drug accumulation compared to the corresponding sensitive cells. Studies on in vitro derived MDR cell lines have shown that

MDR is often associated with increased expression of plasma membrane glycoprotein (P-gp), which is believed to act by the compounds. Transfection studies have the ability to bind the drug, as a carrier for a number of hydrophobic with cloned P-gp have shown that overexpression of P-gp can give cells the MDR phenotype: see, for example, Ann. Rev. Biochem. 58, 137-171 (1989).

The main function of P-gp in normal tissues is to export intracellular toxins from the cell. Obviously, overexpression of P-gp may be clinically significant in terms of multidrug resistance. Elevated levels of P-gp mRNA or protein have been detected in many forms of human cancer - leukemias, lymphomas, sarcomas and carcinomas. Indeed, in some cases elevated levels of P-gp have been found in tumor biopsies obtained after relapse during chemotherapy.

Inhibition of P-gp function in cases of P-gp-mediated MDR resulted in a net accumulation of anticancer agents in cells.

For example, Verapamil, a known calcium blocker, has been shown to cause MDR cell sensitivity to Vinea alkaloids both in vitro and in vivo: Cancer Res.,

Anticipated mechanism of action with anticancer agent for binding to

41, 1967-1972 (1981). consists in the competition of P-gp. A number of structurally unrelated resistance modifying agents have been described which act by the above mechanisms, such as tamoxifen (Nolvadex: ICI) and related compounds, cyclosporin A and derivatives.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as the present compounds) have been found to modulate multidrug resistance activity by biological assays. The results are shown in Example 3. The present compounds can be used as modulators of multidrug resistance, the so-called multidrug resistance. Resistance modifying agent (RMA). The present compounds modulate, i. reduce or eliminate multidrug resistance. .

The present compounds can therefore be used to enhance the cytotoxicity of a drug that is cytotoxic to tumor cells. Such a procedure involves, for example, administering one of the present compounds to a tumor cell that is already under the influence of a particular cytotoxic drug. The therapeutic effect of this chemotherapeutic or antineoplastic agent is thereby increased. Thus, the multidrug resistance of a tumor cell to cytotoxics during chemotherapy is reduced or eliminated.

The present compounds may also be used in a method of treating a disease whose pathogen is multidrug resistant, for example, certain multidrug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery. For example, such a method comprises administering the present compound (alone, simultaneously or sequentially) with a drug to which the pathogen is multidrug resistant. This increases the therapeutic effect of the drug.

A human or animal patient suffering from a cancer can be treated for resistance to a chemotherapeutic by a method comprising administering any of the present compounds. The present compounds are administered in an effective amount that enhances the cytotoxicity of the chemotherapeutic used. Chemotherapeutics or antineoplastics suitable for use with the present compounds are Vinea alkaloids vineristine and vinblastine; the anthracycline antibiotics daunorubicin and doxorubicin; mitoxantrone; actinomycin D; taxanes such as taxol; epipodophyllotoxins such as etopoposide and plicamycin.

A human or animal patient suffering from a disease caused by a multidrug resistant pathogen can be treated for resistance to a chemotherapeutic by a method comprising administering any of the present compounds.

Examples of such diseases are some multidrug resistant forms of malaria (Plasmo'dium 'falciparum), tuberculosis, leishmaniasis, and amoebic dysentery.

MDR modulators have further utility in drug delivery through the blood-brain barrier and in the treatment of AIDS and a complex of related disorders. The present compounds are therefore useful in procedures that facilitate drug delivery through the blood-brain barrier and in the treatment of AIDS and a complex of related disorders. A human or animal patient in need of said treatment may be treated by a method comprising administering any of the present compounds.

The present compounds may be administered in various dosage forms, for example orally in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously. Thus, the present compounds may be administered by injection or infusion.

The dosage depends on a number of factors such as the age, weight and condition of the patient and the route of administration. However, a typical dose for all routes of administration for an adult human is 0.001 to 50 mg / kg, more often 0.01 to 5 mg / kg body weight. This dose can be administered one to five times a day by bolus infusion, infusion over several hours and / or repeated administration.

The piperazinedione derivatives of formula (I) or pharmaceutically acceptable salts thereof may also be formulated as pharmaceutical or veterinary preparations which also contain a pharmaceutical or veterinary carrier or diluent. The formulations can be prepared by conventional methods and are supplied in a pharmaceutical or veterinary form. The present invention provides a medicament comprising any of the present compounds that can be used as a multidrug resistance modulator.

For example, solid oral dosage forms may contain, in addition to the active ingredient, diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binders such as starches, acacia, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginates or sodium starch glycolates; effervescent mixtures; coloring agents; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates. Said formulations may be prepared by known methods, including, for example, mixing, granulating, tabletting, sugar or film coating.

Liquid dispersions for oral administration are, for example, syrups, emulsions and suspensions. Syrups may contain as carriers, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol. In particular, a syrup for diabetic patients may contain as carrier only substances, for example sorbitol, which are not metabolized to glucose or only to a small amount of glucose. The suspensions and emulsions may contain as carrier, for example, a natural resin, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride. Some of the present compounds are insoluble in water. These compounds can be encapsulated into liposomes.

The invention is illustrated in more detail by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Reference example 1

Preparation of the starting compounds of formula IV

Procedure A 1,4-Diacetyl-2,5-piperazinedione (Marcuccio SM, Elix JA; Aust. J. Chem., 1984, 37, 1791) (25.0 g, 126 mmol) was reacted in DMF (200 mL). ), at 120-130 ° C, with triethylamine (17.6 mL, 126 mmol) and benzaldehyde (13.0 mL, 126 mmol). After 4 h, the reaction mixture was cooled to room temperature, poured into EtOAc (1000 mL) and extracted 3 times with brine. All solids formed at this stage were filtered off. The filtrate was dried (MgSO ₄ ) and the solvent was evaporated in vacuo. The residue was recrystallized from EtOAc-hexane to yield 11.78 g (38%) of 1-acetyl-3-benzylidene-2,5-piperazinedione. This compound of formula IV is disclosed in U.S. Pat. 1.1 in Table 1.

Analogously but with the substitution of benzaldehyde for a suitable substituted benzaldehyde R 1 -CH-CHO, where the meanings of R ¹ are given in Table IA, further starting compounds I to II were prepared.

1.10:

Table ΙΑ

Compounds of formula IV

Compound No. R ¹ 1.1 phenyl 1.2 4-chlorophenyl 1.3 2-chlorophenyl 1.4 3-chlorophenyl 1.5 3-furyl 1.6 4-methoxyphenyl 1.7 3-pyridyl 1.8 3-thienyl 1.9 3-methoxyphenyl 1.10 2-thienyl

Procedure B

1,4-Diacetyl-2,5-piperazinedione was reacted with a series of benzaldehydes R ^X -CHO, where R ¹ is given in Table 1B, in the presence of potassium t-butoxide in t-butanol-THF (1: 1) The reaction mixture was allowed to rise to room temperature over the time indicated in the table. The above solvent was used for recrystallization, if any.

Table 1B

Compounds of formula IV

(IV)

Compound No. R ¹ Reaction time Solvent for recrystallization. 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-fury 1 12 74 1.16 l-methyl-2-pyrrolyl 52 EtOAc 80 1.17 l-methyl-2-pyrrolyl 52 EtOAc 8θ 1.18 2-naphthyl 18 98 1.19 l-methyl-3-indolyl 14 33 1.20 3-methyl-benzo [b] thien-2-yl 18 72 1.21 l-methylmorphinan-3-indolyl '14 33 1.22 3-methyl-benzo [b] thien-2-yl 18 72 1.23 Me ₂ CH 12 EtOAc 48 1.24 cyclohexyl 2 80 1.25 cyclohexyl 2 80 1.26 n-butyl 14 EtOAc 60 1.27 n-butyl 14 EtOAc 60 1.28 Me ₂ CH 12 EtOAc 48 1.29 Me ₃ CCH ₂ 18 EtOAc 62 1.30 Me ₃ CCH ₂ 18 EtOAc 62 1.31 (4 S) -4-i2opropenyl- 1-cyclohexenyl 18 1:32 (4 S) -4-R-opropenyll CYF <loheXenyl 18 1:33 4 -AcOC ₆ H ₄ 3 86 1:34 3-AcCO ₅ H ₄ 3 EtOAc-hexane 42 1:35 2-AcOC _€ H ₄ 3 EtOAc-hexane 31 1:36 n-butyl 14 EtOAc 60 1:37 Ph- (CH-) ₂ 16 60

Reference example 2

The preparation of the starting compounds of formula II wherein ---- is a double bond

Procedure A 1-Acetyl-3-benzylidene-2,5-piperazinedione, compound 1.1 prepared in Reference Example 1, was reacted with ethyl bromide and KOtBu / t-BuOH in DMF at 0 ° C. The temperature of the reaction mixture was allowed to rise to room temperature. This gave 1-acetyl-3-benzylidene-4-ethyl-2,5-piperazinedione, a compound of formula II listed under 2.1 in Table 2A.

Other compounds of formula II were prepared by alkylating the compounds 1.2 to 1.10 prepared in Reference Example 1, under the reaction conditions outlined in Table 2A:

Table 2A

Compound of Formula II

(Π)

Compound No. R ² East, compound (IV) Conditions of alkylation 2.1 Me 1.1 (a) KOtBu / tBuOH, DMF, EtBr; 0 ° C to mt; or (b) 1.1 eq NaH, DMF: THF (1: 5); 2 eq EtI, 0 ° C to mt; column chromatography 2.2 ph 1.1 KOtBu / tBuOH, DMF, PhCH ₂ Cl; 2.3 cyclopropyl 1.1 (a) KOtBu / tBuOH, DMF, C ₃ H ₅ CH ₂ Br, 0 ° C to rt; or (b) 1.1 eq NaH, DMF: THF (1: 5); 1.3 eq C ₃ H ₅ CH ₂ Br, 0 ° C to rt; luxeflux 6h; column chromatography 2.4 H 1.2 NaH, Mel, THF, DMF 0 ° C to. rt 2.5 H 1.3 Π II 2.6 H 1.4 Π .11 2.7 H 1.5 ii n 2.8 H 1.6 II 11 2.9 H 1.7 II II 2.10 H 1.8 n « 2.11 H 1.9 II 11 2.12 H 1.10 M. «

Procedure B

Compound 1.11 described in Reference Example 1 was reacted in a mixture of THF-DMF (5: 1) with sodium hydride and Mel at 0 ° C. The temperature of the reaction mixture was allowed to rise to room temperature for 18 h. The product was recrystallized from EtOAc to give the expected compound of formula II in 40% yield. Analogously but with the substitution of compound 1.11 for the other compounds of the general formula IV described in Reference Example 1 and with a modification of the reaction time if necessary, the compounds shown in Table 2B were prepared. In some cases, purification by flash chromatography or recrystallization was performed as described in note.

Table 2B

Compounds of formula II

ABOUT

Compound No. R ² and East. compound (IV) Reaction time Purification procedure see note. Yield I (%) 2.13 H 1.11 18 and 40 2.14 H 1.12 .18 b 8 2.15 H 1.13 18 b 8 2.16 H 1.14 18 and 50 2.17 H 1.15 1.8 and 50 2.18 H 1.16 b 26 2.19 H 1.17 b 26 2.20 H · 1.18 18 and 40 2.21 H. 1.19 72 b 18 2.22 H. 1.20 16 C 10

2.23 H 1.21 72 b 18 2.24 H 1.22 16 C . 10 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 7.0 2:32 H 1.30 18 D 70 2:33 H 1.31 D 4 6 2:34 H 1.32 D 46. 2:35 H 1-33 3 b 33 2:36 H 1:34 72 b 20 2:37 H 1:35 3 b  45 2:38 H 1:36 D 75 2.44 . H 1:37 16th e 37

Note a = recrystallization from EtOAc b = flash chromatography eluting with EtOAc-hexane (1: 1) c = flash chromatography eluting with CH ₂ Cl ₂ d = flash chromatography eluting with Et ₂ O-hexane (1: 1) e = recrystallization from mixture EtOAc-hexane

Procedure 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 temperature was allowed to rise to room temperature for 5 h. The product was purified by flash chromatography (20% EtOAc in hexane) to yield 50% of Compound # 1. 2.39, wherein R ² is -CH = CH ₂ .

Procedure D

Compound 1.1, described in Reference Example 1, was reacted in THF-DMF (5: 1) with sodium hydride and methyl bromoacetate at 0 ° C. The temperature of the reaction mixture was allowed to rise to room temperature for 3 h. The product was recrystallized from EtOAc-hexane to yield 35% of Compound # 1. 2.40 wherein R ² is -COOMe.

Procedure E

Compound 1.1, described in Reference Example 1, was reacted in DMF with sodium hydride and 2-dimethylaminoethyl chloride hydrochloride at 0 ° C. The temperature of the reaction mixture was allowed to rise to 20 ° C and further increased to 80 ° C for another 5 h. The product was recrystallized from 1% MeOH in EtOAc to yield 32% of Compound # 1. 2:41 of formula II wherein R ² is -CH ₂ NMe ₂ ·

Procedure F

Compound 1.1, described in Reference Example 1, was reacted in acetonitrile with Cs ₂ CO ₃ and ethyl bromoacetate at 20 ° C. The temperature of the reaction mixture was allowed to rise to 20 ° C for 2 h. The product was purified by flash chromatography eluting with EtOAc-Hexane (1: 2) to yield 35% of Compound # 1. 2.42, wherein R ² is -CO ₂ Et.

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 at reflux for 3 h to give compound 2.43 of formula II wherein ----- is a single bond, ^R1 is phenyl and ^R2 is H, with a yield of 98%.

Reference example 4

Preparation of 1-methyl-6-benzyl-2,5-piperazinedione

Compound i was reacted with phosgene in THF at 0 ° C, 15 min. The temperature of the reaction mixture was allowed to rise to room temperature overnight. The resulting compound ii was further reacted with glycine methyl ester hydrochloride and triethylamine in CHCl ₃ at -65 ° C, 3 h. The reaction mixture was allowed to return to room temperature overnight and the reaction mixture was further heated at reflux for 16 h to give the desired product in 53% yield.

Reference example 5

Preparation of 4- (2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) aniline (a) The title compound, a compound of formula IX, was prepared according to the following procedure:

OMe

3.4

3.1

Compound in the presence of J 1 CO 2 3.3 in 78% yield.

in concentrated HCl in a yield of 51%.

The reaction was allowed to react for 12 hours, reduced with iron powder

80 ° C, 3 h, to give 3.4 'reduced by hydrogenation

DMF, at 100.33 farther and MeOH at

Alternatively, 3.3 with compound 3.2 gives the compound at 30 psi with palladium on carbon catalysis in methanolic HCl, h, to give 3.4 with quantitative yield.

(b) Analogously to (a), except that Compound 3.1 is replaced by 4-bromomethylbenzoic acid and 4-bromomethylbenzoic acid, respectively. 4- (3-bromopropyl) benzoic acid, two other compounds of formula IX were prepared:

(c) In analogy to (a), but with the substitution of compound 3.2 for 1,2,3,4-tetrahydroisoquinoline hydrochloride, another compound of formula IX was prepared:

(d) Preparation of the amine of compound 3.10:

of formula IX, wherein r = o,

3.10)

6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 3.8 was reacted with chloroacetonitrile in the presence of K ₂ CO ₃ in acetonitrile at reflux for 24 h. Compound 3.9 was obtained in 92% yield. Compound 3.9 was reacted with LiAlH ₄ in ethylene glycol dimethyl ether at room temperature overnight. The temperature was then raised to 40 ° C and the reaction continued for 30 min. The expected amine 3.10 was prepared in 98% yield.

Example 1

Preparation of compounds of formula III

Procedure 1

Compound 3.4, prepared in Reference Example 5, was reacted with 2-chloro-1-methylpyridinium iodide and an acid

3-formylbenzoic acid in CH ₂ Cl ₂ , in the presence of Et 2 N, at 0 ° C. The temperature of the reaction mixture was allowed to rise to room temperature overnight. The product of formula III was prepared in a yield of 43%:

Analogously, only with the substitution of compound 3.4 for compound 3.5 and compound 3.5, respectively. 3.6 the following compounds of formula III were prepared:

4.4

Procedure 2

4-Formylbenzoyl chloride was prepared by acid reaction

Of 4-formylbenzoic acid with thionyl chloride in toluene at reflux. 4-Formylbenzoyl chloride was further reacted with compound 3.4, prepared in Reference Example 5, in CH ₂ Cl ₂ , in the presence of Et ₃ N, at 0 ° C. The reaction mixture was allowed to warm to room temperature overnight. Product 4.2 was prepared with a yield of 53%:

Analogously, only with the substitution of compound 3.4 for compound 3.5 and compound 3.5, respectively. 3.7, two further compounds of formula III were prepared:

Procedure 3

4-Formylbenzoyl chloride, prepared according to Procedure 1, was reacted with Et ₃ N in CH ₂ Cl ₂ at -20 ° C. Compound 3.10, prepared in Reference Example 5, was further added. After aqueous work-up of the reaction mixture and flash chromatography, compound 4.7 was obtained in a yield of 43%.

Analogously, only with the substitution of 4-formylbenzoyl chloride for

3-Formylbenzoyl chloride was prepared as compound 4.8 in a yield of 48%:

OHC

4.8

Example 2

Preparation of compounds of formula I

The present compounds of formula I, shown in Table 3A, were prepared by reaction of a compound of formula

II, prepared in Reference Example 2, and the compound of formula III, prepared in Example 1, under the reaction conditions shown in Table 3A.

Table 3A

Compounds of formula I

Compound I no. Compound II Compound III Reaction conditions 9112 2.1 4.2 KOtBu, tBuOH, THF, 0 ° C to room temperature. 9113 2.2 4.2 · 9114 2.3 4.2 . »» 9091 2.4 4.2 CS 2 CO 3, DMF, 90 ° C, 2-3 h 9092 2.5 4.2 - 9093 2.6 4.2 · · 9108 2.7 4.2 · 9109 2.8 4.2 II 9110 2.9 4.2 · · 9111 2.10 4.2 and 9155 1 2.12 4.1 CS 2 CO 3, DMF, 90 ° C, 2-3 h 9156 2.11 4.1 · 9157 2.6 4.1 It 9158 2.5 4.1 · · 9159 2.7 4.1 · ·

9160 2.10 4.1 9139 2.1 4.1 CS 2 CO 3, DMF, 80 ° C, 2-3 h 9141 2.3 4.1 • t

Example 3

Preparation of salts

compounds ready in Example 2 is converted to the corresponding hydrochlorides reaction with gaseous HCI In THF. Example 4 Preparation of compounds of of formula I submitted compound of of formula I, cited

in Table 4, were prepared by reacting a compound of Formula II, prepared in Reference Example 2 or 3, with a compound of Formula III, prepared in Example 1, in DMF at 80 ° C and in the presence of Cs ₂ CO ₃ , 4. Some products were purified by recrystallization or flash chromatography as also indicated in Table 4.

Table 4

Compounds of formula I

Bile. I č. Bile. II Bile. III Reaction time Purification or elution (see note) 9178 2:39 4.2 3 5% H2O in PrOH (a) 9179 2:39 4.1 3 5 * H2O in PrOH (a) 9193 2.13 4.2 16 EtOÄc (a)

9194 2.14 4.2 5 EtOAc (a) 9195 2.15 4.1 5 EtOAc (a) 9196 2.16 4.2 16 9197 2.17 4.1 16 9198 2.18 4.1 14 nPrOH (a) 9199 2.19 4.1 10 iPrOH (a) 9209 2.20 4.1 10 EtOAc (a) 9210 2.21 4.2 12 EtOAc-MeOH (a) 9211 2.22 4.1 14 EtOAc, MeOH, Et 2 O (a) 9214 2.23 4.1 18 CH2Cl2-Et2O (a) 9215 2.24 4.2 4 EtOAc-Et2O (a) 9217 2:40 4.1 2 EtOAc-hexane (a) 9228 2.25 4.2 8 5% MeOH in Et 2 O (b) 9229 . 2.26 4.2 14 5 * MeOH in Et 2 O (b) 9230 2.27 4.1 18 5% MeOH in Et 2 O (b) 9231 2.28 4.2 14 9232 2.29 4.1 14 5% MeOH in Et ₂ 0 (b) 9233 2.30 4.1 5 5 * MeOH in Et 2 O (b) 9234 2.31 4.2 18 5% MeOH in Et 2 O (b) 9235 2:32 4.1 14 5% MeOH in Et10 (b) 9236 2:33 4.2 14 5% MeOH in Et 2 O (b) 9250 2:34 4.1 14 5% MeOH in Et 2 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 2:36 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 9306 2:38 4.1 14 5 MeOH in Et2O (b) 9308 2:43 4.1 16 10% MeOH in Et 2 O (b)

Note (a) Recrystallisation solvent (b) Flash chromatography eluent

Example 5

Preparation of salts

Selected compounds prepared in Example 4 were converted to the hydrochloride salt reakciou- with gaseous HCl in CH ₂ C1 ₂ · In some cases, the hydrochloride, denoted in Table 5 .HCl extension, recrystallized.

Table 5

hydrochloride

Sol Recrystallization solvent Yield (%) 9193.HCI 9144.HCI EtOAc 21 9195.HCI EtOAc 22 9196.HCI 9197.HCI EtOAc 35 9232.HCI 9306.HCI

Example 6

Interconversion of compounds of formula I

Compounds of formula I were prepared by reacting selected compounds of formula I prepared in Example 4 with the appropriate reagents according to the general synthetic procedures:

Compound 9217 was reacted with LiOH in aqueous THF at room temperature for 2 h to give compound 9241.

2. Compound 9272 was reacted with NaBH 4 in MeOH at 0 ° C, 2 h to give compound 9276 in 73% yield.

3. Compound 9274 was reacted with NaBH 4 CN in MeOH and THF at ’C. The reaction mixture was further heated at 50 ° C for 5 h and the product was recrystallized from 20% EtOH in EtOAc to give compound 9300 in 58% yield.

4. Compound 9273 was treated with NaBH 4 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 preparation

Preparation of tablets weighing 0.15 g and containing 25 mg of a compound of the formula I or a salt thereof:

Composition for 10000 tablets The present compound of formula I or a salt thereof 250 g lactose cereal starch powder talc magnesium stearate

800 g

415 g g

g

Firstly, the compound of formula I or a salt thereof, lactose and half the amount of cereal starch were mixed. The mixture was then passed through a 0.5 mm mesh screen. Cereal starch (10 g) was suspended in warm water (90 ml). The resulting paste was used for powder granulation. The granulate was dried and ground into small fragments on a 1.4 mm mesh screen. Then the rest of the starch, talc and magnesium stearate were added, the mixture was mixed gently and compressed into tablets.

Example 8

Testing compounds of formula I as MDR modulators

Mouse breast cancer EMT6 cell line and MDR resistant subline AR 1.0 were grown in RPMI 1640 medium containing 10% lamb serum and 2 mmol.l ^-1 glutamine, at 37 ° C, in 5% CO ₂ · Cells were passaged between 1 k 200 and 1 to 2000 for the parent cell line, between 1 to 20 and 1 to 200 for the MDR resistant subline, after trypsinization (0.25% trypsin, 0.2 gl ^-1 EDTA).

1. Drug accumulation test

AR 1.0 cells were plated in frosted 96-well culture plates (Canberra Packard). The test medium contained a mixture of tritiated daunorubicin (DNR), a cytotoxic, and unlabeled DNR (0.3 µ Ci / ml; 2 µπιοΐ ^x ). The compounds of formula I were serially diluted in the test medium to a concentration range of 5 nmol.l ^-1 to 100 μιηοΐ.1 ^-1 . Cells were incubated for 1 h at 37 ° C, washed and cell-bound radioactivity was determined. The results were expressed as% of maximum accumulation, with 100% accumulation taking the value of accumulation in the presence of verapamil, a known RMA, at 100 μτηοΐ.ΐ ^- · ¹ ·, or as IC _5Q .

The results are shown in Table 6. Table 6

Compound No. IC5 0 (umol.1 “ ¹ ) 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 5.0 9114 0.6 9139 0.2 9141 0.5 9155 00:06 9156 0.1

9157 0.2 9158 0.6 9159 0.4 .9160 20% 9178 0.080 9179 0.170 .9193.HCI 7.0 9194.HC1 1.800. 9195.HCI 0.210 9196.HCI 0.140 9197th HCl 0.025 9198 0.200 9199 0.140 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 0.13 0 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

9267 5,000 9272 0,4 00 9273 0,070 9274 0.800 9275 0.600 9276 1,900 9276.HCI Ό. 700 9299 0.500 9300 0.200 9301 0,200 -9,308 3,000

2. Enhancing the toxicity of doxorubicin

Compounds of formula I were tested for the ability to enhance the efficacy of doxorubicin in AR 1.0 cells. In the initial proliferation assays, the present compounds were titrated against constant concentrations of doxorubicin (0.86 μιαοΐ.1 ^-1 ), which are not toxic to AR 1.0 cells alone. After four days of incubation with doxorubicin, proliferation was measured using a colorimetric sulforodamine B assay (Skehan et al; J. Natl. Cancer Inst. 82, pp. 1107-1112 (1900)). The results are shown in Table 7.

Compounds that caused a sensitivity of AR 1.0 cells to 0.86 μιηοΐ.ΐ ^-1 doxorubicin and were not very toxic themselves were selected for further studies. Cells were cultured for 4 days with different concentrations of doxorubicin (0.01 to 50 µmol / ^l ) in the presence of a constant concentration of each of the test compounds of the present invention. Proliferation was quantified according to the procedure of Skehan et al; J. Natl. Cancer Inst. 82, p. 1107-1112 (1990). IC ₅₀ values (the concentration necessary to reduce proliferation to 50% of the blank control) for doxorubicin alone and all test compounds were derived and used to calculate potency index (PI):

IC ₅₀ for doxorubicin alone

PI = --------- IC ₅₀ for doxorubicin plus RMA

The results are shown in Table 8:

Table 7

Compound No. Toxicity of compound · (IC5 o umol.1 ¹ ) Toxicity with cytotoxic agent (IC50 umol.1 ¹ ) 9091 1.8 00:15 9092 0.7 00:07 9093 2.0 0.09. 9108 4.0 0.10. 9109 4.0 00:30 . 9110 6.0 1:00 9111 2.5 00:15 9112 2.0 0.015 9113 0.4 0.1 9114 1.0 00:06 9139 4 0.3 9141 2 0.3 9178 1:50 0.008 9179 00:50 0.080 9193.HCI 2:00 0.200 9194.HCI 6:00 0.050

9195.HCI 1:00 0.010 9196.HCI 7:00 0.060 9197.HCI 28.00 0.010 9198 8:00 0.020 9199. 40.00 0.050 9209 45.00 0.070 9210 40.00 0 or 0.80 9211 50.00 0.080 9214 100.00 0.008 9215 10:00 0.030 9228 0.60 0.100 9229 00:50 0.070 9330 00:45 0.100 9231 2:00 ^; 0.120 9232 3:00 0.060 9233 8:00 0.400 9234 1:00 0.080 9235 00:50 0.100 9236 0.80 0.130 9250 2:00 0.080 9260 3:00 0.350 9261 5:00 0.400 9272 9:00 01200 9273 20:00 0.020 9274 40.00 0.050 9275 1.80 0.700 9276 30.00 0.500

Table 8

Compound No. Gain Index PI determined at (mol. 1 ~ ¹ ) 9108 1000 1 9109 250 1 9111 500 1 9112 1000th 1 9139 500 0.5 9141 285 ⁰ - ⁵ 9155 67 0.2 9156 25 0.2 9157 40 0.2 9158 75 0.2 9159 50 0.2 9178 7.1 00:01 27.3 00:03 69.8 00:10 250.0 . 00:30 9193.HCI 20.0 00:30 2.0 00:10 9194.HCI 50.0 00:30 7.5 00:10 1.5 00:03 1.2 00:01 9195.HCI 454.0 00:30 50.0 00:10 2.5 00:03 1-2 00:01 9196.HCI, 37.5 0.30 5.0 00:10 1.5 00:03 1.0 00:10 9197.HCI 65.0 00:30 4.3 00:10 1.3 00:03 1.3 00:10 9198 32.5 00:30 3.3 00:10 1.3 00:03 1.3 00:01

9199 65.0 00:30 2.2 00:10 1.3 00:03 1.3 00:01 9209 125.0 0.3 0 15.0 00:10 1.2 00:03 1.2 00:01 9210 75.0 00:30 8.3 00:10 1.5 00:03 1.3 00:01 9211 1538.0 1:00 1000.0 00:50 9214 200.0 ABOUT. 30 150.0 00:10 20.0 00:03 2.0 00:01 9215 66.7 00:30 15.0 00:10 3.0 00:03 1.5 .0.01 9217 11.0 00:30 1.0 00:10 0.9 00:03 0.8 00:01 9231 20.0 00:30 3.0 00:10 0.9 00:03 1.1 00:01 9232 80.0 00:30 20.0 00:10 3.0 00:03 1.0 00:01 9234 50.0 00:30 5.0 00:10 9235 37.5 00:30 2.3 00:10 9236 16.7 00:30 2.1 00:10 9250 286.0 00:50 9260 3.3 00:30 2.0 00:10

9261 2.2 1.7 00:30 0-.10 9272 175.0 1:00 5.6 00:30 1.4 00:10 9273 100.0 3:00 96.1 1:00 83.3 00:30 29.4 00:10 9274 100.0 3:00 90.9 1:00 71.4 00:30 25.0 00:10 9275 25.0 1:00 6.9 00:30 0.7 00:10 9276 166.6 3:00 25.0 1:00 0.8 00:30 0.8 00:10 9299 16.0 00:30 1.8 00:10 9300 133.3 1:00 61.5 00:30 10 '. 0 00:10 9301.HCI 133.3 1:00 88.9 00:30 28.6 00:10

Example 6

Characterization of the present compounds

The compounds and salts prepared in Examples 1 and 2 were characterized by mass spectroscopy (MS) and proton nuclear magnetic resonance (NMR ^X). The results are shown in Tables 9 and 10:

table

rc 4J <D U e c X. 2.5-4.7 (10H.m.). 2.95 (3H, s); 3.83 (6H, s). 6.88 (1H, s). 6.92 (1H, s), 6.98 (1H, s), 7.15 (1H, s), 7.40 (2H, d). 7.51 (2H, d). 7.59 (2 H, d). 7.83 (2 H, d), 7.90 (2 H.d). 8.12 (2H, d), 10.45 (1H, s). 10.8 (1H, s). 11.1 [(IH.bs) 2.5-3.7 (8H, m). 2.88 (3H, s), 3.84 (6H, S). 4.5 (2Hm), 6.89 (1H, s). 6.93 (1H, s). 7.01 (1H, s). 7.15 (1H, s). 7.40 (2H, d), 7.50 (311, m). 7.65 (1H, int). 7.82 (2H, d). 7.90 (2H, d). 8.14 (2 H, d). 10.47 (1H, s), 10.90 (1H, s). 11.37 (IH.bs) 2.3-4.7 (10H.m.). 2.94 (3H, s). 3:84 (6H, s). 6.89 (1H, s), 6.93 (1H, s). 6.99 (1H, s). 7.16 (1H, s). 7.40 (2H, d). 7.42-7.60 (4H, m). 7.82 (2H, d). 7.90 (2 H, d), 8.14 (2 H.d). 10.45 (1H, s). 10.85 (1H, s). 11.30 (IH.bs) rozp./pole _tsl X O O n About IS> X Q and «Ο NJ □ Z O O CO o 00 X o T XO T> NJ from C3 O CO \ O VO Q XO O MS data mod u · about about matter (i nt enz.) 679 (10). 677 (10). 200 (100) 679 (10). 677 (10). 208 (100) 679 (10). 677 (5). 208 (100). 190 (100) summary formula ABOUT w · » about • · χ £ O x kO o m '* tr · θ ’ about · * Λ ABOUT «V ζε • n Τ ' m O > the CXJ Crc WHAT 2

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Summary _________ MS data_________________________ * H ntnr data formula mass (int.) Blue r / field t /) LxJ ₍

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*about. O in m -inco.co · o in cxj τ vo -  • Em on -r ^ r ^ r-^ -uo CO s-X- • -to - - -xrX CXJ ** - r- < toX WO E - ·· —I '· · -TJ · E CXJ »- <t—« VO iD . - - = - - - - x-. - in> - CO E EX · 10TJ - <zc - -vrr ^ XX «-« - <ZXVD CXJ CXJ <. - CXJ on O <cxi r '»cr cr> cxj ον ^ τττ -σι-ντιηχ. . VO · · -CXJ .12 (1H, S). 10.50 (IH.s) CXJ - - - - cxj m vo <E ΕΌ CXJ. tD - · - · cnro rrzrrnnľ • cxjcxjcocxj z ~ L0 • (/> -OVDTy ♦ - <-zc u> cxj m en EIVD. ... • <- * o · euro · WHAT X LO 1 CO ZS · • zc * - * CO... • · E> z— «. - - -WHAT • Z “x. Z <. vd tn - - - - VO VO · - <WH LfJ 00 - Z ~ \ Z — X · Τ ^ <Λ / Ύ <*> Γν U0 ΙΛ * - * CO z-xz- ^ z-s z — x z ** ο . .... z— < to E X -O in TJ 10. · E • · w0 * o (v / v) c *> * γ * γ * νγχ <n • -en · · · -r ^ -XX ococo · ·· · · ’ ro. m XX XXXXX ZC »- <- < CT> XX XX x TJ . - to - - · -X , ro cí * - * - <cxj · <· LTJ '-'t-' • · · · - ^ CXJ CXJ * - · * - < CXJ ^ X. <- s ^ z-soOvJ ^ Z-«μ» <** t X- ' CXJ * x z ~ x x— * * —z '* - * * —z at ♦ V13Z / / Ό * ·> <Λ * - * E O CO • E v) E F lD CXJ CO O O T T - · Ocovej CXJ · · -CO About CXJ o C T y ΠΤΤ ΓΓ Cľ> VO -t r- in CO Γ 3 LQ X O · · MXXOlOCOO Č x · - - ^ ^ ^ ^ ^ ^ ^ ^ . . . . . . . • oo • CXJCXJ- ^ .... JF f \ j> * -> * -> »- * *> - * ** - * co cxj what co xr vo r> —- CO »-« r-1 CXJ »^ -» - z »^ r '» r'.rx.co «· about· rsj ľn NJ x • rsj ÍV LC about x CO o o TT 00H w about N. ro en 2ľ «" I 0 W O O about 1 w o o about ie about • σ o _l J oo LU ljj E 0 -P Z "> · the _e * 0 n; C w OJ from -P C w < in/ z-x ABOUT 0 G · -. -P s «z O E 693 633 phi . > 1 G about <_J M Φ x '' J M * Λ iC 0 about about ABOUT ω N> from about from  about __y • about he ABOUT Ä C ľ ABOUT LJ> c_? • u tn m VO c \ en O> · - » CH en en

Summary . MS data - H nmr gave

2.98 (2H, m). 3.12 (4H, m). 3.19 (3H, S). 3.40 (2H, m). 3.75 (2x3H, s), 4.26 (1H, s). 4.50 (1H, m). 6.68 (1H, m). 6.79 (1H, s). 6.82 (1H, m + 1H). 6.88 (1H, s). 6.90 (1H, s). 7.30 (2 H, d). 7.70 (2H, d), 7.76 (2H, d). 7.87 (1H, d), 8.01 (2H, d). 10.30 (1H, s), 10.55 (1H, s). 10.60 (1H.s) 2.98 (2H.bd), 3.15 (4H-m), 3.21 (3H, s). 3.42 (2H, m). 3.75 (2x3H, s). 4.28. 4.50 (1H, bd). 6.62 (IH.m), 6.78 (1H, s). 6.82 (1H, d). 6.83 (1H, s). 6.89 (2x 1H, s), 7.30 (2H, d). 7.56 (1H, t). 7.71 - 7.78 (3H.m). 7.90 (2H, m). 8.10 (1H, s). 10.30 (1H, s). 10.70 (1H, s). 10.76 (LH.bs) 2.61 (6H, m), 2.81 (2H, t). 3.06 (3H, s); 3.55 (2H, s). 3.65 (3H, s). 3.70 (6H, s). 6.18 (2H, m), 6.65 (2x1H, b). 6.82 (1H, s). 6.98 . (IH.s + lH, m). 7.25 (1H, d). 7.68 (4H, m), 7.98 (2H, d). 10.15 (1H, s). 10.50 (1H.s) M • ZE X O O χτ O </) x o and X x o o XT o <z> x Q 1 Ό IM x x o o XT δ (Z) x Q 1 Ό υο LjJ <Z) UJ 633 (100) 646 (100) O X * £ · ABOUT • e • n O 13H'W ¹ ' ^tlC 3 O X • n ir. ABOUT ABOUT about\ Ox CJ x σχ CTx co en θ '

from-" · t Z— < - - m * -> * - * * £ . - - (v) · - · * -> . . . . kO o v • - </> vz>. co cz> en · z ~ x z— »4-1 iS ts en - —— »· · cloud -u> v> V> X Ό Ό Ό · 4-> tn v) E · • '• □ Z 4-> VI X X · - - < - - - - <- - -x •. · • CXJsrsV) »-’ • · CO · - <en rs rs rs x x x x x x x · —i O4XD OJ ojoj— IX Z Z O - ΣΟ¾C CM OJVD — iCO · - -X CXJ CXJ ... .z-p s_z V ^ z s z z * —z \ ^ 4 V — z s-z ^ 4 x_z s_z ts. z — x z-s r — 4 <- * ^ zCOUjb * z — x z — x z — x V) VO • 'TD' • —F '* COCD Ό Ό WO · ^ Ωοΐπωιηωιί) Γ- < OOkD ^ OOJ cm m · o · · · nz co uo r - vo cr> cxj vo co · oorsvocoLOXX-C-G: co x co x x x -> K) ........about • · * C \ J 4—4 ♦ - <f—  . · 4—4 4— <CM S ojnrjiOCir'ixrsr-i CMD ^ lxrsszsz · CXJ C) · rs' - zszsz Z-X WHAT · <-SX-p - · - · ...... ΟΊ - - - - - - • - ιλ v) - room - < it z — X Z — x 4 — X 4 — \ O 4— · Z — X 4—, z — X O ^ v z-xzso ^ rx co-vi ^ w-x. .z-sin in r-'s · EwwEwÉ-POw · E «Λ <Λ <Λ Ό · <s - E at> XXj-> · O ......... rc ..... rsrs E3T • · 94-4 xuxacszxxx- · X XX XX -> xx x xx VO C * J CO CM 4 'H »-M 4 - 4 r-4 t-H in CO · - <· - Bad -> - * VOCQCMCM · - <· - · - x »z x ^ * —z with — z> *» z * _Z> ^ 4 N «Z> ~ 4 4—» ZS S — Z X_z x »_z x» _z * »z z — x z — x z — x z — x at </) O EO ^ H ΕΌ-ΟΌΧ3 E ovrmvoin -m — ioud O CO CXJ 4 - «O - · CM envoovovo ..... C i — o vo - <co rc lt> r ~ - -> · in that vo ox that σχ · VOOIS—> XXX xx ..... - ' -about ..... CO 4— <cr »o . . - ... - 4 - 4 CXj C \ J r — 4 • 2T * OJ CO CO VO VO p. rs vO CO - < cxj co vo vo rs' -r —- rs - ‘ cxj n co vo rs s * * - - · - - ' d) rs) rM • M 0 a OMH □ r x o OMH © ABOUT ABOUT • * x ^ \ ^ S. here about about about N 09 09 09 0 <,  x x 2¾ about Q Q * 0 "about x> Ό P Ό about 09 09 09 e UJ V LU UJ. <0 -P CTF ₀ Ό N ω C (D •WITH 4J C WITH-* Z ^ Z-X Z-X © ABOUT about © ABOUT © 4 · Η 4 ^ 4J X ^ Z χ_ » discriminates about within WHAT VO σχ en E © within within JZ > 1 C about ú φ 5 Or cT * n o w> about, ω N - ^ y sT from > • n about 'CQ · *? » with.. OJ 0-J •about σχ σχ -vc% 6026 9210

- CXJ CO CXJ rx co • LO »- <· V CO CO <> · 10 cxj rx. co · CD · - - jz m · -co · · -'- χ • - - σι - i— < m uo co vo cxj m z — z — with z— »- z—» 0Ί - · CO P Ό Ό ΙΛ Z • Έ U-O · ε <n m ZC D · en> * - * CO -r- ^ - - · · .— • - «CO - -r-. · · -ZC . . ., - i -tnix · —— < ε rczczczrx- CO-^ x ZZZZZC ^ H zzzzx '-' zrco --χ • W z — κ ζ /) · · —-4 «-Η« —-4 • · U1U1 -CO CXJ r — tvz CD CD CXJ · - - m χοι /) · * - ** - ** - * in - ** - * σ CXJ — x. -— .— ——. N-z s-z X-zQH * r * Z-V z-s X) ω w -XD rx LOZCZC 4-> o CD ED · -ZC · - * -cdcdcdlo • -co · - <ohlo cxj About CO · - <-XJ- - - -ZC X n x m rx co «- <c ^ zc X XZClOUDCO · R cnr ^ kOCxrz-xZIZZC; - < rxo x cxi · · · · - < H co cxj cxj .— <· · -o E CD OJ xx • '-' (XJD '-' rx.rs.rxCO ·> - ** - <** - <** - * r>. R ** - R **, R— « CXJ CXI CO · Γν · χ_ζν ^ cxj χ> σι zc < x-x ZC CXJ OO · no - · · - * -> ΆΟ CO · - U CO CO · - - - in -cxjcr> en> r-χ • Chtv kD CXJ * - * W x-χ o rx co · —r xr --χ χ- »χ ~ · σ Z — X Z — with Z — S. -Z— * * —r r-s. ABOUT · ΕΌΌΌ · . .... V) Ό Ul m j-> «/> zz m · ο tocxjCD • r · 3 · conn ^ or ^ rv · · -zc . . . _ «. lo rx cd · -> --χ. XXXX-i rx m · - < ZC3ZZC XIV □ · CXJ CXJ «-« r— «s—’ • - - - - - co CXJ CXJ CXJ · - <· - - · CO * - * z— * · ^with “· ''” * - * * - * Cxj * - <z — s z ~ s z · - * - x Z — x z -χ —In ZC </ rx. • 4-> m m ιη ε xr • OTZ> io E - -.— <- co cr> c_> en · - CD - · - · - CD LT> CDX CD OOLDCOCXJin - · - C CD ZC ZC XlxriDcocn · lailZXUDrxr-R CD CD un VO .— <CD ZC 3Z ZC __  CXI CXJ CXJ .— <· · -o • cxj cxj ro · - <xr · ♦ -c ♦. ·. . pole cxj «^ z ·« * - * ^>> - * ·. * - * r ** r ** CXJ —--— xx ^ -xx | x rxcCxH cxj cxj co iD r ^. 0) NJ NJ m 0 g 5Z x Pl about ABOUT about x about about about XT XT * T and · *%. about about about N en he en Σ 2¾ ε U and Q and 10 * 0 * 0 Ό Ό  U Ό 0 (FROM) OO ‘ m. e UJ · LLJ 1 — J 1 <Q -P z-a the _and Ό N, and w about ε -P C • M z-x. ABOUT about β: about about 4J S ^ z ABOUT rt HO ro t-1 en n r *. HO Rs. • jC > 1 C 0 M Φ 1 'RTJ P 1 WITH 2 FROM u *> o U) o about ω > from from • t y rx. ~~ x (J * U7 e? and •about XI- en · - * · -1 x- CXJ CXJ CX) --- about en αχ

rs x> ÍO Ό ύ E C '"ABOUT 7.85 (1H, s). 7.90 (IH, s), 8.10 (1 H) 1.08 (6H.d). 2.69 (6H, m). 2.80 (2H, t). 2.88-2.99 (1H, m); 3.34 (3H, s). 3:55 (2 H, s). 3.70 (6H, s). 5.84 (1H, d). 6.62 (2x 1H, s), 6.78 (1H, s). 7.23 (2H, d). 7.68 (4 H, m), 7.98 (2H.d). 10.18 (1H, s). 10.41 (1H.bs) 1.10-1.38 (5 H, m). 1.60-1.73. 2.50-2.63 (1H, m). 2.63-2.73 (6 H, m). 2.76-2.83 (2H, t). 3.32 (3H, s). 3.55 (2H, s). 3.70 (2x3H.s), 5.86 (1H.d). 6.62 (2x 1H, s). 6.80 (1H, s). 7.23 (2H, d). 7.67 (4H, m), 7.97 (2H, d). 10.15 (1H, s). 10.39 tlH.bs) mo · CD X> inco - • · Λ voZC. * OJ ^e .2io X rO coo * * - 'Γ - * <* mro · cn cm * - * ·. ·· ωΧ O · Γθ x -OCM CM 6.60 (1H, s). 7.10 7.20-7.55 (13 H, m). (IH.s). LO ΣΕ T-4 ω IR | "ARE YOU «Μ 0 fsf § A about about \ about about ·· <D -ςΓ • <5 * P. ABOUT ^ 3 δ δ N **with. it it rj X x 0 about about M y 't T about Ί3 • σ and about about , to LU to LU E they + » p ~ x 10 Ό n C IN) <D x -P C • H X-X C3 about Q ABOUT about ABOUT • H e * +> Q I ch ch e o r ** 09 V o x: > 1 β υ H about '<U M IN. . β 0: about about And, P CA VZ o T FROM * x "T • «e ABOUT f. about about'  C_> r ». WHAT cn CXJ CM \ / CM · cr cr »

* 11 nmr data 'about 1.03-1.35 (5 H, m), 1.60-1.80 (5 H, m). 2.49-2.60 (1H, m). 2.70-2.94 (8H, m); 3.35 (3H, s). 3.63 (2H, s). 3.83 (2 * 3H, s). 5.93 (1H, d). 6.55 (1H, s). 6.60 (1H.s) .7.02 (1H.s). 7.20 (2H, d). 7.507.60 7.86 (1H, m). 7.92 (1H, s), 8.50 (IH, s). 8.98 ClH.bs) 0.92 (3H, t). 1.40 (2H, m). 1.52 (2H, m). 2.43 and 2.76. (2H, two quartet) 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 (1H, t). 6.55 (1H, s). 6.60 (1H, s). 7.00 1H. two singlets). 7.28 (2H, d). 7.50 (2H, d). 7.60 (2H, d). 7.80. (IH.s). 7.85 (1H, s). 7.93 (2H.d) .0) —I o Pu á. N O kl CM x x o Q r-j O O o IM • x z o o <-> O Q O MS daťa Ό O E UJ l) UJ X- * H c d) -p β-K <0 0 e -C o o cn - -c ABOUT 623 (100) > 1 c M '(0 d d ω formula * n o • e zz. · * x O 'o ‘ * n o z r \ » ABOUT •ABOUT O CO r <C '· r- ~ rv

Summary MS data ... 'H nmr data

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Summary _______ MS data__________. Μl nmr data formula mass (int) mod sol / field

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m m m about - • • r *, coco ΙΛ LO CO from"* z—> z — K - <cd ro · o c * · lD · i • · it • · io - m , _t co m · σ - vo CD CD CD CD O z — in z— * z Z v * Z N what • · in m ♦ · - “< . · v> EX tzrvox k> j3 m ru cm n · -cm co cDCO -r * '* • · - < • · ΓΟ “-o Rf. pole s ‘Z — V . about X X '-' O XX XXXOV . • ´ what m * - · with-* • · m - CO CM - < CJ CJ CXJ r ~ 4 r-t · . / - *. of ** · ΙΛ · C / J n ' ^ Z% -ZO · K — z x — z s — z X - Z *> - * Cx. F E ιλΖΌΙ ^ 4-> O · ιλΖ u) LOCO 1 O O O 0 .0 4-0 F . . CO ·· - <(Λ - -x - -n · ldid. ·· · -T- * T * T “Γ * ¹ * XX- < ^ x xx cdcdcd * -4 CD CO CD CO <- < E co ro c \ i · - * r \ j oj * - («-Μ * - *) EOjCj - < n what co vo vo r-. * ABOUT v_z «* —Z <-z - ^ f coco -r * □ Z σ WHAT x **> CJ CD CD CO • ^ s · m. — i CD CD ÚD O • “10 - ······ amrs-fStDiO-- mco · -OrxkO z—> z—> · Z “> Z ~ * <** <»of * · ^ Z ^ X Z“ ‘'X •. · Ο . .. E v> X in E «Λ 4-> 4-> 10 ¾> 4 »> m _ <cmtm m n m * £> O> »O * · w - ^ < o π οιο • -n - xx.xxxx ίθ CD Q WHAT XX XX. Ό ..... ^ CM CM - <- CO CO OJ T- <* - <«-« * -v wx Z- ^ »<- * Z — X j * <* >> Z ~ V Z “X z — x cm - 'E * —Z N_Z «—z s- / E 'x-z' * - ^z * —Z * <^ Z * »- Z in — z T within F f = 4_> tr> V) v. Ό E at> <Λ • v, E V> · ABOUT CO CM X * o o o o o rc E r-s O - · -X C m · * - -r- x x x x.x R xxxm COOCDlOlO what cm vo vo cr> o m r— «OJ Drawbar - ·‘ C \ J what · - <· - » • ΓΟ cxj * - «* - < V-H ······ -4 -4 Jr- y ** cj * -> · »—— ** - * * - * CXiCOCOVO * - ' CM Γ7 CO 10 VO VO · ~ Χ w · '<; rs. ' about fM NJ KJ Dr ' ABOUT CD T7 ΣΣΖ X CD x x o ABOUT *% ,. CD about CD £ V ABOUT * IS · • N U1 about «-> rj 0 X f- r- about ABOUT about about • ABOUT Q ABOUT ABOUT ABOUT about Ό ABOUT GB *. about ό about E what • P Z-> C0 * 0 N β CD ω ε 0) -P VO x ^ * lD c. WHAT • ZH from _ Z ^ about about CD tB about o y < CD -P * _ N »of X-Z lO 0 Γ * Κ r *. C * W- < in-C about G within VO VO LD x > 1 C about ú Φ ' e d o N «/ * C iA O w «Α ABOUT w 1 ω> FROM WITH from CD rj x · * 1 <a <_> about »L> about about cd LD WHAT CD a £) CJ pole C \ j C-J σχ about cn

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Summary HS data. . Data mr data

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Ο O -p U E c K3 2.85 (3 H, s). 2.90-3.30 (8Hm). 3.35 (2H, s). 3.70 (2x3H.s). 6.80-6.95 (5 H.m.). 7.05 (1H, s). 7.10-7.35 (6 H, m), 7.60 (1H, t). 7.75 (211.m). 7.85 (1H, d). 8.10 (1H, S), 9.90 (1H, s). 10:25 (LH.s) 2.70-285 (8H.m). 2.90 (311, s). 3.50 (2H, s). 3.65 (2 * 3H, s). 6.65 (2x 1H). 6.70-6.80 (3H.m). 6.85 (1H, s). 7.0’0 (lH.s). 7.207.85 (9H, m). 8/10 (1H, s). 9.50 (1H.s). 10.20 (1H.s) 0.90 (3 H, t). 1.30-1.52 (4H, m). 2.68 (2 H, q). 2.90- 3.00 (2H, m). 3.10. 3.20 (3 H, s). 3.30 (2H, m). 3.75 (2x311s). 4.25 (IH, dd). 4.50 (III.bd). 5.75 (111.t). 6.78 (1H, s). 6.81 (111, s). 6.83 (1H, s). 7.30 (2H, d). 7.52 (1H, t). 7.69 (1H, d). 7.78 (2H, d). 7.85 (1H, d). 8.06 (1H, s), 10.30 (1H, s). 10:42. (LH.s). 10.56 (IH.bs) 2.60-2.95 (8H, m), 3.15 (3H, s). 3.20 (2H, d). 3.70 (2 H, d). 3.70 (2H, s). 3.85 (2 * 3H, s). 4.30 (1H, t). 6.55 (1H, s). 6.60 (1H, s), 6.65 (1H, s). 7.05-8.50 rozp./pole NJ g and o XT x O en X Q - «λ NJ X x o o . about G O o -JX o O en x o 1 Ό NJ O O '’ζΤ . ra G o o -P «0 • o w έ Ό O E • about zx N. C 0) -P c r4 <S; -P i 0 E r; en KD > 1 β M Λ ä 1 ^w ABOUT Φ! M o N > G ABOUT of o- r ~> o about from <c r> lr r> O i * ° 1 H ---- G Ο »o r * J en o m CN O o Γ-) en CO o m en

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Industrial usability

The present invention provides the compounds of the invention which exhibit efficacy (MDR) of the compounds and compositions of the present invention. The invention provides pharmaceutically useful modulators of multidrug synthetic synthetic processes for the preparation of pharmaceutical and veterinary preparations containing them.

Claims (10)

PATENT CLAIMS 1. A piperazinedione derivative of the general formula I: wherein p = 0 or 2; all of R ^a to R ^e, the same or different, may be selected from H, ^C "6 ^alkyl unsubstituted or substituted by one or more halogen, ^C ~ ^C 6 alkenyl, ^C" 6 ^{alkoxy, C "C} C 6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, -CH 2 OH, -CH 2 COOH; -COOR ^11, -NHCOR ^11, -NHSO 2 R ^13, -SO 2 R ^13, CON (R ^1X R ^12), -SOR ^13, -δΟ ίΚ ^ ¹ ^ ^12), -N (R ^{1 L} R ^12), - O (CH 2) _n N (R ¹¹ R ^12), -O- (CH2 ^ -COOR ^11, -OCOR ^11, -CHjOCOR ^11, -CH HCOR ^11, -CH2NHCOOR ^13, -CH 2 SR ^{1: L, 1 -CH2SCOR:?} ·, -Cl 2 SiO 4 R ¹³ , wherein m = 1 or 2, -CH ₂ NHCO (CH ₂ ) _n COOR ¹¹ , -N (R ^{1: L} ) COR ¹² , -NHCOCF 3, -NHCO (CH ₂ ) _n COOR ¹¹ , - NHCO (CH 2) _n OCOR ^{1 : L} and -NHCO (CH 2) _n OCOR ^{1: L} ; wherein n = 0 or an integer from 1 to 6, all R ^1X and R ^{X 2} are independently H or C 1 -C 6 alkyl and R ¹³ is a C ^ -C alkyl, or any of R ^a and R @ ³ or R @ and R @ ^c and R ^c and R ^ or R ^ and R ^e together form methylenedioxy, or together with the carbon atom to which they are attached, a benzene ring or an optionally substituted benzene ring; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S, wherein the heterocycle may be fused to the benzene ring; (iii) ^{a C -} C alkyl or C ₅ cycloalkyl -CY; or (iv) C ₅ -C 6 cycloalkenyl, unsubstituted or substituted with C ₂ -C ₆ alkenyl; R ² is H, ^{C _C} 6 alkyl optionally substituted with N (R ^{and L} R ^12), C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, -C00R ^11, wherein R ¹¹ is as defined above or is phenyl as defined in (i) but does not represent H when R ¹ is unsubstituted phenyl; and one of R ³ and R ⁴ is H and the other is of formula A: wherein q is an integer from 1 to 4, r = 0 or 1 and R ⁵ and R ⁶ are the same or different and are H or C 1 -C 6 alkoxy, or together R ⁵ and R ⁶ form a methylenedioxy group; and ----- is a double bond, or where the R ¹ is as defined under (i) ----- is a double or single bond; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R ¹ is a phenyl group as defined in (i), wherein one of R ^a to R ^e is selected from hydroxy, C ₁ -C _g alkoxy, NHCOR ^11, -C00R ^11, -N (R ^1: R ^{12 L),} -0 (CH 2) n N (R ¹² R ^{LL '),} -SO 2 R ^13, -CON (R ^{1: L} R ¹² ), -NO ₂ , -SO ₂ N (R ^X1 R ¹² ), -SOR ¹³ , -N (R ¹¹ ) CO ¹² and halogen and the other four of the substituents R ^a to R ^e are H. , η A compound according to claim 1 or 2, wherein R is a phenyl group as defined in (i), wherein all substituents R ^a to R ^e are H, or one of R ^a , R ^b and R ^c is halogen or C 1 -C 8 alkoxy, the others of R ^a to R ^e are H; or R ¹ is pyridyl, furyl or thienyl; R ² is H, Chg, cyclopropyl or phenyl; and one of R ³ and R ⁴ is H and the other is a group of formula A wherein q = 2 and both R ⁵ and R ⁶ are methoxy. A compound according to claim 1, 2 or 3 wherein R ^X is 4-pyridyl, 3-furyl, 2-thienyl or 3-thienyl. 5. A compound selected from: N- (4- (2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -6-benzylidene-1- ethyl-2,5-dioxo-3-piperazinylidene) methylbenzamide hydrochloride (9112) N- (4- (2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -1-benzyl-6 -benzylidene-2,5-dioxo-3-piperazinylidene) methylbenzamide hydrochloride (9113) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -6-benzylidene-l-cyclopropylmethyl -2,5-dioxo-3-piperazinylidene) methylbenzamide hydrochloride (9114) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -6- (3-furylmetylén) -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-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -6- (4-chloro-benzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide hydrochloride (9091) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -6- (2-chloro-benzylidene) -1-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-chloro-benzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide hydrochloride (9093) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-methyl-2,5 -Dioxo-6- (3-pyridylmethylene) -3-piperazinylidene) methylbenzamide hydrochloride (9110) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-methyl-2,5 -dioxo-6- (3-thienylidene) -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 - (3-thienylidene) -3-piperazinylidene) methylbenzamide (9155) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -l-methyl-2,5 -dioxo-6- (3-thienylidene) -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) J N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6- (2-chloro-benzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide (9158) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6- (3-futylmetylén) -1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide (9159) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6- (3-methoxy-benzylidene) -1-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-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6-benzylidene-l-cyclopropylmethyl -2,5-dioxo-3-piperazinylidene) methylbenzamide (9141) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-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-b Enzylidene-2,5-dioxo-3-piperazinylidene) methylbenzamide (9179) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-methyl-6- ( 2-naphthyl) methylene-2,5-dioxo-3-piperazinylidene) methylbenzamide (9193) N- (4- (2- (6,7-Dimethoxy-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) I N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -l-methyl-6- ( 1-naphthyl) methylene-2,5-dioxo-3-piperazinylidene) methylbenzamide (9195) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -6- (2-furyl) methylene-1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide (9196) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6- (2-furyl) methylene-1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide (9197) N (-4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) 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-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-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -l-methyl-6- ( 2-naphthyl) methylene-2,5-dioxo-3-piperazinylidene) methylbenzamide (9209) N- (4- (2- (6,7-Dimethoxy-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-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -l-methyl-6- ( 3-Methylbenzo (b) thien-2-yl) methylene-2,5-dioxo-3-piperazinylidene) methylbenzamide (9211) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -l-methyl-6- ( 1-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) thien-2-yl) methylene-2,5-dioxo-3-piperazinylidene) methylbenzamide (9215) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6-benzylidene-l-methoxycarbonylmethyl -2,5-Dixo-3-piperazinylidene) methylbenzamide (9217) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-methyl-6- ( 2-methylpropylidene) -2,5-dioxo-3-piperazinylidene) methylbenzamide (9228) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -4 - ((3Z, 6Z) -l-methyl-6-cyclohexylmethylene -2,5-dioxo-3-piperazinylidene) methylbenzamide (9229) N- (4- (2- (6,7-Dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -l-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 - ((3, Z, 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- (4- (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- (4- (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- (4- (2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) -3 - ((3Z, 6Z) -1-methyl-2,5-dioxo) 6- (3-fenylpropylidén) -3-piperazine zinylidén ^r) methylbenzamide (9266) e N- (4- (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-l, 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-l, 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-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6-benzylidene-l- ( 2-dimethylaminoethyl) -2,5-dioxo-3-piperazinylidene) methylbenzamide (9275) N- (4- (2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6- (4-hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene) methylbenzamide (9276) N- (4- (2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6Z) -6-benzylidene-1-ethoxycarbonylmethyl) -2,5-dioxo-3-piperazinylidene) methylbenzamide (9299) N- (4- (2- (6,7-Dimethoxy-l, 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-l, 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-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl) phenyl) -3 - ((3Z, 6E) -l-methyl-2,5 -dioxo-6-pentylidene-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) A pharmaceutical or veterinary preparation comprising a pharmaceutically acceptable carrier or diluent and, as an essential active ingredient, a compound as claimed in any one of the preceding claims. A process for the preparation of a compound as defined in claim 1 comprising reacting a compound of formula II wherein R ¹ , R ² of formula III are: as defined in the claim 1, with a compound (ΠΙ) wherein one of R ⁷ and R ⁸ is H and the other is -CHO, and q, r, 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. Use of a compound as defined in any one of claims 1 to 5 as a multidrug resistance modulator. Use of a compound as defined in any one of claims 1 to 5 in the preparation of a medicament for modulating multidrug resistance. 10. Compound of formula III: (m) wherein q, r, R ⁵ and R ⁶ are as defined in claim 1 and one of R ⁷ and R ⁸ is H and the other is -CHO.