HUT77943A - Piperazine 2,5 dione derivatives, process for producing them, their use and their intermediates - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to compounds useful as modulators of multidrug resistance (hereinafter referred to as "multi-drug resistance" (MDR)), to processes for the preparation of the compounds, and to pharmaceutical and veterinary compositions containing the compounds.

Resistance of tumors to treatment with certain cytotoxic agents is a major obstacle to successful chemotherapy of cancer patients. A tumor may become resistant to cytotoxic agents already used in previous treatments. The tumor may also develop intrinsic resistance or cross-resistance to cytotoxic agents that have not been previously exposed to cytotoxic agents and which are structurally or mechanistically unrelated to agents used in the prior treatment of the tumor.

Similarly, certain pathogens may become resistant to drug agents used in the prior treatment of diseases or disorders caused by such pathogens. In addition, pathogens may also develop intrinsic resistance or cross-resistance to drug agents that have not previously been exposed. These include, for example, multi-drug resistant forms of malaria, tuberculosis, leishmaniosis, and amobic dysentery.

These phenomena are collectively referred to as multi-drug re-V A resistance (MDR). As discussed in more detail below, a plasma membrane glycoprotein (P-gp) plays a role in the underlying mechanism of MDR. P-gp has drug binding properties. Certain agents capable of modifying MDR may therefore be used to promote the passage of drugs through the blood-cerebrospinal fluid barrier, and for the treatment of AIDS and AIDS-related complex disease.

Substances used to modify multi-drug resistance are referred to as resistance modifying agents (RMAs). The drawback of resistance modifiers used for too long is that such agents often have a weak pharmacokinetic profile and / or are toxic at the concentrations required to modify the multi-drug resistance.

We have found that certain types of dioxopiperazine derivatives have a multi-drug resistance modifying effect. The present invention relates to a dioxopiperazine derivative of formula (I) or a pharmaceutically acceptable salt thereof, wherein: is (i) a group of formula (a) wherein p is 0 or 2;

Ra ^ b 'Rd ® ^s ^ e each represent the same or different, are independently hydrogen, optionally substituted C1-6 alkyl, C1-6 alkenyl, C1-6 alkoxy, C1-6 one or more halogen C4 alkyl4

-thio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, hydroxy 11,11

-methyl, carboxymethyl, -CO ₂ R, -NHCOR,

-nhso ₂ r ¹³ , -so ₂ r ¹³ ,

-CON (R ¹¹ R ¹² ),

-SOR ¹³ ,

12

-SO ₂ N (RR),

-N (R ^U R ¹² ),

-0 (CH ₂ ) _n N (R ¹¹ R ¹² )

-O (CH ₂ ) _n CO ₂ R ¹¹ , -O COO ¹¹ ,

-ch ₂ nhcoor ¹³ ,

-ch ₂ sr ¹¹ ,

-CH ₂ NHC 0 (CH ₂ ) _n CO ₂ R

-CH ₂ OCOR ⁿ ,

-CHjSCOR ¹¹ ,

-N (R ¹¹ ) COR ¹² ,

-NHCO (CH ₂ ) _n CO ₂ R 11 -NHCO (CH ₂ ) _n OCOR

-CH ₂ NHCOR ⁿ ,

-CH ₂ S (O) _m R ¹³ , -nhcocf ₃ , or

-NHCO (CH ₂ ) _n O R wherein m is 1 or 2, n is 0, 1, 2, 3, 4, 5 or 6,

12

R and R are each independently hydrogen or (C 1 -C 6) alkyl; and

R is C 1-6 alkyl; or R _a and R _b , 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 an optionally substituted benzene ring;

(ii) a five- or six-membered heterocyclic group optionally fused to a benzene ring containing at least one oxygen, nitrogen and / or sulfur atom;

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

• ·

R is hydrogen, optionally above a definite meg11 12 -N (RR) substituted C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or a radical of formula -COOR ¹¹ group wherein

R ¹¹ is phenyl as defined above or as defined above, with the proviso that when R ¹ is unsubstituted phenyl, R 11 is other than hydrogen; and

4

One of R and R is hydrogen and the other is a group of Formula A wherein q is 1, 2, 3 or 4, r is 0 or 1, and r5 and R6 are the same or different hydrogen or C 1-6 atoms alkoxy; or 5 6

R and R together form a methylenedioxy group; and --- is a double bond, or if R ¹ is as defined in (i), a double bond or a single bond.

C 1 -C 6 alkyl groups may be straight or branched. A C 1-6 alkyl group is typically a C 1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl. The term halogen means, for example, fluorine, chlorine, bromine or iodine.

A C 1-6 alkoxy is typically a C 1-4 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy.

A C 2 -C 6 alkenyl group is typically a C 2 -C 4 alkenyl group such as vinyl, 1-propenyl and allyl.

The heterocyclic group may be, for example, pyridyl, pyrrolyl, furyl or thienyl, which may be attached via any of the ring atoms. Such heterocyclic groups include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl and 3-thienyl.

q is 1, 2, 3 or 4, preferably 1 or 2.

6

R and R are preferably the same and preferably C 1-4 alkyl such as methyl.

When R ¹ is as defined in (i), the phenyl group is unsubstituted or substituted in one or more of positions 2-6. The monosubstituted phenyl may carry the substituent at any of positions 2 to 6, such as at the 3 or 4 position, especially at the 4 position. For example, when the phenyl group is monosubstituted, one of Ra ^- Re, preferably R _b or R _c , particularly preferably R _c , is other than hydrogen. When the phenyl is mono-substituted with the R _& R of one of _these groups is preferably a halogen atom such as chlorine, bromine or fluorine; C 1-6 alkoxy such as methoxy; or an acetylamino group of the formula -NHAc wherein Ac is an acetyl group.

In addition, the phenyl group is, for example, 2,3-, 2,4-, 2,5-, 2,63,4- or 3,5-disubstituted, as well as 2,3,4-, 2,3,5-, 2,3 , 6 or 3,4,5-trisubstituted. When the phenyl group is double • · ·

Substituted at Ί, three of R _a -R _e are hydrogen and two are other than hydrogen. For example, R _a and R _b , or R _a and R _c , or R _a and R _d , or R _a and R _e , or R _b and R _c , or R _b and R _d are different from hydrogen, while in each of the above cases the other three of R _a -R _e are hydrogen.

When the phenyl group is triple substituted, two of R _a -R _e are hydrogen and three are other than hydrogen. For example, R _a , R _b and R _c , or R _a , R _b and R _d , or R _a , R _b and R _e , or R _b , R _c, and R _d are other than hydrogen, while in each of the above cases R _the other two _of ~ R _e are hydrogen.

One preferred set of compounds of formula (I) _R ~ R _e are each hydrogen. In another preferred set of compounds, one of R _a -R _e is hydroxy, C 1 -C 6 alkoxy, nitro, -NHCOR ¹¹ , 11 11 t 11/12. ", _ _RT . ", _11" 12 __ "13 __. _T. "11" 12.

-CO2R, -N (RR), -O (CH 2) _n N (RR), -SO2R, -CON (RR), -SO 2 N (R ¹¹ R ^12), -SOR '*' ^3, N (R ¹¹ ) COR ¹² or halogen, and the other four of R a _to R _e are hydrogen. For example, alkoxy means methoxy or butoxy. Typically, -NHCOR ¹¹ is an acetylamino group. Typically, -CO ² R ¹¹ is carboxy or methoxycarbonyl

-group. The group -N (R R) is 11 to 12, typically dimethylamino. For example, -CON (R R) is aminocarbonyl. The

Typically, the group -SO ₂ R represents a bis-12-sulfonyl group. -SO ₂ N (RR) is a group of formula such as (dimethylamino) sulfonyl group. The

-SOR is typically methylsulfinyl11

-group. The group -N (R) COR is, for example, N-methyl-tert-butylcarbonylamino. Halogen is typically fluorine or chlorine. Preferably R _c is alkoxy, particularly preferably methoxy or butoxy; -NHCOR ¹¹ , particularly preferably acetylamino; A group of the formula -CO- ¹¹ , particularly preferably a carboxy group or a methoxycarbonyl group; -CON (RR), in particular 12-aminocarbonyl; nitro; -N (RR), especially dimethylamino;

-SOR, especially methyl11

sulfinyl group; -SO ₂ N (RR), particularly preferably dimethylamino-sulfonyl; or halogen, especially fluorine or chlorine; and R, R _b , R _d and R _e are each hydrogen.

The above-mentioned series of preferred compounds R _-R are each hydrogen, or R ~ R _{than those} of one or two of the hydrogen, while the others are hydrogen atoms. For example, one of R _a , R _b and R _c is other than hydrogen. Alternatively, R _a and R _c , or R _b and R _d are other than hydrogen. Preferably one or two of R _a -R _e other than hydrogen are, inter alia, an alkoxy group such as methoxy or butoxy, a halogen such as chlorine or

12 11 13 fluorine atom, hydroxy group, -N (RR), -CO ₂ R, -CH ₂ SCOR, -CH ₂ SR ⁿ , -NHCOR ¹¹ , -O (CH 2) n N (R ^{1; L} R ¹² ), -O (CH 2) _n CO ₂ R ^U ,

-CH ₂ NHCO (CH _{2) n} CO ₂ R ^11, R ¹¹ NHCOCH ^, -NHCOCH2OCOR ^{13, 13} -CH2NHCOOR radical or a trifluoromethyl radical.

Particularly preferred compounds are those wherein R _a , R _b , R _d and R _e are each hydrogen, R _c is hydrogen, methoxy, acetylamino, carboxy, methoxycarbonyl, aminocarbonyl, nitro, , dimethylamino, methylsulfonyl, methylsulfinyl or (dimethylamino) sulfonyl. Also preferred are compounds wherein _{Ra -Re} are each independently hydrogen, halogen, hydroxy, C1-6 alkoxy, nitro, trifluoromethyl group, _"rT ____13 -CH ₂ SCOR,

-0 (CH ₂ ) _n N (R ^u R ¹² ),

-C ^ SR ¹¹ , 11 τ, ΙΙ —CO 2 R,

-OCOR

-O (CH ₂ ) _n CO ₂ R,

-ch ₂ nhco (CH ₂ ) _n CO ₂ R

-NHCO _{(CH2) n} ^OR11, -N ^{(R11 R12),} -NHCO (CH2) nOCOR ^U, -NHCO (CH 2) _n CO ₂ R 13 and ⁿ -CH ₂ NHCO ₂ R, or R _a and R _b , R _b and R _c , R _c and R _d , and R _d and R _e taken together with the carbon atom to which they are attached form an optionally substituted benzene ring. More preferably, R _a and R _b are each independently hydrogen, nitro or halogen; R _c is hydrogen, hydroxy, C 1-6 alkoxy,

-O (CH ₂ ) _n N (R ¹¹ R ¹² ), -OCOR ¹³ , -O (CH ₂ ) _n CO ₂ R ¹¹ , -CH ₂ NHCO (CH ₂ ) _n CO ₂ R ⁿ ,

-NHCO (CH ₂ ) _n OR ¹¹ , -NHCO (CH 2) hOCOR ¹¹ , -N (R ⁿ R ¹² ), -CH 2 NHCO ₂ R ¹³ , 11 11

-CH ₂ SR or -NHCOR; R _{d is} hydrogen, halogen, C 1 -C 6 alkoxy, -CH ₂ SCOR ¹³ , -CH ₂ R ¹¹ or -CO- R ¹¹ ; and

R _e is hydrogen, nitro or halogen.

When two adjacent substituents of R 1 -R 4 together with the carbon atom to which they are attached form a benzene ring, then the benzene ring may be unsubstituted or substituted as defined above for R _a -R. The benzene ring, together with the phenyl group, forms an optionally substituted naphthyl group.

In one embodiment, in the formula (I), R ¹ is unsubstituted or singly substituted on the 2, 3 or 4 position by a chlorine or methoxy group, or a pyridyl, furyl or thienyl group,

R is hydrogen, methyl, cyclopropyl or fenilcso3 four ports, each of R and R is a hydrogen atom and the other represents a group (A) wherein q is 2 and ^R5 and ^R6 are each methoxy.

In another embodiment, R ¹ is unsubstituted phenyl, R 1 is C 1 -C 4 alkyl, 3 is preferably methyl, phenyl or cyclopropyl, R 4 is hydrogen, and R is a group of formula A wherein q is 2, and R and R are each methoxy.

In a third embodiment, R ¹ is a substituted phenyl group as defined above, or furyl, tie 2 3 nyl or pyridyl, R is hydrogen, R is hydrogen, and R is a radical of formula (A) wherein q is 2, and each of R11 and R11 is a methoxy group.

In a fourth embodiment, a substituted phenyl group as defined above, or a furyl, tie 2 4 nyl or pyridyl group, R is hydrogen, R is hydrogen, and R is a group of general formula (A) wherein q is 2, and R and R are each methoxy.

In a fifth embodiment, R ¹ is unsubstituted phenyl, R 1 is C 1 -C 4 alkyl, preferably 4, methyl, phenyl or cyclopropyl, R 3 is hydrogen, and R is a group of formula A wherein q is 2, and ^R5 and ^R6 are each methoxy.

When in the above embodiments, ^R1 is a furyl, pyridyl tienilvagy, it is preferably 3-furyl, 2-thienyl, 3-tienilvagy 4-pyridyl.

The following are some specific examples of compounds of formula I (numbering of which is related to the remainder of this specification):

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] methyl} -benzamide hydrochloride (Compound 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] methyl} -benzamide hydrochloride (Compound 9113);

N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -6-benzylidene] l- (cyclopropylmethyl) 12

-2,5-dioxo-3-piperazinylidene] methyl} -benzamide hydrochloride (Compound 9114);

N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - [{(3Z, 6Z) -6 - [( 3-Furyl) methylene] -1-methyl-2,5-dioxo-3-piperazinylidene} methyl] -benzamide hydrochloride (Compound 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] methyl} benzamide hydrochloride (9109).

compound);

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] methyl} benzamide hydrochloride (Chapter 9091).

compound);

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] methyl} benzamide hydrochloride (Compound 9092);

N- (4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -6- (3 -chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide hydrochloride

compound);

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-pyridyl) methylene] -3-piperazinylidene} methyl] benzamide hydrochloride (Compound 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-thienylidene) -3-piperazinylidene] methyl} -benzamide hydrochloride (Compound 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-thienylidene) -3-piperazinylidene] methyl} -benzamide (Compound 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] methyl} -benzamide (Compound 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] methyl} benzamide (Compound 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] methyl} benzamide (Compound 9158);

N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(3Z, 6Z) -6 - [(3 -furyl) methylene] -1-methyl-2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 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] methyl} benzamide (Compound 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] -methyl} -benzamide (Compound 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] methyl} benzamide (Compound 9141)

N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)] · ··········································· · »« Φ · ····· ·

-ethyl] -phenyl} -4 - {[(3 S, 6 S) -1-allyl-6-benzylidene-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 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] methyl} -benzamide (Compound 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} methyl] benzamide (Compound 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} methyl] benzamide (Compound 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] methyl] benzamide (Compound 9195);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - [{(3Z, 6Z) -6 - [( 2-furylmethylene] -1-methyl-2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 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] methyl] -benzamide (Compound 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} methyl] benzamide (9198).

compound);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -l-methyl- 6 - [(1-Methyl-3-pyrrolyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (9199).

compound);

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} methyl] benzamide (Compound 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} methyl] benzamide (Compound 9210);

N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(3Z, 6Z) -1-methyl- 6 - [(3-methyl-2-benzo [b] thienyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 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} methyl] -benzamide (9214).

compound);

N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - [{(3Z, 6Z) -1-methyl- 6 - [(3-methyl-2-benzo [b] thienyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9215);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6-benzylidene 1 - [(methoxycarbonyl) methyl] -2,5-dioxo-3-piperazinylidene] methyl] benzamide (Compound 9217);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -l-methyl- 6- (2-methylpropylidene) -2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9228);

N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - {[(32,62) -1-methyl-6 - (cyclohexylmethylene) -2,5-dioxo-3-piperazinylidene] methyl [benzamide (Compound 9229);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -l-methyl-6 - (cyclohexylmethylene) -2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9230);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(32.62) -l-methyl-6 pentylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9231);

N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(32,62) -1-methyl-6 pentylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9232);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(32.62) -l-methyl-6 - (2-methylpropylidene) -2,5-dioxo-3-piperazinylidene] methyl [benzamide (Compound 9233);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(32.62) -6- (3, 3-dimethyl-butylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl [benzamide (Compound 9234)

N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(32,62) -6- (3, 3-Dimethyl-butylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9235)

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(32.62) -6 - ([( 4S) -4-Isopropenyl-1-cyclohexenyl] -methylene} -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9236);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(32.62) -6-benzylidene-l - (carboxymethyl) -2,517 dioxo-3-piperazinylidene] methyl} benzamide (Compound 9241);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6 - {[( 4S) -4-isopropenyl-1-cyclohexenyl] methylene} -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 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} methyl] -benzamide (Compound 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} methyl] -benzamide (Compound 9261);

N- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] -3 - ([(3Z, 6Z) -1-methyl-6- (2-phenyl) - propylidene) -2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9266);

N- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] -4 - {[(3Z, 6Z) -1-methyl-6- (2-phenyl) - propylidene) -2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 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] methyl} benzamide (Compound 9272);

2 - {[4- (2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3 Z, 6 Z) -6- (3- acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9273);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z _r 6Z) -6- (2- acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9274);

N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)]

Ethyl] phenyl} -3 - [{(3Z, 6Z) -6-benzylidene-1- [2- (dimethylamino) ethyl] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (9275th

compound);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6- (4 -hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9276);

N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(3Z, 6Z) -6-benzylidene 1 - [(ethoxycarbonyl) methyl] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (9292).

compound);

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] methyl} benzamide (Compound 9300);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6- (3 -hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9301);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -l-methyl- 6-pentylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9306);

N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z) -l-methyl-6- benzyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9308).

Compounds of formula (I) may be prepared by a process wherein a compound of formula (II) wherein R, R and --- are as defined above, in an organic solvent and in the presence of a base of formula (III) with one of R and R being hydrogen and the other being formyl and q and r, and R ⁵ and g

R is as defined above and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof.

Suitable bases include, for example:

cesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butanolate and triethylamine.

Suitable solvents are, for example, N, N-dimethylformamide (DMF), tetrahydrofuran (THF) and potassium tert-butanolate, as well as mixtures thereof.

When N, N-dimethylformamide is used as the solvent, the temperature will typically be between 0 ° C and reflux temperature, for example when the base used is between 80 ° C and 95 ° C.

When sodium hydride or potassium tert-butanolate is used as the base, the reaction mixture is typically heated from 0 ° C to room temperature or 40 ° C. The reaction is carried out for 1-4 hours, for example 2-3 hours.

Compounds of formula (II) compounds of formula, wherein --- a double bond, are prepared by reacting a compound (IV) - wherein R ¹ is as defined above - with an alkylating agent in an organic solvent and a base. The alkylating agent 2 is currently an alkyl halide of the formula R-CH ₂ X, a 2-alkyl halide

R ₂ CH ₂ OSO ₂ CH ₃ methanesulfonate of general formula 2;

RCH ₂ OSO ₂ C ₆ H ₄ pCH ₃ p-toluenesulfonate or a dialkyl sulfate (R CH ₂ O) ₂ SO ₂ wherein R is as defined above and X is halogen in the general formulas chlorine, bromine or iodine. Suitable bases and solvents include, for example, sodium hydride in tetrahydrofuran or N, N-dimethylformamide or mixtures thereof, and potassium tert-butanolate in tert-butyl alcohol, tetrahydrofuran or N, N-dimethylformamide, or in mixtures thereof. The reaction mixture is typically heated from 0 ° C to room temperature.

Compounds of formula (II), wherein --- represents a single bond wherein the invention may be prepared by reacting a compound (X) of the formula - wherein R ¹ JE2 Lentes defined in paragraph (i) above, and R is the with acetic anhydride as defined above. The reaction is typically carried out at reflux temperature, for example 1-6 hours, typically 3 hours. Compounds of formula (X) may be prepared by reacting a compound of formula (XI) in a solvent, typically chloroform, at a low temperature, typically -50 ° C to -70 ° C, preferably -65 ° C. Reaction with glycine methyl ester hydrochloride for about 6 hours. The reaction mixture is then warmed to room temperature overnight and refluxed in a solvent such as toluene for 12-18 hours to give the desired compound (X).

Compounds of formula (XI) may be prepared by reacting a compound of formula (XII) in tetrahydrofuran with phosgene first at 0 ° C and then warming the reaction mixture to room temperature overnight.

Compounds of formula (IV) may be prepared by reacting 1,4-diacetyl-2,5-dioxopiperazine of formula (V) in an organic solvent and in the presence of a base with an aldehyde of formula R ¹ -CHO, wherein R ¹ has the meaning given above. defined — react.

Suitable bases and solvents include, but are not limited to, triethylamine, cesium carbonate, sodium carbonate, potassium carbonate, and sodium hydride.

N, N-dimethylformamide or tetrahydrofuran or mixtures thereof; and potassium tert-butanolate in tert-butyl alcohol, N, N-dimethylformamide or tetrahydrofuran, or mixtures thereof.

When triethylamine is used in N, N-dimethylformamide, the reaction temperature is typically 100 ° C to 140 ° C, for example 120 ° C to 130 ° C. When potassium tert-butanolate is used as the base, the reaction mixture is typically heated from 0 ° C to room temperature.

1,4-Diacetyl-2,5-dioxopiperazine is known according to known methods [S.

M. Marcuccio and J. A. Elix, Aust. J. Chem., 37, 1791 (1984)].

Compounds of formula (III) may be prepared by a process comprising (i) reacting a compound of formula (VI) in an organic solvent and in the presence of a base with a compound of formula (VII) wherein q is and R and R 22 is as defined above and X is halogen;

(ii) the compound of formula VIII thus obtained -

Wherein q is and R and R are as defined above;

(iii) the resulting compound of formula IX -

Wherein q and R and R are as defined above and r is in the presence of 1 - (a) by reaction with 3-formylbenzoic acid or with a 3-formylbenzoic acid derivative in which the carboxyl group is -COX an acid halide of the formula wherein X is halogen such as fluorine, chlorine, bromine or iodine, preferably chlorine, or a mixed anhydride of formula -CO (OCOR ') wherein

R 'is (C 1 -C 6) -alkyl - pre-activated to give a compound of formula (III) wherein R is hydrogen and R is formyl; or (b) in the presence of a coupling agent, with 4-formylbenzoic acid, or with a 4-formylbenzoic acid derivative in which the carboxylic acid is represented by the formula -COX, to an acid halide, wherein X is halogen, e.g. , bromine or iodine, preferably chlorine, or a mixed anhydride of the formula -CO (OCOR ') wherein R' is a (C1-C6) -alkyl, to give a compound of the formula (III) R is formyl and R · · · · · · is hydrogen.

When the 3- or 4-formylbenzoic acid is pre-activated by the conversion of the carboxyl group to the -COX group, the reaction is carried out in an organic solvent with an excess of the amine of formula IX or in the presence of a base such as a tertiary amine such as triethylamine or pyridine. execute them. The organic solvent is an inert organic solvent such as methylene chloride.

When the preactivation of 3- or 4-formylbenzoic acid is effected by converting the carboxyl group to the formula -CO (OCOR '), the reaction with the compound of formula IX is carried out in an inert organic solvent such as dichloromethane or tetrahydrofuran.

The coupling agent used with 3-formylbenzoic acid in Process (a) and 4-Formylbenzoic acid in Process (b) is, for example, 1-cyclohexyl-3- (2-morpholinoethyl) -carbodiimide-meth-p-toluenesulfonate or 2-formylbenzoic acid. chloro-l-methylpyridinium iodide.

The activated acid halide or mixed anhydride derivative of 3- or 4-formylbenzoic acid may be prepared by conventional methods. For example, the acid halide derivative can be prepared by reacting the carboxylic acid with a halogenating agent such as a chlorinating agent such as sulfinyl chloride, phosphorus (III) chloride, oxalyl dichloride or phosphorus (V) chloride. In the preparation of the mixed anhydride derivative, the carboxylic acid is reacted in the presence of a base with a (C 1 -C 6) alkylformate such as isobutyl chloroformate or ethyl chloroformate.

The reduction of step (ii) is usually carried out using iron powder, concentrated hydrochloric acid and methanol, usually at about 80 ° C for 1 to 4 hours, for example 3 hours. Alternatively, the reduction is effected by catalytic hydrogenation in the presence of palladium on carbon in methanolic hydrogen chloride solution, isopropyl alcohol or acetic acid.

Further starting compounds are known or can be readily prepared from known compounds using conventional techniques.

Conventional methods may be used to convert the compounds of formula (I) to the pharmaceutically acceptable salts or to convert the salts to the free compounds by conventional means. Suitable salts include pharmaceutically acceptable salts with inorganic or organic acids. Such inorganic acids include, for example, hydrochloric acid, sulfuric acid and orthophosphoric acid. Examples of organic acids include p-toluenesulfonic acid, methanesulfonic acid, mucous acid and succinic acid.

Multi-drug resistant cancer cells (MDR cells) exhibit reduced intracellular drug accumulation when compared to cells responsive to the respective drug. Studies using in vitro MDR cell lines have shown that multi-drug resistance is often associated with drug-binding properties.

- Increased expression of 25 plasma membrane glycoprotein (P-gp). THE

P-gp is believed to function as an effluent pump for many hydrophobic compounds; transfection studies with cloned P-gp have shown that overexpression of P-gp can create a multidrug-resistant phenotype in cells [see, e.g., Ann. Port. Biochem. 58: 137-171 (1989)].

In normal tissues, the primary function of P-gp is to remove intracellular toxins from cells. P-gp may play a clinical role in multi-drug resistance. In the past, mRNA or protein with increased levels of P-gp have already been detected in many forms of human cancers (leukemias, lymphomas, sarcomas and carcinomas). In some cases, it was found that tumor biopsies obtained after the completion of chemotherapy had a higher P-gp concentration.

In P-gp-regulated multidrug resistance, inhibition of P-gp function resulted in complete accumulation of the anti-cancer drug in the cells. For example, the known calcium channel blocker verapamil sensitized multidrug-resistant cells to vinca alkaloids in vitro and in vivo (Cancer Res., 41, 1967-1972, 1981). The putative mechanism of action is to compete with the anticancer agent a

For binding to P-gp. Numerous examples of non-structurally related resistance modifiers operating under this mechanism have already been described, such as tamoxifen (Nolvadex: ICI) and related compounds, and cyclosporin A and derivatives.

Biological tests have shown that the compounds of the formula I and their pharmaceutically acceptable salts (hereinafter collectively referred to as the compounds of the invention) are found to have multi-drug resistance modifying activity. The results are summarized in Example 5 below. Accordingly, the compounds of the present invention can be used as multi-drug resistance modifiers, also known as resistance modifiers (RMAs). The compounds of the present invention are useful in modifying, i.e., reducing or eliminating, multi-drug resistance.

The compounds of the invention are therefore useful in a method of potentiating the cytotoxicity of a tumor cell cytotoxic agent. Such methods include, for example, introducing one of the compounds of the invention into the tumor cell while treating the tumor cell with the cytotoxic agent of interest.

In this way, the therapeutic effect of a chemotherapeutic or anti-neoplastic agent can be enhanced. Multi-drug resistance of tumor cells to cytotoxic agents may be reduced or eliminated during chemotherapy.

The compounds of the present invention may also be used in a method of treating a disease which exhibits multi-drug resistance to a particular pathogenic multi-drug, such as malaria (Plasmodium falciparum), tuberculosis, leishmaniosis, and amoebic dysentery. In such a method, a compound of the present invention is administered simultaneously, sequentially or sequentially, with the active agent to which the particular pathogen exhibits multi-drug resistance. In this way, the therapeutic effect of the active ingredient can be enhanced.

In a human or animal patient having a tumor, resistance to chemotherapeutic agents can be treated by a method comprising administering to the patient one of the compounds of the invention. The compounds of the present invention are administered in an amount effective to potentiate the cytotoxicity of the chemotherapeutic agent. Preferred chemotherapeutic or anti-neoplastic agents in the context of the present invention include, but are not limited to: vinca alkaloids such as vincristine and vinblastine; anthracycline antibiotics such as daunorubicin and doxorubicin; mitoxantrone; actinomycin D; taxanes such as taxol; epipodophyllotoxins such as etoposide and plicamycin.

In addition, a human or animal patient suffering from a disease having a pathogenic multi-drug resistance responsible for the disease can be treated for resistance by administering a compound of the invention.

Examples of such diseases include multidrug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniosis and amoebic dysentery.

MDR modulators can be used to deliver drugs through the blood-fluid barrier and to treat AIDS and AIDS-related complex disease. Thus, the compounds of the invention may also be used to promote the passage of drugs through the blood-cerebrospinal fluid barrier, and for the treatment of AIDS and AIDS-related complex disease. A method of treating human or animal patients in need of such treatment comprises administering a compound of the invention.

The compounds of the invention may be administered in a variety of dosage forms, such as tablets, capsules, sugar or film coated tablets for oral administration, liquid solutions or suspensions, or parenteral compositions such as intramuscular, intravenous or subcutaneous administration. Accordingly, the compounds of the invention may be administered by injection or infusion.

The amount of dose depends on various factors such as the age, weight and condition of the patient and the route of administration. In adult humans, when administering a compound of the invention alone, the typical dosage for any route of administration is from 0.001 to 50 mg / kg body weight, most often from 0.01 to 5 mg / kg body weight. These doses may be administered, for example, by bolus infusion, hourly infusion and / or repeated administration, 1 to 5 times daily.

The dioxopiperazine derivatives of formula I, or pharmaceutically acceptable salts thereof, are formulated into pharmaceutical or veterinary compositions containing a pharmaceutically acceptable or diluent carrier or diluent. The compositions are generally prepared by conventional procedures and are administered in pharmaceutically or veterinary acceptable forms. In this way, another agent containing one of the compounds of the invention is prepared for use as a modulator of multi-drug resistance.

For example, 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, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginates or sodium starch glycolate; Hot mix; coloring matter, sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates. Such formulations may be prepared by known methods, for example, by mixing, granulating, tabletting, sugar-coating, or film-coating processes.

Liquid dispersions for oral administration may be, for example, syrups, emulsions or suspensions. Syrups may contain as carrier, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol. Syrups to be administered to diabetic patients may contain as carriers only products which are not, or only to a small extent, metabolised to glucose; for example, sorbitol. Suspensions and emulsions may contain, for example, natural rubber, 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, an appropriate amount of lidocaine hydrochloride. Some of the compounds of the invention are water insoluble. The compounds may be encapsulated in liposomes.

The following examples further illustrate the invention.

Intermediate Preparation Example 1 Preparation of starting compounds of formula (IV)

Procedure A.

25.0 g (126 mmol) of 1,4-diacetyl-2,5-dioxopiperazine [S. M.

Marcuccio and J. A. Elix, Aust. J. Chem., 37, 1791 (1984)], N, N-dimethylformamide (200 mL) was treated with triethylamine (17.6 mL, 126 mmol) and benzaldehyde (13.0 mL, 126 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was heated at 120-130 ° C for 1 hour. The reaction mixture was then cooled to room temperature and poured into 1000 ml of ethyl acetate. The resulting mixture was washed three times with a saturated aqueous sodium chloride solution.

The solid formed in this step was filtered off, the filtrate was dried over anhydrous magnesium sulfate and the solvent removed in vacuo. The residue was recrystallized from ethyl acetate / hexane to give 11.78 g (38%) of 1-acetyl-3-benzylidene-2,5-dioxopiperazine. This product of formula (IV) is illustrated in Figure 1A below. Table 1.1. .

By the same procedure, however, the benzaldehyde is replaced by appropriately substituted benzaldehydes of the formula R ¹ -CHO in which R ¹ is 1A. of Table 1.2 to 1.10. starting compounds.

1A. Table IV Compounds of formula IV

compound Number 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. 2thienyl

Procedure B.

1,4-Diacetyl-2,5-dioxopiperazine was reacted with aldehydes of the formula R ¹ represents

1B. specified in Table. The reaction mixture was allowed to warm to room temperature over the time indicated in the table. Optional recrystallization was performed using the indicated solvent (s).

1A. Table IV Compounds of formula IV

Compound- song R ¹ reactions (Hours) Recrystallization. solvent Yield (*) 1:11. 2-naphthyl 18 98 1:12. 1-naphthyl ¹⁸ 67 1:13. 1-naphthyl 18 67 1:14. 2-furyl 12 74 1:15. 2-furyl 12 74 1:16. 1-methyl-2-pyrrolyl 52 ethyl acetate 80 1.17. 1-pyrrolyl meti1-2 52 ethyl acetate 80 1.18. 2-naphthyl 18  1 1.19. l-methyl-3-indolyl 14 33 1:20. 3-methyl-2-benzo [b] thienyl 18 72 1.21. l-methyl-3-indolyl 14 33 1.22. 3-methyl-2-benzo [b]] thienyl- 18 72 1.23. isopropyl 12 ethyl acetate 48 1.24. cyclohexyl- 2 ⁸⁰ 1:25. cyclohexyl- 2 ⁸⁰

IA. Table (continued)

Compound- song R ¹ reactions (Hours) Recrystallization. solvent n 0 dP N rg 1.26. butyl 14 ethyl acetate 60 1.27. butyl 14 ethyl acetate 60 1.28. isopropyl 12 ethyl acetate 48 1.29. neo 18 ethyl acetate 62 1:30. neo 18 ethyl acetate 62 1.31. (4S) -4-isopropenyl-l-cyclohexenyl 18 1.32. (4S) -4-isopropenyl-l-cyclohexenyl 18 1:33. 4-acetoxyphenyl 3 86 1.34. 3-acetoxyphenyl 3 ethyl acetate hexane 42 1.35. 2-acetoxyphenyl 3 ethyl acetate hexane 31 1.36. butyl 14 ethyl acetate 60 1.37. phenethyl 16 60

Intermediate Preparation Example 2 Preparation of starting compounds of formula (II) wherein --- represents a double bond

Procedure A 1-Acetyl-3-benzylidene-2,5-dioxopiperazine (Intermediate 1 Preparation 1.1) in N, N-dimethylformamide at 0 ° C with ethyl bromide and tert-butyl -alcoholic potassium tert-butanolate solution and allowed to warm to room temperature. As a result, 1-acetyl-3-benzylidene-4-ethyl-2,5-dioxopiperazine was obtained. This product of formula (II) is illustrated in Figure 2A below. Table 2.1. .

2A. Table II Compounds of formula II

Compound- song R ² Kiin. Dry. (ARC) Alkylation conditions 2.1. methyl- 1.1. (a) KOtBu / tBuOH, DMF, ethyl bromide; 0 ° C to room temperature .; obsession (b) 1.1 eq. NaH, 1: 5 DMF / THF; 2 eq. ethyl iodide, 0 ° C to room temperature; followed by column chromatography 2.2. phenyl 1.1. KOtBu / tBuOH, DMF, benzyl chloride; 2.3. cyclo propyl 1.1. (a) KOtBu / tBuOH, DMF, cyclopropylmethyl bromide; 0 'C to room temperature; obsession (b) 1.1 eq. NaH, 1: 5 DMF / THF; 1.3 eq. ethyl iodide, 0 ° C to room temperature; followed by column chromatography 2.4. H 1.2. NaH, methyl iodide, THF, DMF; 0 ° C to room temperature. 2.5. H 1.3. etc. »1 2.6. H 1.4. II II 2.7. H 1.5. »1 II 2.8. H 1.6. II 2.9. H 1.7. II II 2:10. H 1.8. II II 2:11. H 1.9. H ti 2:12. H 1:10. tv ti

Procedure B.

Example 1.11 of Intermediate Preparation 1. Compound No. 1 was reacted with sodium hydride and methyl iodide in a 5: 1 mixture of tetrahydrofuran / N, N-dimethylformamide at 0 'C. The reaction mixture was allowed to warm to room temperature over 18 hours. The product was purified by recrystallization from ethyl acetate to give the corresponding compound of formula II in 40% yield. Repeating this procedure, but with the exception of paragraph 1.11. 2B with another compound of formula IV as described in Intermediate 1 Preparation Example 1 and, if necessary, modifying the reaction time. The compounds listed in Table II are prepared. Purification of the products was carried out by flash chromatography or by recrystallization (see explanation after Table 2B).

2B. Table II Compounds of formula II

Compound closed R ² Kiin. Dry. (ARC) reactions (Hours) cleaning method Yield (%) 2:13. H 1:11. 18 the 40 2.14. H 1:12. 18 b 8 2.15. H 1:13. 18 b 8 2:16. H 1:14. 18 the 50 2.17. H 1:15. 18 the 50 2.18. H 1:16. b 26 2.19. H 1.17. b 26

2Β. Table (continued)

Compound- song R ² Kiin. Dry. (ARC) reactions (Hours) cleaning method Yield (%) 2:20. H 1.18. 18 the 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 70 2.32. H 1:30. 18 d 70 2:33. H 1.31. d 46 2.34. H 1.32. d 46 2.35. H 1:33. 3 b 33 2.36. H 1.34. 72 b 20 2.37. H 1.35. 3 b 45 2.38. H 1.36. d 75 2.44. H 1.37. 16 e 37

a = recrystallization from ethyl acetate;

b = flash chromatography; 1: 1 ethyl acetate / hexane; c = flash chromatography; methylene chloride;

d = flash chromatography; 1: 1 by volume diethyl ether / hexane; e = recrystallization from ethyl acetate / hexane solvent system.

Procedure C.

The preparation of Intermediate 1, Example 1.1. Compound No. 1 in acetonitrile was treated with 2 equivalents of cesium carbonate, 1 equivalent of trimethylsilyl chloride and 1 equivalent of allyl bromide at 0 ° C. The reaction mixture was allowed to warm to room temperature over 5 hours. The product was flash chromatographed using 20:80 ethyl acetate / hexane as eluent. As a result, 2.39 g (50%) of a compound of formula II in which R is vinyl are obtained.

Procedure D.

The preparation of Intermediate 1, Example 1.1. Compound No. 1 was reacted with sodium hydride and methyl bromoacetate in a 5: 1 mixture of tetrahydrofuran / N, N-dimethylformamide at 0 ° C. The reaction mixture was allowed to warm to room temperature over 3 hours. The product was purified by recrystallization from ethyl acetate / hexane to give 2.40 g (35%) of the compound of formula II wherein R is methoxycarbonyl.

Procedure E.

The preparation of Intermediate 1, Example 1.1. Compound No. 1 in N, N-dimethylformamide at 0 ° C was reacted with sodium hydride and 2- (dimethylamino) ethyl chloride hydrochloride. The reaction mixture was first warmed to 20 ° C and then raised to 80 ° C over 5 hours. The product was recrystallized from a 1:99 methanol / ethyl acetate mixture to give 2.41 g (32%) of the compound of formula II wherein R is (dimethylamino) methyl.

Procedure F.

The preparation of Intermediate 1, Example 1.1. Compound No. 1 in acetonitrile was reacted with cesium carbonate and ethyl bromoacetate at -20 ° C. The reaction mixture was heated to 20 ° C over 3 hours. The product was purified by flash chromatography eluting with ethyl acetate / hexane (1: 2). As a result, 2.42 g (35%) of a compound of formula II in which R is ethoxycarbonyl are obtained.

Intermediate Preparation Example 3

Preparation of starting compounds of formula (II) wherein --- represents a single bond

A mixture of 6-benzyl-1-methyl-2,5-dioxopiperazine and acetic anhydride was refluxed for 3 hours to give 2.43 g (98% yield) of a compound of formula II: -1 2 is a single bond, R is phenyl, and R is hydrogen.

Intermediate Preparation Example 4

Preparation of 6-Benzyl-1-raethyl-2,5-dioxopiperazine {Scheme A}

Compound (i) was reacted with phosgene in tetrahydrofuran at 0 ° C for 15 minutes. The reaction mixture was allowed to warm to room temperature overnight. The compound of formula (ii) thus obtained was reacted with glycine methyl ester hydrochloride and triethylamine in chloroform at -65 ° C for 3 hours. The reaction mixture was allowed to warm to room temperature overnight, then refluxed in toluene overnight to give the desired product in 53% yield.

Intermediate Preparation Example 5 Preparation of 4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] aniline (a) The title compound of formula IX Prepared according to Scheme [B].

Reaction of 3.1 with N, N-dimethylformamide at 100 ° C for 12 hours gave 78 in 78% yield. Subsequently, compound (3.3) was reduced with iron powder in a mixture of concentrated hydrochloric acid and methanol at 80 ° C for 3 hours to give compound (3.4) in 51% yield. Alternatively, the reduction of compound (3.3) was carried out by catalytic hydrogenation in methanolic hydrogen chloride solution at 30 psi (207 kPa) in the presence of a palladium on carbon catalyst to give compound (3.4) in quantitative yield.

(b) By following the procedure described in (a), however, the compound of formula (3.1) was prepared by substituting 4- (bromomethyl) benzoic acid and 4- (3-bromopropyl) benzoic acid in the above order. Compounds of formula (3.5) and (3.6) of formula (IX).

(c) Following the procedure described in (a), but substituting 1,2,3,4-tetrahydroisoquinoline hydrochloride for compound (3.2), compound (3.7) of formula (IX) was prepared.

(d) The amines of the formula IX wherein r is 0, for example, the compound of the formula (3.10) may be prepared by the process of Scheme [C].

6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.8) was reacted with chloroacetonitrile under reflux for 24 hours in acetonitrile in the presence of potassium carbonate. Compound (3.9) was obtained in 92% yield. The compound (3.9) was then reacted with lithium aluminum hydride in ethylene glycol dimethyl ether at room temperature overnight. The temperature was raised to 40 ° C and the reaction continued for 30 minutes. The desired amine (3.10) was obtained in 98% yield.

Example 1 Preparation of Compounds of Formula III

1. live in flood

By the procedure of Intermediate Preparation Example 5 • · · ·

41 were prepared by reacting 41 (3.4) with 2-chloro-1-methylpyridinium iodide and 3-formylbenzoic acid in dichloromethane and in the presence of triethylamine and allowing the reaction mixture to warm to room temperature overnight. . As a result, 43% of the compound of formula (4.1) was obtained.

According to the above procedure, however, the compound (3.4) was replaced by the compound (3.5) and (3.6) to give the compound (4.3) and (4.4) of the formula (III), respectively.

Procedure 2

4-Formylbenzoyl acid was reacted with sulfinyl chloride in toluene at reflux to afford 4-formylbenzoyl chloride. The acid chloride was reacted with methylene chloride (3.4) prepared in Intermediate Preparation Example 5 in the presence of methylene chloride and triethylamine at about 0 ° C, and the reaction mixture was warmed to room temperature. As a result, compound (4.2) was obtained in 53% yield.

According to the above procedure, however, the compound (3.4) was replaced by the compound (3.5) and (3.7), respectively, to give the compound (4.5) and (4.6) of the formula (III).

Procedure 3

The 4-formylbenzoyl chloride described in Method 2 was reacted with triethylamine in methylene chloride at -20 ° C. Intermediate Preparation Example 5 was added to the reaction mixture.

- a compound of formula (3.10) obtained by the method of 42. After the usual aqueous work-up and purification by flash chromatography, the compound of formula (4.7) was obtained in 43% yield.

However, according to the above procedure, substituting 4-formylbenzoyl chloride with 3-formylbenzoyl chloride, the compound of formula (4.8) was obtained in 48% yield.

Example 1 Preparation of Compounds of Formula III

A compound of formula (II) prepared according to the procedure of Intermediate Preparation 2 is prepared as described in Example 3A. under the reaction conditions of Table 3A, a compound of formula III prepared according to the procedure of Example 1. The compounds of the invention listed in Table II are prepared.

3Α. Table I: Compounds of Formula I

Compound (I) Compound (II) Compound (III) Conditions 9112th 2.1. 4.2. KOtBu, tBuOH, THF, 0 ° C to room temperature. 9113th 2.2. 4.2. ff 9114th 2.3. 4.2. II 9091st 2.4. 4.2. Cs ₂ CO ₃ , DMF, 90 ° C, 2-3 hours 1 9092. 2.5. 4.2. Irish 9093rd 2.6. 4.2. TV 9108. 2.7. 4.2. ff 9109th 2.8. 4.2. ff 9110. 2.9. 4.2. ff 9111th 2:10. 4.2. ff 9155th 2:12. 4.1. Cs ₂ CO ₃ , DMF, 90 ° C, 2-3 hours 9155th 2:11. 4.1. ff 9157. 2.6. 4.1. ff 9158th 2.5. 4.1. ff 9159th 2.7. 4.1. Π 9160th 2:10. 4.1. fl 9139th 2.1. 4.1. Cs ₂ CO ₃ , DMF, 90 ° C, 2-3 hours 9141st 2.3. 4.1. ff

Example 3

Preparation of salts

The compounds of Example 2 were converted into the corresponding hydrochloride salts by reaction with hydrogen chloride gas in tetrahydrofuran.

Example 4 Preparation of Compounds of Formula I

A compound of formula (II) prepared in either Example 2 or Example 3 is reacted with N, prepared in Example 1, in the presence of N, N-dimethylformamide and cesium carbonate at 80 ° C for a period of time as shown in Table 4. The compounds listed in Table 4 were prepared. Certain compounds were purified by recrystallization or flash chromatography as indicated in the table.

Table 4 Compounds of formula (I)

(I) compound (II) compound (III) compound Response Time (Hours) You are a cleaning solvent eluent 9178. 2.39. 4.2. 3 5:95 water / PrOH (a) 9179th 2.39. 4.1. 3 5:95 water / PrOH (a) 9193rd 2:13. 4.2. 16 EtOAc (a) 9194. 2.14. 4.2. 5 EtOAc (a) 9195 2.15. 4.1. 5 EtOAc (a)

Table 4 (continued)

(I) compound (II) compound (III) compound Response Time (Hours) You are a cleaning solvent eluent 9196th 2:16. 4.2. 16 9197. 2.17. 4.1. 16 9198th 2.18. 4.2. 14 PrOH (a) 9199th 2.19. 4.1. 10 iPrOH (a) 9209th 2:20. 4.1. 10 EtOAc (a) 9210. 2.21. 4.2. 12 EtOAc / MeOH (a) 9211th 2.22. 4.1. 14 MeOH / EtOAc / Et ₂ O (a) 9214. 2.23. 4.1. 18 CH ₂ Cl ₂ / Et ₂ O (a) 9215th 2.24. 4.2. 4 EtOAc / Et ₂ O (a) 9217. 2.40. 4.1. 2 EtOAc / Hexane (a) 9228th 2.25. 4.2. 8 5:95 MeOH / Et ₂ O (b) 9229th 2.26. 4.2. 14 5:95 MeOH / Et ₂ O (b) 9230. 2.27. 4.1. 18 5:95 MeOH / Et ₂ O (b) 9231st 2.28. 4.2. 14 9232. 2.29. 4.1. 14 5:95 MeOH / Et ₂ O (b) 9233rd 2:30. 4.1. 5 5:95 MeOH / Et ₂ O (b) 9234. 2.31. 4.2. 18 5:95 MeOH / Et ₂ O (b) 9235. 2.32. 4.1. 14 5:95 MeOH / Et ₂ O (b) 9236th 2:33. 4.2. 14 5:95 MeOH / Et ₂ O (b) 9250. 2.34. 4.1. 14 5:95 MeOH / Et ₂ 0 (b) 9260. 2:13. 4.7. 4 SSS

Table 4 (continued)

(I) (II) (III) Reaction- - You are a cleaning solvent compound compound compound time (hours) eluent 9261st 2:13. 4.8. 4 EtOAc / heptane (a) 9266th 2.44. 4.8. 16 EtOAc / Hexane (a) 9267th 2.44. 4.7. 16 9272. 2.35. 4.1. 3 EtOAc / Hexane (a) 9273rd 2.36. 4.1. 2 EtOAc / Hexane (a) 9274th 2.37. 4.1. 3 EtOAc / Hexane (a) 9275th 2:41. 4.1. . 3 EtOAc / Hexane (a) 9299th 2.42. 4.1. 3 9306th 2.38. 4.1. 14 5:95 MeOH / Et ₂ O (b) 9308. 2.43. 4.1. 16 10:90 MeOH / Et ₂ O (b)

(a) recrystallization solvent (b) flash chromatography eluent

Example 5

Preparation of salts

Some of the compounds prepared in Example 4 were converted to the corresponding hydrochloride salt by reaction with hydrogen chloride gas in dichloromethane. In Table 5, some of the hydrochlorides labeled with the .HC1 tag were recrystallized from the solvent indicated in the table.

- 47 Table 5

hydrochloride,

Salt Screening solvent Yield: (%) 9193.HC1 9144.HC1 ethyl acetate 21 9195.HC1 ethyl acetate 22 9196.HC1 9197.HC1 ethyl acetate 35 9232.HC1 9306.HC1

β. example

Conversion of compounds of formula (I)

Some of the compounds of formula (I) prepared in Example 4 were reacted with appropriate reagents using standard procedures to provide additional compounds of formula (I).

1. Reaction of compound 9217 with lithium hydroxide in aqueous tetrahydrofuran for 2 hours at room temperature afforded compound 9241.

2. Compound 9272 was reacted with sodium tetrahydroborate (1-) in methanol at 0 ° C for 2 hours to give Compound 9276 in 73% yield.

3. Compound 9274 was reacted with sodium cyano trihydroborate (1-) in a mixture of methanol and tetrahydrofuran at 0 to ⁴ ° C. The reaction mixture was heated to 50 ° C for 5 hours and the product was recrystallized from 20:80 (v / v) ethanol / ethyl acetate in 58% yield.

Compound No. 9300 was obtained.

4. Compound 9273 was treated with sodium cyano trihydroborate (1-) in a mixture of methanol and tetrahydrofuran at reflux for 7 hours. The product was recrystallized from ethyl acetate / hexane (1: 5 v / v) to give 9301 (18%).

Example 7

A pharmaceutical composition

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

Composition for 10,000 tablets Compound of formula I or salt (250 g) lactose (800 g) corn starch (415 g) talcum powder (30 g) magnesium stearate (5 g)

The compound of formula (I) or a salt thereof, lactose and half of the corn starch are mixed. The mixture was passed through a 0.5 mm49 mesh screen. 10 g of corn starch are suspended in 90 ml of warm water. The paste thus obtained is used to granulate the powder. The granulate is dried and broken into small fragments through a 1.4 mesh sieve. The starch residue, talc and magnesium stearate are added to the fragments, the mixture is carefully mixed and then converted to tablets.

Example 8

Testing of compounds of formula I as modulators of multi-drug resistance

Materials and Methods

The EMT6 mouse breast carcinoma cell line and the multi-drug resistant AR 1.0 subunit were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM glutamine at 37 ° C and 5% carbon dioxide. After trypsinization (0.25% trypsin, 0.2 gl ¹ , EDTA), cells were inoculated (passage numbers 1-200 to 1-2000 for the primary cell line, and 1-20 and 1-200 for the multi-drug resistant subline). passage number).

Investigation of drug accumulation

AR 1.0 cells were inoculated into 96-well opaque culture plates (Canberra Packard). The assay medium contained a mixture of tritiated Daunorubicin (DNR) (0.3 μΟί / ητΙ; 2 μΜ), a cytotoxic agent and unlabeled DNA. A series of dilutions of the compounds of formula (I) was prepared in the assay medium at concentrations ranging from 5 nM to 100 μΜ. Cells were incubated at 37 ° C for one hour before washing and counting radioactive cells. All studies included titration using a verapamil as a positive control. Results were expressed as a percentage of maximum accumulation, where 100% accumulation corresponded to that observed in the presence of 100 μΜ verapamil, respectively, and was expressed as IC ₅₀ .

The results are summarized in Table 6 below.

Table 6

compound Number IC ₅₀ (μΜ) accumulation The maximum % of accumulation 9091st 2.0 9092nd 1.2 9093rd 3, 0 9108. 0.7 9109th 2.0 9110. 2.0 9111th 1.0 9112. 0.2 9113th 5, 0 9114. 0, 6 9139th 0.2 9141st 0.5 9155th 0.06 9156th 0.1

Table 6 (continued)

compound Number IC ₅₀ (μΜ) accumulation The maximum % of accumulation 9157th 0.2 9158th 0, 6 9159th 0.4 9160. 20 9178. 0,080 9179th 0,170 9193.HCI 7.0 9194.HCI 1,800 9195.HCI 0.210 9196.HCI 0,140 9197.HCI 0,025 9198th 0,200 9199th 0,140 9209th 0,600 9210. 0,220 9211th 1,400 9214th 0070 9215th 1,100 9217th 0,700 9228th 0, 350 9229th 0,200 9230th 0, 130 9231st 2,000 9232nd 0,020

Table 6 (continued)

compound Number IC ₅₀ (μΜ) accumulation The maximum % of accumulation 9233rd 0, 600 9234. 0,500 9235th 0,600 9236th 2,000 9250. 0,800 9260. 0, 800 9261st 1,200 9266th 1,200 9267. 5,000 9272nd 0,400 9273rd 0,070 9274. 0, 800 9275. 0, 600 9276th 1, 900 9276.HC1 0,700 9299th 0,500 9300. 0,200 9301. 0,200 9308. 3,000

2. Potentiation of doxorubicin toxicity

The compounds of formula (I) were tested for their ability to potentiate the toxicity of doxorubicin in AR 1.0 cells. In the initial proliferation assays, the compounds were titrated with a fixed concentration of doxorubicin (0.86 μΜ) that was not toxic to AR 1.0 cells per se. Incubations with doxorubicin were performed for four days prior to the assay for sulforhodamine B [Skehan et al., J. Natl. Cancer Inst., 82, 1107-1112 (1990)] would have been used to quantify proliferation. The results are shown in Table 7.

For further studies, we selected compounds that were capable of sensitizing AR 1.0 cells to 0.86 μΜ doxorubicin without significant intrinsic toxicity. Cells were cultured for four days with doxorubiricin at a concentration of 0.01 nM to 50 μ, and at fixed concentrations of the compounds of formula (I). Quantification of proliferation was performed according to the Skehan method [Skehan et al., J. Natl. Cancer Inst., 1990, 82, 1107-1112. To calculate the potentiation index (PI) was used, the Doxorubicin alone IC ₅₀ values (IC ₅₀ means the concentration for the untreated control proliferation, 50% reduction), and resulting in concomitant use is made verapramillal IC ^ g are used in the following context :

IC _5Q doxorubicin Pl = IC ₅₀ doxorubicin + RMA

The results are shown in Table 8.

Table 7

compound Number Toxicity of the compound (IC ₅₀ μΜ) Toxicity with a cytotoxic agent (IC ₅₀ μΜ) 9091st 1.8 0.15 . 9092nd 0.7 0.07 9093rd 2.0 0.09 9108th 4.0 0, 10 9109th 4.0 0.30 9110th 6, 0 1, 00 9111th 2.5 0, 15 9112th 2.0 0,015 9113th 0.4 .. 0.1 9114. 1.0 0.06 9139th 4 0.3 9141st 2 0.3 9178th 1.50 0,008 9179th 0.50 0, 080 9193.HC1 2.00 0,200 9194.HC1 6:00 0,050 9195.HC1 1.00 0,010 9196.HC1 7.00 0,060 9197.HC1 28.00 0,010 9198. 8.00 0, 020 9199th 40.00 0,050 9209th 45.00 0,070 9210th 40.00 0,080

• · ·

- 55 Table 7 (cont'd) ·

compound Number Toxicity of the compound (IC ₅₀ μΜ) Toxicity with a cytotoxic agent (IC ₅₀ μΜ) 9211th 50.00 0, 080 9214th 100.00 0,008 9215th 10.00 0,030 9228th 0, 60 0, 100 9229th 0.50 0, 070 9330. 0.45 0, 100 9231st 2.00 0, 120 9232. 3.00 0,060 9233rd 8:00 0, 400 9234th 1.00 0, 080 9235th 0.50 0, 100 9236th 0.80 0, 130 9250th 2.00 0, 080 9260. 3.00 0, 350 9261st 5, 00 0,400 9272. 9:00 0,200 9273. 20, 00 0,020 9274. 40.00 0,050 9275th 1, 80 0,700 9276th 30.00 0, 500

. spreadsheet

compound Number Potency index In the definition of Pl the concentration (μΜ) 9108th 1000 1 9109th 250 1 9111th 500 1 9112th 1000 1 9139th 500 0.5 9141st 285 0.5 9155th 67 0.2 9156th 25 0.2 9157. 40 0.2 9158th 75 0,2 ' 9159th 50 0.2 9178th 7.1 0.01 27.3 0.03 69, 8 0.10 250.0 0.30 9193.HCl 20.0 0, 30 2.0 0.10 9194.HCl 50.0 0.30 7.5 0.10 1.5 0.03 1.2 0.01 9195.HCl 454.0 0.30 50.0 0.10 2.5 0.03 1.2 0.01 9196.HCl 37.5 0.30 5, 0 0.10 1.5 0.03 1.0 0.01

Table 8 (continued)

compound Number Potency index Pl is still delimited the concentration (μΜ) 9197.HCI 65.0 4.3 1.3 1.3 0.30 0, 10 0.03 0.01 9198. 32.5 0, 30 3, 3 0.10 1.3 0, 03 1.3 0.01 9199th 65.0 0, 30 2.2 0, 10 1.3 0.03 1.3 0.01 9209th 125.0 0.30 15.0 0.10 1.2 0.03 1.2 0, 01 9210. 75.0 0.30 8.3 0.10 1.5 0, 03 1.3 0, 01 9211th 1538.0 1.00 1000.0 0.50 9214. 200.0 0.30 150.0 0.10 20.0 0.03 2.0 0, 01 9215th 66, 7 0, 30 15.0 0.10 3, 0 0, 03 1.5 0, 01 9217. 11.0 1.0 0, 9 0.8 0, 30 0.10 0, 03 0.01 9231st 20.0 3, 0 0.9 1.1 0, 30 0.10 0.03 0.01

Table 8 (continued)

compound Number Potency index In the definition of Pl the concentration (μΜ) 9232nd 80.0 20.0 3, 0 1.0 0.30 0, 10 0.03 0, 01 9234. 50.0 5, 0 0.30 0, 10 9235th 37.5 2.3 0.30 0, 10 9236th 16.7 2.1 0.30 0.10 9250th 286, 0 0.50 9260th 3.3 2.0 0.30 0.10 9261st 2.2 1.7 0.30. 0.10 9272nd 175.0 5, 6 1.4 1.00 0.30 0.10 9273rd 100.0 96.1 83.3 29, 4 3.00 1.00 0.30 0, 10 9274. 100.00 90.9 71.4 25.0 3.00 1.00 0.30 0, 10 9275th 25.0 6.9 0.7 1.00 0.30 0, 10 9276th 166, 6 25.0 0.8 0.8 3.00 1.00 0.30 0.10 9299th 16.0 1.8 0.30 0, 10

Table 8 (continued)

compound Number Potency index In the definition of Pl the concentration (μΜ) 9300. 133.3 1.00 61, 5 0.30 10.0 0.10 9301.HC1 133, p 1.00 88, 9 0.30 28, 6 0, 10

Example 9

Characterization of the Compounds of the Invention

The compounds and salts prepared in Examples 1 and 2 are characterized by mass spectroscopy and proton nuclear magnetic resonance spectroscopy. The results are summarized in Tables 9 and 10.

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w "Ο 2.61 (8H, 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, s), 6.82 (1H, s), 6.98 (1H, s + 1H, m), 7.25 (2H, d), 7.68 (4H, m), 7.98 (2H, d), 10.15 (1H, s), 10.50 (1H, s) 2.70 (6H, m), 2.81 (2H, t), 3.06 (3H, s), 3.55 (2H, s), 3.65 (3H, s), 3.70 (6H) , s), 6.16 (2H, m), 6.65 (2x1H, s), 6.85 (1H, s), 6.98 (1H, s + 1H, m), 7.25 (2H, d), 7.55 (1H, t), 7.68 (2H, d), 6.71 (1H, d), 7.85 (1H, d), 8.10 (1H, s), 10.16 (1H, s), 10.60 (1H, wide s) _ 2.60 (6H, m), 2.80 (2H, t), 3.58 (3H, s), 3.70 (6H, s), 6.62 (1H, s), 6.66 (1H, s), 6.91 (1H, s), 7.36 (3H, m), 7.50 (1H, d), 7.52- 7.62 (3H, m), 7.70 (2H, d), 7.76 (1H, d), 7.89 (1H, d), 7.90-7.99 (4H, m), 8.14 (1H, s), 10.20 (1H, s), 10.73 (1H, s) Solvent / field DMSO-d _6/400 MHz 1 N SHE She Kű p 1 She cn 2 Q DMSO-d _6/400 MHz MS Ό 3 ESI ESI ESI Crowd (intensity) 646 (100) 646 (100) 1 693 (100) Molecular formula tendon SHE m C \ co co co SHE m SHE m £ (You CO Ή co co She m SHE 2 She CO U Song 9198. 9199th 1 9209th 1

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Ν

Ν ο

ο \

CQ (—4 U Ω Ο ο

ο \

η r — I υ

Ω

U

Ο -χ ο ο> —I ΙΟ [m ι-4 ι — I Ό ιη σ

m ιη σ

Table ιη (continued) &

• φ

Λ!

Οι

V

Ν η

W ^: Ο ιη

Ο

Ζ

ΙΟ

X ηΟ

Ο

Ζ

ΟΟ

X ιη οο

Ο ιη

Ο «3 ·

Οο

X ιη οο

U r ~

Ο «τ

Ζ ο

X ι — I υ

Ό σ

Ό ιο {Μ σ

Γ ιο σ

(Ν

ΓΟΝ σ

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M

M '0

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Ό • u ι — I o

+>

Λ η

ο »i

Ε- <

θ ′ ^: 0

Eh

C

P

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Table (continued) +>

H

Λ '0

Ο »

N n

n = 0

-S

N

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o o

V ¹ \

co ι — ι O Q O o

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σι

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Μ

Φ

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U

V

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Table Γ (continued) μ

Φ

Η

CU 'φ

X

cn

Φ

Ν α

η = Ο

Γ ο

(Ν

Ί ·

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Ν ω

σ σ

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V

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N

CO

CO: O

N

C0

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o o

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U

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lf)

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co <n oo o

co σ

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co

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CN

Ν 'ra co oo k0

X X X X —— co 2 2 CO CN Ν 'ra m

co <Ν ”χ 2 Ν 'ι — I

CO

*.

ra ra in

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co r- in 2

*. r «t r ~ κ ra σ b r2 CN - '- 4J

00 ca σ x ·. CN

CN o ra r- co

X X cn ra r- cn 2 b

ι-H CO σ x f — I r ~ C σ. She

1-1 b o

Γ co co co n2 i-4 x-x - b r4 χ-χ. - 'to

CO o X x, -4 00

Table 10 <0

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Μ '0

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Μ

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Η

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U

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CO CO cn m * X X r ~ m m

CO - ra n · b m

XXX - co X ε <n

X co 00 00 CN - * · <

X rco ra σ x cn cn co 1

CN CN r- 00 2 cn ra

SHE

O ν '

O 'o

X

I σ

rco co

CN <—I 00 · <O Γ ~ t —t

CN

CN τ-4 X i-4 X X X r ** 00 <0 2 X X x x co 2 X to X X CN X-X 0 ε CN x x X to ^ 0 - lake 1 '4 X ε 00 X x x X X X X 2 CO 'T X X X-X χ-χ <0 2 X-X 00 CN 2 x x co CO X t-4 ε X X 4-r ε r- - ' 2 r- X X X m to X 2 2 X Γ 2 00 X X CO 2 x x CN i-4 X-X σ r4 X CN x x co t-4 co - * b X - CN * · * ' co X - ' r- 1 r ~ X 0 SHE X main X SHE 2 r ~ - m 2 X ca <31 00 2 X CN 1-4 X X CN χ-χ X X X 4-r x x X '-' ca co P 00 CN to b 00 σ X X r- X X X X SHE X X t-4 X-X 2 x x χχ V0 2 χ-χ X ε ε X r4 ε £ CO X CN ε She l> k0 4-r X X X X X X 2 2 X 0 2 2 2 X σ 2 X Ν ' co x x r- t-4 X-X CN CN x x tendon CN X-X --- co x - co - ' co X co r * [** CN Γ ' X m X to x X σ 00 2 X 0 2 σ m 2 X 0 2 X X r-1 x x X i-4 X X i-4 X-X X r4 CN ca b 00 - rh C0 b 00

o o

Ν '\

ra r — c U Q U

X X-X x x 0 0 0 0 00 1-4 L0 • X-- x-x X-X i-4 σ m CO in n

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H

0, '0

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N n

n

SHE

N * o

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CN co

CN

SHE

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Ν '

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4J μ

N n

•She

Table 10 (continued) +>

V i — I ft '<ü

Λ!

0 »

4)

N n

n = o

00 - ^rl χ-χ X X She X (0 χ-χ needle rd χ-χ w x CO X X 00 2 X Z-X 1 X ϊ-1 2 co She 2 CN CN x X She 2 r- τ ^- 1 CN CN σ X C X z Γ- She X —Χ ω X f ( cn 00 co cn 00 X X X x - 2 X zx Z-X cn Ou t — i χ-χ £ £ c-1 £ X X x χ-χ <-i X 2 2 m «-D r — 4 2 cn V * needle X 00 1 '( X. X O 2 needle zH cn She She X X X She τ-d X C \] ζ — X x-x X x cn ω ε cn 00 lake X X lake She 00 00 2 2 Γ * She X X 1-100 X X CN cn CN Γ ' N N

o o

V \

cn

I-I

U

Q

Oh o

She

V * \

cn

I-i

U

Q

Oh i-c u

Z-X X X Z — X She Z-O z-x O o o o Γ0 rd i-d> rd - X— χ — Z Xz »x-z <-1 CN in co o cn σ co cn cn τ-l r-C

v

Claims (10)

PATENT CLAIMS A dioxopiperazine of formula (I) wherein R ¹ is (i) a group of formula (a) wherein p is 0 or 2; R _a , R _d , R _c , R _d and R _e each independently or differently represent hydrogen, C 1-6 alkyl optionally substituted with one or more halogen atoms, C 1-6 alkenyl, C 1-6 alkoxy; C 1-6 alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, · hydroxy -methyl, carboxymethyl, -CO ₂ R, -NHCOR, 13 13 11 12 13 -NHSO ₂ R, -SO ₂ R, -CON (RR), -SOR, 11 12 11 12 11 12 -SO ₂ N (RR), -N (RR), -O (CH ₂ ) _n N (RR), -O (CH ₂ ) _n CO ₂ R ¹¹ , -O COO ¹¹ , -CH ₂ OCOR ⁿ , -CH-jNHCOR ¹¹ , -CH ₂ NHCOOR ¹³ , -CH ₂ S R ⁿ , -C 2 SCOR ¹¹ , -CH ₂ S (O) _m R ¹³ , -CH ₂ NHCO (CH ₂ ) _n CO ₂ R ¹¹ , -N (R ¹¹ ) COR ¹² , -NHCOCF ₃ , -NHCO (CH ₂ ) _n CO ₂ R ¹¹ , -NHCO (CH ₂ ) _n OCOR ¹¹ or -NHCO (CH ₂ ) hOR ¹¹ wherein m is 1 or 2, n is 0, 1, 2, 3, 4, 5 or 6, 11 12 R and R are each independently hydrogen or (C 1 -C 6) alkyl; and is C 1-6 alkyl; obsession • · - 84 R _a and R _b , 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 an optionally substituted benzene ring; (ii) a five- or six-membered heterocyclic group optionally fused to a benzene ring containing at least one oxygen, nitrogen and / or sulfur atom; (iii) C 1-6 alkyl or C 5-7 cycloalkyl; or (iv) C 5 -C 7 cycloalkenyl optionally substituted with C 2 -C 6 alkenyl; R is hydrogen, optionally above a definite meg11 12 -N (RR) substituted C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or a radical of formula -COOR ¹¹ group wherein R ¹¹ is phenyl as defined above or as defined above, with the proviso that when R ¹ is unsubstituted phenyl, R ¹¹ is other than hydrogen; and 3 4 R and R is a hydrogen atom and the other is a group of formula (A) wherein q is 1, 2, 3 or 4, r is 0 or 1 and R5 and ^R6 are the same or different and are hydrogen or C 1-6 alkoxy; or R ⁵ and R ⁶ together form a methylenedioxy group; and --- is a double bond, or when R ¹ is (i) thereof, a double bond or a single bond as defined Ban 85 - or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein R ¹ is a phenyl group as defined in (i), wherein one of R _a -R _e is hydroxy, C 1 -C 6 11 11 11 12 alkoxy, nitro, -NHCOR, -CO ₂ R, -N (RR), 11 12 13 11 12 11 12 13 -O (CH ₂ ) _n N (RR), -SO ₂ R, -CON (RR), -SO ₂ N (RR), -SOR, 11 12 -N (R) COR is a halogen atom, and the other four of R _a- R _e are hydrogen. A compound according to claim 1 or 2, wherein ^R1 is defined phenyl group a in (i) wherein Ra-Re each represent a hydrogen atom, or Ra, Rb and Rc represent a halogen atom .or C1-6 alkoxy, and Ra ^- of Re of the others represents a hydrogen atom; or pyridyl, furyl or thienyl; R is hydrogen, methyl, cyclopropyl or phenyl; as well as 3 4 One of R and R is hydrogen and the other is A, wherein q is 2; and 5 6 R and R are each methoxy. 4. A compound according to any one of claims ¹ to 3, wherein R ¹ is 4-pyridyl, 3-furyl, 2-thienyl or 3-thienyl. A compound according to claim 1, selected from: N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·············· - 86-ethyl] -phenyl} -4 - {[(3Z, 6Z) -6-benzylidene-1-ethyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide hydrochloride (Compound 9112); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -1-benzyl] β-benzylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide hydrochloride (Compound 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] methyl} -benzamide hydrochloride (Compound 9114); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - [{(3Z, 6Z) -6 - [( 3-Furyl) methylene] -1-methyl-2,5-dioxo-3-piperazinylidene} methyl] -benzamide hydrochloride (Compound 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] methyl} benzamide hydrochloride (Compound 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] methyl} benzamide hydrochloride (Compound 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] methyl} benzamide hydrochloride (Compound 9092); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - {[(3 Z, 6 Z) -6- (3 -chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide hydrochloride (Chapter 9093). compound); 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-pyridyl) methylene] -3-piperazinylidene} methyl] benzamide hydrochloride (Compound 9110); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -l-methyl- 2,5-Dioxo-6- (3-thienylidene) -3-piperazinylidene] methyl} -benzamide hydrochloride (Compound 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-thienylidene) -3-piperazinylidene] methyl} benzamide (Compound 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] methyl} -benzamide (Compound 9160); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - ([(3Z, 6Z) -6- (3 -chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9157); N '- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3Z, 62j -6- (2 -chlorobenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9158); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6 - [( 3-furyl) methylene] -1-methyl-2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9159); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6- (3 -methoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 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-388 piperazinylidene] methyl} benzamide (Compound 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] methyl} benzamide (Compound 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] methyl} -benzamide (Compound 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] methyl} -benzamide (Compound 9179); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -4 - [{(3Z, 6Z) -1-methyl-6 - [(2-naphthyl) -ethylene] -2,5-dioxo-3-piperazinylidene} methyl] -benzamide (Compound 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} methyl] benzamide (Compound 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} methyl] benzamide (Compound 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} methyl] benzamide (Compound 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} methyl] benzamide (Compound 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} methyl] benzamide (9198; compound); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(32,6Z) -1-methyl- 6 - [(1-methyl-3-pyrrolyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9199); N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(32,6Z) -1-methyl- 6 - [(2-naphthyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 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} methyl] benzamide (Compound 9210); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(32,62) -1-methyl- 6 - [(3-methyl-2-benzo [b] thienyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9211); N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(32,62) -1-methyl- 6 - [(1-methyl-3-indolyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9214); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - [{(32.62) -l-methyl- 6 - [(3-methyl-2-benzo [b] thienyl) methylene] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9215); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(32,62) -6-benzylidene 1 - [(methoxycarbonyl) methyl] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 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] methyl} benzamide (Compound 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] methyl} -benzamide (Compound 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] methyl} benzamide (Compound 9230); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -l-methyl-6 pentylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9231); N- {4- [2- (β, 7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3 Z, 6 Z) -1-methyl-6 pentylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 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] methyl} benzamide (Compound 9233); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -6- (3, 3-dimethyl-butylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9234); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6- (3, 3-dimethyl-butylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9235); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -4 - {[(3Z, 6Z) -6 - {[( 4S) -4-Isopropenyl-1-cyclohexenyl] -methylene} -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9236); ·· »· • · N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -β-benzylidene-1] - (carboxymethyl) -2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9241); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6 - {[( 4S) -4-Isopropenyl-1-cyclohexenyl] -methylene] -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9250); N- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl] -3 - [((3Z, 6Z) -l-methyl-6 - [(2-naphthyl Methylene] -2,5-dioxo-3-piperazinylidene] methyl] -benzamide (Compound 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} methyl] -benzamide (Compound 9261); N- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolyl) ethyl] -3 - {[(3Z, 6Z) -l-methyl-6- (2-phenyl- propylidene) -2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9266); N- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] -4 - {[(3Z, 6Z) -1-methyl-6- (2-phenyl) - propylidene) -2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 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] methyl} benzamide (Compound 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] methyl} benzamide (Compound 9273); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6- (2- acetoxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9274); • ·. « 92- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(3Z, 6Z) -6- benzylidene-1- [2- (dimethylamino) ethyl] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 9275); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3 Z, Z) -6- (4-Hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9276); N- {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - [{(3Z, 6Z) -6-benzylidene 1 - [(ethoxycarbonyl) methyl] -2,5-dioxo-3-piperazinylidene} methyl] benzamide (Compound 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] methyl} benzamide (Compound 9300); N- {4- [2- (6,7-dimethoxy-l, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -6- (3 -hydroxybenzylidene) -1-methyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9301); N- {4- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3Z, 6Z) -1-methyl- 6-pentylidene-2,5-dioxo-3-piperazinylidene] methyl} -benzamide (Compound 9306); 2 - {4- [2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) ethyl] phenyl} -3 - {[(3 Z) -1-methyl-6- benzyl-2,5-dioxo-3-piperazinylidene] methyl} benzamide (Compound 9308). A pharmaceutical or veterinary composition comprising a pharmaceutically or veterinary acceptable carrier or diluent and an active ingredient according to any one of claims 1-5. A compound according to any one of claims 1 to 6. A process for the preparation of a compound according to claim 1, wherein a compound of formula II wherein R, R and --- are as defined in claim 1. A compound of formula (III) as defined in claim 1, in an organic solvent and in the presence of a base: In formula 7 8 one of R and R is hydrogen and the other is formyl and q and r R and R are as defined in claim 1 and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof. 8. One of claims 1-5. A compound according to any one of claims 1 to 6 for use as a modulator of multidrug resistance. 9. One of claims 1-5. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for use as a modulator of multidrug resistance. A compound of formula (III) wherein: Q and r and R and R are as defined in claim 1; and 7 8 One of R and R is hydrogen and the other is formyl.