AU698828B2 - Piperazine 2,5 dione derivatives as modulators of multi-drug resistance - Google Patents
Piperazine 2,5 dione derivatives as modulators of multi-drug resistance Download PDFInfo
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- AU698828B2 AU698828B2 AU43100/96A AU4310096A AU698828B2 AU 698828 B2 AU698828 B2 AU 698828B2 AU 43100/96 A AU43100/96 A AU 43100/96A AU 4310096 A AU4310096 A AU 4310096A AU 698828 B2 AU698828 B2 AU 698828B2
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- C07—ORGANIC CHEMISTRY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- A—HUMAN NECESSITIES
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Description
SWO96/20190 PCT/GB95/03027 -1- PIPERAZINE 2,5 DIONE DERIVATIVES AS MODULATORS OF MULTI-DRUG RESISTANCE The present invention relates to compounds useful as modulators of multi-drug resistance (MDR), to their preparation and to pharmaceutical and veterinary compositions containing them.
The resistance of tumours to treatment with certain cytotoxic agents is an obstacle to the successful chemotherapeutic treatment of cancer patients. A tumour may acquire resistance to a cytotoxic agent used in a previous treatment. A tumcur may also manifest intrinsic resistance, or cross-resistance, to a cytotoxic agent to which it has not previously been exposed, that agent being unrelated by structure or mechanism of action to any agent used in previous treatments of the tumour.
Analogc-. certain pathogens may acquire resistance to pharmaceutical agents used in previous treatments of the diseases or disorders to which those pathogens give rise.
Pathogens may also manifest intrinsic resistance, or cross resistance, to pharmaceutical agents to which they have not previously been exposed. Examples of this effect include a multi-drug resistant forms of malaria, tuberculosis, leishmaniasis and amoebic dysentery.
The above phenomena are referred to collectively as multi-drug resistance (MDR). As discussed more fully later on, a plasma membrane glycoprotein (P-gp) is implicated in the mechanism which underlies MDR. P-gp has drug binding properties. Certain agents which have the capacity to SSUBSTITUTE SHEET (RULE 26) i 'i iiil____i 7, WO 96120190 PCT/GB95/03027 2 modulate MDR may therefore also be useful in facilitating the delivery of drugs across the blood brain barrier, and in treating AIDS and AIDS-related complex.
Disadvaltages of drugs which have so far been used to modulate MDR, termed resistance modifying agents or RMAs, are that they frequently possess a poor pharmacokinetic profile and/or are toxic at the concentrations required for MDR modulation.
It has now been found that a series of piperazinedione derivatives have activity as modulators of multi-drug resistance. The present invention therefore provides a piperazinedione derivative of formula 1: 0 R1 NH R 3
R
2 N-R4 wherein 0 RI is a group Ra Rb
-(CH
2 )p -2 7 Rc Re Rd
(I)
wherein p is 0 or 2; Seach of Ra to Re, which may be the same or different, is independently selected from hydrogen, alkyl unsubstituted or substituted by one or more halogen atoms, |1i C 1
-C
6 alkenyl, Ci-C 6 alkoxy, C 1
-C
6 alkylthio, halogen, hydroxy, SSUBSTITUTE SHEET (RULE 26) ill
I
3 nitro, phenyl, cyano, -CH, 2 OH, -CH, 2
OH,
-CHCOOH,
-CO
2 R",11 -NHCOR 1
-NHSO
2 R13, -S0 2
R
1 3
-CON(R
11
R
12 -SOR 13,
-SO
2 N (R 1 1
R
12 -N (R 1 1 R 12) -0 (CH2) N (R"R1 2 -0 (CH 2 nCO 2
R
11
-OCOR
11
-CHOCOR
1 1
-CH
2
NHCOR
1 1
-CH
2 NHCOOR1 3
-CH
2
SR
1 1
-CH
2 SCOR", -CH 2 S(O),R13 wherein m is 1 or 2,
-CH
2 NHCO (CH 2
CO
2
R
1
-N(R
11 COR 2
-NHCOCF
3 -NHCO nCO 2
R'
1
-NHCO(CH
2 OCOR" and -NHCO(CH 2 nCO 2 R11; wherein n is 0 or is an integer of from 1 to 6, each of R 11 and R12 is independently H or C 1
-C
6 alkyl and R 13 is C 1
-C
6 alkyl; or any of Ra and Rb, Rb *o and Re, Pc and Rd or Rd and Re together form a methylenedioxy group, or form together with the carbon atoms to which they are attached a benzene ring; (ii) a 5- or 6-membered hetezocyclic group containing at least one heteroatom selected from O, N and S, which S group may be fused to a benzene ring; (iii) a alkyl or cycloalkyl group; or (iv) a C 5 cycloalkenyl group which is unsubstituted or substituted by C 2 alkenyl;
R
2 is H, C 1 -C alkyl optionally substituted by a group
-N(R
1 1
R
12 as defined above, cycloalkyl, C 2
-C
6 alkenyl, -COORn wherein R" is as defined above or a phenyl group as defined under 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
LIAIV
CT
i~ -o
~ATE:
WO 96/20190 PCT/GB95/03027 -4- -C-NH (C H2q -N R
(A)
S \r R6 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 C 1
-C
6 alkoxy, or Rs and R 6 together form a methylenedioxy group; and is a double bond or, when R, is as defined under 1 above, is a double bond or a single bond; or a pharmaceutically acceptable salt thereof.
A C-C 6 alkyl group may be linear or branched. A Cl-C 6 alkyl group is typically a Cz-C 4 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tertbutyl group. A C 3
-C
6 cycloalkyl group may be cyclopropyl, S 15 cyclobutyl, cyclopentyl or cyclohexyl. A halogen is, for example, fluorine, chlorine, bromine or iodine.
SA Cz-C, alkoxy group is typically a C,-C 4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. A C 2
-C
6 alkenyl group is, for example, C 2
-C
4 alkenyl, for example ethenyl, prop-l-enyl or prop-2-enyl.
A heterocyclic group may be, for example, a pyridine, pyrrole, furan or thiophene group which is linked via any one of its constituent ring atoms. It may be, for instance, a 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 furyl, 3-furyl, 2thienyl or 3-thienyl group.
The integer q is from 1 to 4, and is preferably 1 or BISI S TuTEU SHEET (RULE 26) 1 1 I. 1 1 WO 96/20190 PCTiGB95/03027 5
R
5 and R 6 are preferably the same and are preferably C 1 C, alkyl, for instance methyl.
When RI is as defined under above, the phenyl group is unsubstituted or is substituted at one or more of positions 2 to 6. When it is mono-substituted it may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4. Thus for instance, one of Ra to Re is other than hydrogen, preferably Rb or Rc, especially Rc. When the phenyl group is mono-substituted the substituent Ra to Re is preferably selected from a halogen, for instance chlorine, bromine or fluorine; a C,-C, alkoxy group, for instance OMe; and an acetamido group -NHAc in which Ac denotes acetyl.
The phenyl group may instead be 2,6-, 3,4- or 3,5- disubstituted, or 2,3,6- or 3,4,5-trisubstituted. When it is disubstituted, three of Ra to Re are hydrogen and two are other than hydrogen. For example Ra and Rb, or Ra and Rc, or Ra and Rd, or Ra and Re, or Rb and Rc, or Rb and Rd are other than hydrogen whilst, in each case, the other three of Ra to Re are hydrogen.
When the phenyl group is trisubstituted, two of Ra to Rc are hydrogen and three are other than hydrogen. For example, Ra, Rb and Rc, or Ra, Rb and Rd, or Ra, Rb and Re, or Rb, Rc and Rd are other than hydrogen whilst, in each case, the other two of Ra to Re are hydrogen.
In a preferred series of compounds of formula each /j of Ra to Re is hydrogen. In another preferred series of aSUBStTTTE SHEET (RULE 26)
~I
WO 96/20190 PCT/GB95103027 6 compounds, one of Ra to Re is selected from hydroxy, Cl-C, alkoxy, NHCOR11, -CO 2 -N(R"R1 2
-O(CH
2 (R"R1 2 SO2R 13, -CON R1 2 NO, -SO 2 N(R"R 12) -SOR3, COR1 2 and halogen and the other four of Ra to Re are H. Alkoxy may be, for instance, OMe or OBun. NHCOR" is typically -NHAc. CO, 2 R" is typically -COOH or -COOMe. N(R"R12) is typically NMe 2 CON(R"R12) may be -CONH, 2
SO
2 R13 is typically SO 2 Me, SO,N(R"R1 2 is for example -SONMe 2 SOR13 may be SOMe and
-N(R
1 COR1 2 may be -NMeCOBut. Halogen is typically F or Cl.
Preferably Rc is alkoxy, especially OMe or OBun; NHCOR', especially -NHAc; -CO 2 R1, especially -CO 2 H or -CO 2 Me; -CON(R"R1 2 especially -CONH 2
NO
2 N(R"R 2 especially NMe,; -SOR" especially -SOMe; -SO 2 N(R" R1 2 especially -SO 2 NMe 2 or halogen, especially F or Cl; and each of Ra, Rb, Rd and Re is H.
In the above-mentioned series of preferred compounds Ra to Re are all hydrogen, or one or two of Ra to Re are other than hydrogen whilst the others are hydrogen. For instance one of Ra, Rb and Rc is other than hydrogen. Alternatively Ra and Rc, or Rb and Rc, are other than hydrogen. Preferred values for the one or two of Ra to Re which is or are other than hydrogen include alkoxy such as OMe or OBun, halogen such as Cl or F, hydroxy, -N(R"R
CO
2 R11, -CH 2
SCOR
3
-CH
2 SR", -NHCOR", -O(CH 2 N (R1"R12) -O (CH) CO 2
-CH
2
NHCO(CH
2 nCO 2
-NHCOCH
2 OR11, 3
-CH
2 NHCOOR1 3 and CF 3 Particularly preferred compounds are those wherein Ra, ii
H
STITUTE SHEET (RULE 26) j
I::
i
I
-7- Rb, Rd and Re are each H, and Rc is selected from H, OMe -NHAc, -CO 2 H, -CO 2 Me, -CONH,, NO 2 -NMe 2
SO
2 Me, -SOM'e ane
-SO
2 2Me. Also preferred are compounds wherein Ra to Re are preferably each independently selected from H, halogen, hydroxy, C 1 alkoxy, nitro, -CH 2
SCOR
3
-CH
2 SR11, -C0 2
R
1 1 -OCOR', CF 3 -O(CH) N (R 11
R
12 -0O (CH 2 C0 2
R
11
-CH
2 NHCO nCO 2 R1 1 -NHCO (CH 2 nOR 1 -N (R 11 R12)
-NHCO(CH
2 OCOR", THCO(CH 2
CO
2
R
11 and -CH 2 NHC0 2
R
13 or Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re, form a C9 methylenedioxy group or form, with the carbon atoms to which 0000 000*0 they are attached, a benzene ring.
Still more preferably, Ra and Rb are independently H, nitro *0 or halogen, Rc is H, hydroxy, -O(CH 2 )nN(R 1
R
12 -OCOR13, -O (CH 2 nCOR", -CH 2 NHCO (CH 2 nCO 2 R11, C, C 6 alkoxy, -NHCO (CH 2 )nOR", -NHCO (CH 2 nOCOR 1 -N(R"R1 2
-CH
2
NHCO
2
R
3
-CH
2 SR11 or -NHCOR 11 Rd is H, halogen, C,-C, alkoxy, -CH 2 SCOR13, -CH 2 SR11 or -C 2
OR
11 and Re is H, nicro or halogen.
When any two adjacent groups of Ra to Re form, together with the carbon atom to which they are attached, a benzene ring, that benzene ring forms, together with the phenyl group, a naphthalene ring structure.
In one embodiment of formula R 1 is a phenyl group as defined above which is unsubstituted or monosubstituted at position 2, 3 or 4 by Cl or MeO, or is a pyridyl, furyl or 1A 1TE ii WO 96/20190 PCT/GB95103027 8 thienyl group, R 2 is H, CH 3 cyclopropyl or phenyl, and one of R 3 and R 4 is H and the other is a group of formula (A) wherein q is 2 and each of RS and R 6 is a methoxy group.
In a second embodiment, R 1 is unsubstituted phenyl, R 2 is Ci-C 4 alkyl, preferably methyl, or is phenyl or cyclopropyl, R 3 is H and R 4 is a group of formula wherein q is 2 and each of R 5 and R 6 is MeO.
In a third embodiment R 1 is substituted phenyl as defined above or a furyl, thienyl or pyridyl group, R 2 is H,
R
3 is H and R 4 is a group of formula wherein q is 2 and each of R 5 and R 6 is MeO.
In a fourth embodiment R is substituted phenyl as defined above or a furyl, thienyl or pyridyl group, R 2 is H,
R
3 is a group of rormula wherein q is 2 and each of R and R 6 is MeO, and R 4 is H.
In a fifth embodiment R' is unsubstituted phenyl, R 2 is
CI-C
4 alkyl, preferably methyl, phenyl or cyclopropyl, R 3 is a group of formula wherein q is 2 and each of R 5 and R 6 is MeO, and R 4 is H.
When in the above embodiments R 1 is a furyl, thienyl or pyridyl group it is preferably a 3-furyl, 2-thienyl, 3thienyl or 4-pyridyl group.
Examples of preferred compounds of the invention are as follows. The compound numbering is adhered to in the rest of the specification.
N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- |LSUBSTrUTE SHEET (.x l Y IRN: 38276~ WO 96/20190 PCT/GB95/03027 WO'96/20 190 -9 isoquinolyl) ethyl) phenyl) (3Z, 6Z) -6-benzylidene-l- ethyl 2, 5-dioxo-3-piperazinylidele) methylbenzamide, hydrochloride (9112) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 6Z) -3.-benzyl-6-benzylidFe-ne- 2, 5-dioxo-3-piperazinylidene)methylbelzamide, hydrochloride (9113) N 7- Dimet hoxy-1, 2,3, 4 -tetrahydro -2 i soquinolyl) e thyl) phenyl) -4 (3 Z, 6 Z) 6- ben zyl idene -l1cyclopropylme thyl 5 -dioxo piperazinylidene) methylb~enzamide, hydrochloride (9114) N-(4-(2-(6,7-Dimetho\ t ,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) (3Z, 6Z) (3-furylmethylene) -1methyl-2, 5-dioxo-3-piperazinylidene)methylbelzamfide, hydrochloride (9108) N-(4--(2-(6,7-Dim-,ethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) (3Z, 6Z) (4methoxybenzylidene) -l-methyl-2, 5-dioxo-3piperazinylidene)mrethylbenzamile, hydrochloride (9109) pipera N- isoqui chlorol pipei.a N- isoqui chloro p:Lpera N- isoqui (3 -py hydro N- (4-1 isoqu' (3-th hydro N- (4isoqu (2-th N- (4- WO 96120190 N- (4 (2 7 -Dimethoxy-, 2, 3,4 tetrahydro -2 isoquinolyl) ethyl) phenyl) 4- (3 Z, 6 Z) 6- (4 chlorobenzylidene) -1-methyl-2, 5-dioxo-3- -S1JBMIUTE SHEET (RULE 26) I; oil- (Fl Fl WO 96/20190 PCTIGB95IO3027 23 thereof.
IRN: 382762 IIN:\LIBU]21098-MEF WO 96I2O19O PCT/GB95/03027 piperazinylidene) methylbenzamide, hydrochloride (9091) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl)pheny-) 6Z) (2chlorobenzylidene) -i-methyl-2, 5-dioxo-3pipeiazinylidene) methylbenzamide, hydrochloride (9092) N- (4 7-DiP'ethoxy-1, 2, 3, 4-tetrahydro-2.
isoquinolyl)ethyl)phenyl) ((3Z,6Z) (3chlorobenzylidene) -1-methyl-2,5-dioxo-3p:iperazinylidene)rnethylbenzamide, hydrochloride (9093) N- (4 -C2 7-Diethoxy- 1, 2,3,4 tetrahydroisoquinolyl)ethyl)phenyl)-4-((3Z,6Z)lmethyl 2 ,5dioxo-6 (3-pyridylmetnylene) -3-piperazinylidene)methylbelzamide, hydrochloride (9110) N- (4 7-Dimethoxy- 1,2, 3, 4 -tetrahydro- 2 isoquinolyl)ethyl)pheny-) ((3Z,GZ) -l-rnethyl-2,5-dioxo-6- (3-thenylidene) -3-piperazinylidene~'methylbeflzamide, hydrochloride (9111) N- (4 7-Dimfethoxy- 1,2,3, 4 -tetrahydro 2 isoquinolyl)ethyl)pheiyl) ((3Z,6Z) -1-rethyl-2,5-dioxo-6- (2-thenylidene) -3-piperazinylidene)mrethylbenzamide (9155) 2-(,7-iehx- ,2 ,4-erhdo SUBSTITUTE SHEET (RULE 26) WO 96/20190 PCTIGB95IO3027 isoquinolyl)ethyl)phenyl)-3-((3Z.6Z)-l-methyl-2,5-dioxo-6- (3-thenylidene) -3-piperazinylidene)metLhylbenzamide (9160) N-(4-(2-(6,7--Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-(3chlorobenzylidene) -1-methyl-2, 5-dioxo-3piperazinylidene) methylbenzamide (9157) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl)-3-((3Z, 6Z)-6-(2chlorobenzylidene) -1-methyl-2, 5-clioxo-3piperazinylidene) methylbenzamide (9158) N-k--(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl) (3Z,6Z)-6- (3-furylmethylene) -1methyl-2, 5-dioxo-3-piperazinylidene)methylbenzamide (9159) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl) -3-C (3Z,6Z) (3methoxybenzyl idene) 1-methyl 5 -dioxo- 3 piperazinylidene)mrethylbenzamide (9156) N-(4-(2-(6,7-Dimnethoxy-1,2,3,4-tetrahydro-2isoquinolyl)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- SL'BSMrr1TE SHEET (RULE 26)I I I -Tww l 'Mwj Fjjjjwkmkmc--I L WO 96/20190 PCU1GB95/03027 -12i soquino lyl) e thyL) phenyl) 3- (3 6Z) 6-benzyl idene -1 cyclopropylmethy2 5-dioxo- 3piperazinylidene) methylbenzamide (9141) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoqluinolyl) ethy).) phenyl) 4 (3 Z, 6 Z) I- a 1lyl 6-benzyl idene 5 -dioxo -3 pi-perazinylidene) methylbenzanide (9178) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3- GZ) -1-allyl-6-benzylidene-2, 5-dioxo-3piperazinylidene) methylbenzamide (9179) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 4 Z, 6Z) -1--me thyl- 6-C(2 -napht hyl) me thyl ene 5 -dioxo -3 piperazinylidene) methylbenzamide (9193) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 4 (3 Z, 6Z) I- methyl 6- naphthyl) me thyl ene 5 -dioxo -3 piperaziniylidene) methylbenzanide (9194) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2isoquinolyl) ethyl)phenyl) 3 (3 6 Z) 1-met hyl 6- (1 -naphthyl) met.hyl ene 5 -dioxo -3 S I'WHTUTE E-LLTRI f~ WO 96/20190 PCTGB5"5103027 1 j3 piperazinylidene) methylbenzamide (9195) E-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 4 6Z) 6-(2 furyl) methylene 1- methyl 5 -dioxo -3 piperazinylidene)mrethylbenzamide (9196) E- (4 7 -Dinethoxy- 1, 2,3, 4 -tetrahydro -2 isoquinolyl) ethyl) phenyl) 3 6Z) 6-(2 furyl) methylene 1 -methyl 5- dioxo -3 piperazinylidene) methylbenzamide (9197) E-(4-(2-(6,7-Dirnethoxy-l,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 4 6Z) 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-2isoquinolyl) ethyl)phenyl) 3 Z, 6Z) 1-methyl 6- (i-methyl 3-pyrrolyl) met hylene -2,5 dioxo-3--piperazinylidene),iethylbenzamide (9199) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3-((3Z,6Z)-l-methyl-6-(2-naphthyl)methylene-2,5-dicxo-3piperazinylidene) methylbenzamide (9209) MITMT SHEET (RULE 26) WO 96/20190 PTG9/32 PCT/GB95/03027 14 N-(4-(2-(6,7-Dimethoxy-1;2,3,4-tetrahydro-2 isoquinolyl) ethyl) phenyl) dioxo-3-piperazinylidene)methylbelzamide (9210) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2isoquinolyl)ethyl) phenyl) 3-C (3Z, GZ) -i-methyl-6- (3-methylbenzo thien-2-yl)methylene- 2,5-dioxo-3-piperazinylidele)methylbelzamide (9211) N-(4-(2-(6,7-Dimethox-d,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3- GZ) -i-methyl-6- (l-methyl-3-indolyl)methylele-2, dioxo-3-piperazi-nylidele)methylbelzamide (9214) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 4- GZ) -i-methyl-6- (3-methylbenzo thien-2-yl)methylene- 2,5-dioxo-3-piperazin~idele)methylbeflzamide (9215) N-(4-(2-(6,7-Dime hoxy-l,2,3,4-tetrahydro-2isoquinolyl) ethyl) phern',l) 3- GZ) -6-benzylidene-1-Tnethoxycarbonylmethyl-2, 3-piperazinylidenfe) methylbenzamide (9217) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl)phenyl) SUBSTTUTE SHEET (RULE 26) WO 96/20190 PCT/GB95I03027 4-C (3Z,6Z) -1-methyl-6- (2-methylpropylideiie) -2,5-dioxo-3piperazinylidene) methylbenzamide (9228) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquiriolyl)ethyl)phenyl) 4-C (3Z,6Z) -l-methyl-6-cyclohexylrnethylene-2,5-dioxo-3piperazinylidene) methylbenzamide (9229) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl) 3-C (3Z,6Z) -1-methyl-6-cyclohexylmethylene-2,5-dioxo-3piperazinylidene)mrethylbenzamide (9230) N-(4-(2-(6,7-Dirnethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl) 4-((3Z,6Z)-l-rnethyl-2,5-dioxo-6-pentylidene-3p)iperazinylidene)mrethylbenzarnide (9231) N-(4-(2-(6..7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl) -3-C (3Z, 6Z) -1-methyl-2,5-dioxo-6-pentylidene-3piperazinylidene) methylbenzanide (9232) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethJ-)phenyl) 3-C (3Z,6Z)-l-methyl-6-(2-methylpropylidene)-2,5-dioxo-3piperazinylidene) methylbenzanide (9233) SUB3STtl1JTE SHEET (RU LE2) imam
I
SLJBSTITUTE SHEET (RULE 26) mw WO 96/20190 PCT/GB95/03027 16 N(4-C(2- 7-Dimethoxy-1, 2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 4- 6Z) -6-C3,3-dimethylbutylidene) -1-methyl-2, 5-dioxo-3piperazinylidene) methylbenzanide (9234) N- 7-Dimethoxy-1, 2, 3,4-tetrahydro-2- 4soquinolyl) ethyl)phenyi) 3- (3Z, 6Z) 3-dimethylbutylidene) -1-methyl-2, 5-dioxo-3piperazinylidene) methylbenzamide (9235) N- (4 7-Dimethoxy- 1, 2,3, 4 -tetrahydro-2 isoquinolyl) ethyl) phenyl) 4-((3Z,6Z),-6-((4S)-4-isopropenyl-l-cyclohexenyl)meti. 1 mrethyl-2, 5-dioxo-3-piperazinylidene)methylbenzamide (9236) N- (4 7-Dinethoxy-1, 2, 3, 4- tetrahydro-2 isoquinolyl) ethyl) phenyl) 3- 3Z, 6Z) -6-benzylidene-l-carboxymethyl-2, 5-dioxo-3piperazinylidenie) methylbenzamide (9241) N- (4 7-Dimethoxy-1, 2, 3, 4-tetrahydro-2 isoquinolyl) ethyl) phenyl) 3- ((3Z,6Z) -4-isopropenayl-l-cyclohexenyl)methylene-lmethyl-2, 5-dioxo-3-piperazinylidene) methylbenzamide (9250) N- (2 7-Direthoxy-1, 2, 3, 4-tetra' ydro-2 -isoquinolyl) ethyl) 3 (3Z, 6Z) -methyl- 6- (2 -naphthyl) methylene- 2, S- dioxo-3 MMiBTuE SHEET k. LF2I- 0 PCT/GB95103027 17 piperazinylidene) methylbenzamide (9260) r l- 7-Dimethoxy-l,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 4- GZ) -l-methyl-6- (2-naphthyl)methylene-2,5-dioxo-3piperazinylidene) methylbenzamide (9261) N- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 3- GZ) -1-methyl-2,5-dioxo-6- (3-phenyipropylidene) -3piperazinylidene) methylbenzamide (9266) (6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 4-C (3Z, GZ) -l-methyl-2, 5-dioxo-6- (3-phenyipropylidene) -3piperazinylidene) methylbenzamide (9267) is N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3-(C 3Z, 6Z) C4-acetoxybenzylidene) -1-methyl-2, 5-dioxo-3piperazinylidene) methylbenzamide (9272) N-(4,,-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3-(C(3Z, Z) -6-(3-acetoxybenzylidene) -l-methyl-2, 5-dioxo-3piperazinylidene) methylbenzamide (9273) N-(4-(2-(6,7-Dimfethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3-(C(3Z, GZ) C2-acetoxybenzylldene:) -1-methyl-2, 5-dioxo-3- BSTITUTE SHEET, (RULE 26) S1SITUTE SHEET (RQU 26) >sV WO 96/20190 PCUIGB95/03027 -18 I piperazinylidene) methylbeizatnide (9274) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolyl) ethyl)phenyl) 3 Z, 6Z) 6-benzyl idene 1-(2 -dimet hylaminoethyl) 5- dioxo 3-piperazinylidene) methylbenzanide (9275) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoqulinolyl) ethyl) phenyl) 3-((3Z,6Z)-6-(4-hydroxybenzylidene)-l-methyJ-2,5-dioxo-3piperazinylidene) methylbenzamide (9276) U-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3-c( (3Z, 6Z) -6-benzylidene-l-ethoxycarboriylmethyl-2, 5-dioxo-3piperazinylidene) methylbenzanide (9299) N-(4-(2-(6,7-Dimethioxy-1,2,3,4-tetrahydro-2isoquinolyl) ethyl) phenyl) 3- 6Z) (2-hydroxybenzylidene) -1-methyl-2, 5-dioxo-3piperazinylidene) methylbenzamide (9300) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoquinolyl)ethyl)phenyl) 3- 6Z) (3-hydroxybenzylidene) -1-methyl-2, 5,-dioxo-3piperazinylidene) methy-lbenzarnide (9301) SUBSTITUTE SHEET (RULE 26) SUSTITUTE SH-EET (RULE 26) WO 96/20190 PCT/GB95I03027 19 N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2isoqjuinolyl) ethyl) phenyl) 3 (3 Z, 6E) 1- methyl 6-pentyl idene 5 -dioxo-3 piperazinylidei.-)methylbenzamide (9306) 11-(4 7 -Dimethoxy-1, 2,3, 4 -tetrahydro -2 isoquinolyl) ethyl)phenyl) 3 (3 Z) -l1-methyl 6-benzyl 5-dioxo-3 piperazinylidene) methylbenzamide (9308) Compounds of formula may be prepared by a process which comprises treating a compound of formula (II): (11) wherein R 2 and are as defined above, with a compound of formula (III):
(III)
wherein one of R' and R 8 is hydrogen and the other is -CHO, and q, r, R 5 and R 6 are as def ined above; in the presence of a base in an organic solvent; and, if desired, converting the resulting compound into a pharmaceutically acceptable salt SUBSTITJTE SHEET (BLULE 2f) i 13;: 14 f WO 96/20190 PCT/GB95/03027 20 thereof.
Suitable bases include caesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium tbutoxide and triethylamine.
Suitable organic solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and, in the case of potassium t-butoxide, t-butanol and mixtures thereof.
W n DMF is used as solvent the temperature is typically between 0°C and reflux temperature, for example from 80 0 C-95°C when caesium carbonate is used as base.
When sodium hydride or potassium t-butoxide is used as the base the reaction mixture is typically warmed from 0°C to room temperature, or to 40 0 C. The reaction may be performed for a period of 1 to 4 hours, for example 2 or 3 hours.
The compounds of formula (II) wherein is a double bond are prepared by a process which comprises treating a compound of formula (IV):
O
Ri '-NAc
HN
0 Xh
(IV)
wherein R 1 is as defined above, with an alkylating agent, in an organic solvent in the presence of a base. The alkylating agent is typically an alkyl halide R 2
-CH
2 X, a methanesulphonate or p-toluenesulphonate ester R 2
CH
2
OSO
2 Me or
R
2
CH
2
OSO,
2
CH
4 Me, respectively, or a dialkyl sulphate i
SUSTT
U r~r i i i i i r ,v i: JTE SHEET (RULE 26) '.1 WO 96/20190 PCT/GB95/03027 21
(R
2
CH
2 0)OSO 2 wherein R 2 is as defined above and X is a halogen, for instance Cl Br or I. Suitable bases and solvents include sodium hydride in THF or DMF or mixtures thereof, and potassium t-butoxide in t-butanol or THF or DMF or mixtures thereof. The reaction mixture is typically warmed from 0°C to room temperature.
Compounds of formula (II) wherein is a single bond may be prepared by treating a compound of formula 0 R NH (X)
R
2
(N)
0 wherein R 1 is as defined under above and R 2 is as defined above with acetic anhydride. The reaction is typically performed under reflux, for instance for 1 to 6 hours, typically 3 hours. The compound of formula may bt prepared by treating a compound of formula (XI): (xI) with glycine methyl ester hydrochloride and triethylamine in a solvent, typically CHC1 3 at a low temperature, typically 0 C to -70 0 C, preferably -65 0 C, for 1 to 6 hours. This is followed by warming to room temperature overnight. The reaction mixture is then refluxed in a solvent such as toluene for 12-18 hours, typically 16 hours, to give the SUBSTITUTE SHEET (RULE 26) i.
:t ;li:
-I;
i.
22
C
0 2
H
R
2 NH (X1) with phosgene in THF at 0'C, followed by warming to room temperature overnight.
Compounds of formula (IV) may be prepared by a proces which comprises treating 1,4-diacetyl-2,5-piperazinedione of formula (V) 0 NAc 1 AcNR2 (V with an aldehyde of formula: R- CHO wherein R is as defined above, in the presence of a base in an organic solvent.
Suitable bases and solvents include triethylamine, caesium carbonate, sodium carbonate, potassium carbonate and sodium hydric in DMF or TEF or mixtures thereof, and potassium t-butoxide in t-butanol or DMF or THF or mixtures SUBSTITUTE EETT (RULE 26' K I WO 96/20190 PCT/GB95/03027 23 thereof.
When triethylamine in DMF is used the temperature of the reaction is typically from 100-140°C, for instance 120- 130°C When potassium t-butoxide is used as base the reaction mixture is typically warmed from 0°C to room temperature.
1,4-Diacetyl-2,5-piperazinedione may be prepared by the published procedure Marcuccio and J.A. Elix, Aust. J.
Chem., 1984, 37, 1791).
Compounds of formula (III) mpy be prepared by a process which comprises reacting together compounds of the following formulae (VI) and (VII):
VI)
(CHq-X
NO
2 r r R 2 HClHN i
(VII)
wherein q, R 5 and R' are as defined above and X is a halogen, in the presence of a base in an organic solvent; (ii) reducing the resulting compound of formula (VIII):
R
(CH
2 )q-N R 6 (vi ll
I
SUBSTITUTE SHEET (RULE WO 96/20190 PCT/GB95/03027 24 wherein q, R 5 and R 6 are as defined above; and (iii) treating the resulting compound of :-ormula (IX): SI-
(DC)
H
2
N
wherein q, R 5 and RE are as defined above, and r is 1, with either 3-formylbenzoic acid in the presence of a coupling agent, or a derivative of 3-formylbenzoic acid in which the -COOH group has been activated by conversion to the acid halide group -COX in which X is a halogen, for instance F, Cl, Br or I, preferably Cl, or the mixed anhydride group -CO(OCOR') in which R' is C,-C 6 alkyl; in both cases to give a compound of formula (III) wherein R 7 is hydrogen and R' is -CHO; or 4-formylbenzoic acid in the presence of a coupling agent, or a derivative of 4-formylbenzoic acid in which the -COOH group has been activated by conversion to the acid halide group -COX in which X is a halogen, for instance F, Cl, Br or I, preferably Cl, or the mixed anhydride group -CO(OCOR') in which R' is C-C, alkyl; in both cases to give a compound of formula (III) wherein R 7 is -CHO and R 8 is hydrogen.
When the 3- or 4-formylbenzoic acid has been activated by conversion of -COOH to -COX, the reaction is conducted in an organic solvent either with an excess of the amine of formula or in the presence of a base such as a ElB;: 11t 11 iSUBSTITUTE SHEET (RULE 26) WO 96/20190 PCTGB95/03027 tertiary amine, e.g. Et 3 N, or pyridine. The organic solvent is an inert organic solvent such as CH1 2
C
2 When the 3- or 4-formylbenzoic acid has neen activated by conversion of -COOH to -CO(OCOR'), the reaction with the compound of formula (IX) is conducted in an inert organic solvent such as CHCI 2 or THF.
The coupling agent used in or with the 3- or 4formylbenzoic acid, respectively, may be, for instance, 1cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-ptoluenesulphonate or 2-chloro-l-methylpyridinium iodide.
The activated acid halide or mixed anhydride derivative of 3- or 4-formylbenzoic acid may be produced by conventional methods. For instance, the acid halide derivative may be prepared by treatment of the carboxylic acid with a halogenating agent, for instance a chlorinating agent such as SOC1 2 P13, oxalyl chloride or The mixed anhydride derivative may be prepared by treatment of the carboxylic acid with a alkyl haloformate such as iBuOCOC1 or EtOCOC1, in the presence of a base such as Et 3
N.
The reduction step (ii) is typically performed using iron powder and concentrated hydrochloric acid in methanol, usually at a temperature of about 80 0 C and for a period of 1 to 4 hours, for instance 3 hours.. Alternatively it may be carried out by catalytic hydrogenation over a palladium on carbon catalyst in methanolic HC1, isopropanol or acetic acid.
M Other starting compounds are known compounds or can be SsUBSTITUTE SHEET (RULE 26) I 1 1 1 1 m Si1E:T ft 2f) WO 96120190 PCT/GB95103027 26 readily synthesised from known compounds using conventional methods.
Compounds of formula may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods.
Suitable salts include salts with pharmaceutically acceptable inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid. Examples of organic acids include p-toluenesulphonic acid, methanesulphonic acid, mucic acid and succinic acid.
Cancer cells which exhibit multi-drug resistance, referred to as MDR cells, display a reduction in intracellular drug accumulation compared with the corresponding drug-sensitive cells. Studies using in vitro derived MDR cell lines have shown that MDR is often associated with increased expression of a plasma membrane glycoprotein (P-gp) which has drug binding properties. P-gp is thought to function as an efflux pump for many hydrophobic compounds, and transfection studies using clone, P-gp have shown that its overexpression can confer the MDR phenotype on cells: see, for example, Ann. Rev. Biochem 58 137-171 (1989) A major function of P-gp in normal tissues is to export intracellular toxins from the cell. There is evidence to suggest that overexpression of P-gp may play a clinical role in multi-drug resistance. Increased levels of P-gp mRNA or SUBSTITUTE SHEET (RULE 26) j' I 1 8 L fI 7rCT WO 96/20190 PCT/GB95/03027 27 protein have been detected in many forms of human cancers leukaemias, lymphomas, sarcomas and carcinomas. Indeed, in some cases P-gp levels have been found to be increased in tumour biopsies obtained after relapse from chemotherapy.
Inhibition of P-gp function in P-gp mediated MDR has been shown to lead to a net accumulation of anti-cancer agent in the cells. For example, Verapamil a known calcium channel blocker was shown to sensitise MDR cells to Vinca alkaloids in vitro and in vivo: Cancer Res., 41, 1967-1972 (1981). The proposed mechanism of action involves competition with the anti-cancer agent for binding to the Pgp. A range of structurally unrelated resistance-modifying agents acting by this mechanism have been cescribed such as .amoxifen (Nolvadex:ICI) and related compounds, and cyclosporin A and derivatives.
Compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as "the present compounds") have been found in biological tests to have activity in modulating multi-drug resistance. The results are set out in Example 5 which follows. The present compounds may therefore be used as multi-drug resistance modifying agents, also termed resistance-modifying agents, or RMAs. The present compounds can modulate, e.g. reduce, or eliminate multi-drug resistance.
The present compounds can therefore be used in a method of potentiating the cytotoxicity of an agent which is cytotoxic to a tumour cell. Such a method comprises, for it r .;i
I
STB STUE SH
-J
S UBSITE SHEET (RULE 26) ,~~44~CIC~L- ~a~nllDbrt--- I r WO 96120190 PCTIGB9/03027 WO 96/20190 28 instance, administering one of the present compounds to the tumour cell whilst the tumour cell is exposed to the cytotoxic agent in question. The therapeutic effect of a chemotherapeutic, or antineoplastic, agent may thus be enhanced. The multi-drug resistance of a tumour cell to a cytotoxic agent during chemotherapy may be reduced or eliminated.
The present compounds can also be used in a method of treating a disease in which the pathogen concerned exhibits multi-drug resistance, for instance multi-drug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery. Such a method comprises, for instance, administering one of the present compounds with (separately, simultaneously or sequentially) the drug to which the pathogen concerned exhibits multi-drug resistance. The therapeutic effect of the drug may thus be enhanced.
A human rr animal patient harbouring a tumour may be treated for resistance to a chemotherapeutic agent by a method compvising the administration thereto of one of the present compounds. The present compound is administered in an amount effective to potentiate the cytotoxicity of the said chemotherapeutic agent. Examples of chemotherapeutic or antineoplastic agents which are preferred in the context of the present invention include Vinca alkaloids such as vincristine and vinbiastine; anthracycline antibiotics such as daunorubicin and doxorubicin; mitoxantrone; actinomycin
I
D; taxane and plice In E disease drug res therapeu thereto Exa forms of leishma
MD
drugs a of AIDS therefo of drug treatme animal method present
T
of dos tablet! soluti intram 25 presen infusi q !R i ii r 1 PC'TGB95/03027 WO 96120190 WO 96/20190 42 I t d with 3.2 in the presence of SUBSTITUTE SHEET (RUJLE 2E WO 96/20190 PCT/GB95/03027 -29 D; taxanes e.g. taxol; epipodophyllotoxins e.g. etoposide and plicamycin.
In addition, a human or animal patient suffering from a disease in which the responsible pathogen exhibits multidrug resistance may be treated for resistance to a therapeutic agent by a method comprising the administration thereto of one of the present compounds.
Examples of such disease include multi-drug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery.
MDR modulators also have utility in the delivery of drugs across the blood-brain barrier, and in the treatment of AIDS and AIDS-related complex. The present compounds can therefore be used in a method of facilitating the delivery of drugs across the blood brain barrier, and in the treatment of AIDS or AIDS related complex. A human or animal patient in need of such treatment may be treated by a method comprising the administration thereto of cne of the present compounds.
The present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. The present compounds may therefore be given by injection or infusion. The dosage depends on a variety of factors including S* 1 vf^w- WO 96/20190 PCT/GB95/03027 the age, weight and condition of the patient and the route *of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 0.001 to 50 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration.
A piperazinedione derivative of formula or a pharmaceutically acceptable salt thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form. An agent for use as a modulator of multi-drug resistance comprising any one of the present compounds is tl.refore provided.
For example, the solid oral forms may contain, together Swith the active compound, diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners, wetting agents such as SUBSTITUTE SHEET (RULE 26) 1 1 uDOi uIl I JItMET (RULE 26) WO 96/20190 PCT/GB95/03027 31 lecithin, polysorbates, lauryl sulphates. Such preparations may be manufactured in known manners, for example by means of mixing, granulating, tabletting, sugar coating, or film-coating processes.
Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular, a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride. Some of the present compounds are insoluble in water. Such compounds may be encapsulated within liposomes.
The invention will be further illustrated in the Examples which follow.
SJSTITUTE SHEET (RULE 26) SW u SWO 96/20190 PCT/GB95/03027 32 Reference Example 1: Preparation of startinq compounds of formula (IV).
Method A 1,4-Diacetyl-2,5-piperazinedione (25.0g, 126 mmol) Marcuccio and J.A. Elix, loc. cit.) was heated at 120- 130 0 C in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol). After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml), and washed three times with brine.
Any solid formed at this stage was filtered off. The filtrate was dried (MgSO 4 and the solven- removed in vacuo.
The residue was recrystallised from EtOAc:Hexane to give 11.78 g of l-acetyl-3-benzylidene-2,5-piperazinedione.
This compound of formula (IV) is listed as 1.1 in Table 1 below.
Following the same procedure, but replacing benzaldehyde by the appropriately substituted benzaldehyde R1-CHO, where RI is as listed in Table 1A, the further starting compounds 1.2 to 1.10 were prepared: TABLE 1A: Compounds of formula IV Ri NAc HN (IV)
O
SSUBSTITUTE SHEET (RULE 26) 4.'v l 1 1 1 1 1 1 i :y
I
SUBSTITUJTE SHEET (R~ULE 1P r.Pof....MNI Wl a-I WO 96/20190 PCT/GB95/03027 33 Compound Number R 1.1 phenyl 1.2 4-chlorophenyl 1.3 2-chlorophenyl 1 .4 3 -chiorophenyl 3-furyl 1 .6 4 -methoxyphenyl 1..7 3-pyridyl 1.8 3-thienyl 1. 9 3 -methoxyphenyl 1.10 2-thienyl Method B 1,4-diacetyl-2,5-piperazinedione was treated with a series of benzaldehydes R 1 -CHO, where R' is as listed in table 1B, in the presence of potassium t-butoxide in tbutanol-THF at O 0 C. The reaction mixture was allowed to warm to room temperature for the time indicated in the table. Recrystallisation, which was optional, was conducted using the indiicated solvent.
TABLE iB: Compounds of formula (IV) 0 Ri NAc
HNI
0
(IV)
S U 9- -1-rIJTE ShElrET !T~F2 STTsrUT SHEET (M~LE 26) WO 96/20190 PCT1GB95/03027 34 Compuund R1Reaction Recryst. Yield Number time solvent (if M% (hours) used) 1.11 2-naphthyl 18 98 1.12 I-naphthyl 18 67 1.13 l-naphthyl 18 67 1.14 2-furyl 1-2 74 1.15 2-furyl 12 74 1 .1 1-methyl-2-pyrrolyl 52 EtOAc 1.17 l-methyl-2--pyrrolyl 52 EtOAc 1.18 2-naphthyl 18- 98 1.19 1-methyl-3-indolyl 14 33 1.20 3- 18 72 methylbenzo fbithien -2-yl 1.21 1-methyl-3-indolyl 14 33 1.22 3- 18 72 methylbenzo fbithien 1.23 Me 2 ,CI 12 EtOAc 48 1.24 Cyclohexyl 2 1.25 Cyclohexyl 2 1.26 ri-Butyl 14 EtOAc 1.27 n-Butyl 14 EtOAc 1.28 Me-,CH 12 EtOAc 48 1.29 Me,CCH 2 18 EtOAc 62 1.30 MeCCH, 18 EtOAc 62 1.31 (4S)-4-isopropenyl- 18 1 -cyclohexenyl 1.32 (4S)-4-isopropenyl- 18 1- cyclohexenyl 1.33 4 -AcOC 6 H, 3 86 1.34 3-AcC0CH, 3 EtOAc-hexane 42 1.35 2 -AcOC 6 H, 3 EtOAc-hexane 3 1.36 n-Butyl 14 EtOAc 1.37 Ph- 1660 11~~C~ si* WO 96/20190 PCT/GB95/03027 35 Reference Examnle 2: Preparation of starting compounds nf formula (II) wherein----- -I is a double bond Method A 1-Acetyl-3-benzylidene-2,5-piperazinedione, compound 1.1 prepared in Reference Example 1, was treated with ethyl bromide and KOtBu/t-BuOH in DMF at a temperature of about 0 C and allowed to warm to room temperature to give 1-acetyl-3benzylidene-4-ethyl-2,5-piperazinedione. This compound of formula (II) is listed as 2.1 in Table 2A below.
Further compounds of formula II were prepared by alkylating compounds 1.2 to 1.10, prepared in Reference Example 1, under the conditions set out in Table 2A: f, !pf SUBSTITUTE iEE i (RU,.LE2 WO 96/20190 PCTIGB95IO3027 36 Table 2A: Compounds of formula II 0
R
2
N
0 (11) Compound R2Starting A2 Vylat ion Number Compound c _±dit ions 2.1 Me 1.1 KOtBu/tBuOH, DMF, EtBr; OOC to rt; or 1.1 eq NaH, DMF: THF 2 eq ELI, OOC to rt; then column chromatography 2.2 Ph 1.1 KOtBu/tBuOH, DMF, 2 C1; 2.3 cyclo- 1.1 KOtBu/tBuOH, DMF, propyl C,H 5
CH
2 Br, OOC to rt; or 1.1 eq NaH, DMF:THF 1.3 eq
C
3
HCH
2 Br, OOC to rt; ref lux 6h; column chromatography 2.4 H 1.2 NaH, Mel, TEF, DMF 0 0 C to rt H 1.3 it_ 2.6 H 1.4 2.7 -H 1.5 I 2.8 H 1.6 iI I 2.9 H 1.7 UI 2. 19 H 1.8 I 2.11 H 2.12 H 1.10 It Method B Compound 1.11 described in Reference Example 1 was treated, in THF-DMP with sodium hydride and Mel at
C:
V
a S
I
WO 96/20190 PCT/GB95103027 50 t
I
WO 96/20190 PCT/GB95/03027 37 0°C. The reaction mixture was allowed to warm to room temperature for 18 hours. The product was purified by recrystallisation from EcOAc to give the corresponding compo.nd of formula ,II) in 401 yield. Following this procedure, but replacing compound 1:11 by other compounds of formula IV described in Reference Example 1, and modifying the reaction time if necessary, the compounds listed in table 2B were prepared. Where indicated, purification was performed by flash chromatography or by recrystal 1 isation as shown in the 3footnote.
TABLE 2B: Compounds of formula II 0 R1 NAc MO ILI I l)
I
DCompound R 2 Starting Reaction Purification Yield Number Compound time method (IV) (see I^ _footnote) 2.13 H 1.11 18 a 4 2.14 H 1.12 18 b 8 2.15 H 1.13 18 b 8 2.16 H 1.14 18 a 2.17 H 1.15 18 a 2.18 H 1.16 b 26 2.19 H 1.17 b 26 2.20 H 1.18 18 a 2.21 H 1.19 72 b 18 2.22 H 1.2u 16 c 7 C~.
Li__ CC i--
WO,
PCT/GB95/03027 38 2.23 H 1.21 72 b 18 2.24 H 1.22 16 c 2 '5 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 2.29 H 1.27 d 2.30 H 1.28 18 d 73 2.31 H 1.29 18 d 2.32 H 1.30 18 d 2.33 H 1.31 d 48 2.34 H 1.32 d 46 2.35 H 1.33 3 b 33 2.36 H 1.34 72 b 2.37 H 1.35 3 b 2.38 H 1.36 d 2.44 H 1.37 16 e 37 Footnote a recrystallisation from EtOAc b flash chromatography with EtOAc-hexane (1:1) c flash chromatography with CH 2 C1, d flash chromatography with Et20-hexane (1:1) e recrystallisation from EtOAc-hexane Method C Compound 1.1, described in Reference Example 1, was treated with Cs 2 CO Me 3 SiC1 (1 eq.) and allyl bromide (1 eq.) in acetonitrile at 0°C. The reaction mixture was allowed to warm to room temperature for 5 hours. Flash -~ll*l*Y l WO96/20190 PCT/GB95/03027 39 chromatography of the product using 20% EtOAc in hexane gave 2.39 in 50% yield, which is a compound of formula (II) in which R 2 is -CH=CH,.
Method D Compound 1.1, described in Reference Example 1, was treated in THF-DMF with sodium hydride and methyl bromoacetate at 0°C. The reaction mixture was allowed to warm to room temperature for 3 hours. The product was purified by recrystallisation from EtOAc-hexane to give 2.40 in 35% yield, which is a compound of formula (II) in which R 2 is -CO.,Me.
Method E Compound 1.1, described in Reference Example 1, was treated in DMF with sodium hydride and 2-dimethylaminoethyl chloride hydrochloride at 0°C. The reaction mixture was warmed to 20 0 C, and then further warmed to 80 0 C, over a period of 5 hours. The product was purified by recrystallisation from 1% MeOH in EtOAc to give 2.41 in 32% yield, which is a compound of formula (II) wherein R 2 is -CHNMe 2 Method F Compound 1.1, described in Reference Example 1, was treated in acetonitrile with Cs 2
CO
3 and ethyl bromoacetate at 0 C. The reaction mixture was warmed to 20 0 C for 2 hours.
S- SUSITTUTE SHEET (RULE 26 SUBSTITUTE SHEET (RULE 26) WO 96120190 PCT/GB95103027 40 WO 96/20190 f f The product was yurified by flash chromatography using EtOAc-hexane to give 2.42 in 35% yield, which is a compound of formula (II) wherein R 2 is -C0 2 Et.
Reference Example 3: Pxeparation of a compound-of formula- II) wherein is a singKle bond 1-methyl-6-benzyl-2, 5-piperazinediofle was treated with acetic anhydride under ref lux for 3 hours to give compound 2.43 in 98% yield, which :Ls a compound of formula (II) wherein------ is a single bond, R 1 is Ph and R 2 is H.
Reference Example 4: Preparation of 1-methyl-G-benzyj
I
Z Z) LJ.L U L CL 44. -L Al L.L J- AA Ph C0 2
H
MeNH 0 Ph 0 MeN 0 Compound minutes.
temperat treated 5 triethy' mixture and was desired Rel Th
W
0 2
N
02 25
HI
(ii) 1
U
0 Ph NH MeN 0 SUBSTITUJTE SHEET (RULE 26) WO 96/20190 PCT/GB95/03027 WO096120190 54 n WO 96/20190 PCT/GB95/03027 41 Compound was treated with phosgene in THF at 0°C for minutes. The reaction mixture was then warmed to room temperature overnight. The resulting compound (ii) was treated with glycine methyl ester hydrochloride and triethylamine in CHC1 3 at -65 0 C for 3 hours. The reaction mixture was allowed to warm to room temperature overnight and was then refluxed for 16 hours in toluene to give the desired product in 53% yield.
Reference Example 5: Preparation of L0 Dimethoxy-1,2,3,4-tetrahydro -2-isoquinolyl) ethyl) aniline The title compound, which is a compound of formula was prepared according to the following scheme: O 7N Br 3.1 3.1 OMe HCI.HN OMe 3.2 j
''I
.OMe 'OMe 3.4 SBSTITUTE SHEET (RULE ,1* j ll l l 1 1 l 1 1- WO 96/20190 PCT/GB95/03027 42 Compound 3.1 was treated with 3.2 in the presence of
K
2
CO
3 in DMF, at a temperature of 100 0 C for 12 hours, to give 3.3 in 78% yield. 3.3 was then reduced with Fe powder in concentrated HCI and MeOH at 80 0 C for 3 hours to give 3.4 in 51% yield. Alternatively 3.3 was reduced by catalytic hydrogenation at 30psi over a palladium on carbon catalyst in methanolic HC1 for 3 nours to give 3.4 in quantitative yield.
Following the synthetic route described under but replacing compound 3.1 by 4-bromomethylbenzoic acid and 4- (3-bromopropyl)benzoic acid, respectively, the following two further compounds of formula (IX) were prepared: OMe HNN OMe
H
2
N
S1 (3.6) H 2 N OMe Following the synthetic route described under but replacing compound 3.2 by 1,2,3,4-tetrahydroisoquinoline hydrochloride, the following further compound of formula (IX) was prepared: SV"IST!TFurr SH77T "i WO 96/20190 PCT/GB95/03027 43 (3.7) An amine of formula (IX) in which r is 0, compound 3.10, was prepared as follows: OMe HCI.HN OMe 3.8 rOMe NC N- OMe 3.9 OMe
H
2 N O Me 3.10 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was treated with chloroacetonitrile in the presence of K,C0 3 in acetonitrile under reflux for 24 hours. Compound 3.9 was obtained in 92% yield. 3.9 was then treated with LiAlH 4 in ethylene glycol dimethyl ether at room temperature overnight. The temperature was then raised to 40 0 C and the reaction continued for 30 minutes. The desired amine 3.10 was obtained in 98% yield.
iq 1 t'
*"I
Al-
'I
WO 96/20190 PCT/GB95/03027 44 Example 1: Preparation of compounds of formula III Method 1 Compound 3.4 prepared according to Reference Example was treated with 2-chloro-l-methylpyridinium iodide and 3formylbenzoic acid in CH 2 C1 2 in the presence of Et 3 N at a temperature of about 0°C and allowed to warm to room temperature overnight to afford the following compound of formula III in 43% yield: Following the same procedure, but replacing compound 3.4 by compounds 3.5 and 3.6, respectively, the following two further compounds of formula III were prepared: .OMe
OHC
4.4 1 I i WO 96/20190 PCT/GB95/03027 45 Method 2 4-formylbenzoyl chloride was prepared by treating 4formylbenzoic acid with thionyl chloride in toluene under reflux. It was then treated with compound 3.4, prepared according to Reference Example 5, in CH 2 Cl 2 in the presence of Et 3 N at a temperature of about 0°C and allowed to warm to room temperature, to afford the following compound 4.2 in 53% yield:
OWM
0 /OMe
H
OHC
4.2 Following the same procedure, but replacing compound 3.4 by compounds 3.5 and 3.7, respectively, the following two further compounds of formula III were prepared:
I
OMe
OHC
OHC
4.6 STITUTE SHEET (RULE 26) WO 96120190 PCT/GB95/03027 59 1 II~YU~---CI -I WO 96/20190 PCT/GB95/03027 46 Method 3 4-formylbenzoyl chloride, as described in Method 2 above, was treated with Et 3 N in CH2C1 2 at a temperature of 0 C. Compound 3.10 prepared according to Reference Example 5 was then added. Following aqueous work-up and purification by flash chromatography, the following compound 4.7 was obtained in 43% yield: 0 'OMe N N OMe
H
OHC
4.7 Following the same procedure, but replacing 4formylbenzoll chloride by 3-formylbenzoyl chloride, the following compound 4.8 was obtained in 48% yield: OHC
O
4.8 SUBSTITUTE SHEET (RULE 26) SVISTRnMLT SHEET !,11 Lr 26' 'WO 96/20190 PCT/GB95/03027 47 Ex-le2: Pre-naration of Compounds of formula (1) By reacting together a compound of formula (II), prepared in Reference Example 2, and a compound of formula (11I) prepared in Example 1, the following compounds of the invention were prepared under the conditions set out in Table 3A: Table 3A: Compounds of formula MI Compound Compound Compound Conditions No II III 9112 2.1 4.2 KOtBu, tBuOH, THF, 0 0 C to rt 9113 2.2 4.2 I_ 9114 2.3 4.2 9091 2.4 4.2 Cs 2
CO
3
DMF,
0 C, 2-3 hours 9092 2.5 4.2 9093 2.6 4.2 9108 2.7 4.2 9109 2.84.
9110 2.9 4.2 9111 2.10 9155 2.12 4.1 CS 2
CO
3
DMF,
0 C, 2-3 hours 9156 2.11 4.1 9157 2.6 4.1 9158 2.5 4.1 1 9159 2.7 4.1 SBT~FJSHEETM(ULE SU~STSHEF ("PI tIflI '29 WO 96/20190 PCTGB95IO3O27 48 9160 2.10 4.1 9139 2.1 4.1 Cs.,C0 3
DEE,
BC, 2-3 hours 9141 2.3 4.1 Exam-ole 3: Prerparation of salts .The compounds prepared in Example 2 were converted to the corresponding hydrochloride salts by treatment with gaseous HCJ. in THE.
Example 4: Preparatign of com-pounds of formnia (1) By reacting together a compound of formula (II) prepared in Reference Example 2 or 3, and a compound cf formula (III), prepared in Example 1, in DME at 80 0 C in the presence of Cs,C0 3 for the time- specified in Table 4, the compounds of formula listed in the Table were preparked.
Some of the compounds were purified by recrystallisation or flash chromatography, also as indicated in Table 4.
TABLE 4: Compounds of formula (I) Compound Compound Compound Reaction Purification (I (I)(III) time solvent or eluent (see footnote) 9178 2.39 4.2 3 5% H 2 0 in PrOH (a) 9179 2.39 4.1 3 5% H-I20 in PrOH (a) 9193 2.13 4.2 16 EtOAc (a) 9194 2.14 4.2 5 EtOAc (a) 9195 2.15 4.1 5 EtOAc (a) 9196 2.16 4.2 16 1919 2 .17 4.1 1 16 L 9198 1 2.18 4214 InPrOH (a) S~~~8TmjTi~ !3HE~T (FL&V 2~ WO 96/20190 WO 9620190PCT/GB95/03027 49 9199 2.19 4.1 10 iPrOH (a) 9209 2.20 4.1 10 ELOAc (a) 9210 2.21 4.2 12 EtOAc-MeOH (a) 9211 2.22 4.1 14 MeOH, EtOAc, Et 2 0 9214 2.23 4.1 18 CH 2 C1 2 -Et 2 0 (a) 92:5S 2.24 4.2 4 EtOAc-Et 2 O (a) 9217 1 2.40 4.1 2 EtOAc-hexane (a) 9228 2.25 4.2 8 5%5, MeOH in Et 2
O
9229 2.26 4.2 14 MeOH in Et 2
O
(b) 9230 2.27 4.1 18 S06 MeOH- in EtO (b) 9231 2.28 4.2 14 9232 2.29 4.1 14 5%0 MeOH- in Et 2
O
9233 2.30 4.1 5 5%0 MeOH- in Et 2
O
(b) 9234 2.31 4.2 18 MeO- in Et 2 o 9235 2.32 4.1 14 MeOH in Et 2 0 (b) 9236 2.33 4.2 14 5%9 MeOH in Et,O (b) 9250 2.34 4.1 14 50% MeOl in ELO (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 SUBSTITUTE SHEET (RULE 26) :1 I: I ,iiuB :1:111 WO 96/20190 PCTIGB95/03027 50 9306 2.38 4.1 14 5% MeOH in EtO (b) 9308 2.43 4.1 10% MeOH in EtOAc (b) Footnote Recrystallisation solvent Flash chromatography eluent Example 5: Preparation of Salts Selected compounds prepared in Example 4 were converted to the corresponding hydrochloride salts by treatment with gaseous HCl in CHC1 2 The hydrochloride, denoted in Table below by the suffix ".HC1" was in some case. then recrystallised as shown in the table.
TABLE 5: Hvdrochloride salts Salt Recrystallisation Yield solvent 9193.HC1 9144.HC. EtOAc 21 9195.HC1 EtOAc 22 9196.HC1 9197.HC1 EtOAc 9232.HC1 9306.HC1 tI
S
JBSTITUTE SHEET (RULE 26) ii
J
r3?i:teP~77- 1;;:1'117 jt WO 96/20190 PCTIGB95/03027 51 Example 6: Interconversions of compounds of formula
IL
Compounds of formula were prepared treating selected compounds of formula prepared in Example 4 with appropriate reagents using conventional synthet'7 techniques, as follows: 1. 9217 ,was treated with LiOH in aqueous THF at room temperature for 2 hours to give compound 9241.
2. 9272 was treated with NaBH 4 in MeOH at 0°C for 2 hours to give compound 9276 in 73% yield.
3. 9274 was treated with NaBH 3 CN in MeOH and THF at 0°C.
The reaction mixture i/a, then warmed to 50 0 C over 5 hours, and the product recr'stallised from 20% EtOH in EtOAc to give compound 9330 in 58% yield.
4. 9273 was treated with NaBH 3 CN in MeOH and THF at reflux for 7 hours. The product was recrystallised from EtOAchexane to give compound 9301 in 18% yield.
Example 7: Pharmaceutical Composition Tablets, each weighing 0.15 g and containing 25 mg of a compound of formula or salt thereof can be manufactured as follows: SBSTITUTE SHEET (RULE 26) C--i WO 96/20190 PCT/GB95/03027 52 Composition for 10,000 tablets compound of formula or salt thereof (250 g) lactose (.00 g) corn starch (415 g) talc powder (30 g) magnesium stearate (5 g) The compound of formula or salt thereof, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to granulate the powder. The granulate is dried and br ':en up into sma. 1 fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
Example 8: Testing of compounds of formula and their salts as modulators of MDR Materials and Methods The EMT6 mouse mammary carcinoma cell line and the MDR resistant subline AR 1.0 were cultured in RPMI 1640 medium containing 10% foetal calf serum and 2mM glutamine at 37 0 C in
CO
2 Cells were passaged between 1 in 200 and 1 in 2000 in the case of the parental cell line and between 1 in and 1 in 200 in the case of the MDR resistant subline, after V .trypsinisation (0.25% trypsin, 0.2gl 1
EDTA)
i 1. Drug accumulation assay SUBSTITUTE SHEET (RULE 26) SUBSTiTUTE SHEET 7" r J WO 96/20190 PCT/GB95/03027 53 AR 1.0 cells were seeded into 96 well opaque culture plates (Canberra Packard). The assay medium contained a mixture of tritiated Daunorubicin (DNR), a cytotoxic agent, and unlabelled DNR (0.3 Ci/ml; 2AM). Compounds of formula E I were serially diluted in assay medium over a range of concentrations from 5 nM to 100 MM. The cells were incubated at 37 0 C for 1 hr before washing and determination of cell associated radioactivity. Results are expressed as maximum accumulation where 100% accumulation is that observed in the presence of the known RMA verapamil at a concentration of 1uO MM or as an ICso.
The results are set out in the following Table t TABLE 6 K:i Compound No. ICso (MM) Maximum Accumulation Accumulation 9091 9092 1.2 9093 9108 0.7 9109 9110 9111 9112 0.2 9113 9114 0.6 9139 0.2 9141 9155 0.06 9156 0.1 SUBSTITUTE SHEET (RULE 26)
I
SUBSTITUTE SHEET (RULE 26) WO 96/20190 PCTIGB95IO3027 54 9157 0.2 9158 0.6 9159 0.4 9160 9178 0.080____ 9179 0.170 9193.HC1 7.0 9194.HC1 9195.HC1 0.210 9196.HC1 0.140 9197.HC1 0.025 9198 9199 0.140 9209 0.600 9210 0.220 9211 1.400 9214 0.070 9215 1.100 9217 0.700 9228 9229 9230 0.130 9231 2.000 9232 0.020 9233 0.600 9234 0.500 9235 0.600 9236 2.000 9250 0.800 9260 0.800 9261 1.200 9266 1.200 SUBSTITUTE SHEET (ROLE 26) WO 96120190 PCTIGB95/03027 55 9267 5.000 9272 0.400 9273 0.070 9274 0.800 9275 0.600 9276 1.900 9276.HC1 0.700 9299 0.500 9300 0.200 9301 0.200 9308 3.000 2. Potentiation of Doxorubicin toxicity Compounds of formula were examined for their ability to potentiate the toxicity of doxorubicin in AR cells. In initial proliferation assays compounds were titrated against a fixed concentration of doxorubicin (0.86liM) which alone is non-toxic to AR 1.0 cells. After a four day incubation with doxorubicin prolifertion was measured using the colorimetric sulphorhodamine B assay (Skehan et al; J.Natl. Cancer Inst. 82 pp 1107-1112 (1990)).
The results are shown in Table 7.
Compounds which were shown to be able to sensitise AR cells to 0.86pM doxorubicin without high innate toxicity were selected for further study. Cells were cultured for four days with concentrations of doxorubicin over the range of 0.01 nM-50 gM in the presence of fixed concentrations of compounds of formula Proliferation was quantified as susTs SHjE
T
(F.L
I::
I .1 I mI ^195 jrrF SHrFT r 1!, ZAJP,
IT
WO 96120190 PCT/GB95/03027 56 described by Skehan et al, loc cit. The IC, 0 (concentration required to reduce proliferation to 50% of the untreated controls) for doxorubicin alone and for the compounds of formula were derived and used to calculate the potentiation index (PI):
IC,
0 for Doxorubicin alone
PI=
The results IC,, for Doxorubicin are shown in Table 8: TABLE 7 plus RMA Compound No. Compound toxicity Toxicity with (IC, iM) cytotoxic agent
(IC
50
AM)
9091 1.8 0.15 9092 0.7 0.07 9093 2.0 0.09 9108 4.0 0.10 9109 4.0 0.30 9110 6.0 1.00 9111 2.5 0.15 9112 2.0 0.015 9113 0.4 0.1 9114 1.0 0.06 9139 4 0.3 9141 2 0.3 9178 1.50 0.008 9179 0.50 0.080 9193.HC1 2.00 0.200 9194.HC1 6.00 0.050 i~SiTUThS~WET fE ThE7/ WO 96120190 PCTIGB95IO3O27 57 WO 96/20190 9195.HC1 1.00 0.010 9196.HC1 7.00 0.060 9197.HC1 28.00 0.010 9198 8.00 0.020 9199 40.000.5 9209 45.000.7 9210 40.000.8 9211 50.00008 9214 100.00 0.008 9215 10.00 0.030 9228 0.60 0.100 9229 0.50 0.070 9330 0.45 0.100 9231 2.00 0.120 9232 3.00 0.060 9233 8.00 0.400 9234 1.00 0.080 9235 0.50 0.100 9236 0.80 0.130 9250 2.00 0.080 9260 3.00 0.350 9261 5.00 0.400 9.00 0.200 9273 20.00 0.020 9274 40.00 0.050 9275 1.80 0.700 9276 30.00 0.500 WO 96120190 PCT/GB95/03027 WO 96/201l90 ii 4.4 WO 96120190 PCTIGB95/03027 58
S
TABLE 8 Compound No. Potentiation index PI determined at 9108 10001 9109 2501 9111 S00o 9112 10001 9139 500 9141 285 9155 67 0.2 9156 25 0.2 9157 40 0.2 9158 75 0.2 9159 s0 0.2 9178 7.1 0.01 27.? 0.03 69.21 0.10 250.0 0.30 9193.1 20.0 0.30 0.10 9194.1 50.0 0.30 0.10 0.03 1.2 0.01 9195.HC1 454.0 0.30 50.0 0.10 0.03 1.2 0.01 9196.HC1 37.5 0.30 0.10 0.03 0.10 9197.HC1 65.0 0.30 4,,3 0.10 1.3 0.03 1.3 0.10 919832.5 0.30 9163.3 0.10 1.3 0.03 1.3 0.01 4.6 SUB3STITUTE SHEET (RULE 26) 96120190 PCT/GB95 103027 59 9199 65.0 0.30 2.2 0.10 1.3 0.03 1.3 0.01 9209 125.0 0.30 15.0 0.20 1.2 0.03 1.2 0.01 931* 10 75.0 0.30 8.3 0.10 0.03 1.3 0.01 9212. 1538.0 1.00 1000.0 0.50 9214 200.0 0.30 150.0 0.10 20.0 0.03 0.01 9215 66.7 0.30 15.0 0.10 0.03 0.01 9217 11.0 0.30 0.10 0.9 0.03 0.8 0.01 9231 20.0 0.30 0.10 0.9 0.03 1. 1 0.01 9232 80.0 0.30 20.0 0.10 0.03 0.01 9234 50.0 0.30 _5.0 0.10 9235 37.5 0.30 0.10 9236 16.7 0.30 2.1 0.10 9250 286.0 0.50 9260 3.3 0.30 _2.0 0.10 SUBSTITUTE SHEET (RULE 26) WO 96/20190 PCT/GB95/03027 60 9261 2.2 0.30 1.7 0.10 9272 175.0 1.00 5.6 0.30 1.4 0.10 9273 100.0 3.00 96.1 1.00 83.3 0.30 29.4 0.10 9274 100.0 3.00 90.9 1.00 71.4 0.30 25.0 0.10 9275 25.0 1.00 6.9 0.30 0.7 0.10 9276 166.6 3.00 25.0 1.00 0.8 0.30 0.8 0.10 9299 16.0 0.30 1.8 0.10 9300 133.3 1.00 61.5 0.30 10.0 0.10 9301.HC1 133.3 1.00 88.9 0.30 28.6 0.10 Example 6: Characterisation of the present compounds The compounds and salts prepared in Examples 1 and 2 were characterised by mass spectroscopic and proton nmr techniques. The results are set out in Tables 9 and SUBSTITUTE SHEET (RULE 26)
L
_I
~TABLE 9 No. Mol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field j 9091 C 3 9
H
3 7 C1INN 4 0 5 HC1 679(10), 677(10), Cl d 6 -DMSO/300MHz 2.5-4.7 (1OH.m). 2.95 208(100) C3F1.s). 3.83 6.88 6.92 6.98 ClH.s). 7.15 7.40 7.51 7.59 (2HAd) 7.83 7.90 8.12 M2, 10.45 10.8 (HHs). 11.1 (H,bs) 9092 C 3 9
H
37 ClIN 4 O5. HC]1 679(10). 677(10). CI d 6 -OMSO/300MHz 2.5-3.7 2.88 (3H,s), 208(100) 3.84 (611,s), 4.5 (2H,m), 6.89 6.93 (1H,s).
7.01 7.15 (1H.s).
7 40 7.50 (3H~m).
7.55 7.82 (2H~d).
7 A0 8.14 (2H~d), 10.47 10.90 (1H,s).
(1H~bs)
C,,
C-
-e rn :23 i-ri 9093 C 39 H3 7 C IN, 4 Q. HClI 679(10). 677(5).
208(100). 190(100) d 6 -DMSO/30OMHz 2.3-4.7 (1OH.m). 2.94 3.84 6.89 C1H.s), 6.93 6.99 7.16 7.40 7.42-7.60 (4H~m).
7.82 7.90 (2H.d), 8.14 10.45 10.85 (lTH.s). 11.30 (1H.bs)
L
No. J ol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 9108 C 37
H
36 6 HCl1 633(25). 439(40). CId 6 -MO30 3.0-4.7 (OHm). 3.2 (3H~s), 206(85). 91(100) 3.7 (2x3H.s). 6.74 (1H~s).
6.90 6.94 (2xlH~s).
7.00 7.41 (2H~d).
7.80 7.85 (1H~s).
7.86 8.08 (ills), 10.43 (1H~s) 9109 C 40
H
39
N
4 0 6 673(2). 672(5). CI d 6 -DMSO/300MHz 2.9-4.0 (1OH.m). 3.00 246(25). 206(100). 3.81 (2x3H,s), 3.89 164(90). 91(60) 6.81 6.83 6.95 7.09 C2H~d). 7.13 7.37 7.41 7.81 (2x2H~d). 8.09 10.40 (H.s) 9110 C 3 8
H
3 7
N
5 0S. 2HCl I d 6 -DMSO/300MHz 2.96 3.0-4.7 (1OH,m). 3.84 (2x3H.s). 6.90 6.93 7.01 7.19 7.42 7.83 8.12 8.73 8.85 10.45 (1H~s) 91'C 3 7
H
36
N
4 0 5 S HC 1 649(30), 456(30), CI d 6 -DMSO/300MHz 3.0-4.0 3.07 (3H,s).
337(50). 208(100). 3.84 (2x3H.s). 4.41 (2H~bs).
164(60) 6.88 6.92 (iHs).
6.96 7.14 (1H~s).
7.29 7.41 (2H~d).
7.71 (1H,dd). 7.77 (1HAm) 7.81 7.85 (2H~d), 10.45 (1H,s)
CIO
I--
I-D
I 2 r .0 No. Mol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field j 9112 C,,H,,N 2 Q,.HC1 657(7). 286 Cl d 6 -DMSO/300MHz 0.99 3.0-4.7 269 (100) (1OH.r). 3.67 3.84 3.86 6.90 (IHs). 6.93 7.01 7.22 7.42 7.52 (SW 7.82 (2Hd), 7.90 8.14 10.45 11.20 _(H.bs) 9113 C 45 42
N
4 0 5 HC1 719(25). 286(60). CI d 6 -DMSO/300MHz 3.0-4.7 (10H,m). 3.85 269(100) (2x3M,s), 4.85 (2Hs), 6.92 7.04 7.20 7.33 7.40 7.55 (5Mm). 7.85 7.91 8.14 10.45 10.83 11.25 (1M,bs) 9114 C 42
H
42
N
4 0 5 HC1 683(20). 206(40). CI d 6 -DMSO/300MHz 0.0-1.1 3.0-4.7 167(80). 149(100). (12M.m). 3.87 (2x3H,s). 6.90 57(40) 6.94 7.01 (iHs), 7.20 7.40 7.52 7.85 7.90 (2Hd), 8.13 10.45 10.80 10.90 (1M.bs) 9139 C 4
OH
40
N
4 0 5 657(34). 431(57). CI CDCl 3 /400MHz 0.96 (3Ht). 2.72-2.94 206(83). 190(100) 3.63 3.67 3.84 (2x3H.s). 6.55 6.60 (I 7.09 (iHs). 7.18 7.20- 7.52 (8Hi), 7.55 (4H,m).
7.83 7.99 (iH,s).
8.13 (1M.s) ci,
-IY
7-I.
t 7: No. Mol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 6 9141 C 4 2 H4 2
N
4 05 683C8). 614(62). CI CDC1 3 /400MHz 0.05 0.35 (2H.d).
190(100) 0.97 C1Hm). 2.70-2.90 (8HMm), 3.53 3.63 C2H.s), 3.83 C2x3H.s). 6.55 (1Hs) 6.60 7.05 (lis), 7.11 7.20- 7.65 (12H,m). 7.82 (1Hd).
8.00 8.13 (Hs) 9156 C 40
H
4
ON
4 0 6 CDCl 3 /400M1z 2.74-2.95 (8Hm), 3.01 3.68 3.82- 3.85 6.54 C1H.s).
6.62 6.80 (1H,s), 6.82-6.90 7.10 7.20-7.33 7.54-7.60 7.83 7.97 8.08 (1H.s) 9157 C 39
H
37 C1 N 4 0 5 CDCl 3 /400MHz 2.73-2.94 3.00 3.66 3.84 (2x3H.s). 6.55 6.62 (IHs). 7.12 7.20 7.23-7.28 (3H,m).
7.32 7.53-7.60 7.82 7.92 7.97 (Hs) 9158 C 39
H
37 C1N 4 0 5 677(100) ESI CDC13/40OMHz 2.73-2.93 (11H.m). 3.64 3.84 (2x3H.s). 6.56 6.61 7.12 7.19-7.31 (7H,m) 7.45 mH,m), 7.54-7.59 7.84 -HHm), 7.96 (1Hs). 8.00 (H,s)
CO
n-
E
i r L1 No. Mol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 9159 C 3 7H 3 6
N
4 0 6 633(100) ESI GDC1 3 /400MHz 2.73-2.93 3.i8 3.65 (2Hs), 3.84 (2x3Hs). 6.43 6.56 H(is). 6.61 7.00 SH,s). 7.06 7.23 7.48 OlH,m), 7.52- 7.59 7.83 (iHlm).
7.95 (ills). 8.03 (H,s) 9160 C 37
H
36
N
4 0 5 S 649(100) ESI CDC1 3 /400M~z 2.72-2.92 3.09 3.68 (2Hs), 3.84 (2x3H.s). 6.57 6.61 C1H.s), 7.06 C1H.d). /.08 (1N.s) 7.12 (1Hs). 7.22- 7.29 7.38 (1Hm).
7.55-7.59 7.82 7.97 8.04 (lh.s) 9155 C 37
H
36
N
4 0 5 S 649(100) ESI CDC13/40@MHz 2.72-2.93 C8NWm), 3.19 3.65 3.85 (2x3H.s), 6.54 6.60 7.04 7.08- 7.10 7.22-7.29 (3w 7.45 7.52- 7 7.81 (I iH,).
(2H.s) 8.38 (ills) m rn
C
rn
M:
6L- Mol. Formula ms mass spec data mass (intensity) 'H nmr data mode solvent/field 4. 4. 9178
C
4 jI 4 oN 4 0 5 CDC1 3 /40MHz 2.70-2.95 3.50 3.70 4.20 4.65 4.90 5.45 (Ihim). 6.45 6.55 6.95 7.10 7.15 (1Hs), 7.15-7.25 (511.m).
7.40 7.55 (21,d).
7.90 7.95 (2H.d), (8.85 (iHs) 917. HCI ClH4,N45 HC1 669(20) DCI CDC1,< IMHz 2.75-3.65 (8Hm), 3.70 (3Hs). 3.75 3.80 4.25 4.70 5.00 5.55 6.45 6.55 6.90 (ills). 7.10 7.20-7.50 (8H.m).
7.80 8.05 (2H~d).
8.50 8.50 (ll,s).
9.50 (ills) 9179 C 4 jH 4 oN 4 0 5 669(100) [SI CDC1 3 /400MHz 2.70-2.90 (8Hm). 3.60 3.80 (2x3H.s). 4.30 4.75 5.00 5.50 (1Hm). 6.55 (IH.s) 6.60 7.05 (1Hs). 7.15 7.20- 7.60 (11Hm). 7.70 (ll.d).
7.80 7.90 (1H.s), 8.65 (1H.brs) co rn rri rQ3 0) No. Mol. Formula mass spec data H mr data LJ mass (intensity) mode solvent/field 19193 C 43
H
40
N
4 0 5 CDCl 3 /400MHz 2.80-2.90 3.05 3.68 3.82 (2x3H~s), 6.55 6.65 7.10 7.28 7.41 7.49 (ills). 7.51-7.60 (6H.m).
7.78 7.85 (3H,m).
8.05 (1H.s) 9193.HCI C 43 H4ON 4 OS.HCI d 6 -DMSO/400MHz 2.90 2.95 (2H~bs).
3.10 (41-Em), 3.40 (2H,bs).
3.75 (2x3H~s). 4.23 (1H~s).
4.49 (1H~bs). 6.78 (1H~s).
6.80 6.91 (1H.s).
7.25 (ills). 7.30 7.50 (11Idd). 7.53 (2H-lm).
7.75 7.95 (4H~m).
8.2 10.38 10.58 (1H,bs), 10.68 (ills) 9194.HCI C 43
H
40
N
4 0S.HCI 693(100) ESIl d 6 -DMSO/400MHz 2.65 2.95 (2H.m).
3.12 3.42 3.73 (2x3H.s). 4.26 (1H~m), 4.50 (1H~bd). 6.79 (1H~s).
6.82 6.93 (JH~s).
7.30 7.48 (iHAd, 7.50 7.51-7.62 7.76 7.90- 8.02 (5Hin), 10.30 (1H.s).
1.uO 10.69 (1H~s) rn No. Mol. Formula mass spec data nmr data mass (intensity) mode solvent/field 99 4HO4563ESI CDCl 3 /400M~lz 2.74-2.94 2.80 3.65 3.85 (2x3H~s). 6.50 6.600 7.12 7.25 C2H~d). 7.30 7.48 1HAt). 7.54 (6fl.m). 7.68 (lHs). 7.80-7.94 (4H,m).
8.52 C1H,bs) 9195.HCI C 43
H
4
,N
4
O
5 HC I d 6 -DMSO/400MHz 2.65 2.94 (2H,m).
3.12 C4H~m). 3.42 (2dm), 3.73 (2x31-,s). 4.26 4.50 O1HMb). 6.79 (1H,s).
6.80 (ills). 6.95 (1H.s).
7.30 7.49 (1HAd, 7.51 7.52-7.64 7.78 7.85- 8.09 8.12 (1H,s).
10.30 10.50 (1H.s), 10.68 (i~s) 9196 C 3 7H 36
N
4 0 6 633(100) ESI CDC1 3 /400MHz 2.72-2.90 C6H~m). 2.92 3.4 3.62 (21-Is), 3.85 6.52 6.60 (2H~s).
7.08 7.26 (2H~m).
7.50 7.54 (3H~m), 7.82 7.91 (2H.d).
(iHs) No.Mol. Formula mass spec data nmr data mass (intensity) mode solvent/field 65 9196. HCl C 37
H
36 N'0 6 HCl d 6 -DMSO/400MHz 2.98 (21-Im). 3.12 (41-Im).
3.19 C3H~s). 3.40 (2H.m).
3.75 (2x3H.s). 4.26 (1H.bs).
4.50 6.6'8 (1H.
6.79 6.82 (1H,m+I-1s). 6.88 (1H~s), 6.90 7.30 (2H.d).
7.70 7.76 MAd) 7.87 8.01 (2Hnd), 10.30 10.55 (1H,bs), 10.60 (1H,s) 9197.HCI C 37
H
36 N,0 6 HCl 633(100) ESI d 6 -DMSO/400MHz 2.98 (2H.bd). 3.15 (4H.m).
3.21 3.42 (2H,m), 3.75 (2x3H.s). 4.28 (1H,m) 4.50 O1HMb), 6.62 (1H,m), 6.78 6.82 (1f,d), 6.83 6.89 (2xlH~s).
7.30 7.56 (1HA), 7.71-7.78 7.90 8.10 10.30 10.70 10.76 C H .bs) 9198 C38H3 9 N5OS 646(100) ESI d 6 -DMSO/400MHz 2.61 2.81 (2H.t).
3.06 3.55 (2H~s), 3.65 3.70 (61-Is), 6.18 6.65 (2xlHs).
6.82 (1I-Is), 6.98 (1H~s41-1H~m). 7.25 (2H~d).
7.68 7.98 C2H.d), (1I-Is). 10.50 (1I-.s) 0
C.'
0
I-
~0 0 w ~0
U'
0 -3
U.
No. Mol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field6 9199 C 38
H
3 9NSOS 646(100) [SI d 6 -DMSO/400MHz 2.70 2.81 (2H.t).
3.06 C3H~s), 3.55 (2H~s), 3.65 3.70 (61-Is).
6.16 6.65 (2x1H,s).
6.85 6.98 (1H.s+1Hjn,), 7.25 (21-IA).
7.55 (1HA). 7.68 (2H~d).
6.71 7.85 (1H-id).
8.10 10.16 (IH~s), (1H~bs) 9209 C 43
H
40
N
4 0 5 693(100) [SI d 6 -DMSO/400MHz 2.60 (6H, m) 2.80 (2H~t), 3.58 3.70 (SH,s), 6.62 6.66 (11-Es).
6.91 7.36 (31-Em).
7.50 7.52-7.62 (3Mm). 7.70 7.76 7.89 (1HAd. 7.90- 799 8.14 (is).
10.73 (1H~s) 9210 C 42
H
4
)N
5 0 5 696(100) ESi d 6 -DMSO/400MHz 2.69 2.82 (21-It).
3.06 3.55 (2H,s).
3.70 (2x3H~s). 3.88 (3H.s).
6.65 (2xlH~s). 6.85 (is).
7.16 1HAt). 7.20-7.29 (4H-lm). 7.50 (11lAd. 7.58 (11-Ed). 7.63 (lIHEs), 7170 7.75 7.99 10.14 10.45 (H~bs) No. Mol. Formula mass spec data H nmr data mass (intensity) mode solvent/field 9211 C 42
H
40
N
4 O5 713 ESI d 6 -OMSO/400MHz 2.3 2.7 2.82 (2fl.t). 2.98 OHk 3.57 3.7 (2x3di~s). 6.65 (2x1H~s). 6.93 7.12 7.26 7.38- 7.48 7.56 (1HA), 7.69 7.78 (1H~d).
7.80 (11Ad) 7.88 (11Ad) 7.95 (1HAd, 8.15 (HHs).
10.17 10.79 (IH,bs)- 9214 C 42 H4 40 S 696(100) ESI d 6 -DMSO/400MHz 2.63-2.73 2.81 (2HAt). 3.08 (31-Is). 3.55 3.71 (2x3H~s). 3.87 (3H-Is). 6.65 (2x1H-Is). 6.88 7.18 C1HMt) 7.28 (41-im), 71.48-7.57 (3H~m).
7.63 (HH 7.69 (2H~d).
7.75 (1H, 7.85 (11-i).
8.12 10.20 (1H~s).
(1I,s) 9215 C 4 2H 4 0
N
4 0 5 S 713(100) ESI d 6 -DMSO/400MHz 2.30 2.70 (6H.m).
2.80 (2HA). 2.93 (3H- s), 3.55 3.71 6.63 (2x1H.s). 6.89 k!H.s).
7.12 7.24 (2H.d).
7.35-7.45 7.65 7.79 7.97 (1HAd) 8.00 10.15 10.72 (1Hbs)
I
if.
Mol. Formula mass spec data.
mass (intensity) I 'H nmr data mode solvent/field 9217 C 4 jH 40
N
4 0 7 701(100) CI CDC1 3 /400MHz 2.70-2.95 3.65 3.70 3.80 (2x3H-ls). 4.30 6.50 6.60 7.10 7.20-7.55 (131-Im).
7.85 7.90 (is).
(1R,s) 9228 C 36
H
40
N
4 05 609(100) ESI d 6 -DMSO/400MHz 1.08 2.69 (6HMm).
2.80 (2H-1t). 2.88-2.99 (1H, 3.34 3.55 (21-Is). 3.70 5.84 6.62 (2xlH~s). 6.78 7.23 7.68 (4HMm). 7.98 10.18 (is)._10.41_(11-bbs) 9229 C 39
H
44
N
4 0 5 649(100) ESI d 6 -DMSO/400MHz 1.10-1.38 1.60-1.73 2.50-2.63 f1H~m).
2.63-2.73 2.76-2.83 3.32 (3,9Is). 3.55 3.70 (2x3H~s). 5.86 6.62 (2x11-,s), 6.80 7.23 (2HAd) 7.67 7.97 10.15 10.39 ClHbs) No. Mol. Formula mass spe data 1H nimr data mass (intensity) mode solvent/field J 9230 C 39
H
44
N
4 0 5 649(100) ESI CDCl 3 /400MHz 1.03-1.35 (S5m). 1.60-1.80 2.49-2.60 (1Mm) 2.70-2.94 (8Mm), 3.35 3.63 3.83 (2x3H~s). 5.93 (1HAd). 6.55 6.60 (1H~s),7.02 7.20 7.50- 7.60 (4HAm. 7.86 OHM, 7.92 8.50 (l11bs) 9231 C 37
H
42
N
4 0 5 623(100) ESI CDC1 3 /400MHz 0.92 1.40 (2H.m).
1.52 (2Mm). 2.43 and 2.76 (2H. two quartets) 2.71-2.92 (8HMm). 3.31 and 3.46 (3M, two singlets). 3.68 (2H,s).
3.85 5.75 and 6.30 6.55 6.60 7.00 1H. two singlets), 7.28 7.50 7.60 7.80 7.85 (1H~bs). 7.93 (2H.d) st)moesletfedNo. Mol. Formula mas mass spec data H nmr data 9232 C 3. H 4 2,0 5 CDC1 3 /40OMHZ 0.90 1.29-1.50 (4Mm), 2.36 and 2.68 (2H, two quartets). 2.72-2.94 3.27 and 3.36 (3H, two singlets), 3.65 (2H,s).
3.83 (2x3H,s). 5.68 and 6.12 (1W. two triplets), 6.56 6.60 (iHs). 6.98 and 6.90 (1H. two singlets),7.20 (2H.m) 7.52 7.58 (2HMm), 7.85 (1Mm)M. 7.94 (1Mm). 8.35 and 8.40 (1H, two singlets).
8.58 and 8.83 (1W. two broad sinqlets)
C
3 6
H
40
N
4 0 5 609(100) ES! CDC1 3 /400MHz 1.08 2.71-2.92 (9HMm). 3.35 3.65 3.83 (2x3H.s). 5.93 6.55 6.60 (lis). 7.02 (1is). 7.22 7.54 (4HM. 7.82 7.81 8.37 8.82 (1M~bs)
C
3 8
M
44
N
4 05 637(100) ES! CDC] 3 /400MHz 1.01 2.38 (2H~d).
2.74-2.98 (MAm, 3.47 3.67 3.84 (2x3H~s). 6.42 (1M.t. 6.55 6.62 7.28 (211A). 7.52 7.58 7.75 7.82 7.92 (2H,d) No. Mol. Formula mass spec data 'Hnmr data mass (intensity) mode solvent/field 9235 C 3 gH 4 4
N
4 OS 637(100) [SI CDC1 3 /4001Mz 0.99 2.31 and 2.70 (2H, two doublets). 2.71- 2.92 (8Mm). 3.32 and 3.40 (3M. two singlets). 3.65 3.85 (2x3H.s), 5.79 and 6.32 (1H. two triplets), 6.54 6.60 (is).
7.02 (iM. two singlets), 7.25 (2Mm). 7.56 (Mm).
7.80 (1Mm). 7.88 O1H. two singlets). 7.96 8.05 8.22 (1H~bs) 9236 C 42
H
46
N
4 0 5 687(100) [SI d 6 -DMSO/400MHz 1.50 (1Mm). 1.73 (3H~s).
1.83-1.84 (1Mm. 2.10 (1Mm). 2.19 (3Mm). 2.30 (1Mm). 2.70 (6Mm). 2.80 (2Mm). 3.08 3.55 3.70 4.72 5.67 (1Mbs), 6.39 Cl11bs). 6.62 (2xlHs), 6.80 I. two singlets). 7.23 7.68 8.00 10.18 (iHs). 10.55 bs) 9241 C 40
H
3
BN
4 0 7 687(100) [SI CDC1 3 /400M~z 2.65-2.90 (MAm) 3.55 3.70 (2x3M~s). 4.00 6.60 (iHs). 6.65 (iHs). 6.85 UHs). 7.10 7.25 7.35- 7.45 7.55 (1MA).
7.65 7.70 (UdA).
7.85 (NM, 8.10 (is), 10.70 (1M,brs) No. Mol. Formula Imass spec data 1Hnmr data (intensity) mode solvent/field c6 9250 C 42
H
4 6N 4 0 5 6B7(100) ESI d 6 -OMSO/400MHz 1.50-1.60 1.73 1.82 2.1 2.2 2.31 (11Am). 2.71 2.81 3.10 3.56 3.70 (2x3H.S). 4.75 5.68 (1H~bs). 6.38 6.65 (2xlH.s). 6.85 (111, two singlets) 7.25 7.54 C1HAt). 7.70 7.85 (1HAd) 8.07 10.18 10.55 9260 C 37
H
36
N
4 0 5 617(100) CI COC1 3 /400MHz 2.70-2.80 (6Km). 3.05 3.60 3.65 3.75 (2x3d~s), 6.50 6.60 (iHs). 7.0-8.1 921C 37
H
36
N
4 Q5 617(100).615(60) CI COC1 3 /400N1L 2.80 (6HAm) 3.05 (311,s), 3.60 3.65 C2Km).
3.80 (2x3H~s). 6.50 (is), 6.52 (HHs). 7.0-8.10 9266 C 3 5 8 5 595 CI COC] 3 /400MHz 2.80 (8Km). 3.10 (2H.q).
3.20 3.60 (2H~s).
3.65 3.80 (2x3HKs), 5.70 6.50 (iH~s).
6.60 6.80 (1H~brs).
6.95 7.15-7.90 (iH~m) 'H nmr data Mol. Formula mass spec data mass (intensity)I mode sol vent/field 9267 Q 5
H-{JN
4 0 5 595 CI CDC1 3 /400MHZ 2.80 (8Hm). 3.10 (2H,q).
3.20 C3H.s). 3.65 C2H,s).
3.70 3.80 (2x3H.s).
5.70 6.52 (1H.S).
6.60 6.95 (1H.s).
(1H.brs). 7.10-8.10 (9H.m) 9272 C 41
H
40
N
4 0 7 190(100) CI CDC1 3 I400MHz 2.30 2.70-2.90 (8Him). 3.00 (3H.s) 3.65 (2t1.s), 3.80 (2x3H.s). 6.58 CUs). 6.65 7.05 (HHs). 7.10 7.20- 7.30 (5HAm. 7.50-7.60 (4MA. 7.80 (1HAd. 8.00 8.10 8.70 .brs) 9273 CDCl 3 /400MHz 2.30 2.70-2.90 3.00 3.60 3.80 (2x3H.s), 6.55 (IHs), 6.60 (iHs). 7.00 7.00-7.60 7.85 8.05 (is).
(1Ri,s). 8.75 (1R~brs) 9274 CDC] 3 /400MHz 2.25 2.70-2.90 (SHin),. 3.0 3.65 (211.s), 3.85 (2xH,s). 6.55 6.60 7.05 8.45 (12H~brs) I 911I2 9113 9114 9139 11.', No. Nol. Formula mass spec data 'H nmr data mass (intensity) mode solvent/field 9275 C 42
H
4 5N5OS 700(100) ESI CDC] 3 /400MHz 2.00 2.20 (2H~t).
2.75-2.95 (MA. 3.65 3.75 (2fl~t), 3.85 (2x3H~s), 6.55 6.60 (1H~s) 7.05 7.20 7.20-7.60 7.90 7.95 (1H.s), 8.00 8.20 (lh~brs) 9276 C 39
H
38
N
4 0 6 659(100) ci CDC1 3 /400MHz 2.75-2.95 3.00 3.70 3.90 (2xH~s). 6.55 6.65 6.80 (2H-Id). 7.00- 7.30 7.60 (4H,m).
7.80 1HAd). 8.00 (1H.s).
8.60 (i~s) 9299 C 42
H
42
N
4 0 7 715(50) ESI CDCl 3 /400MHz 1.20 3H.L). 2.70-2.90 3.65 3.80 (2x3H~s). 3.90 4.30 6.55 6.60 7.05 7.20- 7.45 (MA. 7.55 (4H~m).
8.00 (iHs). 8.05 (IH,s).
8.45 (HHbrs) 9300 d 6 -DMSO/400MHz 2.65-2.85 2.85 3.55 3.70 (2x3H.s), 6.65 (2xlH,s), 6.85 (3HM, 7.05 (1H,s), 7.10-7.75 7.85 (iHd) 8.10 9.75 10.15 10.60 0 CN~0
K
0
L
No. Mol. Formula mass spec data_ 1H nmr data mass (intensity) mode solvent/field6 9300,HIIC d 6 -DMS0/400MHz 2.85 2.90-3.30 (8Mm). 3.35 3.70 C2x3M~s). 6.80-6.95 7.05 7.10-7.35 7.60 (lil). 7.75 7.85 8.10 (iHs). 9.90 10.25 (iM.s) 9301 CDCl 3 /400M~z 2.70-2.85 2.90 3.50 3.65 (2x3M~s). 6.65 (2xlH.s).
6.70-6.80 6.85 7.00 7.20- 7.85 (9Mm), 8.10 (1H~s).
10.20 (1M~s) 9306. MCI C 3 7H 42
N
4 0 5 HC I d 6 -OMSO/400MHz 0.90 (3HAt) 1.30-1.52 2.68 2.90- 3.00 3.10 (4M1m), 3.20 3.30 (2Mm).
3.75 (WxH,s). 4.25 (IH~dd).
4.50 (1Mbd). 5.75 1HAt), 6.78 6.81 (is).
6.83 7.30 (2M~d).
7.52 (1MA). 7.69 (1MA).
7.78 7.85 (IHA).
8.06 10.30 (is).
(iHs). 10.56 (1M~bs) 9308 C3 9
H
38
N
4 0 5 645 ci COCl 3 /400M~z 2.60-2.95 3.15 3.20 3.70 3.70 3.85 (2x3,s). 4.30 6.55 6.60 6.65 7.05-8.50 1.
I(2x3H~s). 4.30 (I-1.tL. o 6.60 665 I (ils). 7.05-8.50
CD
CD
CD
C,1
CD
CD CD
~CD?
i CD X CD
LCD
CD
OQ
w TABLE No. Mol. Formula mass spe data 1H nmr data mass (intensity) mode solvent/field6 4.1 CDC1 3 /400M~z 2.70-? .94 3.64 (2H~s), 3.83 (2x3H~s). 6.53 6.60 (ills). 7.27 7.57 (2H~d).
7.68 (1HA), 7.93 8.03 8.19 8.34 (1H~s).
(ills) 4.2 CDC1 3 /40OMHZ 2.72-2.96 (8Mm). 3.65 (2H~s), 3.82 (2x3H~s). 6.54 (1ills). 6.61 (ills), 7.28 7.56 (2H.d).
7.82 (ills). 7.97-8.04 (4Mm), (ills) 4.3 C 2 6
H
2 6
N
2 04 431(80) cI COCl 3 /400MlHz 2.92 3.70(2H~s). 3.82- 3.87 (8Mm). 6.50 (IFIs). 6.61 (iHls). 7.47 7.64 (2H.d), 7.70 (1HA). 7.97 (ills), 8.05 8.37 (1Mm). 10.12 (ills)- 4.4 C 28
H
30
N
2 0 4 459(100). 445(60) CI CDCl 3 /400MHz 1.93 '2Mm). 2.47-2.85 (Mm), 3.5/ 3.83 (2x3H,s), 6.53 (ills). 6.60 (ills). 7.24 (2H.d).
7.59 7.68 8.04 8.20 (1Mm), 8.37 (1H,s).
(1H~s) 4.5 C 26
H
26
N
2 0 4 431(3). 192(100) CI CDCl 3 /400MHz 2.86-3.04 3.72 (2H~s).
3.84 (2x3H~s), 3.88 6.48 (1ll.S). 6.61 (Ills). 7.40-8.10 {(8HMm). 10.11 (ills) 4.6 C 2 5
H
2 4
N
2 0 2 385(10). 146(70) CI CDCl 3 /400MHz 2.76-3.04 3.79 (2H.s), 130(100) 7.00-8.10 (13HKm), 10.10 (ills) *0 0.
K)
0 .0 *0(31.
4 Cs a.
.0 2 to
Claims (6)
1. A'piperazinedione derivative of the formula (I) wherein R. is a group 10 oii err o r r Ra Rb -(CH2)p 2 6 RC Re Rd wherein p is 0 or 2; each of Ra to Re, which may be the same or different, is independently selected from hydrogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogen atoms, .i C 2 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, hydroxy, nitro, phenyl-, cyano, -CH 2 OH, -CH 2 OH, -CH 2 COOH, -C0 2 R 1 1 -NHCOR 11 -NHiSO 2 R 1 3 -So 2 R 1 3 -CON (R 1 1 R 12 -SOR' 3 -S 2 N (R' 1 R 12 -N (R 1 R 12 -0 (CH 2 nN (R- 1 R' 2 -O (CH 2 CO 2 R 11 -OCOR 1 1 -CH 2 OCOR", -CH 2 NHCOR 1 1 -CH 2 NHCOOR 1 3 CH 2 SR"', -CH 2 SCOR' 1 -CH 2 S(O)mR 1 3 wherein m is 1 or 2, -CH 2 NHCO (CH 2 ),,CO 2 R 11 -N(R' 1 COR 12 -NHCOCF 3 -NHCO(CH 2 ,CO 2 R 1 -NHCO(CI 2 ),,OCOR 1 and -NUCO(CH 2 ),C0 2 R"; wherein n is 0 or is an integer of from 1 to 6, each of R" i L~ -82 and R 12 is independently H or Ci-C 6 alkyl and R 13 is C -C 6 alkyl; or any of Ra and Rb, Rb and Rc, Rc and Rd or Rd and Re together form a methylenedioxy group, or form together with the carbon atoms to which they are attached a benzene ring. (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S, which group may be fused to a benzene ring; (iii) a Ca-C 6 alkyl or Cs-C, cycloalkyl group; or
7..0 (iv) a C 5 cycloalkenyl group which is 'unsubstituted e or substituted by C 2 -C 6 alkenyl; R 2 is H, C 1 alkyl optionally substituted by a group -N(R"R 2 as defined above, C3-C, cycloalkyl, C 2 -C 6 alkenyl, -COOR": wherein Ral is as defined above or a phenyl group as :8 defined under above, but is other than H when R 1 is unsubstituted phenyl; one of R' and R 4 is hydrogen and the other is a group of formula -C-NH (CH 2 )q-N II I (A O r R6 wherein q is an integer of 1 to 4, r is 0 or 1 and T' and R 6 which may be the same or different, are each H or C,-C, alkoxy, or R 5 and R 6 together form a methylenedioxy group; and is a double bond or, when R, is as .ined un-ir above, is a double bond or a single bond; RA4 WO 96/20190 PCTIGB95/03027 83 or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein R' is a phenyl group as def ined under Wi in which one of Ra to Re is selected from hydroxy, CI-C 6 alkoxy, NHCOR 11 -C0 2 R 11 -N (R'R 12 -o0 (CH 2 ~N (R 1 R 12 -S0 2 R 13 CON CR 1 -R' 2 NO 2 -SO 2 N(R'-'R 1 2 -SOR 3 C0R 12 and halogen, and the other four of Ra to Re are H. 3. A compound according to claim 1 or 2 wherein R 1 is a phenyl group as defined under in which each of Ra to Re is hydrogen, or one of Ra, Rb and Rc is halogen or C,- C. alkoxy ard the rest of Ra to Re are hydrogen; or is a pyridyl, furyl or thienyl group; R 2 is H, CH,, cyclopropyl or phenyl; and one of R 3 and R' is H and the other is a group of f ormula (A) 1s wherein q is 2 and each of R' and R' is a methoxy group. A compound according-to claim 1, 2 or 3 wherein R1 is a 4-pyridyl, 3-furyl, 2-thienyl or 3-thienyl group. A compound selected from: 7-Dimethoxy-1, 2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) (3Z,6Z) -6-benzylidene-1-ethyl- 2, 5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride U (9112) N- 7-Dimethoxy-1, 2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) (3Z,G6Z) -l-benzyl-6-benzylidene- 2, 5-dioxo-3-piperazinylidene)methylbenzamide, hydrochloride (9113) SUBSITUT SHEET (RUJLE- 26) WO 96120190 PCT/GB95/03027 -84 N- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) -4-C (3Z,GZ) -6-benzylidene-1- cyclopropylmethyl-2, 5-dioxo-3- piperazinylidene)mrethylbenzamide, hydrochloride (9114) N-(4-(2-<i5,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyJ~phenyl) -4-(C(3Z,GZ) (3-furylmethylene) -1- methyl-2, 5-dioxo-3-piperazinylidene)methylbezafide, hydrochloii-de (9108) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)-4-( (3Z,6Z)-6-(4- methoxybenzylidene) -methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9109) 1s N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahvdro-2- I ~isoquinolyl) ethyl)phenyl) ((3Z,6Z) (4- chlorobenzylidene) -1-methyl-2, 5-dioxo-3- piperazinylidene)methylbenzamide, hydrochloride (9091) Ni-k4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- ijjjj. isoquinolyl)ethyl)phenyl) ((3Z,6Z) chlorobenzyli'dene) -1-methyl-2, 5-dioxo-3- piperazinylidene)mrethylbenzamide, hydrochloride (9092) E-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl)phenyl) 6Z) (3- OW SITUTE SHEET (RULE 26) WO 96120190 PCTIGB95/03027 chlorobenzylidene) -1-methyl-2, 5-dioxo-3- piparazinylidene)methylbenzamide, hydrochloride (9093) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-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-Dirnethioxy-l,2,3,4-tetrahydro-2- isoquinolyl)ethyl)pheriyl)-4-((3Z,6Z)-1-methyl-2,5-dioxo-6- (3-thenylidene) -3-piperazinylidene)methylbenzami.'de, hydrochloride (9111) N-(4-(2-(G,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-l-methyl-2,5-dioxo-6- (2-thenylidene) -3-piperazinylidene)methylbenzamide (9155) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetralhydro-2- isoqui-nolyl) ethyl) phenyl) GZ) -l-methyl-2, 5-dioxo-6- (3-thenylidene) -3-piperazinylidene)rnethylbenzamide (9160) N-(4I-(2-(6,7-Dimethoxy-1,2,?Z,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) chlorobenzylidene) -l-methyl-2, 5-dioxo-3- piperazinylidene) methylbenzamide (9157) N-(4-(2-(6,7-Dimethox-y-1,2,3,4-tetrahydro-2- SJ BSTITUTE SHEET (RULE 26) WO 96/20190 PCT/GB95/03027 -86 i s ouiniolyl) e thyl) phenyl) 3- (3 Z, 6 Z) 6- (2 chlorobenzylidene) -1-methyl-2, 5-dioxj-3- piperazinylidene) methylbenzamide (9158) -(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) GZ) (3-furylmethylene) -1- rnethyl-2, 5-dioxo-3-piperazinylidene)methylbenzamide (9159) N-C4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 6Z) (3- methoxybenzylii'ene) -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- (3 Z,E671 6-benzylidene -1 -ethyl 2, 5-dioxo-3-piperazinylidene)methylbenzamide (9139) ll-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) (3Z,6GZ) -6-benzylidene-1- cyclopropylnethy2 5-dioxo-3 piperazinylidene) methylbenzamide (9141) N- 7-Dimethoxy-1,2,3, 4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 4- 6Z) -1-a11y1-6-benzylidene-2, 5-dioxo-3- piperazinylidene)nethylbenzarr de (9178) SUJBSTITUTE SHEET (RULE 26)I ri~w~ "Psimr-MIRW WO 96120190 PCTIGB95I03027 W( -87- N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 3- 6Z) -1-allyl-6-benzylidene-.2, 5-dioxo-3- piperazinylidene) methylbenzamide (9179) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- 1isoquinol1-1) ethyl) phenyl) 4 4-((3Z,6Z)-1-rnethyl-6-(2-naphthyl)mfethylefe-2,5-dioxo-3- piperazinylidene) met' lbenzamide (9193) Nl-(4-(2-C6,7-Ditnethoxy-l,2,3,4-tetrahydro-2- j1 1 isoquinolyl)ethyl)phenyl) 4-((3Z,6Z)-1-methyl-6-(1-naphthyl)methylene-2,S-dioxo-3- piperazinylidene)mtethylbenzamide (9194) 155 N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2-I isoquinolyl) ethyl) phenyl) 3- 6Z) -1-methyl-6- (l-naphthyl)methylene-2, 5-dioxo-3- piperazinylidene) methylbenzamide (9195)1 N-1(4-(2-(6,7-Dimethoxy-1,2,3,.4-tetrahydro-2- isoquirolyl) ethyl) phenyl) 4-C (3Z, 6Z) (2-turyl)methylene-1-methyl-2, 5-dioxo-3- piperazinylidene) methylbenzatnide (9196) Ni-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- 2 isoquinolyl) ethyl)phenyl) -f Ii A A SUBSTITUTE SHEET (RULE WO 96/20190 PCT1GB95/03027 -88 -WO 3 (3 Z, 6 Z) 6- (2 furyl) methylenie- 1 -methyl 5-adioxo-3 piperazinylidene)mtethylbenzamide (9197)1 N-( isc N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- 3-( isoquinolyl)ethyl)rphenyl)- i 4 (3 Z, 6 Z) 1 -methyl 6- methyl -3 -pyrrolyl) methylene 5 dioxo-3-piperazinylidene)methylbenzamide (9198) N- isi N- (6,7-Dimethoxy-1,2,3,4-tetrahydro-2- 4- isoquinolyl) ethyl) phenyl) 2, 6Z) -1-methyl-6- (1-methyl-3-pyrrolyl) methylene-2,5S- dioxo-3-piperazinylidene)rnethylbenzamide (9199) N- i Ng-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- 3 isoquinolyl)ethyl)phenyl) 3 3- 6Z) -1-methyl-6- naphthyl) methylene-2, 5-dioxo-3- piperazinylidene)methylbenzamide (9209) I N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) I4-( (3Z, 6Z) -1-rethyl-6- (1-rethyl-3-indolyl) methylene-2, 5- dioxo-3-piperazinylid'ine)methy).benzamide (9210) N-(4-(2-(6,7-Uimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 3- (3Z,G6Z) -1-methyl-6- (3met.ybenzo 11len- yl) methyl~e- 2, 5-dioxo-3-piperazinylidene)mtethylbenzamide (9211) A4 I SUBSIfhf lE ET (RULE W056/I20190 PCT1GB95103027 -89- N-.(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)- 3-((3Z,6Z)-l-methyl-6-(l-methyl-3-ildolyl)methyele-2,5- dioxo.-3-piperazinylidene)methylbenzamnide (9234) isoguinoly.) ethyl) Dhenyl) 4-C (3Z,6Z) -l-methyl---(3-methylbenzo(b)thien-2-yJ.)methylene- 2, 5-dioxo-3-piperazinylidene)methylbenzamide (9215) N-(4-(2.-(6,7-Dimethoxy--l,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 3-(C(3Z, GZ) -6-benzylid(- ne-l--methoxycarbonylmethyl-2, 3 -piperazinylidene) methylbenzamide (9217) N-(4-(2-(6,7--Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 4- GZ) -1-methyl-6- (2-methyipropylidene) 5-dioxo-3- piperazinylidene) methylbenzamide (9228) N-(4-(2-(6,7-Dirnethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl)- (3Z,6Z) -1-methyl-6-cyclohexylmethylene-2,5-dioxo-3- piperazinylidene) methylbenzamide (9229) (2-(6t7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) SUBSTTTE SHEET (RULE 261 WO 96120190 PCTIGB95/03027 3-C (3Z,6Z) -1-methyl-6-cyclohexylmfethylefe-2,5dioxo-3 piperazinylidene) methylbenzamide (9230) N-C4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2 isoquinolyl) ethyl) phenyl) 4-((3Z,6Z)-l-methyl-2,5-dioxo-6-peltylidele-3- piperazinylidene) methylbenzamide (9231) N-(4-(2-(6,7-Dimethoxy-1,2,3,4--tetrahydro-2- isoquinolyl)ethyl)phenyl) -3-(C3Z,6Z)-l-methyl-2,5-dioxo---petylidele-3- piperazinylidene) methylbenzatnide (9232) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- is isoquinolyi)ethyl)phenyl) 3-C (3Z,6Z) -i-methyl-6- (2-methylpropylidene) -2,5-dioxo-3- piperazinylidene) methylbenzatnide (9233) N-C4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) 4-((3Z,6Z)-6-3,3-dimethybutylidele)-methy2,5dioxo-> piperazinylidene) methylbenzamide (9234) N4-(4-(2-(6,7-Dirnethoxy-1,2,3,4-tetrahydro-2- isoquinoiyl)ethyl)phenyl) 3-((3Z,6Z)-6-(3,3-dimethylbutylidefe)--methyl-2,5dioxo- 3 piperazinylidene) methylbenzamide (9235) SUBS~VUT SWIET (IIL 26) WO096120190 PCT/GB95103027 -91~ N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)pheiyl) 4- (3Z, 6Z) -4-isopropenyl-l-cyclohexenyl)methy-ene-l- 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-l-carboxymethyl-2,5-dioxo-3- piperazinylidene) methylbeizaruide (9241) N-(4-(2-(6,7-Dimetho-cy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) -propenyl-l-cyc"Lohexenyl)methylene-l- methyl-2, 5-dioxo-3-piperazinylidene)methylbenzamide J) N- (6,7-DiT, 1-hoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 3- ((3Z,6Z) -l-methyl-6- (2-naphthyl)methylene-2,5-dioxo-3- piperazinylidene)mrethylbenzamide (9260) 20 N- C6,7-Direthoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 4- ((3Z,6Z) -l-methyl-6- (2-naphthyl)methylene-2,5-dioxo-3- pi.perazinylidene)mrethylbenzamide (9261) N- (6,7-Dirnethoxy-1,2,3,4-tetrahydro-2-isoquinoly'L)ethyl) 3-((3Z,6Z)-l-r.iethyl-2,5-dioxo-6-(3-phenylpropylidr--ne)-3- piperazinyIlidene) methylbenzamide (9266) SUBSTITUTE SHEET (RULE 26) WO 96/20190 PCTIGB95.'0D3027 -92- N- (6,7-Dinitthoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl) 4-C (3Z, 6Z) -l-methyl-2,5-dioxo-6- (3-phenylpropfLidene) piperazinylidene)mrethylbenzarnide (9267) isoquinclyl)ethyl)phenyl) 3-C (3Z,6Z) (4-acetoxybenzylidene) -l-rethyl-2,5-dioxo-3- piperazinylidene) methylbenzamide (9272) (6,7-Dimethoxy-1,2,3,4-tetrahydrco-2- isoquinolyl) ethyl) phenyl) 3- EZ) (3-acec-oxybenzylidene) -l-methyl-2, 5-dioxo-3- iperazinylidene) methylbecnzamide (9273) is N -2 -iehx -e rhdo 2 isocruinclyl) ethyl) phenyl) 3- (2-acetoxybenzylidene) -1-methy'L'-2,5-dioxo-3- piperazinylidene) methylbenzamide (9274) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) MA i3- 6Z) -6-benzylidene-l- (2-dimethylaminoethyl) 3-piperazinylidene) methylbenzamide- (9275) N-(4-(2-(6,7-Dirnethoxy-1,2,3,4-tetrahydro-2- isoguinolyl) ethyl)phenyl) 3- ((3Z,6Z) (4-hydroxybenzylidene)-l-methyl-2,5-dioxo-3- SU'BSTrrUTE SHEET (RULE 26) WO 96/20190 PCT/GB95/03027 93 piperazinylidene)methylbenzamide (9276) N-(4-(2-(6,7-Dimethoxy-1,2,3,4-Letrahydro-2- isoquainolyl) ethyl) phenyl) 3- ((3Z,6Z) -6-be-nzylidene-l-ethoxycarbolylmethyl-2,5 dioxo-3- piperazinylidene) methylbenzamide (9299) N-(4-(2-(6,7-Dimethoxy-l,2,3,4-tetrahydro-2- isoquinolyl)o ethyl) phenyl) 3-((3Z,6Z)-6-(2-hydroxybenzylidene)-1-methyl-2,5-dioxo-3- piperazinylidene)mtethylbenzarnide (9300) U-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl) ethyl.)phenyl) 1 3-((3Z,6Z)-6-(3-hydroxvbenzylidene)--nethyl-2,5-dioxo-3- piperazinylidene)mrethylbernzarnide (9301) E-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2- isoquinolyl)ethyl)phenyl) 3- GE) -1-methyl-6-pentylidene-2, 5-dioxo-3- piperazinylidene) methylbenzamide (9306) N-(4-(2-(6,7-Dimethoxy-1,2,3.,4-tetrahydro-2- isoquinolyl) ethyl) phenyl) 3- -1-methyl-6-benzyl-2,5-dioxo-3- piperazinylidene) methy lbenzamide (9308) SUBSTITUTE SHEET (RULE 26) 94 6. A 3-benzylidine-l-methylpiperazine-2,5-dione derivative, substantially as hereinbefore described with reference to any one of the Examples. 7. A pharmaceutical or veterinary composition comprising a pharmaceutically acceptable carrier or diluent and, as an active principle, a compound as claimed in any one of the preceding claims.
8. A process for producing a compound as defined in claim 1, which process comprises treating a compound of formula (II) 0 ,Ac R NAc R N 0 wherein R 1 R 2 and are as defined in claim 1, with a compound of formula (III): -C-NH (C12)q-N R e i R 6 wherein one of R 7 and R 8 is hydrogen 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 thereof.
9. A process for producing a 3-benzylidine-l-methylpiperazine-2,5-dione 15 derivative, substantially as hereinbefore described with reference to any one of the Examples.
10. A method for the treatment or prophylaxis of multi-drug resistance in a patient requiring said treatment or prophylaxis, which method comprises administering to said patient an effective amount of at least one r :mpound according to any one of claims 1 to 20 6, or of a composition according to clair. 7. 0] 'i4 I, [n:\libc]02308:MEF
11. A compound of formula III: (111) wherein q, r, R 5 and R 6 are as defined in claimn 1, one of R 7 and R 8 is hydrogen and the other of R 7 and R 8 is -CHO. Dated 22 july, 1997 Xenova Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON It'' o 0 o 000 0,00 o 0 0 00 0 o 0 000 0 0 00 [n:\libc]02308:MEF O< ~I INTEI RNATIONAL SEARCH REPORT Inwrr.. .naI Application No PCT/GB 95/03027 :u and the A. CLASSIFICATION OF SUBECT MATER IPC 6 C07D401/12 C070241/02 C070217/04 A61K31/495 C070405/14 C07D401/14 C070409/14 According to Intemation il Patent Classification (PC) or to both national classification and IPC B. FIELDS SEARCHF.D Minimum documentation searched (classifiration system followed by classification symbols) IPC 6 C07D Documentation searched other than mmum documentation to the extent that Eruh documents are included in the fields searched Electronic dra base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUM5INTS CONSIDERED TO BE RELEVANT Category' Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No. Y WG,A,94 04513 (XENOVA LTD 3 March 1994 1,6,8,9 see claims Y W0,A,94 01408 (GLAXO LAB SA 20 January 1,6,8,9 1994 see claims A see claims 1,5 A WO,A,94 04512 (XENOVA LTD 3 March 1994 1,6,8,9 see claims Further documents are listed i the continuation of box C. Patent faily members are listed in annex. *Specal categories of cited documents later document published after the international filing date document defining the general state of the art which is not or prionty date and not in conflict with the application but considered to be of prrticular relevance cited to understand the principle or theory underlying the invention 'E earlier document bu lishcd on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the pui cation date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed W document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 7.02.1996 29 January 1996 Name and mailing adress of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 340-2040, Tx. 31651 eponle Fa=c 3170)-303016Henr J Frns PCTIlSA/l10 (econd sheet),(July 19 92, libc]02308:MEF 4;' i P? j; i:. I~ 6r 1-7 ~I:,e %juw i i u i L arcc i mUL rV) INTERNATIONAL SEARCH REPORT Intenona Appadon No 4 ~Interauonal Applicaion No PCT/GB 95/03027 Patent document Publication Patent family Publication cited in search report date member(s) date WO-A-9404513 03-03-94 AU-9- 4726493 15-03-94 AU-B- 4726593 15-03-94 CA-A- 2141938 03-03-94 CA-A- 2141939 03-03-94 CZ-A- 9500383 18-10-95 CZ-A- 9500381 13-09-95 EP-A- 0655060 31-05-95 EP-A- 0672036 20-09-95 FI-A- 950616 13-04-95 FI-A- 950617 13-04-95 WO-A- 9404512 03-03-94 GB-A,B 2284602 14-06-95 GB-A- 2284420 07-06-95 NO-A- 950529 05-04-95 NO-A- 950530 11-04-95 PL-A- 307437 29-05-95 PL-A- 307438 29-05-95 WO-A-9401408 20-01-94 AU-B- 4567193 31-01-94 EP-A- 0649410 26-04-95 WO-A-9404512 03-03-94 AU-B- 4726493 15-03-94 AU-B- 4726593 15-03-94 CA-A- 2141938 03-03-94 CA-A- 2141939 03-03-94 CZ-A- 9500383 18-10-95 CZ-A- 9500381 13-09-95 EP-A- 0655060 31-05-95 EP-A- 0672036 20-09-95 FI-A- 950616 13-04-95 FI-A- 950617 13-04-95 WO-A- 9404513 03-03-94 GB-A,B 2284602 14-06-95 GB-A- 2284420 07-06-95 NO-A- 950529 05-04-95 NO-A- 950530 11-04-95 PL-A- 307437 29-05-95 PL-A- 307438 29-05-95 PCTASNIO (pxtwt family wtnax) (July 1992)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9426224 | 1994-12-23 | ||
| GBGB9426224.3A GB9426224D0 (en) | 1994-12-23 | 1994-12-23 | Pharmaceutical compounds |
| PCT/GB1995/003027 WO1996020190A1 (en) | 1994-12-23 | 1995-12-22 | Piperazine 2,5 dione derivatives as modulators of multi-drug resistance |
Publications (2)
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| AU4310096A AU4310096A (en) | 1996-07-19 |
| AU698828B2 true AU698828B2 (en) | 1998-11-05 |
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| AU43100/96A Ceased AU698828B2 (en) | 1994-12-23 | 1995-12-22 | Piperazine 2,5 dione derivatives as modulators of multi-drug resistance |
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| EP (1) | EP0799222A1 (en) |
| JP (1) | JPH10511384A (en) |
| CN (1) | CN1175253A (en) |
| AU (1) | AU698828B2 (en) |
| BG (1) | BG101602A (en) |
| BR (1) | BR9510410A (en) |
| CA (1) | CA2207500A1 (en) |
| CZ (1) | CZ190097A3 (en) |
| FI (1) | FI972660A (en) |
| GB (1) | GB9426224D0 (en) |
| HU (1) | HUT77943A (en) |
| IL (1) | IL116525A0 (en) |
| NO (1) | NO972937L (en) |
| NZ (1) | NZ297847A (en) |
| PL (1) | PL320916A1 (en) |
| SK (1) | SK83697A3 (en) |
| TW (1) | TW358094B (en) |
| WO (1) | WO1996020190A1 (en) |
| ZA (1) | ZA9510909B (en) |
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| ZA979329B (en) * | 1996-10-18 | 1999-04-19 | Xenova Ltd | Pharmaceutical compounds |
| GB9717576D0 (en) * | 1997-08-19 | 1997-10-22 | Xenova Ltd | Pharmaceutical compounds |
| GB9708805D0 (en) | 1997-05-01 | 1997-06-25 | Smithkline Beecham Plc | Compounds |
| GB9810876D0 (en) | 1998-05-20 | 1998-07-22 | Smithkline Beecham Plc | Compounds |
| CA2346689A1 (en) | 1998-10-08 | 2000-04-20 | Gregor James Macdonald | Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents) |
| IL150430A0 (en) * | 2000-01-18 | 2002-12-01 | Nereus Pharmaceuticals Inc | Cell division inhibitors and process for producing the same |
| US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
| US7919497B2 (en) | 2002-08-02 | 2011-04-05 | Nereus Pharmaceuticals, Inc. | Analogs of dehydrophenylahistins and their therapeutic use |
| US7935704B2 (en) | 2003-08-01 | 2011-05-03 | Nereus Pharmaceuticals, Inc. | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof |
| IL166628A0 (en) | 2002-08-02 | 2006-01-15 | Nereus Pharmaceuticals Inc | Dehydrophenyl lahistins and analogs thereof and the synthesis of dehydrophenyllahistins and analogs thereof |
| US8129527B2 (en) | 2006-11-03 | 2012-03-06 | Nereus Pharmacuticals, Inc. | Analogs of dehydrophenylahistins and their therapeutic use |
| CN103396372B (en) * | 2013-08-09 | 2015-05-20 | 中国科学院南海海洋研究所 | 2,5-diketopiperazine derivative, as well as preparation method and application thereof in preparing control agent for resisting marine fouling organisms |
| US10076518B2 (en) | 2015-03-06 | 2018-09-18 | Beyondspring Pharmaceuticals, Inc. | Method of treating a brain tumor |
| US10238650B2 (en) | 2015-03-06 | 2019-03-26 | Beyondspring Pharmaceuticals, Inc. | Method of treating cancer associated with a RAS mutation |
| MX2018000451A (en) | 2015-07-13 | 2018-05-07 | Beyondspring Pharmaceuticals Inc | Plinabulin compositions. |
| RU2753543C1 (en) | 2016-02-08 | 2021-08-17 | Бейондспринг Фармасьютикалс, Инк. | Compositions containing tucaresol or analogues thereof |
| WO2017214052A1 (en) | 2016-06-06 | 2017-12-14 | Beyondspring Pharmaceuticals, Inc. | Composition and method for reducing neutropenia |
| WO2018129381A1 (en) | 2017-01-06 | 2018-07-12 | Beyondspring Pharmaceuticals, Inc. | Tubulin binding compounds and therapeutic use thereof |
| JP2020514412A (en) | 2017-02-01 | 2020-05-21 | ビヨンドスプリング ファーマシューティカルズ，インコーポレイテッド | Methods for reducing neutropenia |
| KR20200112881A (en) | 2018-01-24 | 2020-10-05 | 비욘드스프링 파마수티컬스, 인코포레이티드. | Composition and method for reducing thrombocytopenia through administration of plinabulin |
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| EP0649410B1 (en) * | 1992-07-10 | 1997-05-02 | Laboratoires Glaxo Sa | Anilide derivatives |
| GB9217331D0 (en) * | 1992-08-14 | 1992-09-30 | Xenova Ltd | Pharmaceutical compounds |
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1994
- 1994-12-23 GB GBGB9426224.3A patent/GB9426224D0/en active Pending
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1995
- 1995-12-21 ZA ZA9510909A patent/ZA9510909B/en unknown
- 1995-12-22 WO PCT/GB1995/003027 patent/WO1996020190A1/en not_active Application Discontinuation
- 1995-12-22 CN CN95197672A patent/CN1175253A/en active Pending
- 1995-12-22 PL PL95320916A patent/PL320916A1/en unknown
- 1995-12-22 CZ CZ971900A patent/CZ190097A3/en unknown
- 1995-12-22 AU AU43100/96A patent/AU698828B2/en not_active Ceased
- 1995-12-22 SK SK836-97A patent/SK83697A3/en unknown
- 1995-12-22 NZ NZ297847A patent/NZ297847A/en unknown
- 1995-12-22 JP JP8520301A patent/JPH10511384A/en active Pending
- 1995-12-22 IL IL11652595A patent/IL116525A0/en unknown
- 1995-12-22 BR BR9510410-0A patent/BR9510410A/en not_active Application Discontinuation
- 1995-12-22 CA CA002207500A patent/CA2207500A1/en not_active Abandoned
- 1995-12-22 HU HU9800398A patent/HUT77943A/en unknown
- 1995-12-22 EP EP95941797A patent/EP0799222A1/en not_active Withdrawn
- 1995-12-23 TW TW084113836A patent/TW358094B/en active
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1997
- 1997-06-11 BG BG101602A patent/BG101602A/en unknown
- 1997-06-19 FI FI972660A patent/FI972660A/en unknown
- 1997-06-23 NO NO972937A patent/NO972937L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL116525A0 (en) | 1996-03-31 |
| WO1996020190A1 (en) | 1996-07-04 |
| BG101602A (en) | 1998-02-27 |
| ZA9510909B (en) | 1996-08-30 |
| AU4310096A (en) | 1996-07-19 |
| FI972660A0 (en) | 1997-06-19 |
| NO972937D0 (en) | 1997-06-23 |
| NO972937L (en) | 1997-06-23 |
| GB9426224D0 (en) | 1995-02-22 |
| TW358094B (en) | 1999-05-11 |
| EP0799222A1 (en) | 1997-10-08 |
| HUT77943A (en) | 1998-12-28 |
| CA2207500A1 (en) | 1996-07-04 |
| JPH10511384A (en) | 1998-11-04 |
| PL320916A1 (en) | 1997-11-10 |
| SK83697A3 (en) | 1998-05-06 |
| CZ190097A3 (en) | 1998-01-14 |
| BR9510410A (en) | 1999-09-08 |
| NZ297847A (en) | 1999-04-29 |
| FI972660A (en) | 1997-08-22 |
| CN1175253A (en) | 1998-03-04 |
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