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CA2182877A1 - Pharmaceutical piperazine compounds - Google Patents

Pharmaceutical piperazine compounds

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Publication number
CA2182877A1
CA2182877A1 CA002182877A CA2182877A CA2182877A1 CA 2182877 A1 CA2182877 A1 CA 2182877A1 CA 002182877 A CA002182877 A CA 002182877A CA 2182877 A CA2182877 A CA 2182877A CA 2182877 A1 CA2182877 A1 CA 2182877A1
Authority
CA
Canada
Prior art keywords
benzylidene
piperazinedione
group
formula
dimethylaminopropoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002182877A
Other languages
French (fr)
Inventor
Stephen James Brocchini
Justin Stephen Bryans
Adrian John Folkes
Christopher John Latham
Julie Elizabeth Brumwell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xenova Ltd
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2182877A1 publication Critical patent/CA2182877A1/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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  • Plural Heterocyclic Compounds (AREA)

Abstract

A diketopiperazine of formula (A), wherein one or both of R1 and R2, which may be the same or different, is: (I) X, or a phenyl group which is substituted by X, C(O)X, OC(O)CH2X, OCH2CH2X, CH2X, CONH(CH2)nX, O(CH2)nCH(OH) (CH2)nX or (a) or which is fused to a group X; (II) a phenyl group substituted by CH2NR12R13, OC(O) (CH2)nZ, CH(OR12)(OR13), (CH2)nNR14C(O) (CH2)mNR12R13 or O(CH2)nCH(OH) (CH2)nN(R12R13); (III) a group CH=C(W)V; or (IV) a cyclohexyl group; and where appropriate, the other of R1 and R2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NHC(O)R12, CO2H, O(CH2)nN(R12R13) and CH2Y(CH2)nN(R12R13); R3 is C1-C4 alkyl or (CH2)nC(O)OR12; Y is O or S; Z is a C3-C6 cycloalkyl group; W is hydrogen or a phenyl group; and the pharmaceutically acceptable salts and esters thereof having activity as inhibitors of plasminogen activator inhibitor.

Description

W 9S/21832 . ~ .. s ~
o -- ` 2182877 PHARMACEUTICAL PIPERAZINE COMPOUNDS

The present invention relates to 'q useful as inhibitors of pli~P-;nnr~n activator inhibitor (PAI), to their preparation and to pharmaceutical and veterinary 5 compositions ronti~;n;nr them.
plAP~;nr,r~n activators (Pas) are serine proteases which control the activation of the zymogen, pli~P"~;nrr~n, to the active enzyme plasmin. Plasmin is important in a number of physiological and pathological processes 10 including fibrinolysis, tissue L~ '-llinr, tumour growth and metastasis. The glycoprotein rli~r^;n~gen activator inhibitor (PAI) is an endogenous fast-acting inhibitor of PA activity. PAI is a member of the serpin family and is synthesised by a variety of cells including endothelial 15 cells . An ; ' - l iqnre between PAs and PAI contributes to a number of pi~thnlorir~l conditions including haemostasis, ;n~li tirn, tumour growth and metastasis.
The present invention provides a diketopiperazine of formula (A):

R1~NH (A) HN~R2 wherein one or both of R1 and Ri, which may be the same or different, is:

SUBSTI~UTE SHEET tRULE 26~
2 -}~ C 2182817 I ~ ~

(I) X, or a phenyl group which is substituted by X, C (O) X~ OC ~O) CX2X OCHzCX2X~ CH~X CONH (CH~) nX

(CH2) ~C~ (OH) (CHl) nX or ~3)NH~cHbnx n 5 or which i8 fused to a group X;

(II) a phenyl group substituted by CX,NR12Rl3, OC(O) (CH2)nZ, CX(ORl,) (ORl3), (cH2)nNRl~c(o) ~CH2)~NRl2Rl3~ -CX2NRl2- (CH2)nNRlsRl6 or O(cH~)ncH~oH) (cH2)nN(Rl2Rl3);
(III) a group CH=C(W)V; or lO (IV) a cyclohexyl group;
and where appropriate, the other of R1 and R2 is a phenyl group optionally substituted by one or more groups in~ ntly gelected from halogen, nitro, methoxy, NXC ( O ) Rl2, CO2H O ( CH2 ) nN ( Rl2Rl3 ) ~ CH~ Y ( CH~ ) nN ( R"Rl3 ) 15 C1-C~ alkyl and (CX~) nC (O) ORl2;
X is a naphthyl group or a ~ive- or six-membered saturated or unsaturated heterocyclic group r~nt~in;n~ one or more heteroatoms, which heteroatoms may be the same or dif ~erent and are innl~ron~Pntly selected from 0, N and S; the 20 heteroatom~s) ~hen nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, ~ ~CH~) nCX~OH or SO~Me; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O(CX,)nNRl,R~3, -N(Rl,) (CH,)nN(Rl,Rl3) ~ ~ (CH,)"N(Rl,Rl3) or 25 -O~CH,)nO(CX,)nN(R12R13), or the heterocyclic ring optionally containing one or more carbonyl groups and being optionally fused to a benzene ring, which benzene ring is optionally substituted by l or 2 C1-C~ alkoxy groups;

SUBSTITUTE SHEET (RULE 26~
_ _ , _ _ _ WO95/21832 , ~ 2 ~ ~ P~,/~Ls~
Y is O or S;
Z is a C3-C6 cycloalkyl group;
Rl2, Rl3 and RL~, which may be the same or dif f erent, are 11YdLUYt:~1 or C1-C6 alkyl;
Rls and Rl6, which may be the same or different, are ~lydLu~ or Cl-C6 alkyl, or Rls and Rl6 fûrm, together with the nitrogen atom to which they are attached, a 5- or 6-d heterocyclic group;
W i8 hydrogen or a phenyl group;
V is a phenyl group optionally substituted by one or more groups in~PrPn~Pntly selected from nitro, alkoxy, O(CH2) ,NRl2Rl3, and NRl2Rl3; and m and n are each, ;n~lPrPn~ntly, o or an integer having the value 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or ester thereof.
A Cl-C6 alkyl group is, for example, a Cl-C~ alkyl group, such as a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group.
A halogen may be F, Cl, Br or I.
In: , .u--~s of formula A free rotation may occur at room temperature about the single bonds connecting substituents Rl and R2 to the double bonds at positions 3 and 6 of the pipera2 ine-2 j 5 -dione ring.
In one ~ ; at least one of Rl and R2, which may be the same or different, is chosen from a naphthyl group, X, a phenyl group substituted by X, C (O) X, OC (O) CX2X, OCH2CH2X, or CX2X and a phenyl group which is fused to a group X; wherein X is a five- or six-- ' ~ saturated or SU~STlrUTE StiEET ~RULE 26~

WO 95/21832 ., 2 1 6 2 ~ 7 7 1~ I ~ r ~ ~
unsaturated heterocyclic group cnnt~in;n~ one or two heteroatoms, which heteroatoms may be the same or different and are independently selected from 0, N and S, the heteroatom(s) when nitrogen being optionally substituted by 5 I1YdLUYe~ methyl, oxygen, tertiary-butyloxycarbonyl, - (CH2) nCH20H or Sû2Me, the heterocyclic ri~g being optionally substituted by hydroge~, halogen, methyl, MeS, phenyl, O ( CH2 ) nNRl2RL3, û ( CH2 ) nN ( RL2R13 ) or -O(CH,)=O(CH,)nN(Rl2R13); the heterocyclic ring optionally 0 rnnt~;n;n~ one or more carbonyl groups, and being optionally fused to a benzene ring; and the other of R1 and R, is a phenyl group optionally substituted at the 2, 3 or 4-position by CH,NR12R13, ~CH2)nNR1~C(O) (CH2)mNR~,R13, halogen, nitro, -NHC(O)R1~, -O(CH,)nN(Rl2R13) or -CH,Y(CH2)=N(R1,R~3) 15 wherein Y iB O or S. In a particularly preferred series of ~, '- the said other of R1 and R, is a phenyl group substituted at the 4-position by -O(CH,)nN(R12Rl3), -CH2Y(CH2)nN(R12R~3) or - (CH,)nNR1~C(O) (CH2)~2R13 In a further: ' '; one of R1 and R2 is X, a 20 phenyl group substituted by X, -CH2X, -OCH2CH2X, O (CH2) nCH (OH) CH2X or ~,", ; wherein X is a 5 or 6-membered saturated or unsaturated heterocyclic group as defined above which is optionally substituted and 25 optionally fused to a benzene ring, for instance a pyridyl, imidazolyl, furyl, pyrrolyl, pyrrolidinyl, thienyl, piperazinyl, piperidinyl, morpholinyl, quinolyl, isoquinolyl or indolyl group; and the other of R1 and R2 is SUBSTITUTE SHEET ~P~ULE 26~

~ W09~5/21832 ~ -' 2182877 P~ r a phenyl group optionally substituted at the ~-position by - O ( CH2 ) nN ( Rl2Rl3 ), - CH2Y ( CH2 ) nN ( Rl2Rl, ) or -(CH,)nNRl,C(0) (CH2)mNRl~Rl3. In this embodiment it is particularly preferred for X to be a furyl, imidazolyl, 5 pyrrolyl, thienyl, morpholinyl, piperidinyl or isoquinolyl group .
In a further ~ , Rl~ and Rl3, which may be the same or different, are hydrogen or C3-C3 alkyl and n is an integer of value 1 or 2.
In a yet further F ' -'i ' one of Rl and R2 is a phenyl group which is substituted by X, C0 (X), OC0 (0) CH2X, OCH2CH2X, CH2X or which is fused to a group X, wherein X is a five- or six-~ ' ~ ed heterocyclic ring e~nnt~inin~ one or two heteroatoms which may be the same or different, 15 infiPrPn~Pntly selected from 0, N and S, the heteroatom(s) when nitrogen being optionally substituted by methyl, and the heterocyclic ring being nptinnAl ly fused to a benzene ring .
In another, :~; t one of Rl and R2 is a phenyl 20 group substituted by CH2NR~,Rl3, OC(0) (CH2)nZ, CH~ORl2) ~ORl3), ~CH2)nNRl~C~O) ~CH2)mN(Rl2Rl3); wherein Rl2, Rl3 and Rl" which may be the same or different, are independently selected from hy~iL-/y-Ll or Cl-C3 alkyl; Z is a Cs or C6 cycloalkyl group; and m and n are, ;n~PrPn~iPntly, integers having the 25 values 1, 2 or 3.
In a further .o -';rnPnt Rl2, Rl3 and Rl" which may be the same or different, are infiPrPnrlPntly selected from hydrogen and Cl-C2 alkyl; Z is a cyclopentyl group; and _SUBSTITUTE SHEtT ~RULE 26~

wo 9S/21832 ~ S 2 1 g 2 8 7 7 1 l r ~ ~
m and n are, inrl-~p~n~ntly, integers having the values of 1 or 2.
In a yet further: ' - 'i L one of R1 and R~ is a phenyl group optionally substituted by one or more group6 inde~e,lde11tly selected from chloro, nitro, methoxy, NHCOR12, CO2H and 0 (CH2) nNRl2Rl3; R12 and RL3~ which may be the same or different, are independently selected from hydrogen or methyl and n is an integer having the value l or 2.
In another ' _~;r t one of R1 and R2 is a group CH-C (W) V, W is a phenyl group optionally substituted by one of more groups ;n~rPn~l~ntly selected from nitro, methoxy and O(CH2)n~.3Me2 and n is an integer having the value l, 2,3 or 4.
In a f urther - ~; r ' n is l or 2 .
In a yet further ~mhQ~l;r one of R~ and R2 is a phenyl group optionally substituted by NHAc or methoxy.
In another . ' ', ~ one of Rl and R2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC (O) Rl2 .
In a further: ' '; one of R1 and R2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC (0) Me .
In a further f~mhol1;r t R, is Cl-C2 alkyl or (CH2)=C(O)OR12; R12 is hydrogen or C1-C2 alkyl and n is an integer of value l or 2.
In a yet further ~ ' -';- t R3 is methyl or CH,C~O)OR12 and Rl2 is I1YdL~YeII or methyl.
Certain f~;k~t~p;r~razines have been disclosed as SUî~S,~TUTE SHEET (RULE 26~
_ _ ~ WO95/21832 , ~ ; 2 ~ 8~7 ~ r~ .. 5l having utility as bioactive agents. Yokoi et al in ~.
Antibiotics vol XLI No. 4, pp 494-501 (1988) describe structure-cytotoxicity rP1~tin~qh;p studies on a series of diketopiperazines related to neihumicin, a ~
S obtained from the micro-organism Micromonosl~ora r~P; hllPnql8 .
Kamei et ~ in J. Antibiotics vol ~ No. 8, 1018-1020 disclo8e that two diketopiperazines, designated piperafizines A and B, have utility as potPnt;~qrs of the cytotoxicity of vincristine.
Examples of specific: ,_ 'q of formula A are as follows. The ~ ~ numbering is adhered to in the rest of the specif ication:
1926 (3Z,6Z)-3-Benzylidene-6-(4-;m;~nlyl)methylene-2,5-piper~7; nP~I; rnP .
lS 1930 (3Z,6Z)-3-Benzylidene-6-t4-(l-imidazolyl)benzylidene)-2, 5-piperazinedione.
1929 (3Z, 6Z) -3-Benzylidene-6- (4- (1-;m;~1~701ylmethyl)benzylidene) -2~5-piper;~7;nP~;nnP.
1959 (3Z,6Z) -3,Benzylidene-6- (4- (2-dimethylaminoethoxy) -3-20 methoxybenzylidene)-2,5-piper~7; nP~l;nn P hydrochloride.
1927 ~3Z, 6Z) -3-Benzylidene-6- (4- ~5-methyl ;m;~l~7o~yl) )methylene-2,s-piper/7;n~;nnP.
1921 ~3Z, 6Z) -3-Benzylidene-6- ~4-dimethy~ ~m; nnc; nn~mylidene) -2, 5-piperazinedione .
25 1976 (3Z,6Z)-3-(4-(3-Dimethylaminuyluyu~y)benzylidene)-6 (4- (l-imidazolyl)benzylidene-2~5-piper~7;np~;rmp.
1910 (3Z, 6Z) -3-Benzylidene-6- (4- (2-; m; r~701ylethoxy) benzylidene) -2, 5-piper~7; n~.~; nnP .

SV~St~TUTE SEI~ET (RU'E 26~

WO95121832 ~ -~ ~ t ~ 5 ~

1923 ~3Z,6Z)-3-Benzylidene-6-~4-nitrocinr~amylidene-2,5-piperazinedione .
1657 (3Z, 6Z) -3- (4-Aminomethylbenzylidene) -6- (4-methoxybenzylidene~-2,5-piperA7:;n~ nP
5 1693 (3Z,6Z)-3-(1-methanesulfonyl-3-indolyl)methylene-6-(4-methoxybenzylidene) -2, 5-piper~7; nPrl; ~1n~, 1886 (3Z, 6Z) -3- (4-Methu,-yL~ ylidene) -6- (4-~ht h~ l; m; d~ retoxybenzyl idene ) - 2, s -piperA 7; nP~; nnP, 1922 (3Z, 6Z) -3-3enzylidene-6- (~-phenylcinnamylidene) -2, 5-10 piperaz; n!~rl; onP,1618 ( 3 Z, 6 Z ) - 3 - ( 1- tert -butu,.y~:aL Lully 1- 3 - indolyl ) methylene -6- (2-thenylidene) -2,5-piper:~7;nPr~ nP
1560 (3Z, 6Z) -3- (2, 6-DichlùLubenzylidene) -6- (1-tert-butoxycarbonyl - 3 - indolyl ) methylene - 2, s -piper~ 7; n~ P, 15 1950 (3Z, 6Z) -3-Benzylidene-6- (4- (2-dimethylaminoethoxy) -3-methoxycinnamylidene)-2, 5-piper;17;rlP~ no, 1975 ( 3Z, 6Z) -3 - (4 - (3 -Dimethylaminu~Lu~u~y ) benzylidene) -6-(4- (l-imidazolylmethyl)benzylidene) -2,5-piperi~7inP~ nP.
1983 (3Z, 6Z) -3-Benzylidene-6- (4-N-methyl-~- (4- (N-20 methylpiperidinyl) ) -~inl -~hylbenzylidene-2,5-piperazinedione .
1509 (3Z, 6Z) -3-Benzylidene-6- (3-indolylmethylene) -2, 5-piper~7;nP~ nP
1542 (3Z, 6Z) -3 - (2, 6-Dichlorobenzylidene) -6- (3-25 furylmethylene) -2, 5-piper~7- nPr~ nP .
1545 (3Z, 6Z) -3- (3-Indolylmethylene) -6- (4-methoxybenzylidene) -2, 5 -piper~71 nPr~; nnp .
1507 (3Z, 6Z) -3- (4-Methu~.y},ell~ylidene) -6- (2- (1-SU~STITUT~ SHEET (~ULE 26) _, _ _ _ , . . . . . . .

~ Wo 9S/21832 2 1 8 2 ~ 7 7 P.l ~s~
tertbutoxycarbonyl)pyrrolyl)methylene-2,5-piper~7;n,~;nnF.

1506 (3Z,6Z) -3- (4-Methoxybenzylidene) -6- (3- (1-tert-butoxycarbonyl)indolyl)m.ethylene-2,5-piperi7;nPrlinnf~, 1471 (3Z, 6Z) -3-Benzylidene-6- (3- ~l-tert-5 butu~y~ u,l~l)indolyl)methylene-2~5-pipera7in~in 1474 (3Z, 6Z) -3- (4-Methu--y~ zylidene) -6- (2-thienylmethylene) -2, 5 -piper~7; n~ri; nn,~ .
1476 (3Z, 6Z) -3- (4-Methoxybenzylidene) -6- ~3-furylmethylene) -2, 5-piperA7i n.-r1; nTl~
10 1672 (3Z, 6Z) -3- (~et~m; ~nhF~n7ylidene) -6-cyclohexylmethylene-2, 5-piper~7; n.-fl; nnf~
1676 (3Z, 6Z) -3- (4-A~ ,ot~mi ~nhenzylidene) -6-cinnamylidene-2, 5-piperazinedione.
1891 (3Z, 6Z) -3-Benzylidene-6- (diethu~y, thylbenzylidene) -15 2, 5-piperazinedione .
lss2 (3z, 6Z) -3-Benzylidene-6- (4- (N-methyl-N- (2-dimethyl~m;nnf-thyl):~m; hylbenzylidene-2,5-piper~ 7; n.~-i i nn~ hydrochloride .
1884 (3Z, 6Z) -3-Benzylidene-6-cyclohexylmethylene-2, 5-20 piper: l7i n~r~; nn~1845 (3Z, 6Z) -3- (4-A~-etAm; ~lnh~n7ylidene) -6- (3, 4 -methylenedioxybenzylidene) -2,5-piper~7in~rlinnf-1950 (3Z, 6Z) -3-benzylidene-6- (4- (2-dimethylaminoethoxy) -3-methoxycinnamylidene) -2, 5-piperazinedione.

SU~;STITUTE SHE~T (RULE 26) ~1 ~2~77 Wo 9512 1832 1718 l3Z, 6Z) -3- (2-Indolylmethylene) -6- (4-methoxybenzylidene) -2, 5-piperazinedione.
1808 (3Z, 6Z) -3-Benzylidene-6- (3, 4-methylenedioxybenzylidene) -2, 5-piperA7; n~l; nn,~ .
1809 (3Z,6Z)-3-(4-Methu~ybe:n~ylidene)-6-(3~4-methylenedioxybenzylidene) -2, s-piperaz; nPrl; nn,~, 1470 ( 3Z , 6Z ) - 3 -Benzylidene- 6 - ( 2 -.( 1 -tertbutoxycarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
5 0 2 3 ( 3 Z, 6 Z ) - 3 - ( 4 - Dime thyl A m; r thylbenzyl idene ) - 6 - ( 4 - ( 3 -dimethylaminu~Lu~u~y)benzylidene-2~5-piperA7;n~ ;nnr~
5026 (3Z, 6Z) -3- (4- (3-Dimethyl r~; n. `1~' u~u~-y) benzylidene) -6 -(4- (l-;ml~lA7Olyl)methylbenzylidene) -2,5-piperA7;n~l;nn-~.
5030 (3Z, 6Z) -3- (4- (3-Dimethylaminu~uLu~u~y) benzylidene) -6-(4 - (l-imidazolyl) benzylidene) -2, 5-piperazinedione .
5367 (2- (4- ( (3Z, 6Z) -6- (4- (3-Dimethyl ~m ; n~ v~u~y ) benzyl idene ) - 2, 5 - dioxo - 3 -piperazinylidene)methylbenzoyl) -1,2,3,4-tetrahydroigos~l; nnl; n~, 5386 N- (2- (1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl) -4-( (3Z, 6Z) -6- (4- (3-dimethylaminu,uLu~ù,.y) benzylidene) -2, 5-dioxo - 3 -piperazinyl idene ) methyl hon 7 d~ .
5397 N- (4- (l~2~3~4-Tetrahydro-2-iso~uinolyl)butyl) -4-( (3Z, 6Z) -6- (4- (3-dimethylaminu~Lu,uu~y) benzylidene) -2, 5-dioxo-3 -piperazinylidene) methylbenzamide.
5027 (3Z, 6Z) -6- (4- (3-Dimethyl . nnpropoxy) benzylidene-3- (4-pyridylmethylene) -2,5-piperA7;n~r~;nn~.
5028 (3Z, 6Z) -6- (4- (3-Dimethylaminu~Lu~u,.y) benzylidene) -3-(3-pyridylmethylene) -2, 5-piperazinedione.
SU~S~lTiJ~E S~iEET (~ULE 26~

wo 9~121832 .; ~ 2 i 8 2 8 7 7 ~ r ~
5041 (3Z, 6Z) -6- (4- (3-Dimethylaminu~Lu~y) benzylidene) -3-furfurylidene-2, 5-piper~7inP~;nnP.
5042 ( 3Z, 6Z ) - 6- (4 - (3 -Dimethylaminopropoxy) benzylidene) -3 -(3-Thenylidene) -2, 5-piperazinedione .
5 5046 (3Z,6Z)-6-(4-(3-Dimethylamin~.~Lu~.,~y)benzylidene)-3-(2-Thenylidene)-2,5-piperA7;nP~ nP
5052 ( 3Z, 6Z) -6- (4- (3 -Dimethylaminu~ u~y) benzylidene) -3 -(3 -Furylmethylene) -2, 5-piper;37; n~i nnp, 5188 (3Z, 6Z) -6- (4- (3-Dimethyl i:lmi r~npropoxy) benzylidene) -3 -10 (2-Naphthylmethylene)-2,5-piper~7;nPrli,nP.
5200 (3Z, 6Z) -6- (4- (3 -Dimethyl :~mi n~ u~u~y) benzylidene) -3-(1-Naphthylmethylene) -2, s-piperazi nP~ nP .
5032 (3Z, 6Z) -6-Benzylidene-3- (4- (3-dimethylamino-2-hydroxypropoxy)benzylidene) -2,5-piper~;nP~;nnP.
15 5040 (3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-morpholinu~- u~u~y) benzylidene) -2, 5-piperazinedione .
5057 (3Z, 6Z) -6-Benzylidene-3- (4- (2-hydroxy-3- (1-imidazolyl)propoxy)benzylidene) -2,5-piper~7;nP~i;nnP.
5043 (3Z, 6Z) -6-Benzylidene-3- (4- (2-hydroxy-3- (4- (2-20 hydroxyethyl) -1-piperazinyl)propoxy) benzylidene) -2, 5-piper~7; nP-i; nnl~ .
5062 (3Z, 6Z) -6- (4 - (2-Dimethylaminoethoxy) benzylidene) -3- (3-furylmethylene) -2, 5-piperazinedione.
5071 (3Z,6Z) -6- (4- (2-Dimethyl~m;nne~hn~y)benzylidene) -3- (3-25 thenylidene) -2, 5-piper~; nP-l; nnP
5072 (3Z, 6Z) -6- ~4- (2-Dimethylaminoethoxy) benzylidene) -3- (5-methylthio-2-thenylidene)-2,5-piper~7;nP~ nP.
5054 (3Z, 6Z) -6-Benzylidene-3- (4- (2-SUBS~ITU~E SIIEET (P~ULE 26) WO 95121832 ; - l~ `, 2 ~ ~ 2 8 7 7 f~ c 1~

morpholinoethoxy) benzylidene) -2, 5-piperazinedione.
5055 (3Z, 6Z) -6-Benzylidene-3- (4- (2- (1-; m; l~ 701yl ) ethoxy) benzylidene) 2, 5 -piperazinedione .
5053 (3Z, 6Z) -6-Benzylidene-3- (4- (2- (1-pyrrolidinyl)ethoxy)benzylidene)2,5-piperA~inF.~innP.
5069 (3Z, 6Z) -6- (4- (2-Dimethyl Am; nnet h~ , t hyl ) benzyl idene ) - 3 - ( 3 - thenyl idene ) -2, 5-piperazinedione .
5077 (3Z, 6Z) -6- (4- (2-Dimethylaminoetllu--~, thyl) benzylidene) -3- (3-furylmethylene ) - 2, 5 -~; r~A 7; nF~rl; nnP .
5074 (3Z, 6Z) -6- (4 -Dimethyl Am; nnar~t~m; ~' thyl benzylidene) -3- (3-thenylidene) -2,5-pip~rA7inF~rlinnF~.
5079 (3Z,6Z)-3-(2-Br, ' 7ylidene)-6-(4-dimethyl Am; nnAr~tAm; 1' thylbenzylidene) -2, 5-piperazinedione .
5 0 81 ( 3 Z, 6Z ) - 6 - ( 4 -DimethylAm i nnAcet~m; ,~ - hylbenzylidene) -
3 - ( 3 - ~urylmethylene ) -2, 5 -piperA 7 i n.o~i i nn~. .
5061 (3Z, 6Z) -6-Benzylidene-3- (4-dimethylAm;nnaret~ hylbenzylidene)-2,5-piperA7; n~ ; nn~ .
5073 (3Z, 6Z) -6- (4- (2-Dimethylaminoethylthiomethyl) benzylidene) -3- (3-f urylmethylene ) - 2, 5 -piperA 7; n~ i nn ~ .
5078 (3Z,6Z) -6- (4- (2-Dimethylaminoethylthiomethyl)benzylidene) -3- (3-thenylidene) -2, 5-piperA7; n~l; nn~. .
lgli ( 3Z, 6Z ) - 6 -Benzylidene - 3 - ( 4 -SU35TITU,-E SHE~T ~ ULE 26) ~ W0 95~2s832 ~ ~ 2 1 8 2 ~ 7 7 P~ I /~iD~

dimethyl~m;n~rPt~m;~n~min~ -thylbenzylidene) -2,5-piperazinedione .
5324 ~3Z, 6Z) -6-Benzylidene-3- (5- (2-dimethylaminoethoxy) -2-thienylmethylene ) - 2, 5 -piperazinedione .
5327 (3Z, 6Z) -6-Benzylidene-3- (4- ~2-dimethylaminoethoxy) -2-thienylmethylene)-2,5-piper~ 71n~ nP, 5335 (3Z, 6Z) - 6-Benzylidene-3 - (5 - (2 -dimethyl Am; nme~hyl) -2 -thienylme t hyl ene ) - 2, 5 -piper~ 7 i n Prl; nn ~, 5388 (3Z, 6Z) -6-Benzylidene-3- (5- (2- (2-dimethylaminoethoxy) ethoxy) -2-thienylmethylene) -2, 5-piper~ 7; n p~; onP .
5389 (3Z, 6Z) - 6-Benzylidene-3 - (5 - ( 6-dimethyl ~mi nr~hPYylOXy) _ 2-thienylmethylene) -2,5-piperaZ;nP~i- n~.
5299 (3Z,6Z) -6-Benzylidene-3- (5- (2-dimethylaminoethyl ) methylamino - 2 - thienylmethylene ) - 2, 5 -piperazinedione .
5075 (3Z, 6Z) -3- (2, 5-~ichloro-3-thenylidene) -6-benzylidene-2, 5-piperaz; nP-l; ,.nP .
5371 N- (4- (1,2,3,4-Tetrahydro-2-isoquinolyl)butyl) -4-( (3Z, 6Z) -6-benzylidene-2, 5-dioxo-3-piperazinylidene) methyl hPn7:1m; ~1P .
5391 N- (2- (1, 2, 3, 4-Tetrahydro-2-iso~uinolyl) ethyl) -4 -( (3Z,6Z) -6-benzylidene-2,5-dioxo-3-piperazinylidene) methyl h-~n7~m; tl~, 5394 N-(3-(1,2,3,4-Tetrahydro-2-isos~uinolyl)propyl)-4-( (3z, 6Z) -6-benzylidene-2, 5-dioxo-3-piperazinylidene) methyl hPn7:~m; ,~p .
5393 N- (4- (2- (1, 2, 3, 4-Tetrahydro-2-SUB~T~TUTE SHEET (I~ULE 26) WO 9~/2l832 ; ` ~ 8 2 8 7 7 P~
isoquinolyl ) ethyl ) phenyl -4 - ( (3Z, 6Z) -6 -benzylidene-2, 5 -dioxo-3 -piperazinylidene) methyl hF.~7~3m; ~, 5402 N- (4 - (2- (1, 2, 3, 4-Tetrahydro-2 -i 5 oquinolyl ) e thyl ) phenyl ) - 4 - ( ( 3 Z, 6 Z ) - 2, 5 - dioxo - 6 - ( 4 -S nitrobenzylidene) -3 -piperazinylidene) methyl h-~n7~m; AP, ~ ' 'q of formula A, may be prepared by a process which comprises either (i) condensing ,~ ' of formula N~H
0 AC-N~b,R2 (1) o wherein R2 is as defined above and is optionally protected, with a ~1 of formula (II):

Rl--CHO (Il) wherein Rl is as defined abovç and is optionally protected, in the presence of a base in an organic solvent; or (ii~
nnn~ nq;n~ a, ~ul-d of formula (I' ):
O
Rl~N,Ac --N~
wherein R~ is as def ined above and is optionally protected, 25 with a compound of formula (III):

R2--CHO (lil) wherein R2 is as defined above and is optionally protected, SUBSTlrUTE SI~E~T (P~ULE 26) wo ssl~l832 ~ J - 2 7 8 2 8 7 7 ~ c in the presence of a base in an organic solvent; and, in either case (i) or (ii), if required, removing optionally present protecting groups and/or, if desired, converting one ~ 1 of formula A into another ~ of formula S A, and/or, if desired, converti~g a -, In~l of formula A
into a pharmaceutically acceptable salt or ester thereof, and/or, if desired, converting a salt or ester into a free c ~, and/or, if desired, separating a mixture of isomers of , 'q of formula A into the single isomers.
A compound of formula A produced directly by the rnn~ nq~t;nn reaction between (I) and (II) or (I') and ~III) may be modified, if desired, by converting R1 into a different R1 group. These optional conversions may be carried out by methods known in themselves. For example, a ' ' of 3~ormula A in which Rl comprises an ester group may be converted to a compound of formula A wherein the correqpnr~iin~ substituent is a free -COOH or OH group, by acid or ~lk~l ;n~ hydrolysis at a suitable temperature, for example from ambient temperature to 100C.
A ,_ ' of formula A in which either or both of R
and R2 includes an -OH group may be converted into a ~ of formula A wherein the corr~qpnrrl; n~ substituent is esterified, for example by treating with a suitable carboxylic acid in the presence of an appropriate coupling agent, acid anhydride or acid chloride ir. an inert solvent.
A compound of formula A in which either or both of R

and R2 includes a -CO,H group may be converted into a SUBSTITUTE S~I~E~ (~V~ 26~

WO g5/2183~ 2 1 ~ 2 ~ 7 7 ~ ,75,C ~ ~

compound of formula A wherein the corr~qpc-n~;n~ substituent is esterified, for example by treating the carboxylic acid with a suitable Cl-C6 alkyl alcohol in the presence of l, 3-dicyclohexyln:~rho~ m;~l~ in an inert solvent.
A ~ ol~n~ of formula A in which either or both of R
and R2 includes a free -C02X group may be converted into a of formula A in which the .c~ .ding substituent is a group -CON~Rl1R1~), wherein R1l and R12 are as defined above, for example by treatment with ammonia or an amine in the presence of l,3-dicyclohexylrArho~;;m;~o in an inert solvent.
A compound of formula A in which either or both of and R2 include3 a free -C02H group may be converted into a , ' of formula A wherein the corr~q~pnn~l;ns substituent iB a -CX20~i group by r~ nt;nn, for example using borane in a suitable solvent such as tetrahydrofuran.
A, , iu1.d of formula A in which either or both of R1 and R2 is a nitro group may be converted into a ~ ' of formula A in which the corr~qp^n~; n~ substituent is an amino group by reduction under standard conditions, for example by catalytic hydrogPn;-t; nn .
Protecting groups for substituents on Rl and/or R2 in any of the, ~ llnflq of formulae (I~, (I' ), ~TI) and (III) are optionally introduced prior to step (i) or step (ii) when either or both Rl and R2 include one or more groups which are sensitive to the cnnrl~nc~tion reaction conditions or ;n~ ;hle with the n nn~nq~tion reaction, for example a -COOX, -CX2OH or amino group. The protecting groups are SU~ 53-lLET ~h~L~ ~6~
. _ _ _ _ _ _, , . ,,, . . . .. . _ . . . . , ... . , _ _ Wo 9~12183z ' ~ 2 1 8 2 8 7 7 r~ 7-~

then removed at the end of the process. Any convpnt;~n~
protecting group suitable for the group Rl and/or Rz in question may be employed, and may be introduced and subse~uently removed by well-known standard methods.
The rnn~pncation reaction between . '~ (I) and (II) or (I' ) and (III) is suitably performed in the presence of a base which is potassium t-bl~tnY; dP, sodium hydride, potassium r~rhrn~te, sodium carbonate, caesium r~rhnn~te, sodium acetate, potassium fluoride on alumina, or triethylamine in a solvent such as dimethylformamide, potassium t-bUtn~ P in t-butanol, or a mixture of t-butanol and dimethylf.,L, rlP (DMF) . The reaction is typically performed at a temperature from OoC to the reflux temperature of the solvent.
The compounds of f ormula ( I ) may be prepared by a process comprising reacting 1, 4-diacetyl-2, 5-piperazinedione with a ~ ' of formula (III) as defined akove, in the presence of a base in an organic solvent.
Similarly, the compounds of formula (I' ) may be prepared by a process which comprises reacting 1,4-diacetyl-2,5-piperazinedione with a ~ ' of formula (II) as defined a~ove, in the presence of a base in an organic solvent.
If nPcPcs~ry, the resulting i of formula (I) or (I' ) can be separated from other reaction products by chromatography.
The reaction of 1,4-diacetyl-2,5-piper~; n~rl;rnP with the ~ Ju,-d of formula (III) or (II) is suitably performed under the same cnn~itirnc as described above for the SUBSTITIJT~ SHEET (P~UI E 26~
... . _ _ .. _ . . . , ... . . . _ _ _ _ _ _ . . .

W0 9~/21832 ~ 2 ~ 8 2 ~-7 7 . ~ .s~

r~nn~l~nqation between ,- , lnr3q (I) and ~II), or (I' ) and (III) The substituted aldehydes of formulae (II) and (III) are known _ ul.ds or can be prepared from readily available starting materials by conv~ontinn~l methods. The l,4-diacetyl-2,5-piper~7;nP~linn~ used as a starting material in the preparation of compounds of formula (I) may be prepared by treating 2~5-piperaz;n~ nn~ (glycine anhydride) with an acetylating agent. The acetylation may be p~Loll -d using any conv~ntion~l acetylating agent, for example acetic anhydride under reflux or, alternatively, acetic anhydride at a temperature below reflux in the of 4-dimethylaminopyridine.
r _ul-d8 of formula (I) may algo be prepared by the microwave irrA~;~tinn of a mixture comprising 1,4-diacetyl-2,5-piperazinedione, a, , d of formula (III) and potassium fluoride on alumina (as base) in the absence of solvent .
r~ of formula (I) may alternatively be prepared directly from 2, 5-piperazinedione (glycine anhydride) by a process which comprises treating the 2,5-piper~7in~;n with a mixture compri6ing a ~ ~ 1 of formula (III), sodium acetate and acetic anhydride at an elevated temperature, for example under reflux.
C , _ Aq of formula (I' ) may be prepared by analogous processes, r~rl~-in~ , 1 (III) in each case by a compound of formula (II).
rn~,rolln-lc of formula A may also be prepared by a SUi;STITEJTE SHEET lRULE 26) -~'VO 95~21832 ~!; ' ' ' ~. ~t 2 1 8 2 8 7 7 r~ 1/~ ~

process comprising the microwave ;rr~;At;nn of (i) a mixture comprising a, , u.-d of formula (I) as defined above, a compound of formula (II) and potassium fluoride on alumina, or (ii) a mixture comprising a compound of formula 5 (I' ) a compound of formula (III) and potassium fluoride on alumina, or (iii) a mixture comprising 1,4-diacetyl-2,5-piper~7;nf~fl;nnP, a ~ , ' of formuIa (II), a, ~1 Of formula (III) and potassium fluoride on alumina. The irradiation iB performed in the absence of a solvent.
C ,_u.lds of formula (A) may also be nht~;n~d directly by a process which comprises condensing together l,4-diacetyl-2,5-piperA7;n~l;nn~, a compound of formula (II) and a compound of formula (III) in the presence of a base in an organic solvent. Suitable bases, solvents and reaction conditions are as described above for the cnn~l~nqAt;nn reaction between, for example,, , nr~
and (II).
An alternative direct process for the ~Le~Lc~tion of ~ , uL-ds of formula (A) comprises condensing together 2, 5-piperA7;no~;nn~ a ~ of formula (II) and a c of formula (III) in the presence of sodium acetate and acetic anhydride at elevated temperature, for example under ref lux .
An alternative process for the preparation of , 3q of formula (I) comprises treating a ~ , lu~ld of formula (V):
SVBSTITIJTE SHE~T (~ULE 26 WO 95/21832 ; ~~ 2 ~ 7 7 r~

~NH
R'O~R2 (\/~

wherein R6 to R~ are as defined above, X is a halogen and R' is a Cl-C6 alkyl group, with ammonia followed by acetic anhydride .
r ul~ds of formula (I' ) may be prepared by an 10 analogous process which comprises treating a ' , ' of f ormula (V~ ):

R1/~OR' O
wherei~ R~ to Rs~ X and R' are as defined above, with ammonia followed by acetic anhydride.
X in formula (V) or (V~ ) is typically iodine. R' is, for example, a C,-C~ alkyl group such as a methyl, ethyl, 20 propyl, i-propyl, butyl, sec-butyl or tert-butyl group.
A review of synthetic approaches to ul~at.u~c~ted 3-monosubstituted and 3,6-disubstituted-2,5-piper;-~;n.o~ n~c, is provided in HeterocYcles. 1983, 20, 1407 (C.Shin).
r ~c of formula (A) may be optionally washed 25 after any of the above preparative procedures with one or more of the following: water, ethanol, ethyl acetate and diethyl ether.
Where appropriate ~ ol~n~C of formula (A) may be SUBSTITU,E SHEET ~ 26~
_ __ _ _ _ . ., . _ ~ ~ . f, ,. ,~
wo g~/21~32 . .~ 2 ~ 8 2 8 7 7 P l~D ~ ~

optionally recrystallised from a suitable solvent such as methanol or acetic acid.
Compounds of formula (A) may be converted into pharmaceutically acceptable salts, aIld salts may be 5 converted into the free ~ , u--d, by conv~ntir~n~l methods.
Suitable salts include salts with phar~ PIlt;r~lly acceptable, inorganic or organic, acids or bases. r - 1PC
of inorganic bases include ammonia and r~rhr,n~tPR, hydroxides and 1-yd~ d~l r:~rhrn:~t~q of group I and group II
lO metals such as sodium, potassium, magnesium and calcium.
Examples of organic bases include ~1 ;rh~t;c and aL~ t;C
amines such as methylamine, triethylamine, benzylamine, dibenzylamine or ~- or ~;-phenylethylamine, and heterocyclic bases such as piperidine, l-methylpiperidine and 15 morpholine. Examples of inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid.
Examples of organic acids include p-tolll~n~ql~l phr,n; C acid, methansulphonic acid, mucic acid and succinic acid.
Compounds of formula (A) may also be converted into 20 pharmaceutically acceptable esters. Suitable esters include branched or unbranched, satllr~tPd or unsaturated Cl-C6 alkyl esters, for example methyl, ethyl and vinyl esters .
The diketopiperazines of formula (A), both novel and 25 known and their pharmaceutically acceptable salts and esters (referred to hereinafter as the ~present ~ , rlq~ ) have utility as inhibitors of PAI Elevated levels of PAI-l, by reducing the net endogenous fibrinolytic capacity, SUBSTliUrE S~EEr ~ ULE 26~

- t~ ;;` 2 ~ 82~77 Wo 9512183Z ~ J

can contribute to the pathogenesis of various thrombotic disorders including myocardial infarction, deep vein thrombosis and ~; c,c~m; n~ted intravascular coagulation. The present ~ ~~ therefore can act as inhibitors of the 5 tPA/PAI-l interaction. The pre5ent ~ v~ lC can be used in the treatment of haemostatic disorders. A human or animal, e . g . a mammal, can therefore be treated by a method comprising administration of a therapeutically effective amount of a diketopiperazine of formula (A) or a 10 ph~ e1~t i cally or veterinarily acceptable salt thereof .
Tis8ue ~l~r~"inrg~n activator ~tPA) is used as a fibrinolytic agent in the treatment of thrombotic disorders. The efficacy of the tPA in this role may be ~nhs~nrod if it is administered together with a PAI
15 inhibitor. A human or animal, e.g. a mammal, can therefore be treated by a method comprising the i n~d administration of a therir~o11t;r~l1y effective amount of tPA
and a therapeutically effective amount of any one of the present ,: ~u~.ds. The present invention also provides 20 products r~nt~;n;nrJ a diketop;~ 7;n~o of formula (A) or a ~h~ ~ellt i cally acceptable salt or ester thereof and tPA
as a . ' in~d preparation for simultaneous, separate or sequential use in the treatment of thrombotic disorders, for example where there is inappropriate PAI activity. In 25 such products the preBent ~ i5 formulated for oral or parenteral ~intravenous, intramuscular or subcutaneous) administration and the tPA is formulated for intravenous administration .

SU85T~TUrE SHEET (RULE 26) wo gsnl832 ~ 1 8 2 8 7 7 As one example, during acute myocardial infarction (MI) one of the present compounds may be administered to a patient together with tPA to enhance the efficacy of the tPA treatment. A8 a further example, early re-occlusion 5 following treatment of a patient with tPA may be prevented by the post-MI administration of one of the present ~ ,~c .
The ~ ~1c of formula ~A) have been tested in a PAI
functional assay. In this assay, a compound is incubated 10 with PAI-1 prior to addition to the tPA assay system.
Inhibition of PAI-1 results in the pro~ rtlrn of pla8min from ~1 :qr-~; nrs.Qn . In turn, plasmin cleaves the .1~ .liC
substrate S2251 (Kabi Vitrum) producing pNA (p-nitro~n; 1 i nf-) which is detected spectrophotometrically at 15 405 nm (K.Nilsson et al, Fibrinolysis (1987) L, 163-168).
The results of the assay are reported below.
The present c ~lq 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 20 solutions or suspensions or parenterally, for example rly, intravenously or sl~hc~lt~n~ollq1y. The present ~ c may therefore be given by injection or infusion .
The dosage depends on a variety of factors including 25 the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted ~or each route o~ administration when a ~ _ ' of the invention is administered alone to adult humans is 0 . 001 to 5UBSTITUTE SIIEET !RULE 263 WOg5/2l832 ~ ' Z ~ ~$77 P

lO mg/kg, most commonly in the range of 0 . 01 to S mg/kg, body weight. Such a dosage may be given, for example, from 1 to S times daily by bolus infusion, infusion over several hours and/or repeated administration.
When one of the present compounds is administered ln combination with tPA to adult humans, the dosage adopted for each route of administration is typically from 0 . 001 to lO mg, more typically 0 . 01 to S mg per kg body weight for a ~i of the invention and from 5 to SOOmg administered intravenously for the tPA. A suitable dosage regimen for the tPA is lO0 mg given iL~LL~vel.~,usly over 3 hours as follows: 109~ of the total dose as an i.v. bolus over 1-2 minutes, 509~ of the total dose as an infusion over 1 hour, 409~ of the total dose as an infusion over the subsequent 2 hours.
A diketopiperazine of f ormula (A) or a pharmaceutically acceptable salt or ester thereof is fùLl l~t~d for use as a pharm=~e-~tir~l 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 phar"~- -eu~ i r;~ 1 1 y or veterinarily suitable form. An agent for use as an inhibitor of PAI comprising any one of the present ,- ~ '- is therefore provided.
For example, the solid oral forms may contain, together with the active ~ LlU~ , diluents such as lactose, dextrose, saccharose, cellulose, corn starch or SUBSTITUTE SHEET (~ULE 26~

W09~/21832 ` " '`' ;~ 2 ~ 7~ r~l ~5~
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 5 polyvinyl pyrrolidone; disintegrating agent6 such as starch, alginic acid, alginates or sodium starch glycolate;
effervescing mixtures; dyestuffs, sweeteners; wetting agents such as lecithi~, polysorbates, lauryl sulphates.
Such preparations may be manufactured in known manners, for 10 example by means of mixing, srAnlllA~in~, tabletti~g, sugar coating, or f ilm-coating processes .
~ iquid dispersions for oral administration may be syrups, emulsions and suspensions. The 8yrups may contain as carrier, for example, saccharose or saccharose with 15 glycerol and/or mannitol and/or sorbitol. In particular, a syrup for diahetic patients can contain as carriers only products, for example sorbitol, which do not ~Ahnlice to glucose or which only metabolise a very small amount to glucose . The suspensions and the 1 c; nnC may contain as 20 carrier, for example, a natural gum, agar, sodium alginate, pecti~, methylc~ nse, carboxymethylc~ oce or polyvinyl alcohol.
S--cr~ncinnc or solutions for i~tramuscular injections may contain, together with the active ~ u.-d, a 25 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 SUBSTITUTE SHEET (~ULE 26~

Wo 95/2183~ 2 i 8 2 8 7 7 ~ il; c c ~

in water. A, , ~nrl may be Pnr~rsll~ ~tPd within liposomes .
TESTING OF TEIE PRESENT
~NL~S AS PAI lN~ L~RS

t'~ '- of ~ormula ~A) were tested in a PAI
~:}~LI ~ .liC substrate assay. In the assay ~K.Nilsson, Fibrinolysis ~1987) 1, 163-168) eacX ~ ' was inrllh~tpd with PAI-l prio~ to addition to the tPA as3ay system.
Inhibition of PAI-l by the c ' of formula ~A) resulted 10 in the production of plasmin from pl ~r-; n~rjon . In turn, the plasmin cleaved the ~:}"~ , ; c substrate S2251 ~Kabi-Vitrum) producing pNA ~I2-nitroaniline) which was detected ~e.L,u~hotometrically at 405 nm.
The degrees of inhibition obgerved in the c}.~ 3~- i r 15 substrate assay at various concentration8, and/or ICso values, of compounds of formula ~A) are presented in Table 1. ICs~ values for some _ '~, not shown in Table 1, are listed in Table 2 which follows Table 1.

TI~RT.T' 1: ~TTRTTION OF PAI-l IN Tl}E: SZ2Sl r~nvn~ TC SIJRSTT ~TTC Il~ q~'Y
t~,r~ tlon .n ~m 100 50 25 12.5 6.25 147C) 70 20 2 0 o SU..ST~UT-r C'~E~T (RULF 26 .. . . . ..

WO95/21832 ;~ f~ , 2 1 828 77 i~

SUBST~UTE SilE~T (RULE 26) Wo95/21~32 ' '~ ~ ~ ~ 2 1 8 2~ 7 7 .~ S'C~ - ~

~' _ _ ' Conce Itr~tiO~ i /~M IC50 lOO~M 50~M 20~M

5032 65 62 63 25 . 0-12 . 0 5042 77 64 42 20 . 0-10 . o 5048 55 19 11 100 . 0-S0 . 0 5052 77 76 86 12 . 0 -6 . 0 15 5053 68 64 56 25 . 0-12 . 0 5054 5 57 48 50 . 0-25 . 0 5055 69 69 70 6.0-3.0 5061 43 48 60 25 . 0-12 . 0 20 5062 78 81 87 12 . 0-6 . 0 5069 70 71 75 10 . 0-5 . 0 5071 80 82 73 10 . 0-5 . 0 5072 60 61 61 10.0-5.0 5073 63 70 14 20 . 0-10 . 0 25 5074 47 57 26 20 . 0-10 . 0 5075 88 88 52 25.0-12.0 5078 60 67 11 20.0-10.0 5079 44 58 14 20 . 0-10 . 0 30 5081 25 34 50 6 . 0-3 . 0 5188 90 94 3 . 50 5205 56 33 100 . 0 SUBST~TUTE ~HEET (~ULE 26~

~ Wo95/21832 ." ~ 2 ~ 82 8 7 7 P~ . S ~_ 5206 72 78 3 . 0 5299 7 . 00 5324 9.00 55335 22 . 0 5367 18 . 00 5371 12 . 00 5376 12 . 00 5379 65 15 . 00 105386 18.00 5388 58 9.00 5388 .HCl 60 12 . 00 5389 55 2 . 50 5389 HCl 57 2 . 50 5391 64 6.50 5391.HCl 100 3.50 5393 76 14.00 5393 .HCl 58 20 . 00 5394 59 16 . 00 5394 .HCl 62 17 . 00 5397.HCl 21 5402.HCl 37 TA2~ 2 r _ ' No. IC50 (~
1470 50 . 0 - 100 . 0 1471 25 . 0 - 50 . 0 1474 25 . 0 - 50 . 0 1476 50 . 0 - 100 . 0 1506 25 . 0 - 50 . 0 1507 25 . 0 - 50 . 0 SU;3S~ITUT~ SHEET (RULE 26) WO9~/21832 ~ 218281'7 P~

1509 50 . 0 - lO0 . 0 1542 50 . 0 - 100 . 0 1560 50 . 0 - 100 . 0 1618 S0 . 0 - 100 . 0 51652 25 . 0 - 50 . 0 1657 25 . 0 - 50 . 0 1672 50 . 0 - 100 . 0 1676 12 . 0 - 25 . 0 1693 50 . 0 - 100 . 0 1718 50 . 0 - 100 . 0 1808 25 . 0 - 12 . 0 1809 25 . 0 - 12 . 0 1845 10 . 0 - 5 . 0 1888 50 . 0 - 100, 0 1910 5 . 0 - 10 . 0 1912 25 . 0 - 50 . 0 1921 100 . 0 - 50 . 0 1928 25 . 0 - 50 . 0 1929 25 . 0 - 12 . 0 1930 25.0 - 12.0 1982 50 . 0 - 25 . 0 Refer~nce ExamDle 1: PreT~r~tlon o~ (3Z)~ cetvl-3-b~nzYl~de~e-2, 5-piDer~7~n~ nn~
1, 4-Diacetyl-2, 5-piperazinedione (25 . Og, 126 mmol), which i8 com?ol~n~ ~8) mentioned in Reference Example 3, was 30 heated at 120-130C in DMF (200 ml) with triethylamine ~17.6 ml, 126 mmol) and bPn7~lrl.ohyde (13.0 ml, 126 mmol).
A~ter 4 h the mixture was cooled to room temperature and SUBSTITUTE SHEET (RULE 26~

~ WO '7`5/21832 ~ 2 ~ ~ 2 8 7 7 poured into EtOAc (1000 ml), and washed three times with brine. ~ny solid formed at this stage was filtered o~f.
The filtrate was dried (MgS0~) and the solveIlt removed ~
vacuo. The residue was recryst~ll;qP-I from EtOAc:Hexane to 5 give 11. 78 g (38~) of the title compound as a yellow solid.
H NMR (CDCl3 400 MHz) ~=2.69 (3X, 5) 4.54 (2H, 8) 7.20 (lX, 8) 7.40 (3H, m), 7.48 (2H, m), 7.93 (lH, br.s~
MS(DCI,NH3): 262 (MNH~-, 209f), 245 (MH~, 539 10 220 (52~), 204 (1009~), 203 (100~) Mlcroan~lysi~ C E~ N
Calc 63.93 4.95 11.47 Found 64 .11 5 . 02 11. 41 15 Found 64 . 05 4 . go 11. 44 Alternatively (3Z) -l-acetyl-3-benzylidene-2, 5-piper~7;n~l;cnl~ can be produced as follows:

o ~1 OEt C ~I HN
O O
(16) ~17) (1 8) SV5STITUTE SHEET ~RULE 26) _ wo 95nl832 ` `~ 1 8 2 8 7 7 i ~ 95, ul~d 16 is treated with ammonia and subsequently with acetic anhydride to yield the title ~ '.

Refe~--. ,c6 r ~le 2: pr~Daration 0~ t3Z) ~ cetYl-3- ~4-~ce~f~ h~n7ylide~ne) -2, 5-l:~lDer3l7ined~ ~no 1,4-Diacetyl-2,5-piperA7~nP~ nP (10.Og, 50 mmol), prepared by the pl~hl;RhPd procedure r t;~nP~ in Example 3, was stirred in DMF (40 ml) with 4-acetAm; ~l~hpn7~ phyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 120C. After 2~ h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid ~ormed was collected, washed with EtOAc and dried to give 8.46 g (569f) o~ a yellow solid.

lH NMR (CDC13+TFA, 400 MHz) ~=2.32 (3H, 8) 2.72 (3H, 8)
4.68 (2H, 8) 7.36 (lH, 8) 7.45 (2H, d, J-8Hz) 7.60 (2H, d, J= 8Hz ) 20Microanz-ly~i~ C }~ N
Calc 5g . 80 5 . 02 13 . 95 Found 60 . 08 5 . 09 13 . 89 60 . 11 5 . 07 13 . 86 25Re~rence Exa~nDle 3: ProDar~tion 0~ 1,4-DiacetYl-2,5-DiDer~ 7 ~ no~ ~ one O O
~NH ~NAc HN~DJ AcN~
O O
(7~ (ô) SUBSTITUT~ ~H~T (P~UL~ 26) wo9512l832 .~ r ~ f ~ 828 77 r~

1,4-Diacetyl-2,5-piperazine dione (8) was ~"el~aL~:d by the published procedure (S.M. Marcuccio and J.A. Elix, Aust. J. Chem., 1984, 37, 1791).

Reference Ex~ll:~le 4: (3Z) -l-AcetYl-3- (4-methoxybenzYlidene) -2, 5-DiD erA 7 ~ rZ ~ ~n ~
o 0 ~NAc ~NH
ACN~J AcN~
(8) (9) (3Z) -l-Acetyl-3- (4-methoxybenzylidene) -2, 5-piperazinedione (9) was prepared by the F~7hl;~h~d p~u~ed (T. Yokoi, ~-M. Yang, T. Yokoi, R-Y. Wu, and K-H. Lee, J.
Ant;hiot., 1988, 41, 494) -20 Reference EX21mDle 5: PreD~rAtion of (32:)-1-~cetYl-3-(2,6-) V~ Ylidene) -2, 5-r~n~r~7~n~ n--1,4-Diacetyl-2,5-piperA7;n~ n~ prepared by the published procedure r tionod in Reference Example 3, was 25 stirred in DMF with 2, 6-dichlor~h~n7~ ohyde and triethylamine and heated to 120-130C for 1-3h. The title , ~i was obtained with a yield of 40~.

SUBSTITUTE SHEET (~ULE 26) Wo 95/2183~ 2 1 ~ 2 ~ ~ 7 P~

Re~erence EXamD1e 6: PreD~ratioIl of (3Z) ~ cetYl-3- (4-(3 -dimethYl Am; nn ) 1~ Y"~,,.Yl.c.,zYlidene) ~
2, 5-Piver~-~; n~ I nn~
1,4-Diacetyl-2,5-piperazinedione, prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 4- (3-dimethylamino) ~Iv~u~yL~z~ ldehyde and triethylamine and heated to 120-130C for 2-4h to give the title _ ~1 By the same method, using 4- (2-dimethylamino) ethu~yL~ v~ ohyde in place o~ the above-v t;rnPd aldehyde, (3Z) -l-acetyl-3- (4- (2-dimethylamino)etllu-~yL~n~.ylidene)-2l5-piper~7i nP~ nP was prepared .

Refer~nce EXa~nD1e 7: (3Z,6Z)-3-(4-l}~l ~,,.yL~ Ylidene)-6-(4-m~ YL_ -,.Ylideno) -2, 5-DiDerA-~ n~7~ nn~
(3Z,6Z) -3- (4-Acetoxybenzylidene) -6- (4-methoxybenzylidene)-2l5-piperi7;np~i;rn~ was treated with acueous sodium hydroxide in THF at room temperature for 8 hrs to give the title compound (lSl9) in 309~ yield.

r le l: Pre~/lration of 1470 25 3 (Z) -l-Acetyl-3-benzylidene-2,5-piperA7;n~irn,o (one e auivalent), which is ~ , iUlld 18 prepared according to Reference Example 1, was treated with l-tert-butoxycarbonylpyrrole-2-r~rh^~ Phyde in the presence of SUBS~ITUTE SHE~T (RULE 26) -WO 95/21832 ~ 2 1 8 2 8 7 7 P. l ~ ~

C82C03 ~ e~uivalents) in DMF at 80-100C for 1-6 hours. The title compound was obtained in 249t yield.
- The crude product was optionally, washed with water, methanol, ethyl acetate or diethylether and optionally
5 recryst~l 1; qP~l from methanol as appropriate.
By the same method, l~ut replacing l-tert-butu..y~-crL~vl~ylpyrrole-2-r~rhoy~ phyde by the appropriately substituted aldehyde or bPn7~ Phyde, the following , , ~q were prepared:

~ ' Yi-ld (%) 5~3STI~IJTE SHEET (P~ULE 26!

WO 9~/21832 ~ - 2 7 8 2 ~ ~ 7 1 ~I/.JB ~ ~ ~

r 1~ 2 Pre~Ar~tion of 1474 3 (Z) -l-Acetyl-3- (4-methoYybenzylidene) -2,5-piperazinedione prepared according to Reference Example 4, was treated with 2-thir,Fh~n~r~rhryA~ hyde in the presence 5 of Cs2CO3 (1-1.1 equivalents) in DMF at 80-100C for 1-6 hours. The title , u-~d was obtained in 76~ yield.
By the same method, but r~pl~r~n~ 2-~h; ~rh~nF-r~rhrY~l dehyde by the appropriately substituted aldehyde, the following ~ were prepared:

C _ ' Yl ld (96) The crude product was optionally washed with water, methanol, ethyl acetate and diethylether and optionally recrystallised ~rom acetic acid or methanol as appropriate.

20 r 1~ 3: Pr~1~ar~tion o~ 1 884 3 ( Z ) -1 -Acetyl - 3 -benzyl idene- 2, 5 -piper~ 7 i le~l; rn~
equivalent), prepared according to Reference Example 1, was treated with cycl nh~Y~n~cArhry~ hyde (4 equivalents) in the presence of 0.5M potassium tert-butoxide in tertiary 25 butanol (2 equivalents) in DMF at 0-100C for 2 hours. The title compound was obtained with a yield of 58~.

Purification was effected by recrystallisation from acetic acid .
1672 was prepared as above but replacing the 3 (Z) -1-Sl.7~STITlJTE SHE~T ~P~U!E 26) ~ Wo 95l21832 ; ~ 7 / I ~ I . .
acetyl-3-benzylidene-2,5-piperaz;n~ n.o with 3 (Z) -1-acetyl-3- (4-acetamidobenzylidene) -2, 5-piper~7in~ n~. The reaction was -~;nt~in~-l for 18 hours. A low yield was obtained .

r 1 e 4 Pre~aration of 1676 1-Acetyl-3 - (4-Aret~mi ~mh~n7ylidene) -2, 5-piperaz; n~ n-~ (one equivalent), ~ aLed according to Reference Example 2, was treated with c;nn~ hyde in the 10 presence of Cs2C03 (1-l.1 equivalents) in DMF at 80-100C
for 1-6 hours. The title, , _ ' was rlht~;nf~l in 46 yield .

15 Exam~le 5: Pre~aration of 1618 1,4-Diacetyl-2,5-piper~7in~iionp~ prepared by the pl1hl;qh~.d procedure Ir tinnF~i in Reference Example 3, was stirred in DMF with 2-th;mrh~n~m~rh~y~ldehyde (1 20 equivalent) and triethylamine (l equivalent) at 120C ~or 2-4h. (3Z)-1-Acetyl-3-(2-thenylidene)-2,s-piper:~7in.~i,nO
was obtained with a yield of 369.
(3Z) -1-Acetyl-3- (2-thenylidene) -2,5-piper~7in~;
(1 equivalent) was stirred in DMF with 3-1-tert-25 but~.~y.~ -ylindole-3-carboxyaldehye (1 equivalent) in the presence of Cs2C0, (1-1.1 e~uivalents) at 80-100C for 2-3h. The title ,_ ~ was ~ht~;nP-l with a yield of 14~.

5~J85,1T~T~ S3~E'T (~5LE 26~

WO g~/21832 ~ 2 ~3 7 7 r~ ~ Bs ~ c ~
6: Pr~r~ ~tion of 1542 3 (Z) -1-Acetyl-3- (2, 6-dichlorobenzylidene) -2, 5-piperaz;nP~iinnp (1 equivalent), prepared according to Reference Example 5 was treated with 3-furaldehyde ~1 5 equivalent) in the presence of Cs2CO3 (1-1.1 eguivalents) in DMF at 80-100C for 2-5 hours. The title 1 was obtained in 46" yield.
By the same method, but rPrl~i n~ 3 -furaldehyde by the appropriately substituted aldehyde, 1560 was obtained 10 with a yield of 399~.

r l ~ 7: Pr~aration of lssa 3(Z)-l-Acetyl-3-benzylidene-2,5-piper~7inP~ nP (1 equivalent), as prepared in Reference Example l, was 15 treated wi~h 4- (N- (3-dimethylaminoethyl) -N-methyl)~min~ thylhPn7~l~Phyde in the presence of C5,CO3 (1-1.1 equivalent5) in DMF at 80-100C for 1-6h to give (3Z, 6Z) -3-Benzylidene-6- (4- (N-dimethyl ~mi nr1ethyl) -N-methyl)~mi -thylbenzylidene)-2,5-piper~7inPr~ np in a 20 yield of 509~.
r ' 1982, the hydrochloride salt of (3Z,6Z)-3-Benzylidene-6- (4- (N- (3-dimethyl~minnpthyl) -N-methyl)aminomethylbenzylidene)-2,5-piper~7;nP~ nP, was prepared by bubbling XCl gas through a solution of the 25 corrpqpmn~lin~ free base in TXF, followed by evaporation to dryness. The yield was 45~.

SU135TI~UTE S~;EET (RUL~ 26~

~ wogS/21832 ~ ~ . 2 ~ 828 77 ~ Sl'i r 7~ 8 PreT~aration of 1976 3 (Z) -1-Acetyl-3- (4- (3-dimethylamino)~u~u~y~ zylidene)-2,5-piperaz;n~ nP (1 equivalent), prepared according to Reference Example 6 was 5 treated with 3- (imidazol-1-yl)benzaldehyde (1 equivalent) in the presence of Cs2C03 (1-l.1 equivalent) in DMF at 80-9ooC for 2-4 hours. The title compound was ~bt~;n~od in 52t yield .

10 r l ~ 9: Pre~r~tion o~ 1886 1519 (1 equivalent), prepared in Reference Example 7, was treated in DMF with sodium hydride (1 e~uivalent) and N-phthaloylglycyl chloride (1 equivalen~) in DMF at room temperature for 4h. The title compound was oht~;n,od with a 15 yield of 303f.
l ~ lO proD~rAtion o~ 5026 \I~CHO oç)~ ~NMe2 IQI I O
` ' i,, NH ~ , , J NMe2 5U3STITUTE S~EET (RULE 26) WO 95/21832 ' ~ ~' 2 ~ ~ 2 8 7 7 ' - --(3Z) -l-acetyl-3- (4- (3-dimethylamino)propoxy-benzylidene)-2,5-piper~7lno~ n~, prepared as in Reference Example 6, was treated with ~ ,_ ' 10 1 in dimethylf~ mi ri- (DMF) in the presence of Cs~CO3 at a 5 temperature of 80C-90C for 2-4 hours (' ~ 5026 was obtained in 955~ yield.
By an analogous process, using the appropriately substituted benzaldehyde in place of ~ ~ .u.-d 10 1, the following ~ ~ _u.~ds were prepared:

'- __ ' No. Y~ld 96 5188 , 70 15 r ~ prel~Ar~tio~ o~ 5027 ~3 + ACN~ æJ NMe2 11.1 l ~ ~' NH ~ ~NMe2 N HN~
O

SUBSTITUTE SHEE~(RULE 26 WO9S/21832 `~ 2 ~ 828 7 7 r ~ 5~ .

(3Z) -i-acetyl-3- (4- (3-dimethylamino)propoxybenzylidene) -2,5-piperazinedione, prepared as in Reference Example 6, was treated with ~ _ ' 11.1 in DMF in the presence of Cs2CO3 at 80C-90C ~or 2-4 hours. Compound 5027 was 5 produced in 33~ yield.
~3y the same method, but rPrl ~,~; n~ 11.1 by the appropriately substituted aldehyde, the following were prepared:

' No. Yi~ld (96) 502~ 44 5042 ~ 39 I!x~l~le 12: Pre~ration of 5023 ~D~NAC ~o~/ - NMe2 Me2N HN~J OHCJ~J

12.1 O

Me2N I HN~)N~ NMC2 SU~STIT~'TE S~rET (I~uLE 26 WO 9~/21832 ~ ` 2 1 8 2 8 7 7 P~ r ~

, _ ~1 12.1 wag treated with 4- (3-dimethylamino) ~ u~y~enzaldehyde in DMF in the presence of Cs2Cû3 at a temperature of 80C-90'C fûr 2-~ hours.
5023 was obtained in 369~ yield.

1 e 13 . Prel~aration o~ 5062 o 0 C A~
13.1 1 ~O3 HN~ I ~NMe2 2 0 ( 3 Z ) - 1 - acetyl - 3 - ( 4 - ( 2 - dimethylamino ) eth~ yl,el.~.yl idene ) - 2, 5 -piperA~inP~;onp~ prepared a5 in Reference Example 6, was treated with, , _ ' 13 . l in DMF in the presence of CB2CO3 at a temperature of 80'C-90C for 2-4 hours. Compound 5062 was obtained in 12~6 yield.
By the same method, but using the appropriately substituted aldehyde in place of compound 13 . l, the following compounds were prepared:
SUGSTITUTE SH~ET (RULE 26)~

WO95121832 ~ 21 82~77 P~
. ~

~, ' No. Yield ~%) 5072 . 86 r 1 e 14: Pre~ r~tiOn o~ r~ Of ~ 1 n (I) Ar ~ ~c + ~¢~Subst.

14.1 1 14.2 Ar/~NH ~Subst.
HN~sJ
o C 1 a) 20 The 2t5-piper~7:;n~ ;r~n~ derivative 14.1 was treated with the aldehyde 14 . 2, the groups Ar and Subst . being as sper;fie-l below, in DMF in the presence of Cs2C0~ at 80C-90C for 2-4 hours. The compounds of ~ormula (I) listed below were prepared:
2~

SUBSTITUTE SHEET ~RU~E 26)-WO 9S/21832 ... , .. , ~ 2 1 ~ 2 ~ 7 7 P~ ,S.'i Ar Su~st. C ~ ' Yl~ld (9 of formul~
(I) Phenyl -CH2S (CX2) 2NMe2 5058 16 3 -furyl -CHzS (C~2) 2NMe2 5073 33 3-thienyl -CX2S (CX2) 2N~e2 507B 38 53 -thienyl -C~2rlHC (O) CH2NMe2 5074 83 2-bromophenyl -CH2NHC (O) CE~2NMe2 5079 28 3 -furyl -CH2NHC (O) CX2~Me2 5081 68 3-thienyl -CH2O(CH2)2NMe2 5069 29 3 -furyl -CH20 (CH2) 2NMe2 5077 20 r 1- 15: Pre~r~,tion of _ "A Of - 1 A (I) ~o~ N'A`N~RR=
15.1 l lS.2 HN 1' ~ ' ` RX
' SUBSTITUTE SHEET (RULE 26)~

~ WO 9~/21832 ~ . 2 l ~3 2 8 7 J . ~ r The 2, 5 -piperA7; n-o~; nn/~ derivative 15 .1 was treated with the aldehyde 15 . 2 in which R,~ and R2~ are both H or are bo~h OMe, the substituent Ar and linking group A being as specified below, in DMF in the presence of Cs2CO~ at 80C to 5 90C for 2-4 hours. The ~ ~ u.lds of formula (I) listed below were prepared. In 5391, 5394 and 5371 R20 and R21 are both H. In 5393 and 5402 R2~ and R2l are OMe.

Ar ~ ~ _ ' Yield (%) of Formul~
(I) 10Phenyl - (CH2) 2- 5391 21 Phenyl - (CH2) 3- 5394 47 Phenyl - (CH2) j- 5371 56 Phe 1 5393 44 ny ~CH~

4-nitrophenyl _~ 5gO2 62 r 1~ 16 Pre~ar~tloP~ o~ 3 of - lA (I) ~

O

18 1 16.
o SUBSTITUTE SHEET (~ULE 26~.
. .

WO 95/21832 ~ r ~ 2 1 8 2 ~ 7 7 P

(3Z)-l-acetyl-3-benzylidene-2,5-dione prepared as in Reference ~Yample 1 (~ _ ~ 18), was treated with the aldehyde 16.1 in which substituent Y was as indicated 5below, in DMF in the presence of CszC03 at 80C-90C for 2-4 hours. The _ ~c of formula (I) listed below were prepared:

y c _ ~ of Yl~ld %) formula (I) 5_0 (CH2) ,NMe2 5324 34 104-O (CH2) 2NMez 5327 51 5- (CH2)2NMe2 5335 45 5-o (CH2) 2 (CH2) 2NMe2 5388 12 5-o (CH2) 6NMe2 5389 35 5-N(Me) (CH2)2NMe2 5299 2 By the same method, but using 2,5-dichloroth;oph~n~-4-rA7-hrY~ldehyde in place of _ 1 16.1, 5075 was prepared in 31~ yield.

20 r 1~ 17 ProD~r~tlon of s~lt~

1. Hydrochloride salts of the following ~_ rlq of formula (I) were prepared by b~lhhl ;nrJ HCl gas through a solution of the corresponding free base in tetrahydrofuran 25 (THF) at room temperature. The salt was recovered in the yield indicated.

SUBSTITUTE SHEET (~ULE 2b) - ~ =
~WO9S/21832 ~ 2 1 82 8 7 7 r of Hydrochloride Yl~ld formula (I) s~lt 55048 5048.HCl 72 5397 5397 . 2HCl 36 105041 5041.ECl 63 5042 5042.HC1 51 5046 5046.HCl 32 5052 5052.HCl 58 155062 5062.HCl 5071 5071.HCl 5072 5072.HCl 205032 5032.HCl 39 5053 5053.HCl 90 5054 5053.HCl 88 5073 5073.HCl 76 5078 5078.HCl 78 5074 5074.HCl 51 5079 5079.HCl 73 5081 5081.HCl 76 5069 5069.HCl 305077 5077.E~Cl 5324 5324.HCl 68 5336 5336.HCl 74 5335 5335.HCl SUE;STI~UT~ SHeET ~P~ULE 26)~

Wo9~/21832 ; . . ' ' 21 828 7 17 r~

5388 5388.HC1 79 5389 5389.HC1 75 53 91 53 91. HCl 5394 5394.HC1 75 2.Hydrochloride salts of the following _ '- of formula (I) were prepared by bl~hhl in~ HCl gas through a solution of the ~orrP~p~n~in~ free base in hot DMF. The lD salt was recovered in the yield indicated.

C _ _ ' o~ }Iydrocblorid~ Y~ ~ld f ormula ( I ) a~l t 5386 5386.2~C1 79 155393 5393.HC1 60 5402 5402.HC1 52 3. Hydrochloride salts of the following ~ , _ '~ of formula (I) were prepared by treating the free base with 2M
2 0 HCl:

C _ ' of ilydro~hlorid~ YlQld (96) ~ormul~ alt 5027 5027.HC1 67 255028 5028.HC1 92 5029 5029.HC1 76 5040 5040.HCl 90 SUBST~TUTE SHEET (~ULE 26)~

~ WO 95/21832 ~~ e 2 1 ~ 2 8 7 P~ I ~'J"'5 ~

4. 5043.E~Cl, the hydrochloride salt of 5043, was prepared by bubbling HCl gas through a solution of 5043 in MeOH. 5057.HCl, the salt of 5057, was prepared by bubbling E~Cl gas through a solution of 5057 in THF following by 5 recrys~ atin~ from MeOH.

r 1~ 18: pTTl~T~l`~T~TrTIr:~T. COliPO~lr_ Tablets, each weighing 0.15 g and c~n~;n;n~ 25 mg of 10 a _ ~ulld of the invention can be --n~f~ctured as follows:
Coml~osition for 10, 000 tablet8 compound of the invention (250 g) lactose (800 g) corn starch (415 g) 15 talc powder (30 g) magnesium stearate (5 g) The compound of the invention, lactose and half of the corn starch are mixed . The mixture is then f orced through a sieve 0.5 mm mesh size. Corn starch (10 g) is 20 suspended in warm water (90 ml). The resulting paste is used to granulate the powder. The granulate is dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The r ;nin~ quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into 25 tablets.
SUE35T~TUTE SHEET (RUL 26 W0 95/21832 ~ 8 2 ~ 7 7 P~ ,.,,5.'~

19: ~'h-racterisat~on of _ 1~ of for~ul~
A
The ~ c prepared in the preceding E3xamples, were characterised by mass spectroscopic,.microanalytical, 5 proton nuclear magnetic resonance and, in some cases, infra-red techni~ues. The results are set out in the Tables which follow:

SUBSTilU~E SHEET ~ULE 26) WO 95~2~83~ 5 ~ `, 2 1 ~ 2 8 7 7 . ~I/~D: _.

:~ N E _~ , E V~ ~ 5A E Vl E v~
N C T N N I ~1- N _ N N ~ T _ N _ N--~D O ~ o ~ ~ ~ ~ ~~
_ ` 01 _l~r_ ~_0 ~0_ NC:I~a~ -O N ~ 'D 1~ r~
o o u~ o o ~ ~1~ _ 1~ o _ ^ E N O N l~ ~' ~r ~D O O ~ O O U~
~_ NO E v)c:~ E~V v) ~ <~ E~ ~ E~ E ~7 o _ o N--l o ~ N = 0 ~ U7 C ~ _ ~ U~ I O O ~ ON~ = =
~O N t--~ _ N _ 1_1~ ~1 _ N ~) ~_ C~ N ~r 1~ CO N ~r 1_1_ 0 _ _ S
C~ ~ ~
V _ O er t~
'O ~ ~ O ~ ~
a~
~0 ~ O O
V7._ E-- o C
T ~, 0 0~ C.. Z Z
~ ~ T ~
O ~~> I~ ~ O
Z'~ U~ N N ~ ~
SU8STITUTE SHE~(RULE 26) W0 95121832 ' i~ ' 2 1 ~ 2 ~ ~ 7 r~ l/W

O 1~ O
E ~ ,~ O E E ~ E ~ 0 E v~
T _ T T _ _ T ~ T T T ~ I . _ T T _ T
O D C~ 1~ _ T T T ~--~ G ~ _ ~ E
E 1:2 ~ E U~ ~1~ r~ ~') v~ E v) ~ Vl ~ E E ~ ~ E E
____ ~___ _____I _____~ ._ ~ ____ N ~ O U~ E Vl E G ~ G C~ 1~ ~t cn ~ _ ~
~ E ~ E ~- ~ ~ ~ ~ E ~ ~ ~ ~ E ~ ~ e ~ ~ ~ o E ~ ~ E
G G r~ ~r ~ N = = = = g o ,G~ C` Ln g O O ~ N o - - . g O O G--I
. oN ~ ~ N ~t O
-V ~ ~o I ~
~
_ __ _ _ _ CL ~ `
~ N cq u~
e _ o O ~ G C
e ~~ ~ V = v C C, Ci. Z~ Z~ ~.
O G~ ~ C ~ ~
Z ~U~ U~ ~
SUBST~TUTE SHEET (RULE 26~
.. .. _ . . . . . . . .

~ WO 95/21832 ~ , 2 ~ 8 2 8 7 7 o ~ _ ~ v~ ~.c E v~ ~ E ~I E E C V~
~D _ T ~ C~ l r~ ~ ' _ I~ ' V) E - -vl-r = vl E E
o ~ ~ vl ~_ ~ I _ _ T I T
~i V;5 O ~ cq ~ E T _ ~, ~
E~^~-- v5 ~ 5 v5 E E vl E,_C~i ~ o~c5~,_ ~oT ~ D = C~ '`J C`J V5 ~ ^ E E D
~ ~'') O ~ g ~ I ~ T T 2 ~
1~5 ~ ~1~ 1~ ~ v~ ~ E ~ ~r ~o~ _~ E ~
, Vl , , , , , ~ Vl ~ ~ ~ _ O
Vl E v~ ~c5 E ' V~ U~ E E V, E o C~ E V V, ,~ ~ _ ,~
u~ , ~ _ E v~ O , E ~ E v~
-- On C~l ~ ~ ~ _ C~ D C~l g ~ ~ O T ~ ~ 1~ T T . g T = T =
~ g g tl'~ ~ o G~
O~o_ ~ O
Vl Cl E
,~,, V~.~
U~ g -- V~
E-'U~ _ E
C~ ' C' C' ~c , 2 ~ 3, ~,, O ~ ~ . 7 ~
2 ooo o o o SUBSTITUTE SHEET !RULE 261 WO 9~i/21832 ' `~ ' ~ .' t ~ 2 1 ~ 2 8 7 7 - 54 _ Q ,, . ... _ . - - - - -E C~ , N ~-.--~-- N ~, I ~ I ~
T O, ~ . ~ _ _ _ _ _ _ ~r ~ 0 ~ 0 r~ o ~ U'~ ~
~T----0--~ E ~ V) E V~ ~ ~ ~ v) , , 3 T T T T I T T T T = = T ,~ = = T
. ~ ~ 0 Ln 0 ~Oq 0 G 0 0 ~r 0 0-- Q 1 (O0 0 ~ - - ~ C ~ ' . . _ . . . O
~ u7 ~ IA ~ 7 E C~ 7 E E ~ ~
T N v~ ~~ E o _ _ _ _ __ __ a~ ~-- ., ~-, N N N
O = ¢1 = =0 ~r) = N ~D ~5 o ~ 0 ~ 0 O 01~ ~ ~ = U~ ~ o N _ ~ _ ~1 0 O N ~D ~1~ _ N ~ ~
-T T
C1V~ V) ~ I
O , ,~o ~o ~ ~, ~o ", E
E-- O C~
V~, ,, , V, V,, ~r -COD N O~ ~ N
SUBSTITUTE SHEET (~ULE 261 WO 95J21832 ' . ~ 2 ~ 7 7 P~ .. ,.5,'~
-- 5s ---= ~ T C~ _ T T O = T I ' ' ' LO
C`J _ _ ~.,~ _ _ _ _ _ O ~ -------- --~----O Ul ' I ' ' ~ ~ ~ ;~;
E--C~ o ~ ~ E ,_ = T T C~ .C T T ~ T = = ~ =
O~ ~ O ~ O~
~ ~~^ ~ a~ U~ o ~ Vl o ~ ~ .~ . O
-- 151 G LO I = = I G C~ I V ~ ~ G O V~
r.
o C~ C ~ ~ ~ ~ o o o o S ~ o a~ y o O O O y > " o O ~ O
V V ~f V
~' ~E
V LlJ
~, ~n .
S V~ 0 ~0 0 Vl _ _ _ _ E ~ _ o .a _ E V V Z~, C' C~
T T T
T
O O O O O O
In ~ V, ~
SUBSTiTUTE SHE~T (RUi-.i-. 26~

WO 95/21832 ~ 2 1 ~ 2 8 7 7 ~ S .

~ 0 ~ C~ ^ E ^ ~ ~ ~ ~ cn ^ co ~I E ~ J T O t~ ~` . . T
V~ T C~ ----~ ~ _ _ _ C~ ~ _ E
_ ,~ _ ,~ _ _ _ _ ~, _ _ _ ~ = CO ,~ ~D U~
~ - ,n _ o o l.o ~ ) o ~ ' N ~
E ~5 ~` E 0 ~ D _I o 1~ ~ _ I =--C~
I~ ~O _ ~ = = = = = A = = T ~ ~
~ E Vl ~ 2 ~ N ~r ~o o o = ~ D = Q = = C~
-q_ O O ~ O
-- O O O O O
V ~' _ ~r S ~t E
V~
U~ .
_ _ E ~ e E V~ C' C' 'q ~
~ 2 z C~ C~ o Z o o Q G o SUBSTITUT 51~EET ~RULE 26~

WO 95/2 1 832 , 2 1 8 2 ~ 7 7 -- 57 _ C~ .
~ O E ~ ~ E ~ ~ . . . ~ T ~ V~ U~ ' ~J ~ E
~ o Q T T C~ o N ~ ,_ ~ _ _ _ _ T U~ E q~ U~ C:~ ~r o 01-- , , , _ . . . o ~ ~ E V) ~ E E ~ C~
Q ~ O ~:1 ~O ~ C~ v7 = = =
- - 3 _ ~ o = C~.l CO C~.l o ~ ~ l Q
. ~ . ~ O V~ ~ ~ V 5 Itl 1~ E v~ 5 V~
~O G = ~ ~f = = 5 = ~C _, = 5 T 5 I ._ I = I = _I
E vl E _ E O
E~_ _ .~, . ~ ,7f7 QC~ -~ 0G~el' ----I`-- '`J----~--' ~ ~ ~ ~ ~ ~ ~71` N ~7 ~ 0 . 0 -o o o o -- O O O O O O
C ~ O

~ O O O O O
E ` f ~ G G ~G7 G
~r 7 C" ~ C~
~0 _ _ _.
E t- ~r 7 _~ C
o T 7 -- 7 T
T

O O O ~
SUBSmUTE SHEE~ (RULE 26) . _ .

WO 95/21832 ~ 2 1 8 ~ 8 7 7 P(,ll .,,'.'~ . o ` O E-- N--- - ~ E ~ o-- cs~ 'D ~ "~
~ ~ _ T C~l T _ E E ~C
E E ~ . . _ ~ = T ~ ~ , C~l ~----r~ _ ~
C~ i L" __ ~ _7 cq " = U~ ~ ~ E E ~ ~ ~O--E
' E _. o Lr~ Lq ~ ) ,, L~ T T T T T
= I C~J ~J E ~ Ctl--1~ CD E E ' '--I E r~ U~
~ ~ O O--~ --Q--O C~ L. ----E ~ O ~`----O ~
T ~ T Q N = I~ ~ = _ ~o o ~ r` = O N C - Q
l_ ~ T = ~ ~ I~ = ~ = = Q = ~ 3 ~ = = o Q = = 1~
r~l I
er ~ LL O O
O ~ ' O O
0~ O O .o ~o CJ
~' E
.`~ .
V~ o o o ~ ~ ~ ~ o _ E-- L c~
~a E :r L_ = z 2 O =~ = -r,, =, Z ~ Q
SUBSI~TUTE SHET ~RULE 2q ~ 1 .. , t. 21 82~77 ~r WO 9512L832 ` ' ' ~ ' f `~ P~
_ 59 _ U~ _ C7 .1_7 T ~) ~ ~ ~:1 E v1 E . . v~
~ T ~C T T t~ ~ r~ E ~ E
T , ~ ~ N ~ ,~ _ ~ E T ~ f--- ~1~ ' ,~ E v~ ~ ~ ~
1~ r~ T _ T ~ T T T T T T T T ID T = T T T
~ D O G ~ G ~ c~ '7 E
t C~ D If ~ 0 - (.D O U~
~a ~ m E v~ E ~ E E ~ V E
C ~ ~ ~5 n ~ n ~ N C~ n ~ ~ ~ ~ o ~ ~ ~ ~ s~ G v~ -a ~ ~ ~D ~ ~ o _I T ~ O T ~ q ~ ~ T C~l T T T ~ cq r~ _f G
-O o O O O
~r c ~ ~t ~r o ~
m ~f ~ ~ r`J ~
c1 '~.
n : , ~n ^ _ n~
E _ ~ ~r ~ , =
E c~ V v~
o c~ c C~ C, 2~ 2 n 2 n 21~ 2 ~ T T
O ~ ~1 ~ G G
Z
SU~ST~TUTE SHEET (RULE 26~

WO 9~5/21832 ' - ' ' 2 1 ~ 2 8 7 7 O V~ V~ ~ ~ T N v~ ~1~ ~ E u E E _ E E - - h _ h h _ ~ ~ h h h o E h ~ E
h~ ~ ~ ~ N ~ o o u~ ~ o h o o ~
~~~ ~~ ~nI~o ~ ~DN~o ~O
~J ~C h N -- G` T ~ n N
_ N C''J ~--~ -- E----E ~ --^ ^ E ~ I N ~
C~ O ~ N O l~ T ~ ' ' ' ~
~C'~ ~ ~r~----= _____ ~____0 N--_r_ E E E _ E E E h N C N ~ ~ ~ E ~ E N ~ E
E ~ n E ~ - E V) E ~ ' ' V~ -E N L~ ON ~ = ~~ ~ h Q N - O a:l N ~ CI _ _ C-- N _ _I N _ V~ _ ' N
N _ _ N C''~ N ~ N
T
~ T T
o 2, E -- V~
~ C~
U~ _ _ _ V7 0 o o C~ ~ C~ N
E ~r ~
O o~ C~ o C O
O =o 3,, ~ ~ ~
T
Z ~ ~
SU5STITU~E SHET (RULE 26), WO95/21832 . ;S 'J ~ ~ i7 2 1 828 7~ , ~"~
., ~ `.

t~s _ N_~qæ~ ~ _~ ~
E E ~ N ~ ~O E N C~ E ~q N N O N ~ N N n ---- ' ~ I~ ~ ~ ~D ~ ~ eq c~ _ ~ D u~ O ^ ~ ~O C`S cn o o r~ = r_ ~ o I T . ~ C~ T
^~ N U~ _ O E ~ _ _ ~N ~ T ~ _~ ~"
~ s O ~ T N ~ E ~ ~ ~ E "' ~ ~
N Cq ~ _ N _ _ _ ,,, ~ ~0 N ~ ~ c~S _ - ~ 0 U~ - 0 ~ . - U~ - 0 0 O _ ~ N _I
-- E C ~ E N C~ = ~ ~) E E ~ . , O
N ~ N O -- ~ ~ N U~ - N N ~
~_ O ~ N ~ O ~ C
C _ ~ N _ Vl N T ~ ~ , ~ 2 Vl ~D ~ ~ C ~5 Vl N ~ ~ ^ ~ ~ V~ E -7 ~0 ~ ' E E----~ ----------~ ~ ~ T ~C N T ~ T ~ T T ~ D ~ ~ T 1~ ~OO = ~O ~O GO ~ N
N~r_~__-- _--N--_~_ _N_--~G-- NCq~l--Cl T T
-- S ~ O
J~ ~` O
C~ Vl ~ 0~
~ æ
~ E
u~ _ S ~. o E-- N
E ~ C~
o ~_ ~ , z N
O 0~ 51 ~ O
z ~
SUBSr,TU.E SltEET (RULE 26) WO95/21832 V ~ 3 ~ ~ 77 ~"~

o ~
o v~ vr E
~:D _ ~ ~ = 2 T T T U~ V~
V ' ' ' ~1 ' T ~--= = V~ co O ~ =
T T
o ~2D C~ r . ~ o , O
l o o --u~ D V~ V ~ V V~ v~ O
r~ - 1~ ~ ,~ T = T T = =
E .----'r--~ E C~l N C~ I~ N U~--~ ~ ~ ~ ~ ~J ~ C~l O ID g V~ O
V O ~D D r~ _I I O r~ 't r~ I_ v~ V v~ E v~ vr c In --' C`J ~ v~ ~ = = = U2~ 2 . E vr~ VO , E ~ V~ ~ ~ ~ E
g 2 = = 2 o ~ = = = 2 = = _~ 'r C~ ~ ~ ,~ =
C~____._ C~i______ ~-~1~ C~i~o--V
-- I S S S
o . O O
~r ~' ~ O
V ~ V
~ .
v E
V ~ r~l ~
".
V~ ~
~ v~ 0 o ~
E-- ~ o ~D v.~ et ,-- -- V
C- C. Z~ Z
. ~ T

I~ N O~
~r V.~
SUBSTITUTE SIIEET (RULE 26~

- - -2 1 82877 I~,,~h~

O
O .n Q U~
r~ O
a~ C ,,, V. ~ ~^ E E Vl'D ~ --~
1-- T T 1~ T T ~ T ~ T ~ C T T ~ T
E ") ~", V' C~ E ,~, =o E ,., O
v~ E ~ o z t~ C--J ~ 2 O ~ ' Z
O S ~ C~ "' ~ ~ U~ , U~ ~
Z
S~J~STITUTE SHEET (RULE 26) ~182~77 n ~ C~ u~ C~J
C CD ~ _ G u~ cn ~ ID O G U~ o~
~ ~ C~
`G u~ c~
c_~ T Z C_~ T Z

o . . Q o ~ "~
~ E
r E ~ C,~ o~
~ ~ ~ ~ ~ O ~ V~ ~ ~ ~ ~ O
~ C O ~ = C = C_) = = = = = = = . ~ ~ C~l _ ~ C'~ ~
Cc~ c~l O O ~ _ v~ D c~J - o ~ cn o - r'r~ n o r_ Q ~ ~n o In ~ C~ ~ ~D T C'D T ~ .D ~ ~ T O l~ J O ~ ~ C~ N o cn E
-. .
~ ~ ~., .. o~ ~o .~ ., ~ E Z ~ Z _ N C~J O Z O o G ~~
o C ~ q ,~ ~ = z E Cq Cq -- cq cq cq ~
-V Z~ ~3 ~ =
:~ _ c~ c~ - c~ ~r cn c~ ~o z SUE~STITUTE SHEET (RULE 261 W0 9S/21832 .
f ~
- 6~ --) ~ ~
~o ~ ~ r~ ~r ~ o ~ o o O U~
C_~ T Z T Z <_~ 5 Z
` ..
-- ~ ^ ~ ~ - - - o E E ~ - -~o . . . . ~ , , , 1~ E ~ E ~ ~ ,~ T = T T
~ = ~ T ~ T = T T C_~ T T ~ ~
~ ~ C`J ~ o o~ r~ o~ ~ ~ ~ ~0 O~ --~ ~ o Yi~ æ ~ o l_ E
'-- Cq T Cq ;~ C~ ~ O I O
T
E C~ , S
E ~ o O
3 . _ _ ~ O ,~
Z ~ I~ o SUBSFITUTE SHEET (RULE 26~
, WO 95/21832 ~ ~2~ 77 . ~lI~iD, ~ C

., .
1~
'', -^ - . . _ _ , , , , , , , V
v) - v~ E ~ ~ E v~ vl v~ ~ v~ ~ E v~ ~ vl v~ v~
0 T ' ' ' ' ' ' ~ ' ' ' ' ' C Q ~l ' ' - ' E ~ o ~ o C~l V~ o- Q o U~ Q Q Q Q r~ ~ o C~
O--I _ 0'1 1_ 1_ r~ 1_ ~G 0 ~ r~ ~ 1~ 1_ 1_ ~ ~ C'~ C_~ _ I_ V~ v~ V~ Q
Q
æ
.~ .
V~
O G' v E ~D 2 Q 2 _I Q
T E
V~ V
~ Q
Z _ ~D
SUBSTITUTE SHEET (RU~E 26~

~ WO 9~/21832 ~ , . ~. . 2 1 8 2 ~ 7 7 r~
- 67 _ o o ~ ~ . I~ .
E E =
Vl v~ 8 m D 8 Vl V~ ~ r18 E
= = T ~ ~ T ~ = = V1 = T n T T = ~ 1~ T I = =
E:~ o c~ O ~ O c,~ o, a~
~ .
T
, O
O ~
~ O ~ C~J
J ~ --CO
O~ ;o E o ~ o-- Z C~ Z I ~
~ o ~ ~
--E ' ~ ` '~ 'q ~r o _~
o O o T l_ T
I _ C_ ~ ~ O
O O
O~ ~ ~
Z~ _. _I
SUBSTITUTE S~IEET (RULE 26) wo 95/21832 ~ C 2 1 8 2 8 7 7 r~ 5~ ~

", O ~ ~ ~
O~ C ~ ~ Q D
I VU~ ~ r~
~D
o ~
~ T Z ~ = Z
' ' O r~J ~ ~ ~ '~ ~ - ^ ' = a~ D E~C E .~ ~SO~E
,o U~ Ul V U~ U~ V VV ~ U~ o J~_O ~ V V~ o ;~ U~ U, V ~ ~ t~l N ~1 C~ + C'' C~J + t~
_ O O~ O C~l cq c~ ~ ~D Q ~ T ~ ~ ~ o Q ~ Q
~ , .
E ' _ C~l S
? Q QU'~
~ .. .
U TT 3~ T ~-- Z ~-- Z
n~
' O ~ ~ Z Z Z
S i C_) =i~' CO = ~ =;, ~ r o Z r-- ~ Q Q
SU~ST~TUT SHEET (RULE 26)~

~ WO 9~i121832 . . ', .~ 2 ~ 8 2 ~ 7 7 r "~

o ~ ~q ~ ~ C
,~ o _ ~
S N C~
~ r Q
~, T Z
o --E
~ o , . . ._ -~ C V 1,~ V~ = T ~ ~ T T
Y + _ r~ + ~ ---- + ------i _ _ _ ~ o o~ ,7~ CD ~ ~ ~ ~ C~ O
E
---I o v~ E , 2 ~ 2 (~S E ~
E
0~ O, O ~ ~ e~ , O
a~ o O ~ O Cl 2 _ _ _ SU{3STITUTE S!~EET ¦~ULE 26'~

W0 95/21832 2 1 ~ 2~ 7 7 ~ ~bJ o~ - ~
- 7 0 o E v)~ v)~ E v) E E C E v7~5 E E u 5 T T T ~C T T T = T T ~5 = T ~ T ~ T
-- ~ ~q o ~r ~ ~r ~) C~ ,O ~ "~ O ~ G G U') U~ U') G
E ..
--- o ~
C~J ~ ' ' v~ E U~ I T ~ .. , It) ~D ~ _ O G
-- E C~ ~1 ~ t o _ O ~ Z,, O ~
SUBS'rlTUTE SHEET tRULE 26) - 2 1 8 2 ~ 7 7 P~
wo ssnl~3~
;.~ .
--, .
o T S T S S T ~ S ,~ ~--r ~ ~ ~ S T T
~~ ~ Ir~ o C~ O C~ 0 O 1~ ~ ~ ~r ~ o 1_ O ~C~ ~ o _ ~ _ N N ~J
.
T T O
2~ (a o ~,0 0 07 E --' <J
E G ~ C C ~ L~J
S
O " CJ~ C~ Z~
O ~: ~ O
~ ~
Z _ _ SUST~TUTE SHEET (RULE 261 WO95/21832 '~ ' C ~ 828 77 - ?2 -o _I o . - cq ~ o J ` _ ~
~ T Z
T Cl~ E ~, E v~
3 N N _ ~I N N N N N _ 3 . N - N . ~O . _ N . _ C _ _ _ _ _ _ _ _-- ~ n ' V~ N o t ..
U , ~
E ~r~ O , ' ~: E = C'~
E o~ O
o a~ ~ _ SUESSTITUT~ SHEET (RULE 26) . . _ . . .

W095~21832 ~ .s~ 8~B ~ r~ r., r ~ o .
~; - E X

. .~ , ~ O T T
_ . _ _ _ ~ ~O, _ _ _ _ _ _ a~ T T m ~ C~ ~ T ~ T O ~ V~
. O ~ + a~
æ ~ ~ ~ r~ T ~ O T C ~ +~
T V~i~; ~ N ~ ~ ' ~`J
-E
_ .
' ~
E ` -- -- _ ~ O
- E G Z l~J ~ _ E
O, O
O ~ o ~ ~, SUBSTI~UTE SHEET (RULE 26) .. . . .

WO 95/21832 ,- -- ~, r- " r ~- . 2 ~ ~ 2 8 7 7 , ~11~7~.C ~

~q ,~
O
~ ~ o N ro ~D
~q <~ = z n~ S v~ ~ E ~ V ~ .~ E ~ ~1 r ~ ~ _ _ _ ~ ~ ~q ~ ~ + ~ ~ ~ _ I ~ o ~ ~ = ~q I I I
V~ ~` ~ q ~q ~ ~ q ~
o o o ~q o v~ o rq ~ ~ rcq~ =
E C~ " 2 r~
Z
SUEST~TUT Sti~-T ~RULE 26) WO 95/21832 - 2 1 ~ 2 8 7 7 r. l, r ~
7s tr~ C~l 'J
tD --' , 2 ,? o o ~ ~1 0 _ u~
Z
=
O . . ...

O' --~ _ O ' -- t~ ~ C ~ ~ t~ ' _ T = ~ T T I ~ T T T 1~ C~, o o o ~ V~ ~ E o E
C ~~ ~ Q o tr~ _ CoO ~ t~ ~ ~ t~ T CD ,r~ t~ ~ ~ ~7 , ~ UO Z
~
c~,v7 ~ T ,~ ~ T
v7. _ .. _ _ --E
O _ O ~ O
3 Z ,~,~ &
& ~ ~&
Z
SU~STI~UT~ '.YEEr (RULE 26~

~ . ~ r ~, !
W0 9512l832 o Ir~ ~ Q
U 1~ ~ O
Z
~ _ ,0 v~ ~ Eo~/
y 2 T T ~O 2 T O ~ O
~æ
.?
E . T
'3 E ~ ~
~ V C_ S ' --Z --' SU35TITUTE SI~EET (RULE 2~

Claims (10)

- 77 -
1. A piperazine of general formula (A):
(A) wherein one or both of R1 and R2, which may be the same or different, is:
(I) X, or a phenyl group which is substituted by X, C(O)X, OC(O)CH2X, OCH2CH2X, CH2X, CONH(CH2)nX, O(CH2)nCH(OH)(CH2)nX or or which is fused to a group X;
(II) a phenyl group substituted by CH2NR12R13, OC(O)(CH2)nZ, CH(OR12)(OR13), (CH2)nNR14C(O)(CH2)mNR12R13, -CH2NR12-(CH2)nNR15Rl6, O(CH2)nCH(OH)(CH2)nN(R12R13);
(III) a group CH=C(W)V; or (IV) a cyclohexyl group;
and where appropriate, the other of R1 and R2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NHC(O)R12, CO2H, O(CH2)nN(R12R13), CH2Y(CH2)nN(R12R13), C1-C4 alkyl and (CH2)nC(O)OR12;
X is a five- or six-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms, which heteroatoms may be the same or different and are independently selected from O, N and S; the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, -(CH2)nCH2OH or SO2Me; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O(CH2)nNR12R13, -N(R12)(CH2)nN(R12R13), -(CH2)nN(R12R13) or -O(CH2)nO(CH2)nN(R12R13), or the heterocyclic ring optionally containing one or more carbonyl groups and being optionally fused to a benzene ring, which benzene ring is optionally substituted by 1 or 2 C1-C6 alkoxy groups;
Y is O or S;
Z is a C3-C6 cycloalkyl group;
R12, R13 and R14, which may be the same or different, are hydrogen or C1-C6 alkyl;
R15 and R16, which may be the same or different, are hydrogen or C1-C6 alkyl, or R15 and R16 form, together with the atom to which they are attached, a 5- or 6-membered heterocyclic group;
W is hydrogen or a phenyl group;
V is a phenyl group optionally substituted by one or more groups independently selected from nitro, alkoxy and O(CH2)nNR12R13; and m and n are each, independently, O or an integer having the value 1, 2, 3 or 4; or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein one or both of R1 and R2, which may be the same or different, is chosen from X and a phenyl group substituted by X, C(O)X, OC(O)CH2X, OCH2CH2X, CH2X or which is fused to a group X;
X is a five- or six-membered heterocyclic ring containing one or two heteroatoms, which may be the same or different, independently selected from O, N and S, the heteroatoms(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl; or SO2Me, the heterocyclic ring being optionally substituted by hydrogen, methyl, phenyl, O(CH2)nN(R12R13) or optically containing one or more carbonyl groups and being optionally fused to a benzene ring; Y, R12, R13 and n are as defined in claim 1.
3. A compound according to claim 1 or 2, wherein R12 and R13, which may be the same or different, are hydrogen or C1-C3 alkyl and n is an integer of value 1 or 2.
4. A compound according to claim 1, 2, or 3 wherein one of R1 and R2 is a phenyl group which is substituted by X, C(X), OCO(O)CH2X, OCH2CH2X, CH2X or which is fused to a group X; wherein X is a five- or six-membered heterocyclic ring containing one or two heteroatoms which may be the same or different, independently selected from O, N and S, the heteroatoms(s) when nitrogen being optionally substituted by methyl, the heterocyclic ring being optionally fused to a benzene ring.
5. A compound according to claim 1, wherein one of R1 and R2 is a phenyl group substituted by CH2NR12R13, OC(O)(CH2)nZ, CH(OR12)(OR13), (CH2)nNR14C(O)(CH2)mNR12R13;
wherein R12, R13 and R14, which may be the same or different, are independently selected from hydrogen or C1-C3 alkyl;

Z is a C5 or C6 cycloalkyl group;
and m and n are, independently, integers having the values 1, 2 or 3.
6. A compound according to claim 1 or 5, wherein R12, R13 and R14, which may be the same or different, are independently selected from hydrogen and C1-C2 alkyl;
Z is a cyclopentyl group; and m and n are, independently, integers having the values of 1 or 2.
7. A compound selected from (3Z,6Z)-3-Benzylidene-6-(4-imidazolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-(1-imidazolyl)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-(1-imidazolylmethyl)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-3,Benzylidene-6-(4-(2-dimethylaminoethoxy)-3-methoxybenzylidene)-2,5-piperazinedione hydrochloride.
(3Z,6Z)-3-Benzylidene-6-(4-(5-methylimidazolyl))methylene-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-dimethylaminocinnamylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-(1-imidazolyl)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-(2-imidazolylethoxy)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-nitrocinnamylidene-2,5-piperazinedione.

(3Z,6Z)-3-(4-Aminomethylbenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
Methyl (3Z,6Z)-3-benzylidene-6-(4-methoxybenzylidene)-2-oxo-1,2,3,6-tetrahydro-5-pyrazonyloxyacetate.
(3Z,6Z)-3-(1-methanesulfonyl-3-indolyl)methylene-6-(4-methoxybenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-phthalimidoacetoxybenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(.gamma.-phenylcinnamylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(1-tert-butoxycarbonyl-3-indolyl)methylene-6-(2-thenylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(1-tert-butoxycarbonyl-3-indolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)-3-methoxycinnamylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-(1-imidazolylmethyl)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-N-methyl-N-(4-(N-methylpiperidinyl))aminomethylbenzylidene-2,5-piperazinedione.
((3Z,6Z)-3-Benzylidene-6-(3-indolylmethylene)-2,5-piperazinedione.
(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(3-furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-3-(3-Indoxylmethylene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(3-(1-tertbutoxycarbonyl)indolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(2-(1-tertbutoxycarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3-(1-tert-butoxyarbonyl)indolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(3-(1-tert-butoxycarbonyl)indolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-(4-Mehtoxybenzylidene)-6-(2-thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3-furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-3-(Acetamidobenzylidene)-6-cyclohexylmethylene-2,5-piperazinedione.
(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-cinnamylidene-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(diethoxymethylbenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(4-(N-methyl-N-(2-dimethylaminoethyl)aminomethylbenzylidene-2,5-piperazinedione hydrochloride.
(3Z,6Z)-3-Benzylidene-6-cyclohexylmethylene-2,5-piperazinedione.
(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(3,4-methylenedioxybenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(2-Indolylmethylene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(3,4-methylenedioxybenzylidene)-2,5-piperazinedione.

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3,4-methylenedioxybenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-Benzylidene-6-(2-(1-tertbutoxycarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
(3Z,6Z)-3-(4-Dimethylaminomethylbenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-(1-imidazolyl)methylbenzylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-(1-imidazolyl)benzylidene.
(2-(4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline.
N-(2-(l,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
N-(4-(1,2,3,4-Tetrahydro-2-isoquinolyl)butyl)-4-((3Z,6Z)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene-3-(4-pyridylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-pyridylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-furfurylidene-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-Thenylidene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-Thenylidene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-Furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-Naphthylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(1-Naphthylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylamino-2-hydroxypropoxy)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-morpholinopropoxy)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-(1-imidazolyl)propoxy)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-(4-(2-hydroxyethyl)-1-piperazinyl)propoxy)benzylidene)-2, 5-piperazinedione.
(3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3-(3-Furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3-(3-thenylidene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3-(5-methylthio-2-thenylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-morpholinoethoxy)benzylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-(1-imidazolyl)ethoxy)benzylidene)2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-(1-pyrrolidinyl)ethoxy)benzylidene)2,5-piperazinedione.

(3Z,6Z)-6-(4-(2-Dimethylaminoethoxymethyl)benzylidene)-3-(3-thenylidene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(2-Dimethylaminoethoxymethyl)benzylidene)-3-(3-furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-Dimethylaminoacetamidomethyl benzylidene)-3-(3-thenylidene)-2,5-piperazinedione.
(3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-dimethylaminoacetamidomethylbenzylidene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-Dimethylaminoacetamidomethylbenzylidene)-3-(3-furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-dimethylaminoacetamidomethylbenzyldiene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(2-Dimethylaminoethylthiomethyl)benzylidene)-3-(3-furylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-(4-(2-Dimethylaminoethylthiomethyl)benzylidene)-3-(3-thenylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-dimethylaminoacetamidoaminomethylbenzylidene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(5-(2-dimethylaminoethoxy)-2-thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(4-(2-dimethylaminoethoxy)-2 -thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(5-(2-dimethylaminoethyl)-2-thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(5-(2-(2-dimethylaminoethoxy)ethoxy)-2-thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(5-(6-dimethylaminohexyloxy)-2-thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-6-Benzylidene-3-(5-(2-dimethylaminoethyl)methylamino-2-thienylmethylene)-2,5-piperazinedione.
(3Z,6Z)-3-(2,5-Dichloro-3-thenylidene)-6-benzylidene-2,5-piperazinedione.
N-(4-(1,2,3,4-Tetrahydro-2-isoquinolyl)butyl)-4-((3Z,6Z)-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide.
N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide.
N-(3-(1,2,3,4-Tetrahydro-2-isoquinolyl)propoyl)-4-((3Z,6Z)-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide.
N-(4-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)phenyl-4 ((3Z,6Z)-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide.
N-(4-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-2,5-dioxo-6-(4-nitrobenzylidene)-3-piperazinylidene)methylbenzamide.
8. A pharmaceutical or veterinary composition comprising a pharmaceutically or veterinarily acceptable carrier or diluent and, as an active principle, a compound as defined in claim 1.
9. A process for preparing a compound of formula (A) as defined in claim 1, the process comprising:
(a) condensing a compound of formula (I):

(I) wherein R2 is as defined in claim 1 and is optionally protected, with a compound of formula (II):

R1-CHO (II) wherein R1 is as defined in claim 1 and is optionally protected, in the presence of a base in an organic solvent;
or (b) condensing a compound of formula (I'):

(I') wherein R1 is as defined in claim 1 and is optionally protected with a compound of formula (III):

R2-CHO (III) wherein R2 is as defined in claim 1 and is optionally protected, in the presence of a base in an organic solvent;
and (c) if required, removing optionally present protecting groups, and/or, if desired, converting one compound of formula A into another compound of formula A, and/or, if desired, converting a compound of formula A into a pharmaceutically acceptable salt or ester thereof, and/or, if desired, converting a salt or ester into a free compound, and/or, if desired, separating a mixture of isomers into the single isomers.
10. Use of a diketopiperazine of formula (A):

(A) wherein one or both of R1 and R2, which may be the same or different, is:
(I) X, or a phenyl group which is substituted by X, C(O)X, OC(O)CH2X, OCH2CH2X, CH2X, CONH(CH2)nX, O(CH2)nCH(OH)(CH2)nX or or which is fused to a group X;
(II) a phenyl group substituted by CH2NR12R13, OC(O)(CH2)nZ, CH(OR12)(OR13), (CH2)nNR14C(O)(CH2)mNR12R13 or O(CH2)nCH(OH)(CH2)nN(R12R13);
(III) a group CH=C(W)V; or (IV) a cyclohexyl group;
and where appropriate, the other of R1 and R2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NHC(O)R12, CO2H, O(CH2)nN(R12R13) and CH2Y(CH2)nN(R12R13);
R3 is C1-C4 alkyl or (CH2)nC(O)OR12;

X is a five- or six-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms, which heteroatoms may be the same or different and are independently selected from O, N and S; the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, -(CH2)nCH2OH or SO2Me; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O(CH2)nNR12R13, -N(R12)(CH2)nN(R12R13), -(CH2)nN(R12R13) or -O(CH2)nO(CH2)nN(R12R13), or the heterocyclic ring optionally containing one or more carbonyl groups and being optionally fused to a benzene ring, which benzene ring is optionally substituted by 1 or 2 C1-C6 alkoxy groups;
Y is O or S;
Z is a C3-C6 cycloalkyl group;
R12, R13 and R14, which may be the same or different, are hydrogen or C1-C6 alkyl;
W is hydrogen or a phenyl group;
V is a phenyl group optionally substituted by one or more groups independently selected from nitro, alkoxy and O(CH2)nNR12R13; and m and n are each, independently, 0 or an integer having the value 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or ester thereof; in the manufacture of a medicament for use as an inhibitor of plasminogen activator inhibitor.
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CA3080677A1 (en) 2017-11-06 2019-05-09 Jubilant Prodel LLC Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation
FI3704120T3 (en) 2017-11-24 2024-06-03 Jubilant Episcribe Llc Heterocyclic compounds as prmt5 inhibitors
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CN116239578B (en) * 2022-12-08 2024-09-13 中国海洋大学 Piperazine dione ring compound, synthesis method thereof and application thereof in preparation of antitumor drugs
CN116400068B (en) * 2023-02-13 2023-09-22 泉州圣源警用侦察设备有限公司 Reagent for revealing potential biological trace containing DNA and revealing method

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