GB2286395A - Pharmaceutical piperazines - Google Patents

Pharmaceutical piperazines Download PDF

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GB2286395A
GB2286395A GB9502874A GB9502874A GB2286395A GB 2286395 A GB2286395 A GB 2286395A GB 9502874 A GB9502874 A GB 9502874A GB 9502874 A GB9502874 A GB 9502874A GB 2286395 A GB2286395 A GB 2286395A
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benzylidene
piperazinedione
compound
group
formula
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GB9502874D0 (en
GB2286395B (en
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Stephen James Brocchini
Justin Stephen Bryans
Adrian John Folkes
Christopher John Latham
Jule Elizabeth Brumwell
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Xenova Ltd
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Xenova Ltd
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    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • C07D403/12—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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D405/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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

Abstract

A diketopiperazine of formula (A): <IMAGE> wherein one or both of R1 and R2, which may be the same or different, is: X, substituted phenyl, CH=C(W)V or cyclohexyl; and where appropriate, the other of R1 and R2 is an optionally substituted phenyl group X is a naphthyl group or an optionally substituted five- or six-membered saturated or unsaturated heterocyclic group W is hydrogen or a phenyl group; V is an optionally substituted phenyl group, and the pharmaceutically acceptable salts and esters thereof have activity as inhibitors of plasminogen activator inhibitor.

Description

PRBRMACEUTICAL COMPOUNDS The present invention relates to compounds useful as inhibitors of plasminogen activator inhibitor (PAI), to their preparation and to pharmaceutical and veterinary compositions containing them.
Plasminogen activators (Pas) are serine proteases which control the activation of the zymogen, plasminogen, to the active enzyme plasmin. Plasmin is important in a number of physiological and pathological processes including fibrinolysis, tissue remodelling, tumour growth and metastasis. The glycoprotein plasminogen 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 cells. An imbalance between PAs and PAI contributes to a number of pathological conditions including haemostasis, inflammation, tumour growth and metastasis.
The present invention provides 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
or which is fused to a group X; (II) a phenyl group substituted by CH2NRl2Rl3l OC(O) (CH2) nZ, CH (OR12) (OR13), (CH2) nNR14C(O) (CH2) mNR12R13, CH2NR12-(CH2) nNR15R16 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) t CH2Y(CH2)nN(R12R13) c1-C4 alkyl and (CH2)nC(O)ORl2; X is a naphthyl group or 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 0, 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; R121 R13 and R14, which may be the same or different, are hydrogen or C1-C6 alkyl; R15 and R161 which may be the same or different, are hydrogen or C1-C6 alkyl, or R15 and R16 form, together with the nitrogen atom to which they are attached, a 5- or 6membered 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, O(CH2)nNRl2Rl3l and NRl2Rl3; 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.
A C1-C6 alkyl group is, for example, a C1-C4 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 compounds of formula A free rotation may occur at room temperature about the single bonds connecting substituents R1 and R2 to the double bonds at positions 3 and 6 of the piperazine-2,5-dione ring.
In one embodiment at least one of R1 and R21 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)CH2X, OCH2CH2X, or CH2X and a phenyl group which is fused to a group X; wherein X is a five- or six-membered saturated or unsaturated heterocyclic group containing 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 hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, -(CH2)nCH2OH or SO2Me, the heterocyclic ring being optionally substituted by hydrogen, halogen, methyl, MeS, phenyl, O(CH2) nNR12R13, O(CH2) nN(R12R13) or -O (CH2) nO (CH2) nN (R12R13) ; the heterocyclic ring optionally containing one or more carbonyl groups, and being optionally fused to a benzene ring; and the other of R1 and R2 is a phenyl group optionally substituted at the 2, 3 or 4-position by CH2NRl2Rl3, (CH2) nNR14C(O) (CH2)mNR12R13, halogen, nitro, -NHC (O) R12, -O (CH2) nN (R12R13) or - CH2Y (CH2) nN(R12R13) wherein Y is O or S. In a particularly preferred series of compounds the said other of R1 and R2 is a phenyl group substituted at the 4-position by -O (CH2) nN (R12R13), -CH2Y (CH2) nN (R12R13) or - (CH2) nNR14C(O) (CH2) mNR12R13.
In a further embodiment one of R1 and R2 is X, a 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 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 a phenyl group optionally substituted at the 4-position by -O (CH2) nN (R12R13) , -CH2Y (CH2) nN (R12R13) or - (CH2) nNR14C(O) (CH2) mNR12R13. In this embodiment it is particularly preferred for X to be a furyl, imidazolyl, pyrrolyl, thienyl, morpholinyl, piperidinyl or isoquinolyl group.
In a further embodiment, R12 and R13l which may be the same or different, are hydrogen or C1-C3 alkyl and n is an integer of value 1 or 2.
In a yet further embodiment one of R1 and R2 is a phenyl group which is substituted by X, CO(X), OCO (O) CH2X, OCH2CH2X/ CR2X 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 0, N and S, the heteroatom(s) when nitrogen being optionally substituted by methyl, and the heterocyclic ring being optionally fused to a benzene ring.
In another embodiment one of R1 and R2 is a phenyl group substituted by CH2NR12R13, OC(O) (CH2) nZ, CH (OR12) (OR13), (CH2) nNR14C(O) (CH2) mN (R12R13) ; wherein R121 R13 and R141 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.
In a further embodiment R121 R13 and R141 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.
In a yet further embodiment one of R1 and R2 is a phenyl group optionally substituted by one or more groups independently selected from chloro, nitro, methoxy, NHCOR12, CO2H and O(CH2)nNRl2Rl3; R12 and R131 which may be the same or different, are independently selected from hydrogen or methyl and n is an integer having the value 1 or 2.
In another embodiment one of R1 and R2 is a group CH=C(W)V, W is a phenyl group optionally substituted by one of more groups independently selected from nitro, methoxy and O(CH2)nNMe2 and n is an integer having the value 1, 2,3 or 4.
In a further embodiment n is 1 or 2.
In a yet further embodiment one of R1 and R2 is a phenyl group optionally substituted by NHAc or methoxy.
In another embodiment one of R1 and R2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC (O) R12.
In a further embodiment one of R1 and R2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC (O) Me.
In a further embodiment R3 is C1-C2 alkyl or (CH2)nC(O)ORl2; R12 is hydrogen or C1-C2 alkyl and n is an integer of value 1 or 2.
In a yet further embodiment R3 is methyl or CH2C(O)OR12 and R12 is hydrogen or methyl.
Certain diketopiperazines have been disclosed as having utility as bioactive agents. Yokoi et al in J.
Antibiotics vol XLI No. 4, pp 494-501 (1988) describe structure-cytotoxicity relationship studies on a series of diketopiperazines related to neihumicin, a compound obtained from the micro-organism Micromonospora neihuensis.
Kamei et al in J. Antibiotics vol XLIII No. 8, 1018-1020 disclose that two diketopiperazines, designated piperafizines A and B, have utility as potentiators of the cytotoxicity of vincristine.
Examples of specific compounds of formula A are as follows. The compound numbering is adhered to in the rest of the specification: 1926 (3Z,6Z) -3-Benzylidene-6-(4-imidazolyl)methylene-2,5piperazinedione.
1930 (3Z,6Z) -3-Benzylidene-6-(4- (1-imidazolyl)benzylidene) - 2,5-piperazinedione.
1929 (3Z,6Z)-3-Benzylidene-6-(4-(1imidazolylmethyl)benzylidene) -2,5-piperazinedione.
1959 (3Z,6Z) -3,Benzylidene-6-(4- (2-dimethylaminoethoxy) -3- methoxybenzylidene)-2,5-piperazinedione hydrochloride.
1927 (3Z,6Z)-3-Benzylidene-6-(4-(5 methylimidazolyl) ) methylene-2, 5-piperazinedione.
1921 (3Z,6Z)-3-Benzylidene-6-(4 dimethylaminocinnamylidene) -2, 5-piperazinedione.
1976 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4- (1-imidazolyl)benzylidene-2,5-piperazinedione.
1910 (3Z,6Z)-3-Benzylidene-6-(4-(2 imidazolylethoxy)benzylidene)-2,5-piperazinedione.
1923 (3Z,6Z)-3-Benzylidene-6-(4-nitrocinnamylidene-2,5- piperazinedione.
1657 (3Z,6Z)-3-(4-Aminomethylbenzylidene)-6- (4methoxybenzylidene)-2,5-piperazinedione.
1693 (3Z,6Z)-3-(1-methanesulfonyl-3-indolyl)methylene-6-(4methoxybenzylidene)-2,5-piperazinedione.
1886 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4phehalimidoacetoxybenzylidene) -2,5-piperazinecione.
1922 (3Z,6Z)-3-Benzylidene-6-(Y-phenylcinnamylidene)-2,5- piperazinedione.
1618 (3Z,6Z) -3- (1-tert-butoxycarbonyl-3-indolyl) methylene 6 - (2 -thenylidene) -2,5 -piperazinedione.
1560 (3Z,6Z) -3- (2,6-Dichlorobenzylidene) -6- (1-tert butoxyCarbonyl-3-indolyl)methylene-2,5-piperazinedione.
1950 (3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethOxy)-3- methoxycinnamylidene) -2,5 -piperazinedione.
1975 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4-(1-imidazolylmethyl)benzylidene)-2,5-piperazinedione.
1983 (3Z,6Z) -3- Benzylidene-6-(4-N-methyl-N- (4- (N methylpiperidinyl))aminomethylbenzylidene-2,5- piperazinedione.
1509 (3Z,6Z) -3- Benzylidene-6- (3-indolylmethylene) -2,5piperazinedione.
1542 (3Z,6Z) -3- (2,6-Dichlorobenzylidene) -6- (3furylmethylene)-2,5-piperazinedione.
1545 (3Z,6Z) -3- (3-Indolylmethylene) -6- (4- methoxybenzylidene)-2,5-piperazinedione.
1507 (3Z,6Z) -3- (4-Methoxybenzylidene) -6- (2- (1 tertbutoxyCarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
1506 (3Z,6Z) -3- (4-Methoxybenzylidene) -6- (3- (1-tertbutoxycarbonyl) indolyl) methylene-2, 5-piperazinedione.
1471 (3Z,6Z)-3-Benzylidene-6-(3-(1-tert- butoxycarbonyl) indolyl)methylene-2,5-piperazinedione.
1474 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(2thienylmethylene)-2,5-piperazinedione.
1476 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3-furylmethylene)2,5-piperazinedione.
1672 (3Z,6Z)-3-(Acetamidobenzylidene)-6cyclohexylmethylene-2,5-piperazinedione.
1676 (3Z,6Z)-3-(4-Acetamidobenzylidene)-6-cinnamylidene2,5-piperazinedione.
1891 (3Z,6Z)-3-Benzylidene-6-(diethoxymethylbenzylidene)2,5-piperazinedione.
1982 (3Z,6Z) -3-Benzylidene-6- (4- (N-methyl-N- (2 dimethylaminoethyl)aminomethylbenzylidene-2,5- piperazinedione hydrochloride.
1884 (3Z,6Z) -3-Benzylidene-6-cyclohexylmethylene-2,5piperazinedione.
1845 (3Z,6Z) -3- (4-Acetamidobenzylidene) -6- (3,4 methylenedioxybenzylidene) -2, 5-piperazinedione.
1950 (3Z,6Z) -3-benzylidene-6- (4- (2-dimethylaminoethoxy) -3- methoxycinnamylidene) -2, 5-piperazinedione.
1718 (3Z,6Z)-3-(2-Indolylmethylene)-6-(4methoxybenzylidene)-2,5-piperazinedione.
1808 (3Z,6Z)-3-Benzylidene-6-(3,4- methylenedioxybenzylidene) -2, 5-piperazinedione.
1809 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3,4 methylenedioxybenzylidene) -2, 5-piperazinedione.
1470 (3Z,6Z)-3-Benzylidene-6-(2-(1 tertbutoxyCarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
5023 (3Z,6Z)-3-(4-Dimethylaminomethylbenzylidene)-6-(4-(3dimethylaminopropoxy) benzylidene-2,5-piperazinedione.
5026 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4-(1-imidazolyl)methylbenzylidene)-2,5-piperazinedione.
5030 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4- (1-imidazolyl)benzylidene) -2,5-piperazinedione.
5367 (2- (4- ((3Z,6Z) -6- (4- (3 Dimethylaminopropoxy) benzylidene) -2,5-dioxo-3 piperazinylidene)methylbenzoyl)-1,2,3,4- tetrahydroisoquinoline.
5386 N- (2- (1,2,3,4-Tetrahydro-2-isoquinolyl) ethyl) -4 ((3Z,6Z)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5 dioxo-3 -piperazinylidene) methylbenzamide.
5397 N- (4- (1,2,3,4-Tetrahydro-2-isoquinolyl) butyl) -4 ((3Z,6Z)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5 dioxo-3 -piperazinylidene) methylbenzamide.
5027 (3%, 6%) -6- (4- (3-Dimethylaminopropoxy)benzylidene-3- (4- pyridylmethylene) -2,5-piperazinedione.
5028 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (3-pyridylmethylene) -2, 5-piperazinedione.
5041 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3furfurylidene-2,5-piperazinedione.
5042 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (3-Thenylidene)-2,5-piperazinedione.
5046 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (2-Thenylidene)-2,5-piperazinedione.
5052 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (3-Furylmethylene)-2,5-piperazinedione.
5188 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (2-Naphthylmethylene) -2, 5-piperazinedione.
5200 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (1-Naphthylmethylene) -2, 5-piperazinedione.
5032 (3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylamino-2- hydroxypropoxy) benzylidene) -2, 5-piperazinedione.
5040 (3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3- morpholinopropoxy)benzylidene)-2,5-piperazinedione.
5057 (3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-(1- imidazolyl)propoxy)benzylidene)-2,5-piperazinedione.
5043 (3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-(4-(2- hydroxyethyl) -1 -piperazinyl) propoxy) benzylidene) -2,5piperazinedione.
5062 (3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3-(3 furylmethylene) -2, 5-piperazinedione.
5071 (3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3-(3thenylidene)-2,5-piperazinedione.
5072 (3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3-(5 methylthio-2-thenylidene) -2, 5-piperazinedione.
5054 (3Z,6Z)-6-Benzylidene-3-(4-(2- morpholinoethoxy) benzylidene) -2,5-piperazinedione.
5055 (3Z,6Z) -6-Benzylidene-3- (4- (2- (1imidazolyl) ethoxy) benzylidene) 2,5-piperazinedione.
5053 (3Z,6Z) -6-Benzylidene-3-(4- (2- (1pyrrolidinyl) ethoxy) benzylidene) 2,5-piperazinedione.
5069 (3Z,6Z)-6-(4-(2- Dimethylaminoethoxymethyl)benzylidene)-3-(3-thenylidene)2,5-piperazinedione.
5077 (3Z,6Z)-6-(4-(2- Dimethylaminoethoxymethyl) benzylidene) -3- (3furylmethylene)-2,5-piperazinedione.
5074 (3Z,6Z) -6- (4-Dimethylaminoacetamidomethyl benzylidene)-3-(3-thenylidene)-2,5-piperazinedione.
5079 (3Z,6Z)-3-(2-Bromobenzylidene)-6-(4dimethylaminoacetamidomethylbenzylidene) -2,5piperazinedione.
5081 (3Z,6Z)-6-(4-Dimethylaminoacetamidomethylbenzylidene)3- (3-furylmethylene) -2,5-piperazinedione.
5061 (32,62) -6-Benzylidene-3- (4- dimethylaminoacetamidomethylbenzylidene) -2,5piperazinedione.
5073 (3Z,6Z)-6-(4-(2- Dimethylaminoethylthiomethyl)benzylidene)-3-(3- furylmethylene)-2,5-piperazinedione.
5078 (3Z,6Z)-6-(4-(2- Dimethylaminoethylthiomethyl)benzylidene)-3-(3- thenylidene)-2,5-piperazinedione.
1912 (3Z,6Z) -6-Benzylidene-3- (4 dimethylaminoacetamidoaminomethylbenzylidene)-2,5piperazinedione.
5324 (3Z,6Z)-6-Benzylidene-3-(5-(2-dimethylaminoethOxy)-2- thienylmethylene)-2,5-piperazinedione.
5327 (3%,6Z) -6-Benzylidene-3-(4- (2-dimethylaminoethoxy) -2- thienylmethylene)-2,5-piperazinedione.
5335 (3Z,6Z)-6-Benzylidene-3-(5-(2-dimethylaminoethyl)-2 thienylmethylene) -2, 5-piperazinedione.
5388 (3Z,6Z)-6-Benzylidene-3-(5-(2-(2dimethylaminoethoxy)ethoxy)-2-thienylmethylene)-2,5piperazinedione.
5389 (3Z,6Z)-6-Benzylidene-3-(5-(6-dimethylaminohexylOxy)- 2-thienylmethylene) -2, 5-piperazinedione.
5299 (3Z,6Z)-6-Benzylidene-3-(5-(2dimethylaminoethyl)methylamino-2-thienylmethylene)-2t5piperazinedione.
5075 (3Z,6Z)-3-(2,5-Dichloro-3-thenylidene)-6-benzylidene2,5-piperazinedione.
5371 N-(4-(1,2,3,4-Tetrahydro-2-isoquinolyl)butyl)-4- ((3Z,6Z)-6-benzylidene-2,5-dioxo-3piperazinylidene)methylbenzamide.
5391 N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4- ((3Z,6Z)-6-benzylidene-2,5-dioxo-3piperazinylidene)methylbenzamide.
5394 N-(3-(1,2,3,4-Tetrahydro-2-isoquinolyl)propyl)-4- ((3Z,6Z)-6-benzylidene-2,5-dioxo-3piperazinylidene)methylbenzamide.
5393 N-(4-(2-(1,2,3,4-Tetrahydro-2 isOquinolyl)ethyl)phenyl-4-((3Z,6Z)-6-benzylidene-2,5- dioxo-3 -piperazinylidene) methylbenzamide.
5402 N-(4-(2-(1,2,3,4-Tetrahydro-2isoquinolyl) ethyl) phenyl) -4- ((3Z,6Z) -2,5-dioxo-6- (4nitrobenzylidene)-3-piperazinylidene)methylbenzamide.
Compounds of formula A, may be prepared by a process which comprises either (i) condensing compound of formula
wherein R2 is as defined above and is optionally protected, with a compound of formula (II): RlKHO (II) wherein R1 is as defined above and is optionally protected, in the presence of a base in an organic solvent; or (ii) condensing a compound of formula (I'):
wherein R1 is as defined above and is optionally protected, with a compound of formula (III): R2~CHO (III) wherein R2 is as defined above and is optionally protected, 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 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 of compounds of formula A into the single isomers.
A compound of formula A produced directly by the condensation reaction between (I) and (II) or (I') and (III) may be modified, if desired, by converting Rl into a different R1 group. These optional conversions may be carried out by methods known in themselves. For example, a compound of formula A in which Rl comprises an ester group may be converted to a compound of formula A wherein the corresponding substituent is a free -COOH or OH group, by acid or alkaline hydrolysis at a suitable temperature, for example from ambient temperature to 100oC.
A compound of formula A in which either or both of R and R2 includes an -OH group may be converted into a compound of formula A wherein the corresponding 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 in an inert solvent.
A compound of formula A in which either or both of R and R2 includes a -CO2H group may be converted into a compound of formula A wherein the corresponding substituent is esterified, for example by treating the carboxylic acid with a suitable C1-C6 alkyl alcohol in the presence of 1,3dicyclohexylcarbodiimide in an inert solvent.
A compound of formula A in which either or both of R1 and R2 includes a free -CO2H group may be converted into a compound of formula A in which the corresponding substituent is a group -CON(RllRl2), wherein R11 and Rl2 are as defined above, for example by treatment with ammonia or an amine in the presence of l,3-dicyclohexylcarbodiimide in an inert solvent.
A compound of formula A in which either or both of R1 and R2 includes a free -CO2H group may be converted into a compound of formula A wherein the corresponding substituent is a -CH2OH group by reduction, for example using borane in a suitable solvent such as tetrahydrofuran.
A compound of formula A in which either or both of Rl and R2 is a nitro group may be converted into a compound of formula A in which the corresponding substituent is an amino group by reduction under standard conditions, for example by catalytic hydrogenation.
Protecting groups for substituents on Rl and/or R2 in any of the compounds of formulae (I), (1'), (II) 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 condensation reaction conditions or incompatible with the condensation reaction, for example a -COOH, -CH2OH or amino group. The protecting groups are then removed at the end of the process. Any conventional protecting group suitable for the group Rl and/or R2 in question may be employed, and may be introduced and subsequently removed by well-known standard methods.
The condensation reaction between compounds (I) and (II) or (I') and (III) is suitably performed in the presence of a base which is potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, caesium carbonate, sodium acetate, potassium fluoride on alumina, or triethylamine in a solvent such as dimethylformamide, potassium t-butoxide in t-butanol, or a mixture of tbutanol and dimethylformamide (DMF). The reaction is typically performed at a temperature from 0OC to the reflux temperature of the solvent.
The compounds of formula (I) may be prepared by a process comprising reacting 1,4-diacetyl-2,5piperazinedione with a compound of formula (III) as defined above, 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-2,5piperazinedione with a compound of formula (II) as defined above, in the presence of a base in an organic solvent.
If necessary, the resulting compound of formula (I) or (I') can be separated from other reaction products by chromatography.
The reaction of 1,4-diacetyl-2,5-piperazinedione with the compound of formula (III) or (II) is suitably performed under the same conditions as described above for the condensation between compounds (I) and (II), or (I') and (III).
The substituted aldehydes of formulae (II) and (III) are known compounds or can be prepared from readily available starting materials by conventional methods. The 1,4-diacetyl-2,5-piperazinedione used as a starting material in the preparation of compounds of formula (I) may be prepared by treating 2,5-piperazinedione (glycine anhydride) with an acetylating agent. The acetylation may be performed using any conventional acetylating agent, for example acetic anhydride under reflux or, alternatively, acetic anhydride at a temperature below reflux in the presence of 4-dimethylaminopyridine.
Compounds of formula (I) may also be prepared by the microwave irradiation of a mixture comprising 1,4-diacetyl2,5-piperazinedione, a compound of formula (III) and potassium fluoride on alumina (as base) in the absence of solvent.
Compounds of formula (I) may alternatively be prepared directly from 2,5-piperazinedione (glycine anhydride) by a process which comprises treating the 2,5-piperazinedione with a mixture comprising a compound of formula (III), sodium acetate and acetic anhydride at an elevated temperature, for example under reflux.
Compounds of formula (I') may be prepared by analogous processes, replacing compound (III) in each case by a compound of formula (II).
Compounds of formula A may also be prepared by a process comprising the microwave irradiation of (i) a mixture comprising a compound 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 (I') a compound of formula (III) and potassium fluoride on alumina, or (iii) a mixture comprising 1,4-diacetyl-2,5piperazinedione, a compound of formula (II), a compound of formula (III) and potassium fluoride on alumina. The irradiation is performed in the absence of a solvent.
Compounds of formula (A) may also be obtained directly by a process which comprises condensing together 1,4diacetyl-2,5-piperazinedione, 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 condensation reaction between, for example, compounds (I) and (II).
An alternative direct process for the preparation of compounds of formula (A) comprises condensing together 2,5piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of sodium acetate and acetic anhydride at elevated temperature, for example under reflux.
An alternative process for the preparation of compounds of formula (I) comprises treating a compound of formula (V):
wherein R6 to R10 are as defined above, X is a halogen and R' is a C1-C6 alkyl group, with ammonia followed by acetic anhydride.
Compounds of formula (I') may be prepared by an analogous process which comprises treating a compound of formula (V'):
wherein Rl to R5, 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 C1-C4 alkyl group such as a methyl, ethyl, propyl, i-propyl, butyl, sec-butyl or tert-butyl group.
A review of synthetic approaches to unsaturated 3monosubstituted and 3,6-disubstituted-2,5-piperazinediones is provided in Heterocycles, 1983, 20, 1407 (C.Shin).
Compounds of formula (A) may be optionally washed after any of the above preparative procedures with one or more of the following: water, ethanol, ethyl acetate and diethyl ether.
Where appropriate compounds of formula (A) may be optionally recrystallised from a suitable solvent such as methanol or acetic acid.
Compounds of formula (A) 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 or bases. Examples of inorganic bases include ammonia and carbonates, hydroxides and hydrogen carbonates of group I and group II metals such as sodium, potassium, magnesium and calcium.
Examples of organic bases include aliphatic and aromatic amines such can contribute to the pathogenesis of various thrombotic disorders including myocardial infarction, deep vein thrombosis and disseminated intravascular coagulation. The present compounds therefore can act as inhibitors of the tPA/PAI-1 interaction. The present compounds 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 pharmaceutically or veterinarily acceptable salt thereof.
Tissue plasminogen activator (tPA) is used as a fibrinolytic agent in the treatment of thrombotic disorders. The efficacy of the tPA in this role may be enhanced if it is administered together with a PAI inhibitor. A human or animal, e.g. a mammal, can therefore be treated by a method comprising the combined administration of a therapeutically effective amount of tPA and a therapeutically effective amount of any one of the present compounds. The present invention also provides products containing a diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof and tPA as a combined preparation for simultaneous, separate or sequential use in the treatment of thrombotic disorders, for example where there is inappropriate PAI activity. In such products the present compound is formulated for oral or parenteral (intravenous, intramuscular or subcutaneous) administration and the tPA is formulated for intravenous administration.
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. As a further example, early re-occlusion following treatment of a patient with tPA may be prevented by the post-MI administration of one of the present compounds.
The compounds of formula (A) have been tested in a PAI functional assay. In this assay, a compound is incubated with PAI-1 prior to addition to the tPA assay system.
Inhibition of PAI-1 results in the production of plasmin from plasminogen. In turn, plasmin cleaves the chromogenic substrate S2251 (Kabi Vitrum) producing pNA (pnitroaniline) which is detected spectrophotometrically at 405 nm (K.Nilsson et al, Fibrinolysis (1987) 1, 163-168).
The results of the assay are reported below.
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 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 10 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.
When one of the present compounds is administered in combination with tPA to adult humans, the dosage adopted for each route of administration is typically from 0.001 to 10 mg, more typically 0.01 to 5 mg per kg body weight for a compound of the invention and from 5 to 500mg administered intravenously for the tPA. A suitable dosage regimen for the tPA is 100 mg given intravenously over 3 hours as follows: 10t of the total dose as an i.v. bolus over 1-2 minutes, 50 of the total dose as an infusion over 1 hour, 40% of the total dose as an infusion over the subsequent 2 hours.
A diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester 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 an inhibitor of PAI comprising any one of the present compounds is therefore provided.
For example, the solid oral forms may contain, together with 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 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. A compound may be encapsulated within liposomes.
TESTING OF TIE PRESENT COMPOUNDS AS PAI INHIBITORS Compounds of formula (A) were tested in a PAI chromogenic substrate assay. In the assay (K.Nilsson, Fibrinolysis (1987) 1, 163-168) each compound was incubated with PAI-1 prior to addition to the tPA assay system.
Inhibition of PAI-1 by the compound of formula (A) resulted in the production of plasmin from plasminogen. In turn, the plasmin cleaved the chromogenic substrate S2251 (Kabi Vitrum) producing pNA (p-nitroaniline) which was detected spectrophotometrically at 405 nm.
The degrees of inhibition observed in the chromogenic substrate assay at various concentrations, and/or IC50 values, of compounds of formula (A) are presented in Table 1. IC50 values for some compounds, not shown in Table 1, are listed in Table 2 which follows Table 1.
TABLE 1: INHIBITION OF PAI-1 IN THE S2251 CHROMOGENIC SUBSTRATE ASSAY
Compound Concentration in pm No. 100 r 50 25 12.5 6.25 1470 70 20 2 0 0 1471 80 60 20 6 0 1474 64 52 28 1476 68 48 18 1506 75 58 26 4 2 1507 78 62 45 1 1
1509 @ 58 @ 35 1 1 1 1542 75 41 9 1 1 1545 87 64 39 5 1 1560 50 48 46 34 13 1618 51 32 3 1 1649 34 0 1 0 1657 53 60 46 2 1672 70 44 13 4 1 1676 29 51 52 12 1 1693 89 2 1 0 1718 62 1 0 0 0 1 1808 76 48 73 2 1 1809 81 76 84 7 1 1845 14 30 49 60 53 1884 40 14 0 0 0 1886 42 40 18 6 0 1891 28 36 17 3 3 1910 27 36 50 61 63 1912 30 55 29 22 17 1921 65 43 25 14 16 1922 13 11 26 13 14 1923 38 31 20 12 13 1926 36 35 12 6 10 1927 33 39 20 22 14 1928 67 60 47 24 19 1929 27 45 59 48 16 1930 54 61 79 38 30 1959 5 1 2 2 1 1975 7 0 0 , 0 0 1976 3 0 0 0 0 1950 19 3 2 2 1 1982 48 49 28 6 1 1983 34 14 0 0 0
Compound Concentration in gN ICso No. 100 M 50 M 20 M 5023 1 5026 34 10 5027 12 8 8 5028 11 4 4 5030 20 7 6 5032 65 62 63 25.0-12.0 5040 0 1 0 5041 1 0 0 5042 77 64 42 20.0-10.0 5043 21 15 1 5048 55 19 11 100.0-50.0 5052 77 76 86 12.0-6.0 5053 68 64 56 25.0-12.0 5054 5 57 48 50.0-25.0 5055 69 69 70 6.0-3.0 5057 44 29 37 5061 43 48 60 25.0-12.0 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 5074 47 57 26 20.0-10.0 5075 88 88 52 25.0-12.0 5077 34 46 42 5078 60 67 11 20.0-10.0 5079 44 58 14 20.0-10.0 5081 25 34 50 6.0-3.0 5188 90 @ 94 3.50 5200 10 10 5205 56 33 100.0
5206 72 78 3.0 5299 7.00 5324 9.00 5327 17 5335 22.0 5367 18.00 5371 12.00 5376 12.00 5379 65 15.00 5386 18.00 5388 58 9.00 5388.HCl 60 12.00 5389 55 2.50 5389.HC1 57 2.50 5391 64 6.50 5391.HC1 100 3.50 5393 76 14.00 5393 .HCl 58 20.00 5394 59 16.00 5394.HC1 62 17.00 5397 42 5397.HCl 21 5402 37 5402.HC1 37 TABLE 2
Compound No. IC50 ( m) 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
1509 50.0 - 100.0 1542 50.0 - 100.0 1560 50.0 - 100.0 1618 50.0 - 100.0 1652 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 Reference Example 1= PreParation of (3Z)-1-acetyl-3- benzvlidene-2,5-iperazinedione 1,4-Diacetyl-2,5-piperazinedione (25.0g, 126 mmol), which is compound (8) mentioned in Reference Example 3, was heated at 120-1300C 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 (MgS04) and the solvent removed in vacuo. The residue was recrystallised from EtOAc:Hexane to give 11.78 g (38k) of the title compound as a yellow solid.
1H NMR (CDCl3 400 MHz) 6=2.69 (3H, s) 4.54 (2H, s) 7.20 (1H, s) 7.40 (3H, m), 7.48 (2H, m), 7.93 (1H, br.s) MS(DCI,NH3): 262 (MNH4+, 206 , 245 (MH+, 53%), 220 (52%), 204 (100%), 203 (100%)
Microanalysis C H N Cale 63.93 4.95 11.47 Found 64.11 5.02 11.41 Found 64.05 4.90 11.44 Alternatively (3Z)-l-acetyl-3-benzylidene-2,5piperazinedione can be produced as follows:
Compound 16 is treated with ammonia and subsequently with acetic anhydride to yield the title compound.
Reference Example 2: PreParation of (3Z)-1-acetvl-3-(4 acetamidobenzvlidene) -2.5- piperazinedione 1,4-Diacetyl-2,5-piperazinedione (10.0g, 50 mmol), prepared by the published procedure mentioned in Example 3, was stirred in DMF (40 ml) with 4-acetamidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 1200C. After 2 h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g (56%) of a yellow solid.
1H NMR (CDCls+TFA, 400 MHz) b=2.32 (3H, s) 2.72 (3H, s) 4.68 (2H, s) 7.36 (1H, s) 7.45 (2H, d, J=8Hz) 7.60 (2H, d, J=8Hz)
Microanalysis C H N Calc 59.80 5.02 13.95 Found 60.08 5.09 13.89 60.11 5.07 13.86 Reference Example 3: PreParation of 1,4-Diacetvl-2,5- PiPerazinedione
1,4-Diacetyl-2,5-piperazine dione (8) was prepared by the published procedure (S.M. Marcuccio and J.A. Elix, Aust. J. Chem., 1984, 37, 1791).
Reference Example 4: (3Z)-1-Acetol-3-(4- methoxvbenzvlidene) -2,5 Piperazinedione
(3Z)-1-Acetyl-3- (4-methoxybenzylidene) -2,5piperazinedione (9) was prepared by the published procedure (T. Yokoi, L-M. Yang, T. Yokoi, R-Y. Wu, and K-H. Lee, J.
Antibiot., 1988, 41, 494).
Reference Example 5: Preparation of (3Z)-1-acetvl-3-(2,6- dichlorobenzolidene)-2,5- piperazinedione 1, 4-Diacetyl-2, 5-piperazinedione prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 2,6-dichlorobenzaldehyde and triethylamine and heated to 120-1300C for 1-3h. The title compound was obtained with a yield of 40%.
Referene Example 6: Preparation of (3Z) -1-acetyl-3- (4 (3 dimethylamino) propoxybenzylidene) 2,5-piperazinedione 1, 4-Diacetyl-2, 5-piperazinedione, prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 4-(3-dimethylamino)propoxybenzaldehyde and triethylamine and heated to 120-1300C for 2-4h to give the title compound.
By the same method, using 4-(2 dimethylamino)ethoxybenzaldehyde in place of the abovementioned aldehyde, (3Z)-1-acetyl-3-(4-(2 dimethylamino)ethoxybenzylidene) -2,5-piperazinedione was prepared.
Reference Example 7: (3Z.6Z)-3-(4-Hydroxvbenzvlidene)-6- (4-methoxvbenzvlidene)-2,5- piDerazinedione (3Z,6Z)-3-(4-Acetoxybenzylidene)-6-(4methoxybenzylidene) -2,5-piperazinedione was treated with aqueous sodium hydroxide in THF at room temperature for 8 hrs to give the title compound (1519) in 30t yield.
Example 1: PreDaration of 1470 3 (Z) -1-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent), which is compound 18 prepared according to Reference Example 1, was treated with 1-tertbutoxycarbonylpyrrole-2-carboxaldehyde in the presence of Cs2C03 (1-1.1 equivalents) in DMF at 80-100 C for 1-6 hours. The title compound was obtained in 24% yield.
The crude product was optionally, washed with water, methanol, ethyl acetate or diethylether and optionally recrystallised from methanol as appropriate.
By the same method, but replacing l-tertbutoxycarbonylpyrrole-2-carboxaldehyde by the appropriately substituted aldehyde or benzaldehyde, the following compounds were prepared:
Compound Yield (%) 1471 52 1652 37 1983 45 1921 54 1922 43 1924 44 1910 31 1926 27 1927 26 1928 20 1929 1930 1912 33 5032 50 5040 45 5043 24 5053 44 5054 22 5057 43 5058 16 Example 2: Preparation of 1474 3(Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5- piperazinedione prepared according to Reference Example 4, was treated with 2-thiophenecarboxaldehyde in the presence of Cs2CO3 (1-1.1 equivalents) in DMF at 80-1000C for 1-6 hours. The title compound was obtained in 76% yield.
By the same method, but replacing 2thiophenecarboxaldehyde by the appropriately substituted aldehyde, the following compounds were prepared:
Compound Yield (%) 1476 54 1479 84 1506 67 1507 7 The crude product was optionally washed with water, methanol, ethyl acetate and diethylether and optionally recrystallised from acetic acid or methanol as appropriate.
Example 3: Preparation of 1884 3(Z)-1-Acetyl-3-benzylidene-2,5-piperazinedione (1 equivalent), prepared according to Reference Example 1, was treated with cyclohexanecarboxaldehyde (4 equivalents) in the presence of 0.5M potassium tert-butoxide in tertiary butanol (2 equivalents) in DMF at 0-100 C 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(2)-1- acetyl-3-benzylidene-2,5-piperazinedione with 3(2)-1- acetyl-3-(4-acetamidobenzylidene)-2,5-piperazinedione. The reaction was maintained for 18 hours. A low yield was obtained.
Example 4: PreDaration of 1676 1-Acetyl-3- (4-acetamidobenzylidene) -2,5piperazinedione (one equivalent), prepared according to Reference Example 2, was treated with cinnamaldehyde in the presence of CS2CO3 (1-1.1 equivalents) in DMF at 80-1000C for 1-6 hours. The title compound was obtained in 46% yield.
Example 5: Preparation of 1618 1,4 -Diacetyl-2, 5-piperazinedione, prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 2-thiophenecarboxaldehyde (1 equivalent) and triethylamine (1 equivalent) at 1200C for 2-4h. (3Z)-1-Acetyl-3-(2-thenylidene) -2,5-piperazinedione was obtained with a yield of 36%.
(3Z)-1-Acetyl-3- (2-thenylidene) -2,5-piperazinedione (1 equivalent) was stirred in DMF with 3-1-tertbutoxycarbonylindole-3-carboxyaldehye (1 equivalent) in the presence of Cs2CO3 (1-1.1 equivalents) at 80-lOOoC for 23h. The title compound was obtained with a yield of 14%.
Example 6: Prenaration of 1542 3(Z)-1-Acetyl-3-(2,6-dichlorobenzylidene)-2,5- piperazinedione (1 equivalent), prepared according to Reference Example 5 was treated with 3-furaldehyde (1 equivalent) in the presence of Cs2CO3 (1-1.1 equivalents) in DMF at 80-100 C for 2-5 hours. The title compound was obtained in 46% yield.
By the same method, but replacing 3-furaldehyde by the appropriately substituted aldehyde, 1560 was obtained with a yield of 39%.
Example 7: PreParation of 1982 3(Z)-1-Acetyl-3-benzylidene-2,5-piperazinedione (1 equivalent), as prepared in Reference Example 1, was treated with 4- (N- (3-dimethylaminoethyl) -N- methyl)aminomethylbenzaldehyde in the presence of Cs2CO3 (1-1.1 equivalents) in DMF at 80-100 C for 1-6h to give (3Z,6Z)-3-Benzylidene-6-(4-(N-dimethylaminoethyl)-Nmethyl)aminomethylbenzylidene) -2,5-piperazinedione in a yield of 50 .
Compound 1982, the hydrochloride salt of (3Z,6Z)-3 Benzylidene-6-(4-(N-(3-dimethylaminoethyl)-N- methyl) aminomethylbenzylidene) -2,5-piperazinedione, was prepared by bubbling HCl gas through a solution of the corresponding free base in THF, followed by evaporation to dryness. The yield was 45%.
Example 8: Preparation of 1976 3 (Z) -1-Acetyl-3- (4- (3dimethylamino) propoxybenzylidene) -2,5-piperazinedione 91 equivalent), prepared according to Reference Example 6 was treated with 3-(imidazol-l-yl)benzaldehyde (1 equivalent) in the presence of Cs2CO3 (1-1.1 equivalent) in DMF at 80900C for 2-4 hours. The title compound was obtained in 52% yield.
Example 9: Preparation of 1886 1519 (1 equivalent), prepared in Reference Example 7, was treated in DMF with sodium hydride (1 equivalent) and N-phthaloylglycyl chloride (1 equivalent) in DMF at room temperature for 4h. The title compound was obtained with a yield of 30k.
Example 10: Preparation of 5026
(3Z)-1-acetyl-3-(4-(3-dimethylamino)propoxy- benzylidene)-2,5-piperazinedione, prepared as in Reference Example 6, was treated with compound 10.1 in dimethylformamide (DMF) in the presence of Cs2CO3 at a temperature of 80"C-900C for 2-4 hours. Compound 5026 was obtained in 95% yield.
By an analogous process, using the appropriately substituted benzaldehyde in place of compound 10.1, the following compounds were prepared:
Compound No. Yield % 5030 30 5048 72 5188 70 Example 11: Preparation of 5027
(3Z)-l-acetyl-3-(4-(3-dimethylamino)propoxybenzylidene)- 2,5-piperazinedione, prepared as in Reference Example 6, was treated with compound 11.1 in DMF in the presence of Cs2CO3 at 800C-900C for 2-4 hours. Compound 5027 was produced in 33% yield.
By the same method, but replacing 11.1 by the appropriately substituted aldehyde, the following compounds were prepared:
Compound No. Yield (%) 5028 44 5029 25 5041 39 5042 39 5046 37 5052 58 Example 12: Preparation of 5023
Compound 12.1 was treated with 4-(3dimethylamino)propoxybenzaldehyde in DMF in the presence of Cs2CO3 at a temperature of 80"C-90"C for 2-4 hours.
Compound 5023 was obtained in 36% yield.
Example 13: Preparatgon of 5062
(3Z) -l-acetyl-3- (4- (2-dimethylamino) ethoxybenzylidene) -2,5piperazinedione, prepared as in Reference Example 6, was treated with compound 13.1 in DMF in the presence of Cs2CO3 at a temperature of 800C-900C for 2-4 hours. Compound 5062 was obtained in 12% yield.
By the same method, but using the appropriately substituted aldehyde in place of compound 13.1, the following compounds were prepared:
Compound No. @ Yield (%) 5071 41 5072 86 Example 14: PreDaration of compounds of formula (I)
0 Ar < )? Ac + subset.
HNy OHC 14.1 4 14.2 0 Ar \NH Subst.
0 Compound (D The 2,5-piperazinedione derivative 14.1 was treated with the aldehyde 14.2, the groups Ar and Subset being as specified below, in DMF in the presence of Cs2CO3 at 800C90 C for 2-4 hours. The compounds of formula (I) listed below were prepared:
Ar Subst. Compound Yield (%) of formula (I) Phyenyl -CH2S (CH2) 2NMe2 5058 16 3-furyl -CH2S (CH2) 2NMe2 5073 33 3-thienyl -CH2S (CH2) 2NMe2 5078 38 3-thienyl -CH2NHC (O) CH2NMe2 5074 83 2-bromophenyl -CH2NHC (O) CH2NMe2 5079 28 3-furyl -CH2NHC(O) CH2NMe2 5081 68 3-thienyl -CH2O (CH2) 2NMe2 5069 29 3-furyl -CH2O (CH2) 2NMe2 5077 20 Example 15: PreParation of compounds of formula (I)
Compound (I) The 2,5-piperazinedione derivative 15.1 was treated with the aldehyde 15.2 in which R20 and R21 are both H or are both OMe, the substituent Ar and linking group A being as specified below, in DMF in the presence of Cs2CO3 at 800C to 90"C for 2-4 hours. The compounds of formula (I) listed below were prepared. In 5391, 5394 and 5371 R20 and R21 are both H. In 5393 and 5402 R20 and R21 are OMe.
II Ar A Compound Yield (%) of Formula (I) Phenyl Phenyl - Hz 5391 21 Phenyl phenol -(CR2)3- 5394 47 Phenyl -(CR2)4- 5371 56 Phenyl phenol oH;7 5393 44 4-nitrophenyl 5402 5402 62 Example 16: Preparation of comPounds of formula (I)
(3Z)-l-acetyl-3-benzylidene-2,5-dione prepared as in Reference Example 1 (compound 18), was treated with the aldehyde 16.1 in which substituent Y was as indicated below, in DMF in the presence of Cs2CO3 at 800C-900C for 2-4 hours. The compounds of formula (I) listed below were prepared:
Y Compound of Yield %) formula (I) 5-O (CH2) 2NMe2 5324 34 4-O (CH2) 2NMe2 5327 51 5-(CH2)2NMe2 5335 45 5-O(CH2)20(CH2)2NMe2 5388 12 5-O(CH2)6NMe2 5389 35 5-N (Me) (CH2)2NMe2 5299 By the same method, but using 2,5-dichlorothiophene4-carboxaldehyde in place of compound 16.1, 5075 was prepared in 31% yield.
Example 17: Prenaration of salts 1. Hydrochloride salts of the following compounds of formula (I) were prepared by bubbling HCl gas through a solution of the corresponding free base in tetrahydrofuran (THF) at room temperature. The salt was recovered in the yield indicated.
compound of Hydrochloride Yield (%) formula (I) salt 1975 5026 95 1976 5030 30 5048 5048.HCl 72 5188 5206 24 5200 5205 31 5367 5376 47 5397 5397.2HCl 36 5041 5041.HCl 63 5042 5042.HCl 51 5046 5046.HCl 32 5052 5052.HCl 58 5023 1988 50 5062 5062.HCl 5071 5071.HC1 072 5072.HCl 1910 5055 57 1912 5061 47 5032 5032.HCl 39 5053 5053.HCl 90 5054 5053.HCl 88 5073 5073.HCl 76 5078 5078.HCl 78 1912 5061 47 5074 5074.HCl 51 5079 5079.HCl 73 5081 5081.HCl 76 5069 5069.HCl 5077 5077.HCl 5324 5324.HCl 68 5336 5336.HCl 74 5335 5335.HCl
5388 5388.HCl 79 5389 5389.HCl 75 5391 5391.HCl 5394 5394.HCl 75 5371 5379 65 2. Hydrochloride salts of the following compounds of formula (I) were prepared by bubbling HC1 gas through a solution of the corresponding free base in hot DMF. The salt was recovered in the yield indicated.
Compound of Hydrochloride Yield formula (I) salt 5386 5386.2HCl 79 5393 5393.HCl 60 5402 5402.HCl 52 3. Hydrochloride salts of the following compounds of formula (I) were prepared by treating the free base with 2M HC1:
Compound of Hydrochloride Yield (%) formula (I) salt 5027 5027.HCl 67 5028 5028.HCl 92 5029 5029.HCl 76 5040 5040.HC1 90 4. 5043.HCl, 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 HCl gas through a solution of 5057 in THF following by recrystallisation from MeOH.
Example 18: PHARMACEUTICAL COMPOSITION Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention can be manufactured as follows: Composition for 10,000 tablets compound of the invention (250 g) lactose (800 g) corn starch (415 g) 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 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 broken up into small 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 19: Characterisation of compounds of formula A The compounds prepared in the preceding Examples, were characterised by mass spectroscopic, microanalytical, proton nuclear magnetic resonance and, in some cases, infra-red techniques. The results are set out in the Tables which follow:
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1910 C23H20N4O3 401 (10) CI d6-DMSO/400MHz 4.28-4.32 (2H.t). 4.35-4.40 (2H.t).
6.75-7.70 (14H.m). 10.15 (2H,brs).
5023 C26H32N4O3 449(100 EI CDCl3/400MHz 2.00 (2H.m). 2.25 (12H,s). 2.46 (2H.t).
3.45 (2H.s). 4.05 (2H,t). 6.95-7.42 (10H.M). 8.15 92H,brs).
5026 C27H29N5O3.2HCl d6-DMSO/400MHz 2.12 (2H.m). 2.73 (6H.s). .21 (2H.m).
4.11 (2H.t). 5.48 (2H.s). 6.76 (2H.s).
7.00 (2H.d). 7.47 (2H.d). 7.50 (2H.d).
7.55 (2H.d). 7.65 (1H.s). 7.77 (1H.s).
9.21 (1H.s). 10.12 (2H.brs). 10.45 (1H.brs).
5027 C22H24N4O3.2HCl CDCl3+CF3CO2H/400 MHZ 2.00 (2H.t). 3.00 (6H.s). 3.45 (2H.m).
*3.90 (2H.t). 7.00 (2H.d). 7.15 (1H.s).
7.35 (1H.d). 7.45 (2H.d), 8.00 (2H.d), 8.95 (2H.d).
5028 C22H24N4O3.2HCl CDCl3+CF3CO2D/400MHZ 2.35 (2H.m). 3.00 (6H.s). 3.45 (2H.t).
4.15 (2H.t). 7.00 (2H.d). 7.15 (1H.s).
7.30 (1H.s) 7.45 (2H.d). 8.10 (1H.t).
8.50 (1H.d). 8.95 (1H.d). 9.15 (1Hs).
5030 d6-DMSO/400MHz 2.18 (2H.M). 2.77 (6H.s). 3.20 (2H.m).
4.10 (2H.t). 6.77 (1H.s). 6.81 (1H.s).
7.00 (2H.d). 7.51 (2H.d). 7.65 (2H.m).
7.71 (1H.m). 7.85 (1H,s), 7.96 (1H,s).
8.29 (1H.s). 9.60 (1H.s). 10.21 (1H.brs). 10.50 (1H.brs). 10.61 (1H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5032 C23H25N3O4.HCl 408(20). CI d6-DMSO/400MHz 2.83 (6H.s). 3.23 (2H.m). 4.02 (2H.d).
306(30) 4.30 (1H.m). 5.96 (1H.brd). 6.77 (1H.s).
6.78 (1H.s). 7.02 (2H.d). 7.33 (1H.m), 7.42 (2H.m). 7.55 (4H.m). 9.70 (1H.brs).
10.12 (2H.br).
5040 C25H27N3O5.HCl 450(10) CI d6-DMSO/400MHz 3.20-3.55 (6H.m). 3.75-4.00 (4H.M). 4.02 (2H.d). 4.39 (1H.m). 5.99 (1H.brs). 6.77 (1H.s). 6.78 (1H.s). 7.02 (2H.d). 7.33 (1H.m). 7.45 (2H.m). 7.55 (4H.m). 10.20 (3H.br) 5041 C21H23N3O4.HCl 382(100) EI d6-DMSO/400MHz 2.09 (2H.m). 2.80 (6H.s). 3.20 (2H.m).
4.09 (2H.t). 6.68 (1H.s). 6.64 (1H.m).
6.78 (1H.s). 6.89 (1H.m) 7.0 (2H.d).
7.54 (2H.d). 7.90 (1H.s). 9.45 (1H.brs).
9.75 (1Y.brs). 10.14 (1H.brs) 5042 C21H23N3O3S.HCl 398(35) EI d6-DMSO/400MHz 2.09 (2H.m). 2.79 (6H.s). 3.18 92H.m).
4.10 (2H.t). 6.76 (1H.s). 6.85 (1H.s).
7.00 (2H.d). 7.41 (1H.m). 7.51 (2H.d).
7.62 (1H.m). 7.94 (1H.m). 9.89 (1H.brs).
9.92 (1H.brs). 10.10 (1H.brs).
5043 C27H32N4O5.HCl 49(100) CI d6-DMSO/400MHz 3.10-3.85 (14H.m). 4.02 (2H.d). 4.40 (1H.brs). 6.77 (1H.s). 6.78 (1H.s). 7.02 (2H.d). 7.32 (1H.m). 7.42 (2H.m). 7.55 (4H.m). 10.20 (2H.S).
5046 C21H23N3O3S.HCl 398(23), EI d6-DMSO/400MHz 2.09 (2H.m). 7.28 (6H.s). 3.12 (2H.m).
169(100) 4.10 (2H.t). 6.78 (1H.s). 6.94 (1H.s).
7.00 (2H.d). 7.18 (1H.m). 7.54 (2H.d).
7.58 (1H.m). 7.76 (1H.m). 9.75 (1H.brs).
10.16 (1H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5048 C25H28N4O4.HCl 485 (100) EI d6-DMSO/400MHz 2.05 (2H.s). 2.14 (2H.m). 2.79 (6H.d).
3.20 (2H.m). 4.13 (2H.t). 6.70 (1H.s).
6.75 (1H.s). 7.0 (2H.d). 7.48 (2H.d).
7.51 (2H.d). 7.62 (2H.d). 9.94 (1H.brs).
10.15 (1H.brs). 10.20 (1H.brs).
5052 d6-DMSO/400MHz 2.15 (2H.m). 2.28 (6H.s). 3.20 (2H.m).
4.10 (2H.t). 6.68 (1H.s). 6.75 (1H.s).
6.94 (1H.s). 7.00 (2H.d). 7.754 (2H.d).
7.76 (1H.s). 8.23 (1H.s).
5053 C24H25N3O3.HCl CDCl3+CF3CO2D/400MHz 2.20 (4H.m). 3.20 (2H.m). 3.70 (2H.m).
4.00 (2H.m). 4.45 (2H.m). 7.00 (2H.d).
7.23 (1H.s). 7.39 (1H.S). 7.45 (7H.M).
5054 C24H25N3O4.HCl CDCl3+CF3CO2D/400MHz 3.25 (2H.m). 3.67 (2H.m). 3.85 (2H.m).
4.05-4.20 (4H.m). 4.47 (2H.m). 6.97 (2H.d) 7.20 (1H.s). 7.26 (1H.s). 7.397.51 (7H.m).
5055 C23H20N4O3.HCl 401(100) ESI d6-DMSO/400MHz 4.40 (2H.t). 4.60 (2H.t). 6.73 (1H.s).
6.75 (1H.s). 6.99 (2H.d). 7.30 -7.55 (7H.m). 7.65 (1H.s). 7.90 (1H.s). 9.10 (1H.s). 10.10 (1H.s). 10.15 (1H.s).
10.20 (1H.brs) 5057 C24H22N4O4.HCl d6-DMSO/400MHz 4.00-4.05 (2H.m). 4.20-4.32 (2H.m). 4.48 (1H.m). 6.77 (1H.s). 6.78 (1H.s). 7.03 (2H.d). 7.32 (2H.m). 7.42 (2H.m). 7.55 (4H.m). 7.71 (1H.m). 7.77 (1H.m). 9.12 (1H.s). 10.20 (2H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5058.HCl C23H25N3O2S.HCl 409(15) CI d6-DMSO/400MHz 2.70-2.75 (8H.m). 3.20-3.25 (2H.m). 3.85 (2H.s). 6.78 (2H.s). 7.32-7.55 (9H.m,).
9.68 (1H.brs). 10.22 (1H.s). 10.24 (1H.s) 5061 C23H24N4O3.HCl d6-DMSO/400MHz 2.84 (6H.S). 3.95 (2H.s). 4.40 (2H.d).
6.75 (1H.s). 6.77 (1H.s). 7.33-7.55 (9H.m). 9.15 (1H.t). 9.85 (1H.brs).
10.20 (1H.brs). 10.25 (1H.brs).
5062 C20H21N3O4.HCl d6-DMSO/400MHz 2.76 (YH.d). 3.51 (2H.m). 4.38 (2H.t).
6.66 (1H.s). 6.75 (1H.s). 6.91 (1H.s).
7.05 (2H.d). 7.55 (2H.d). 7.74 (1H.s).
8.22 (1H.s). 9.76 (1H.s).
5069 C21H23N3O3S.HCl 397(10) CI d6-DMSO/400MHz 2.80 (6H.s). 3.30 (2H.t). 3.76 (2H.t).
4.58 (2H.s). 6.82 (1H.s). 6.87 (1H.s).
7.45 (2H.m). 7.58 (2H.d). 7.65 (1H.m).
8.00 (1H.s). 9.78 (1H.s). 10.02 (1H.s).
10.18 (1H.s).
5071 C20H21N3O3S.HCl d6-DMSO/400MHz 2.86 (6H.d). 3.53 (2H.m). 4.38 (2H.t).
6.78 (1H.s). 6.84 (1H.s). 7.07 (2H.d).
7.43 (1H.m). 7.58 (2H.d). 7.65 (1H.m).
7.96 (1H.m). 9.55 (1H.s). 10.05 (1H.brs). 10.13 (1H.brs).
5072 C21H23N3O3S2.HCl d6-DMSO/400MHz 2.58 (3H.s). 2.78 (6H.s). 3.44 (2H.m).
4.36 (2H.t). 6.77 (1H.s). 6.85 (1H.s).
7.05 (2H.d). 7.12 (1H.d). 7.52 (1H.d).
7.58 (2H.d). 10.20 (1H.s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5073 C21H23N3O3S 398(15). EI CDCl3+CF3CO2D/400MHz 2.75 (2H.t). 2.90 (6H.s). 3.25 (2H.t).
293(100) 3.78 (2H.s). 6.70 (1H.s). 7.10 (1H.s).
7.40 (4H.s). 7.60 (1H.s). 7.85 (1H.s).
5073.HCl C21H23N3O3S.HCl d6-DMSO/400MHz 2.75 (6H.s). 2.75-2.80 (2H.m). 3.20 (2H.m). 3.84 (2H.s). 6.70 (1H.s). 6.77 (1H.s). 6.90 (1H.s). 7.40 (2H.d). 7.52 (2H.d). 7.75 (1H.s). 8.20 (1H.s). 9.78 (1H.brs). 10.00 (1H.brs). 10.10 (1H.brs) 5074 d6-DMSO/400MHz 2.82 (6H.s). 4.00 (2H.s). 4.41 (2H.d).
6.81 (1H.s). 6.88 (1H.s). 7.98 (2H.m).
9.15 (1H.brs). 9.90 (1H.brs0. 10.04 (1H.brs). 10.18 (1H.brs).
5075 C16H10Cl2N2O2S d6-DMSO/400MHz 6.50 (1H.s). 6.80 (1H.s). 7.35 (1H.t).
7.39-7.4 (3H.m). 7.55 (2H.d).
5077 C21H23N3O4.HCl d6-DMSO/400MHz 2.55 (2H.t). 2.80 (6H.s). 3.80 (2H.t).
4.55 (2H.s). 6.70 (1H.s). 6.80 (1H.s).
6.95 (1H.s). 7.45 (2H.d). 7.60 (2H.d).
7.85 (1H.s). 8.30 (1H.s). 9.90 )1H.s).
10.01 (1H.s).
5078 C21H23N3O2S2 414(15). EI CDCl3+CF3CO2D/400MHz 2.75 (2H.t). 2.88 (6H.s). 3.25 (2H.t).
309(100) 3.88 (2H.s). 7.22-7.28 (3H.m). 7.45 (4H.s). 7.50-7.54 (1H.m). 7.64 (-7.66 (1H.s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5078.HCl C21H23N3O2S2.HCl d6-DMSO/400MHz 2.72-2.78 (2H.m). 2.75 (6H.s). 3.20-3.25 (2H.m). 3.84 (2H.s). 6.75 (1H.s). 6.85 (1H.s). 7.40-7.45 (3H.m). 7.55 (2H.d).
7.64-7.67 (1H.m). 7.96-7.99 (1H.m). 9.85 (1H.brs). 10.05 (1H.brs). 10.18 (1H.brs).
5079 C23H23BrN4O3.HCl d6-DMSO/400MHz 2.82 (6H.s). 4.00 (2H.s). 4.41 (2H.d).
6.74 (H.s). 6.80 (1H.s). 7.30 (1H.m).
7.36 (2H.d). 7.45 (1H.m). 7.54 (2H.d).
7.60 (1H.d). 7.68 (1H.d) 9.56 (1H.brt).
9.90 (1H.brs). 10.36 91H.brs). 10.48 (1H.brs).
5081 C21H22N4O4.HCl d6-DMSO/400MHz 2.83 (6H.s). 4.01 (2H.s). 4.39 (2H.d).
6.68 (1H.s). 6.789 (1H.s). 6.94 (1H.s).
7.35 (2H.d). 7.54 (2H.d). 7.76 (1H.s).
8.22 (1H.s). 9.12 (1H.brt). 9.82 (2H.brs) 10.12 (1H.brs).
5188 C27H27N3O3 442(100) ESI d6-DMSO/400MHz 1.8-1.9 (2H.m). 2.15 (6H.s). 2.38 (2H.t). 4.05 (2H.t). 6.78 (1H.s). 6.90 (1H.s). 6.99 (2H.d). 7.50-7.58 (4H.m).
7.61-7.65 (1H.m). 7.39-7.98 (3H.m). 8.11 (1H.s). 10.28 (2H.brs).
5200 C27H27N3O3 442(100) ESI d6-DMSO/400MHz 1.81-1.91 (2H.m). 2.15 (6H.s). 2.35 (2H.t). 4.09 (2H.t). 6.75 (1H.s). 6.96 (2H.d). 7.21 (1H.s). 7.5-7.65 (7H.m).
7.94 (2H.d). 10.15 (2H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5205 C27H27N3O3.HCl 442(40) CI d6-DMSO/400MHz 2.12-2.20 (2H.m). 2.80(6H.s). 3.20-3.25 (2H.m). 4.10 (2H.t). 6.75 (1H.s). 7.01 (2H.d). 7.24 (1H.s). 7.51 - 7.67 (6H.m).
7.92 (2H.d). 7.98-8.01 (1H.m). 10.1 (2H.brs). 10.25 (1H.brs).
5206 C27H27N3O3.HCl d6-DMSO/400MHz 2.11-2.21 (2H.m). 2.60 (6H.s). 2.85-2.98 (2H.m). 4.09 (2H.t). 6.78 (1H.s). 6.94 (1H.s). 7.0 (2H.d). 7.50-7.59 (4H.m).
7.64 (1H.d). 7.90-7.99 (3H.m). 8.12 (1H.m). 10.21 (1H.brs0. 10.43 (1H.BRS).
5324 C20H21N3O3S.HCl 384(100) CI d6-DMSO/400MHz 2.85 (6H.s). 3.52 (2H.t). 4.50 (2H.t).
6.52 (1H.d). 6.78 (1H.s). 6.81 (1H.s).
7.31 (1H.d). 7.32 (1H.m). 7.45 (2H.m) 7.57 (2H.d). 9.70 (1H.s). 10.15 (1H.s).
10.41 (1H.brs).
5327 C20H21N3O3S 384(20) CI d6-DMSO/400MHz 2.22 (6H.s). 2.63 (2H.t). 4.05 (2H.t).
6.76 (1H.s). 6.82 (2x1H.s). 7.30 (1H.s).
7.33 (1H.m). 7.42 (2H.m). 7.55 (2H.d).
5335 C20H21N3O2S.HCl 368(20) CI d6-DMSO/400MHz 2.78 (6H.s). 3.28 (4H.m). 6.78 (1H.s).
6.89 (1H.s). 7.02 (1H.d). 7.38-7.45 (4H.m). 7.55 (2H.d). 9.68 (1H.brs).
10.40 (1H.br).
5336 C20H21N3O3S.HCl 384(10) CI d6-DMSO/400MHz 2.82 (6H.s). 3.49 (2H.t). 4.38 (2H.t).
6.78 (1H.s). 6.80 (1H.s). 6.94 (1H.s).
7.31 (1H.s). 7.32 (1H.m). 7.42 (2H.m).
7.55 (2H.d). 9.78 (1H.s). 10.25 (1Y.s).
10.45 (1H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5367 C33H34N4O4 551(100) CI CDCl3+CF3CO2D/400MHz 1.72 (2H.m). 1.95-2.01 (2H.m). 2.24 (6H.m). 2.48 (2H.t). 2.96 (2H.m). 3.70 (1H.m). 4.07 (2H.t). 4.89 (1H.m). 7.0 (2H.d). 7.01 ((2H.s). 7.5-7.25 (4H.m).
7.35 (2H.d). 7.48 (2H.d). 7.57 (2H.d).
8.17 (2H.brs).
5371 C32H32N4O3 521(100) CI CDCl3/400MHz 1.75-1.80 (4H.m). 2.55-2.60 (2H.m). 2.75 (2H.t). 2.88 (2H.t). 3.50-3.55 (2H.m).
3.65 (2H.s). 6.95 (1H,s). 6.98-7.02 (1H.m). 7.05-7.10 (4H.m). 7.15-7.20 (2H.m) 7.38-7.50 (5H.m). 7.65 (2H.d).
7.85 (1H.brs). 8.00 (1H.brs). 8.15 (1H.brs).
5379 C32H32N4O3.HCl d6-DMSO/400MHz 1.60-1,68 (2H.m). 1.80-1.88 (2H.m).
3.00-3.06 (1H.m). 3.15-3.35 (6H.m). 3.65 -3.75 (1H.m). 4.25-4.55 (2H.m). 6.80 (2H.brs). 7.18-7.45 (7H.m). 7.55-7.65 (4H.m). 7.89 (2H.d). 8.57 (1H.brs).
10.29 (2H.brs). 10.36 (1H.brs).
5386 C35H39N5O4 594(100). ESI d6-DMSO/400MHz 1.81-1.90 92H.m). 2.15 (6H.s). 2.35 (2H.t). 2.62-2.70 (2H.m). 2.79-2.83 (2H.m). 3.46-3.53 (2H.m). 4.02 (2H.t).
6.73 (1H.s). 6.75 (1H.s). 6.73 (1H.s).
6.75 (1H.s). 6.98 (2H.d). 7.02-7.11 (4H.m) 7.50 (2H.d). 7.60 (2H.d). 7.78 (2H.d). 8.41-8.48 (1H.m). 10.22 (1H.brs)
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5386.2HCl C35H39N5O4.2HCl 594(100). ESI d6-DMSO/400MHz 2.12-2.21 (2H.m). 2.72 (6H.s). 3.1-3.25 (4H.m). 3.76-3.82 (2H.m). 4.12 92H.t).
4.41 (2H.brs). 6.78 (1H.s). 6.79 (1H.s).
7.02 (2H.d). 9.05 (1H.brs). 10.19 (1H.brs). 10.35 (1H.brs).
5388 C22H25N3O4S d6-DMSO/400MHz 2.16 (6H.s). 2.42 (2H.t). 3.55 (2H.t).
3.75 (2H.t). 4.23 (2H.t). 6.43 (1H.d).
6.72 (1H.s). 6.78 (1H.s). 7.22 (1H.d).
7.32 (1H.m). 7.42 (2H.m). 7.53 92H.d).
5388.HCl C22H25N3O4S.HCl 428(5) CI d6-DMSO/400MHz 2.72 (6H.s). 3.25 (2H.t). 3.81 (4H.m).
4.32 (2H.t). 6.47 (1H.d). 6.76 (1H.s).
6.81 (1H.s). 7.27 (1H.d). 7.32 (1H.m).
7.42 (2H.m). 7.55 (2H.d). 10.15 (1H.brs).
5389 C24H29N3O3S 440(5) CI d6-DMSO/400MHz 1.28-1.45 (6H.m). 1.57 (2H.m). 2.12 (6H.s). 2.20 (2H.t). 4.13 (2H.t). 6.41 (1H.d). 6.76 (1H.s). 6.79 (1H.s). 7.23 (1H.d). 7.32 (1H.m). 7.42 (2H.m). 7.55 (2H.d).
5389.HCl C24H29N3O3S.HCl 440(5) CI d6-DMSO/400MHz 1.36 (2H.m). 1.45 (2H.m). 1.66 (2H.m).
1.76 (2H.m). 2.72 (6H.s). 30.. (2H.t).
4.13 (2H.t). 6.42 (1H.d). 6.75 (1H.s).
6.80 (1H.s). 7.25 (1H.d). 7.32 (1H.m).
7.41 (2H.m). 7.55 (2H.d). 10.06 (3H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5191 C30H28N4O3 493(100). ESI CDCl3+CF3CO2D/400MHz 3.15-3.25 (1H.m). 3.28-3.40 (1H.m).
489(50) 3.48-3.57 (1H.m). 3.60-3.68 (2H.m).
3.92-4.02 (3H.m). 4.33 (2H.d). 4.77 (1H.d). 7.11 (1H.d). 7.22-7.56 (12H.m).
7.85 (2H.d).
5391.HCl C30H28N4O3.HCl 493(100) ESI d6-DMSO/400MHz 3.01-3.10 (1H.m). 3.38-3.45 (4H.m).
3.80-3.85 93H.m). 4.32-4.41 (1H.m).
4.61-4.70 (1H.m). 6.80 (2H.s). 7.18-7.36 (5H.m). 7.41 (2H.t). 7.58 (2H.d). 7.67 (2H.d). 7.99 (2H.d). 9.02 (1H.t). 10.29 (1H.brs). 10.39 (1H.brs). 10.99 (1H.brs).
5393 C38H36N4O5 d6-DMSO/400MHz 2.70 (6H.m). 2.80 (2H.m). 3.55 (2H.s).
3.70 (6H.s). 6.63 (1H.s). 6.65 (1H.s).
6.80 (1H.s). 6.83 (1H.s). 7.22 (2H.d).
7.32 (1H.m). 7.42 (2H.m). 7.55 (2H.d).
7.68 (4H.d). 7.99 (2H.d). 10.15 (1H.s).
10.35 (2H.br).
5393.HCl C38H36N4O5.HCl 629(100) CI d6-DMSO/400MHz 2.95-3.45 (8H.m). 3.75 (2x3H.s). 4.254.50 (2H,m). 6.79 (1H.s). 6.80 (1H,s), 6.82 (1H,s). 6.83 (1H,s). 7.30 (2H.d).
7.32 (1H,m). 7.41 (2H.m). 7.55 (2H.d).
7.68 (2H.d). 7.77 (2H.d). 8.01 (2H,d).
10.28 (2H,s), 10.40 (1H,s), 10.80 (1H,brs).
5394 C31H30N4O3 507(15) CI d6-DMSO/400MHz 1.75-1.85 (2H.m). 2.52-2.57 (2H.m). 2.67 (2H.t). 2.84 (2H.t). 3.34-3.40 (2Hm).
3.57 (2H,s), 6.75 (1H,s), 6.80 (1H,s), 7.05-7.10 (4H,m), 7.30-7.55 (7H,m). 7.84 (2H,d), 8.57 (1H,brt), 10.25 (2H,brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5394.HCl C31H304O3.HCl d6-DMSO/400MHz 2.02-2.10 (2H,m), 2.95-3.01 (1H,m), 3.18-3.43 (6H.m). 3.65-3.70 (1H.m).
4.23-4.53 (2H.m). 6.79 (1H.s). 6.81 (1H.s). 7.20-7.45 (7H.m) 7.55 (2H.d).
7.65 (2H.d). 7.90 (2H.d). 8.70 (1H.t).
10.25 (1Y,s). 10.35 (1H.s). 10.60 (1H.brs).
5397 C37H43N5O4 622(80) CI CDCl3/400MHz 1.75-1.83 (4H.m). 1.95-2.00 (2H.m). 2.25 (6H,s), 2.45 (2H.t). 2.58-2.61 (2H.m).
2.
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 5402.HCl C38H35N5O7.HCl 674(80) ESI d6-DMSO/400MHz 3.00=3.50 (8H.m). 3.73 (2x3H.s). 4.25 (2H.m). 6.75 (1H.s). 6.79 (1H.s). 6.86 (1H.s). 6.88 (1H.s). 7.29 (2H.d). 7.69 (2H.d). 7.77 (4H.m). 8.00 (2H.d). 8.25 (2H.d). 10.25 (1H.s). 10.55 (1H.brs).
10.70 (1H.brs).
5376 C33H34N4O4.HCl 551(100) ESI d6-DMSO/400MHz 2.11-2.20 (2H.m). 2.78 (6H.s). 2.83-2.82 (2H.m). 3.20 (2H.m). 3.62 (2H.brs). 4.09 (2H.t). 4.75 (2H.brs). 6.77 (1H.s). 6.79 (1H.s). 7.00 (2H.d). 7.19 (4H.brs). 7.50 (2H.d). 7.55 (2H.d). 7.60 )2H.d). 10.19 (1H.brs). 10.32 (1H.brs). 10.55 (1H.brs).
5299 C21H24N4O2S d6-DMSO/400MHz 2.18 (6H.s). 2.47 (2H.t). 3.01 (3H.s).
3.40 (2H.d). 5.98 (1H.d). 6.71 (1H.s).
6.85 (1H.s). 7.26 (1H.d). 7.31 (1H.m).
7.41 (2H.m). 7.52 (2H.d). 9.85 (1H.brs).
1912 C23H24N4O3 404(55) EI d6-DMSO/400MHz 2.25 (6H.s). 2.93 (2H.s). 4.30 (2H.d).
6.74 (1H.s). 6.76 (1H.s). 7.28-7.55 (9H.m). 8.25 (1H.t). 10.20 (2H.brs).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1927 C6H14N4O2 291. 30%: 295. MH+ 100% CDCl3 + TFA 2.45 (3H, s). 6.85 294 (DCI. NH3) (1H.s).
7.38 (1H.s). 7.48 (5H.m).
8.95 (1H,s).
1926 C15H12N4O2 281 MH+ 100% CDCl3 + TFA 7.20 (1H,s), 7.45 280 (DCI, NH3) (8H,m).
1545 C21H17N3O3 192. 20%; 292, 10%, CDCl3 ~+ CF3CO2D NH+ 360 7.82 (1H,d), 359 7.75 (1H,d).
(DCI NH3) 7.65 (1H. ).
7.48 (3H.m).
7.35 (2H.m).
7.25 (1H.s).
7.06 (2H.d).
3.98 (3H.s).
1542 C16H10N2O3Cl2 349, 351, 353, 100%; CDCl/TFA 366, 368. 370, 50%; 6.72 (1H,s), 313, 39%. 7.18 (2H,2xs).
348 7.34 (1H,t).
(DCI NH3) 7.43 92H,d).
7.59 (1H,s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1509 C20H15N3O2 347 MNH4~. 1%; CDCl3/TFA 330 MH+. 100% 7.22-7.40 (3H.m).
7.40-7.52 (6H,M).
(DCI NH3) 7.60 (1H,s). 7.78 (1H,d, J=7Hz), 7.81 (1H,s), 8.10 (1H,s).
1507 C22H23NO5 310, 100%; CDCl3 + CF3CO2D C 64.54 64.45 64.39 336, 20%; 7.65 (1H,s).
407 351, 20%: 7.48 (1H.brs). H 5.66 5.61 5.62 MH+ 40. 5% 7.42 (2H.d). 7.22 MNH4+, 427, 2% (1H,s), N 10.26 10.46 10.43 7.00 (2H,d).
(DCI NH3) 6.72 (1H,brd).
6.39 (1H,brd).
3.90 (3H,s). 1.65 (9H.s).
1506 C26H25N3O5 360, 100%; CDCl3 + CF3CO2D C 67.96 67.54 67.63 MH+ 460, 8.27 (1H,d) 459 MNH4+ 477. 2% 8.05 (1H.s) H 5.48 5.35 5.30 7.70 (1H.d).
(DCI NH3) 7.47 (3H,m). N 9.14 9.21 9.22 7.38 (2H.pt).
7.25 (1H,s).
7.05 (2H,d).
3.90 (3H,s).
1.65 (9H,s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1476 C17H14N2O4 279, 5%; MH+. 311: CDCl3 + CF3CO2D C 65.80 65.87 65.68 MNH4+. 328. 2% 7.85 (1H,s).
310 7.60 (1H,brs), H 4.55 4.44 4.54 (DCI NH3) 7M42 (2H.d).
7.21 (1H.s). N 9.03 9.03 8.98 7.08 (1H.s).
7.02 (2H.d).
6.72 (1H.brs), 3.90 (3H,s).
1474 C17H14N2O3 279, 10%; MH+, 327 CDCl3 + CF3CO2D C 62.56 62.41 62.39 7.60 (1H.d).
326 (DCI NH3) 7.45 (3H.m). H 4.32 4.41 4.46 7.35 (1H.s).
7.23 (2H.m). N 8.58 8.57 8.55 7.05 92H.d).
3.90 (3H.s).
1950 C25H27N3O4 MH+ (100%) 434 CDCl3 CF3CO2D 400 MHz C 69.57 68.98 69.06 7.50-7.42 (m.5H). H 6.28 6.25 6.25 433 CI/NH3 7.25-7.15 (m. 4H). N 9.69 9.59 9.60 7.00 (d.1H).
6.96 (d.1H).
6.90 (d.1H).
4.41 (t.2H).
*3.90 (2.3H).
3.67 (t.2H).
3.12 (s.6H).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1718 C21H17N3O3 MH+ 360. 10% DMSO 11.4 (1H,s), 359 (DCI NH3) 10.08 (1H.s).
9.82 (1H.s).
7.55 (3H.m).
7.39 (1H.d).
7.18 (1H,t).
7.01 (4H.m) 6.85 (1H,s).
6.78 (1H.s).
3.80 (3H,s).
1693 C22H19N3O5S 360, 85% ; 402. 25%, MH+438 7.98 (1H,d).
7.88 (1H.s).
437 (DCI NH3) 7.75 (1H,d).
7.45 (5H.m).
7.35 (1H,s).
7.02 (2H.d).
3.90 (3H.s).
3.30 (2.33H,s) 1618 C23H21N3O4S 436, 100% ; CDCl3 TFA 336, 82% 1.75 (9H,s), 435 7.22-7.28 (overlapping solvent & sample signals).
7.36-7.50 (6H, overlapping signals), 7.61 (2H, overlapping signals), 8.10 (1H.s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1560 C25H21N3O4Cl2 498/500/502 DMSO-D6 (100/69/15)% 1.68 (9H,s).
497 398/400/402 6.66 (1H,s).
(49/31/7)% 6.92 (1H,s).
7.30-7.44 (3H,c).
7.49 (2H,d).
7.68 (1H,d).
8.08 (1H,d).
8.17 (1H,s).
1470 C21H21N3O4 397, MNH4. 4% ; 380, MH+, CDCl3 13%, 280, 100% 1.64 (9H, s). 6.33 (1H.br.s).
(DCI NH3) 6.57 (1H.br.s).
7.00 (1H,s).
7.35-7.50 (7H,m).
8.10 (1H,br.s).
8.18 (1H,br.s) 1471 C25H23N3O4 447, MNH4+, 17%; 430. MH+, CDCl3 100% ; 330. 82% 1.72 (9H,s). 7.07 (1H,s), 7.14 (1H. s).
7.30-7.50 (7H,m).
7.66 (1H,d, J=7Hz).
7.84 (1H.s).
8.03 (1H,br.s), 8.18 (2H,m)
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1729 C23H19N3O5 435, MNH4+. 23%; 418, MH+, CDCl3 100% 3.09 (4H,s).
3.92 (3H,s).
(DCI NH3) 7.07 (2H,d, J=7Hz).
7.28 (1H,s).
7.30 (1H.s).
7.39 (2H,d, J=6Hz), 7.45 (2H,d, J=7Hz), 7.60 (2H,d, J=6HZ) 1647 C23H21N3O3 405, M+NH4, 7%; 388, M+H, CDCl3 100% ; 317, 43% ; 459, 29% 1.84-2.00 (4H,m).
387 3.13 (2H,t). 3.67 DCI NH3 (2H,t).
6.98 (1H,s), 7.03 (1H,s).
7.32-7.50 (9H.m).
8.10 (1H.brs), 8.32 (1H,brs) 1845 C21H17N3O5 409, M+NH4, 35%; 392, MH+, CDCl3 + TFA C 64.45 63.99 63.94 100% 2.35 (3H, s.Ac).
391 6.05 92H,s. OCH2O), H 4.38 4.42 4.37 (DCI NH3) 6.85-7.60 (9H,mn) N 10.74 10.99 11.01 1809 C20H16N2O5 382. M++NH4, 5% ; 365, MH+, CDCl3 + TFA C 65.93 65.85 65.96 100% 3.85 (3H,s.OMe).
364 6.05 92H,s.OCH2O). H 4.43 4.38 4.37 (DCI NH3) 6.90-7.45 (9H,M) N 7.69 7.60 7.65
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1808 C19H14N2O4 335, M++1. 100% CDCl3 + TFA C 68.26 68.07 68.00 6.05 (2H,s.OCH2O), 334 6.90-7.50 (10H,m) H 4.22 4.15 4.17 N 8.38 8.35 8.35 1929 C22H18N4O2 MH+, 371 CDCl3 + TFA 5.45 (2H,s), 370 (DCI NH3) 7.18 (1H,s).
7.26 (1H,s), 7.30 (1H,s), 7.45 (10H,m), 8.88 (1H,s) 1930 MH+, 357. 100% CDCl3 + TFA 7.27 (1H,s).
(DCI NH3) 7.30 (1H,s), 7.50 (1H,m).
7.65 (5H,m).
7.75 (1H,t).
9.10 (1H,s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1975 C27H29N5O3 236. 25%; 257, 1005 ; 376. CDCl3 + TFA 20% ; MH+, 472, 20%. 2.35 92H,m), 3.01 (6H.S).
DCI NH3 3.45 (2H.t).
4.18 (2H,t).
5.40 (2H.s).
6.95 (2H,d).
7.20 (1H,m).
7.25 (1H,s).
7.40 (3H,m).
7.50 (3H,m).
1976 C26H27N5O3 230, 100% ; 247, 60% ; MH+, CDCl3 + TFA 458, 90%. 2.30 (2H,m).
457 2.05 (6H,s).
DCI NH3 3.45 92H.t).
4.18 (2H.t).
6.98 (2H,d).
7.25 (2H,d).
7.45 (2H,d).
7.55 (3H,m).
7.75 (3H,m).
9.18 (1H,s).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1982 C24H28N4O3.2HCl 405, 100%, MH+ D2O 2.98 (3H.s).
404+73 EI+ 3.09 (6H,s).
3.75 (4H,brs).
4.50 (2H,s), 7.09 (1H,s), 7.13 (1H,s).
7.52-7.68 (5H,c).
7.67-7.77 (4H,overlapping signals).
1983 C26H30N4O2 431, 25%, MH+; DMSO-D6 332, 30% ; 303, 18% ; 1.53 (2H,m), 84. 92%; 118, 100%. 1.71 (2H,d), 1.83 (2H,t).
EI+ 2.12 (3H,s), 2.14 (3H,s).
2.35 (1H,m).
2.80 (2H,d).
3.57 (2H,s).
6.78 (2H.overlapping signals).
7.34 (3H.overlapping signals), 7.43 (2H,t), 7.50 (2H,d).
7.57 (2H,d).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1886 C29H21N3O7 COCl3 / TFA 3.90 (3H.s).
4.79 (2H.s).
7.01 (2H.d.J=8Hz), 7.21 (1H.s).
7.24 (1H.s).
7.27 (2H.d),J=8Hz).
7.41 (2H.d. J=8Hz).
7.47 (2H,d. J=8Hz).
7.82 (2H.m).
7.97 (2H,m).
1657 C20H19N3O3 MH+, 350, 125 ; M+, 349, 13% ; CDCl3 / TFA 333. 100%. 3.92 (3H.s). 4.32 349 (2H,s).
CI NH3 7.05 92H.d). 7.24 (2H,d).
7.45 92H,d), 7.52 (4H.s).
1891 C23H24N2O4 392, M+, 25%; 347, M± DMSO C 70.39 70.31 70.03 OCH2CH3. 100% .115 (6H.t. J=6Hz.
392 CH3). H 6.16 6.16 6.16 EI 3.45-3.60 (4H.m.
CH2CH3). N 7.14 7.03 7.09 5.50 (1H,s. O2CH).
6.75 92H,s).
7.28-7.55 (9H,m.Ar).
10.25 (2H.br.s.NH)
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1912 C23H24N4O3 404. M+, 55%; 303, M± DMSO NHC(O)CH2NMe2, 30% ; 2.25 (6H,s. 2xME).
404 2.95 (2H,s), EI 4.30 (2H.d.J=6Hz).
6.74 (1H,s), 6.76 (1H.s), 7.28-7.55 (9H.m).
8.24-8.27 (1H.br.m.NH).
10.20 92H,br.s, 2xNH) 1676 C22H19O3N3 NH+, 100%, 374 CCl3, CF3CO2D 7.65 (2H,d). 7.58 373 (DCI/NH3) (2H,d).
7.48 (2H,d).
7.41-7.35 (4H,m).
7.24 (1H,s).
7.12-7.07 (2H.m).
2.36+2.23 (3H,s. rotamers).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1959 C25H28N3O4Cl CI/NH3 d6-DMSO 400 MHz 10.85 (1H,s).
469/471 10.10 (1H.brs).
10.02 (1H,s), 7.6-7.30 (7H.m).
7.10 (2H,m).
6.85 (1H.d).
6,80 (1H,s).
6.58 (1H.d).
4.36 92H,t).
3.7 (3H,s).
3.50 (2H,t).
2.88 (6H.s).
1921 C22H21N3O2 MH+, 100%, 360 CDCl3 + CF3CO2D C 73.52 73.24 73.11 7.81 (2H.d).
359 CI/NH3 7.52 (2H.d). H 5.89 5.82 5.77 7.40-7.50 (6H,m), 7.24 (1H.s). N 11.69 11.50 11.52 6.98 (1H.d), 6.96 (1H,d).
3.33 (6H,s).
1922 C26H20N2O2 MH+, 393, 10% ; MNH+, 410, d6-DMSO 10% 11.15 (1H,brs).
392 10.00 (1H,brs).
CI/NH3 7.66 (1H.d).
7.51-7.30 (13H.m).
7.20 (2H.m).
6.78 (1H,s).
6.83 (1H.d).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1923 C20H15N3O4 MH+, 362, 100% CDCl3 CF3CO2D C 66.48 66.61 66.54 8.25 (2H.d).
361 (DCI NH3) 7.83 (2H,d). H 4.18 4.23 4.26 7.63 (1H,dd), 7.55-7.45 (5H.m). N 11.63 11.40 11.48 7.35 (1H, s).
7.12 (1H,d).
7.08 (1H,d).
1672 C20H23N3O3 MH~+, 354, 100%; MNH+, 371, CDCl3,CF3CO2D 10%; 271, 10%; 260, 10% 7.59 (2H.d).
353 7.45 (2H,d).
(DCI NH3) 7.18 (1H.s).
6.29 (1H.d).
2.55-2.47 (1H,m).
2.36-2.22 (3H,s.rotamers).
1.82-1.70 (5H,s).
1.51-1.40 (2H,m).
1.32-1.20 (3H,m).
1884 C18H20N2O2 MH+, 297, 100%; MNH+, 315, CDCl3, CF3CO2D 10% 7.48-7.38 (5H,m).
296 7.21 (1H.s).
(DCI NH3) 6.26 (1H,d).
2.48 (1H.m).
1.83-1.70 (1H,m).
1.35 (2H,m).
1.30-1.19 (3H.m).
No. Mol. Formula Mass spec. data 1H nmr data mass mode solvent (field) # (intensity) 1570 C17H14N2O2S 311, M+H, 100% CDCl3 C 65.79 65.24 65.20 4.13 (3H,s).
310 DCI-NH3 6.59 (1H.s). H 4.55 4.53 4.49 7.10 (1H,M).
7.30-7.60 (8H,m). N 9.03 8.73 8.79 8.09 (1H,brs).

Claims (10)

  1. CLAIMS 1. A piperazine of general 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
    or which is fused to a group X; (II) a phenyl group substituted by CH2NR12Rl3, OC(O) (CH2) nZ, CH(OR12) (OR13) , (CH2) nNR14C(O) (CH2) mNR12R13, -CH2NR12- (CH2) nNR15R16, 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) Cl-C4 alkyl and (CH2) nC (O) OR12; X is a naphthyl group or 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 0, 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; Rl2, Rl3 and R14, which may be the same or different, are hydrogen or Cl-C6 alkyl; R15 and Rl6, which may be the same or different, are hydrogen or Cl-C6 alkyl, or Rl5 and Rl6 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 ; m and n are each, independently, 0 or an integer having the value 1, 2, 3 or 4; O (CH2) nNR12R13 or containing one or more carbonyl groups and being optionally fused to a benzene ring; Z is a C3-C6 cycloalkyl group; Rl2, Rl3 and Rl4, which may be the same or different, are hydrogen or Cl-C4 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)nNRl2Rl3; and m and n are, independently, integers having the values 1, 2, 3 or 4; or a pharmaceutically acceptable salt or ester thereof.
  2. 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, CR2X 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 0, 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(Rl2Rl3) or optically containing one or more carbonyl groups and being optionally fused to a benzene ring; Y, Rl2, Rl3 and n are as defined in claim 1.
  3. 3. A compound according to claim 1 or 2, wherein R12 and Rl3, which may be the same or different, are hydrogen or Cl-C3 alkyl and n is an integer of value 1 or 2.
  4. 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. 5. A compound according to claim 1, wherein one of R1 and R2 is a phenyl group substituted by CH2NRl2Rl3, OC(O) (CH2) nZ, CH(OR12) (OR13), (CH2)n NR14C(O) (CH2) mNR12R13; wherein Rl2, Rl3 and Rl4, which may be the same or different, are independently selected from hydrogen or Cl-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. 6. A compound according to claim 1 or 5, wherein Rl2, Rl3 and Rl4, which may be the same or different, are independently selected from hydrogen and Cl-C2 alkyl; Z is a cyclopentyl group; and m and n are, independently, integers having the values of 1 or 2.
  7. 7. A compound selected from 1926 (3Z,6Z) -3-Benzylidene-6-(4-imidazolyl)methylene-2,5piperazinedione.
    1930 (3%, 6Z) -3-Benzylidene-6- (4- (1-imidazolyl)benzylidene)- 2,5-piperazinedione.
    1929 (3Z,6Z)-3-Benzylidene-6-(4-(1imidazolylmethyl)benzylidene)-2,5-piperazinedione.
    1959 (3Z,6Z)-3,Benzylidene-6-(4-(2-dimethylaminoethOxy)-3- methoxybenzylidene)-2,5-piperazinedione hydrochloride.
    1927 (3Z,6Z)-3-Benzylidene-6-(4-(5- methylimidazolyl) )methylene-2, 5-piperazinedione.
    1921 (3Z,6Z)-3-Benzylidene-6-(4 dimethylaminocinnamylidene) -2, 5-piperazinedione.
    1976 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4-(1-imidazolyl)benzylidene-2,5-piperazinedione.
    1910 (3Z,6Z)-3-Benzylidene-6-(4-(2- imidazolylethoxy)benzylidene)-2,5-piperazinedione.
    1923 (3Z,6Z)-3-Benzylidene-6-(4-nitrocinnamylidene-2,5- piperazinedione.
    1657 (3Z,6Z) -3- (4-Aminomethylbenzylidene) -6- (4 methoxybenzylidene) -2, 5-piperazinedione.
    1491 Methyl (3Z,6Z)-3-benzylidene-6-(4-methoxybenzylidene)- 2-oxo-1,2,3,6-tetrahydro-5-pyrazonyloxyacetate.
    1693 (3Z,6Z)-3-(1-methanesulfonyl-3-indolyl)methylene-6-(4methoxybenzylidene)-2,5-piperazinedione.
    1886 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4phthalimidoacetoxybenzylidene) -2,5-piperazinedione.
    1922 (3Z,6Z)-3-Benzylidene-6-(Y-phenylcinnamylidene)-2,5- piperazinedione.
    1618 (3Z,6Z)-3-(1-tert-butoxycarbonyl-3-indolyl)methylene6-(2-thenylidene)-2,5-piperazinedione.
    1560 (3Z,6Z) -3- (2,6-Dichlorobenzylidene) -6- (1-tertbutoxycarbonyl-3-indolyl) methylene-2,5-iperazinedione.
    1950 (3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethOxy)-3- methoxycinnamylidene) -2, 5-piperazinedione.
    1975 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4- (1-imidazolylmethyl) benzylidene) -2,5-piperazinedione.
    1983 (3Z,6Z)-3-Benzylidene-6-(4-N-methyl-N-(4-(N- methylpiperidinyl) ) aminomethylbenzylidene-2, 5- piperazinedione.
    1509 ((3Z,6Z)-3-Benzylidene-6-(3-indolylmethylene)-2,5- piperazinedione.
    1542 (3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(3- furylmethylene)-2,5-piperazinedione.
    1545 (3Z,6Z)-3-(3-Indoxylmethylene)-6-(4 methoxybenzylidene) -2, 5-piperazinedione.
    1560 (3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(3-(1- tertbutoxycarbonyl) indolyl)methylene-2,5-piperazinedione.
    1507 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(2-(1- tertbutoxyCarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
    1506 (3Z,6Z) -3- (4-Methoxybenzylidene) -6- (3- (1-tertbutoxyarbonyl)indolyl) methylene-2,5-piperazinedione.
    1471 (3Z,6Z)-3-Benzylidene-6-(3-(1-tertbutoxycarbonyl) indolyl) methylene-2,5-pieprazinedione.
    1474 (3%,6%) -3- (4-Mehtoxybenzylidene) -6- (2- thienylmethylene)-2,5-piperazinedione.
    1476 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3-furylmethylene)2,5-piperazinedione.
    1672 (3Z,6Z)-3-(Acetamidobenzylidene)-6- cyclohexylmethylene-2,5-piperazinedione.
    1676 (3Z,6Z)-3-(4-Acetamidobenzylidene)-6-cinnamylidene2,5-piperazinedione.
    1891 (3Z,6Z)-3-Benzylidene-6-(diethoxymethylbenzylidene)2,5-piperazinedione.
    1982 (3Z,6Z) -3- Benzylidene-6-(4- (N-methyl-N- (2 dimethylaminoethyl)aminomethylbenzylidene-2,5- piperazinedione hydrochloride.
    1884 (3Z,6Z) -3-Benzylidene-6-cyclohexylmethylene-2,5piperazinedione.
    1845 (3Z,6Z) -3- (4-Acetamidobenzylidene) -6- (3,4 methylenedioxybenzylidene) -2, 5-piperazinedione.
    1718 (3Z,6Z)-3-(2-Indolylmethylene)-6-(4methoxybenzylidene)-2,5-piperazinedione.
    1808 (3Z,6Z)-3-Benzylidene-6-(3,4 methylenedioxybenzylidene) -2, 5-piperazinedione.
    1809 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3,4 methylenedioxybenzylidene) -2, 5-piperazinedione.
    1470 (3Z,6Z)-3-Benzylidene-6-(2-(1 tertbutoxyCarbonyl)pyrrolyl)methylene-2,5-piperazinedione.
    5023 (3Z,6Z) -3- (4-Dimethylaminomethylbenzylidene) -6- (4- (3dimethylaminopropxy) benzylidene-2,5-piperazinedione.
    5026 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4-(1-imidazolyl) methylbenzylidene0 -2,5-piperazinedione.
    5030 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6 (4-(l-imidazolyl)benzylidene.
    5367 (2-(4-((3Z,6Z)-6-(4-(3 Dimethylaminopropoxy)benzylidene) -2,5-dioxo-3 piperazinylidene)methylbenzoyl)-1,2,3,4- tetrahydroisoquinoline.
    5386 N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4- ((3Z,6Z)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5 dioxo-3 -piperazinylidene) methylbenzamide.
    5397 N-(4-(1,2,3,4-Tetrahydro-2-isoquinolyl)butyl)-4 ((3Z,6Z)-6-(4-(3-dimethylaminopropOxy)benzylidene)-2,5- dioxo-3 -piperazinylidene) methylbenzamide.
    5027 (3Z,6Z) -6- (4- (3-Dimethylaminopropoxy) benzylidene-3 (4-pyridylmethylene) -2, 5-piperazinedione.
    5028 (3Z, 6Z) -6- (4- (3-Dimethylaminopropoxy) benzylidene) -3- (3-pyridylmethylene) -2, 5-piperazinedione.
    5041 (3Z,6Z) -6- (4- (3-Dimethylaminopropoxy)benzylidene) -3furfurylidene-2,5-piperazinedione.
    5042 (3Z, 6Z) -6- (4- (3-Dimethylaminopropoxy) benzylidene) -3- (3-Thenylidene)-2,5-piperazinedione.
    5046 (3Z,6Z) -6- (4- (3-Dimethylaminopropoxy)benzylidene) -3 (2-Thenylidene)-2,5-piperazinedione.
    5052 (3Z, 6Z) -6- (4- (3-Dimethylaminopropoxy) benzylidene) -3 (3-Furylmethylene)-2,5-piperazinedione.
    5188 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (2-Naphthylmethylene) -2, 5-piperazinedione.
    5200 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3 (1-Naphthylmethylene) -2, 5-piperazinedione.
    5032 (3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylamino-2- hydroxypropoxy) benzylidene) -2, 5-piperazinedione.
    5040 (3Z, 6Z) -6-Benzylidene-3- (4- (2-hydroxy-3- morpholinopropoxy)benzylidene)-2,5-piperazinedione.
    5057 (3Z, 6Z) -6-Benzylidene-3- (4- (2-hydroxy-3- (1- imidazolyl)propoxy)benzylidene)-2,5-piperazinedione.
    5043 (3Z, 6Z) -6-Benzylidene-3- (4- (2-hydroxy-3- (4- (2- hydroxyethyl) -1-piperazinyl) propoxy) benzylidene) -2,5 piperazinedione.
    5062 (3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3 (3-Furylmethylene) -2,5-piperazinedione.
    5071 (3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3 (3-thenylidene)-2,5-piperazinedione.
    5072 (3Z,6Z)-6-(4-(2-Dimethylaminoethoxy)benzylidene)-3 (5-methylthio-2-thenylidene0-2,5-piperazinedione.
    5054 (3Z,6Z)-6-Benzylidene-3-(4-(2- morpholinoethoxy)benzylidene)-2,5-piperazinedione.
    5055 (3Z,6Z)-6-Benzylidene-3-(4-(2-(1- imidazolyl) ethoxy) benzylidene) 2,5-piperazinedione.
    5053 (3Z,6Z)-6-Benzylidene-3-(4-(2-(1 pyrrolidinyl) ethoxy) benzylidene) 2, 5-piperazinedione.
    5069 (3Z,6Z)-6-(4-(2- Dimethylaminoethoxymethyl)benzylidene)-3-(3-thenylidene)2,5-piperazinedione.
    5077 (3Z,6Z)-6-(4-(2- Dimethylaminoethoxymethyl) benzylidene) -3- (3furylmethylene)-2,5-piperazinedione.
    5074 (3Z,6Z) -6- (4-Dimethylaminoacetamidomethyl benzylidene)-3-(3-thenylidene)-2,5-piperazinedione.
    5079 (3Z,6Z)-3-(2-Bromobenzylidene)-6-(4 dimethylaminoacetamidomethylbenzylidene)-2,5- piperazinedione.
    5081 (3Z,6Z)-6-(4- Dimethylaminoacetamidomethylbenzylidene) -3- (3furylmethylene)-2,5-piperazinedione.
    5061 (3Z,6Z)-6-Benzylidene-3-(4 dimethylaminoacetamidomethylbenzylidene)-2,5- piperazinedione.
    5073 (3Z,6Z)-6-(4-(2- Dimethylaminoethylthiomethyl)benzylidene)-3-(3- furylmethylene)-2,5-piperazinedione.
    5078 (3Z,6Z)-6-(4-(2- Dimethylaminoethylthiomethyl)benzylidene)-3-(3- thenylidene)-2,5-piperazinedione.
    1912 (3Z,6Z)-6-Benzylidene-3-(4- dimethylaminoacetamidoaminomethylbenzylidene)-2,5piperazinedione.
    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-piperazinedione.
    5335 (3Z,6Z)-6-Benzylidene-3-(5-(2-dimethylaminoethyl)-2thienylmethylene)-2,5-piperazinedione.
    5388 (3Z,6Z)-6-Benzylidene-3-(5-(2-(2dimethylaminoethoxy)ethoxy)-2-thienylmethylene)-2,5piperazinedione.
    5389 (3Z,6Z)-6-Benzylidene-3-(5-(6-dimethylaminohexylOxy)- 2-thienylmethylene)-2,5-piperazinedione.
    5299 (3Z,6Z)-6-Benzylidene-3-(5-(2 d.imethylaminoethyl)methylamino-2-thienylmethylene)-2,5- piperazinedione.
    5075 (3Z,6Z)-3-(2,5-Dichloro-3-thenylidene)-6-benzylidene2,5-piperazinedione.
    5371 N- (4- (1,2,3,4-Tetrahydro-2-isoquinolyl)butyl)-4- ((3Z,6Z)-6-benzylidene-2,5-dioxo-3 piperazinylidene)methylbenzamide.
    5391 N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4- ((32,6Z)-6-benzylidene-2,5-dioxo-3- piperazinylidene)methylbenzamide.
    5394 N- (3- (1,2,3,4-Tetrahydro-2-isoquinolyl)propoyl) -4- ((3Z,6Z)-6-benzylidene-2,5-dioxo-3piperazinylidene)methylbenzamide.
    5393 N-(4-(2-(1,2,3,4-Tetrahydro-2 isOquinolyl)ethyl)phenyl-4-((3Z,6Z)-6-benzylidene-2,5- dioxo-3 -piperazinylidene) methylbenzamide.
    5402 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. 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. 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):
    wherein R2 are as defined in claim 1 and is optionally protected, with a compound of formula (II): R1-CHO (II) wherein Rl 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'):
    wherein R1 is as defined in claim 1 and are optionally protected with a compound of formula (III): R2-CHO (ffl) 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. 10. Use of 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
    or which is fused to a group X; (II) a phenyl group substituted by CH2NRl2Rl3, 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 Cl-C4 alkyl or (CH2)nC(O)ORl2; X is a naphthyl group or 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 0, 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; Rl2, 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 ; m and n are each, independently, 0 or an integer having the value 1, 2, 3 or 4; O (CH2) nNR12R13 or containing one or more carbonyl groups and being optionally fused to a benzene ring; Z is a C3-C6 cycloalkyl group; Rl2, R13 and R14, which may be the same or different, are hydrogen or Cl-C4 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)NR12R13; m and n are, independently, integers having the values 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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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2372740A (en) * 2001-01-17 2002-09-04 Xenova Ltd Diketopiperazines
WO2003000649A1 (en) * 2001-06-20 2003-01-03 Wyeth 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (pai-1)
US10005792B2 (en) 2014-09-03 2018-06-26 Ctxt Pty. Ltd. Aminoindane-, aminotetrahydronaphthalene- and aminobenzocyclobutane-derived PRMT5-inhibitors
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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL112627A0 (en) * 1994-02-14 1995-05-26 Xenova Ltd Diketopiperazines, their preparation and pharmaceutical or veterinary compositions containing them
GB9426090D0 (en) * 1994-12-23 1995-02-22 Xenova Ltd Pharmaceutical compounds
GB9708805D0 (en) 1997-05-01 1997-06-25 Smithkline Beecham Plc Compounds
JP2002501506A (en) 1997-05-03 2002-01-15 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー Dopamine D (3) Tetrahydroisoquinoline derivative as receptor modulator
EP2288165B1 (en) 1997-06-09 2015-12-16 Hitachi, Ltd. Image decoding method
GB9810876D0 (en) 1998-05-20 1998-07-22 Smithkline Beecham Plc Compounds
NZ511018A (en) 1998-10-08 2003-09-26 Smithkline Beecham Plc Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
JP4810043B2 (en) * 2000-01-18 2011-11-09 ネリアス・ファーマシュティカルズ・インコーポレーテッド Cell division inhibitor and method for producing the same
CZ301743B6 (en) * 2000-05-09 2010-06-09 Angiorx Corporation Piperazinedione compounds and their use for treating neoplastic diseases
NZ522680A (en) * 2000-05-09 2005-08-26 Adpharma Inc Piperazinedione compounds
US7288545B2 (en) 2000-05-09 2007-10-30 Angiorx Corporation Piperazinedione compounds
AU2003302721B2 (en) 2002-08-02 2009-10-08 Beyondspring Pharmaceuticals, Inc. Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
US7935704B2 (en) 2003-08-01 2011-05-03 Nereus Pharmaceuticals, Inc. Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
US7919497B2 (en) 2002-08-02 2011-04-05 Nereus Pharmaceuticals, Inc. Analogs of dehydrophenylahistins and their therapeutic use
EP1711487A1 (en) * 2004-02-04 2006-10-18 Nereus Pharmaceuticals, Inc. Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
NZ551144A (en) 2004-05-26 2009-12-24 Eisai R&D Man Co Ltd Cinnamide compound
ES2338904T3 (en) 2004-10-26 2010-05-13 EISAI R&amp;D MANAGEMENT CO., LTD. FORM AMORFA OF CINAMIDE COMPOUNDS.
TWI370130B (en) 2005-11-24 2012-08-11 Eisai R&D Man Co Ltd Two cyclic cinnamide compound
TWI378091B (en) 2006-03-09 2012-12-01 Eisai R&D Man Co Ltd Multi-cyclic cinnamide derivatives
AU2007307599A1 (en) 2006-10-12 2008-04-17 Institute Of Medicinal Molecular Design. Inc. N-phenyloxamic acid derivatives
EP2080751A4 (en) 2006-10-12 2011-06-22 Inst Med Molecular Design Inc Carboxylic acid derivative
US8129527B2 (en) 2006-11-03 2012-03-06 Nereus Pharmacuticals, Inc. Analogs of dehydrophenylahistins and their therapeutic use
PE20081791A1 (en) 2007-02-28 2009-02-07 Eisai Randd Man Co Ltd TWO CYCLIC DERIVATIVES OF OXOMORPHOLIN
PE20090674A1 (en) 2007-08-31 2009-06-19 Eisai Randd Man Co Ltd MULTICICLIC COMPOUNDS
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
CA2703494A1 (en) 2007-10-23 2009-04-30 Institute Of Medicinal Molecular Design, Inc. Inhibitor of pai-1 production
KR20100132073A (en) 2008-04-11 2010-12-16 가부시키가이샤 이야쿠 분지 셋케이 겐쿠쇼 Pai-1 inhibitor
JP2011530559A (en) * 2008-08-13 2011-12-22 ビーエーエスエフ ソシエタス・ヨーロピア Process for preparing piperazinedione derivatives
WO2014100719A2 (en) * 2012-12-21 2014-06-26 Epizyme, Inc. Prmt5 inhibitors and uses thereof
CN105272968B (en) * 2014-06-10 2018-03-13 首都医科大学 The diketone of (3S, 6R) 3,6 disubstituted piperazine 2,5, it is prepared and application
MY190034A (en) 2015-03-06 2022-03-22 Beyondspring Pharmaceuticals Inc Method of treating cancer associated with a ras mutation
MX2017011375A (en) 2015-03-06 2018-01-23 Beyondspring Pharmaceuticals Inc Method of treating a brain tumor.
JP6969848B2 (en) 2015-07-13 2021-11-24 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 Prinabrin composition
US10912748B2 (en) 2016-02-08 2021-02-09 Beyondspring Pharmaceuticals, Inc. Compositions containing tucaresol or its analogs
TWI777957B (en) 2016-06-06 2022-09-21 中國大陸商大連萬春布林醫藥有限公司 Composition and method for reducing neutropenia
CN106565686B (en) * 2016-10-11 2019-03-01 深圳海王医药科技研究院有限公司 Antitubulin
EP3565812B1 (en) 2017-01-06 2023-12-27 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
KR20190109479A (en) 2017-02-01 2019-09-25 비욘드스프링 파마수티컬스, 인코포레이티드. How to reduce neutropenia
JP7065951B2 (en) 2017-09-22 2022-05-12 ジュビラント エピパッド エルエルシー Heterocyclic compound as a PAD inhibitor
AU2018352142B2 (en) 2017-10-18 2022-08-25 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
SG11202004537UA (en) 2017-11-24 2020-06-29 Jubilant Episcribe Llc Heterocyclic compounds as prmt5 inhibitors
CN112135614A (en) 2018-01-24 2020-12-25 大连万春布林医药有限公司 Compositions and methods for reducing thrombocytopenia by administering plinabulin
KR20200131845A (en) 2018-03-13 2020-11-24 주빌런트 프로델 엘엘씨 Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE621862C (en) * 1932-07-01 1935-11-14 Guenther Schiemann Dr Process for the preparation of condensation products of nucleus fluorinated aryl aldehydes
GB9217331D0 (en) * 1992-08-14 1992-09-30 Xenova Ltd Pharmaceutical compounds
JPH08247357A (en) * 1995-03-13 1996-09-27 Zexel Corp Flange joint and forming method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts 65:16969e *

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WO2003000649A1 (en) * 2001-06-20 2003-01-03 Wyeth 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (pai-1)
US6589970B2 (en) 2001-06-20 2003-07-08 Wyeth 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US10005792B2 (en) 2014-09-03 2018-06-26 Ctxt Pty. Ltd. Aminoindane-, aminotetrahydronaphthalene- and aminobenzocyclobutane-derived PRMT5-inhibitors
US10647708B2 (en) 2014-09-03 2020-05-12 Ctxt Pty. Ltd Tetrahydroisoquinoline derived PRMT5-inhibitors
US10494376B2 (en) 2014-09-03 2019-12-03 Ctxt Pty. Ltd. Tetrahydroisoquinoline derived PRMT5-inhibitors
US10519167B2 (en) 2016-03-09 2019-12-31 Ctxt Pty Ltd 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies
US10550096B2 (en) 2016-03-09 2020-02-04 Ctxt Pty Ltd Tetrahydroisoquinolines as PRMT5 inhibitors
US10421743B2 (en) 2016-03-09 2019-09-24 Ctxt Pty Ltd Tetrahydroisoquinolines as PRMT5 inhibitors
US10745380B2 (en) 2016-03-09 2020-08-18 Ctxt Pty Ltd Pyridine derivatives and their use in the treatment of cancer and hemoglobinopathies
US10787434B2 (en) 2016-03-09 2020-09-29 Ctxt Pty, Ltd Benzopiperdine derivatives and their use in the treatment of cancer and hemoglobinopathies
US10961256B2 (en) 2016-03-09 2021-03-30 Ctxt Pty Ltd PRMT5 inhibitors
US11028101B2 (en) 2016-03-09 2021-06-08 Ctxt Pty Ltd 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies

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IL112624A0 (en) 1995-05-26
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AU693159B2 (en) 1998-06-25
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EP0745070A1 (en) 1996-12-04
GB2286395B (en) 1998-08-26

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