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WO1995021832A1 - Composes pharmaceutiques a base de piperazine - Google Patents

Composes pharmaceutiques a base de piperazine Download PDF

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Publication number
WO1995021832A1
WO1995021832A1 PCT/GB1995/000302 GB9500302W WO9521832A1 WO 1995021832 A1 WO1995021832 A1 WO 1995021832A1 GB 9500302 W GB9500302 W GB 9500302W WO 9521832 A1 WO9521832 A1 WO 9521832A1
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Prior art keywords
piperazinedione
benzylidene
group
compound
formula
Prior art date
Application number
PCT/GB1995/000302
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English (en)
Inventor
Stephen James Brocchini
Justin Stephen Bryans
Adrian John Folkes
Christopher John Latham
Julie Elizabeth Brumwell
Original Assignee
Xenova Limited
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Filing date
Publication date
Application filed by Xenova Limited filed Critical Xenova Limited
Priority to US08/693,172 priority Critical patent/US5891877A/en
Priority to AU16677/95A priority patent/AU693159B2/en
Priority to EP95908314A priority patent/EP0745070A1/fr
Priority to JP7521082A priority patent/JPH09509157A/ja
Publication of WO1995021832A1 publication Critical patent/WO1995021832A1/fr

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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

Definitions

  • 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.
  • PAI plasminogen activator inhibitor
  • Plasminogen activators 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):
  • R 1 and R 2 which may be the same or different, is: (I) X, or a phenyl group which is substituted by X, C(O)X, OC(O)CH 2 X, OCH 2 CH 2 X, CH 2 X, CONH (CH 2 ) n X,
  • R 1 and R 2 are phenyl groups optionally substituted by one or more groups
  • NHC(O)R 12 CO 2 H, O(CH 2 ) n N(R 12 R 13 ), CH 2 Y(CH 2 ) n N(R 12 R 13 ),
  • 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 O, N and S; the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl,
  • Z is a C 3 -C 6 cycloalkyl group
  • R 12 , R 13 and R 14 which may be the same or different, are hydrogen or C 1 -C 6 alkyl;
  • R 15 and R 16 which may be the same or different, are
  • R 15 and R 16 form, together with the nitrogen 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,
  • n are each, independently, 0 or an integer having the value 1, 2, 3 or 4;
  • a C 1 -C 6 alkyl group is, for example, a C 1 -C 4 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.
  • At least one of R 1 and R 2 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)CH 2 X,
  • 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,
  • heterocyclic ring optionally containing one or more carbonyl groups, and being
  • R 1 and R 2 is a phenyl group optionally substituted at the 2, 3 or 4-position by CH 2 NR 12 R 13 , (CH 2 ) n NR 14 C(O)(CH 2 ) m NR 12 R 13 , halogen, nitro, -NHC(O)R 12 , -O(CH 2 ) n N(R 12 R 13 ) or -CH 2 Y(CH 2 ) n N(R 12 R 13 ) wherein Y is O or S.
  • the said other of R 1 and R 2 is a phenyl group substituted at the 4-position by -O(CH 2 ) n N(R 12 R 13 ),
  • one of R 1 and R 2 is X, a phenyl group substituted by X, -CH 2 X, -OCH 2 CH 2 X,
  • R 1 and R 2 is a phenyl group optionally substituted at the 4-position by
  • X is particularly preferred for X to be a furyl, imidazolyl, pyrrolyl, thienyl, morpholinyl, piperidinyl or isoquinolyl group.
  • R 12 and R 13 which may be the same or different, are hydrogen or C 1 -C 3 alkyl and n is an integer of value 1 or 2.
  • one of R 1 and R 2 is a phenyl group which is substituted by X, CO(X), OCO(O)CH 2 X, OCH 2 CH 2 X, CH 2 X 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 heteroatom(s) when nitrogen being optionally substituted by methyl, and the heterocyclic ring being optionally fused to a benzene ring.
  • R 1 and R 2 is a phenyl group substituted by CH 2 NR 12 R 13 , OC(O) (CH 2 ) n Z, CH(OR 12 ) (OR 13 ), (CH 2 ) n NR 14 C(O)(CH 2 ) m N(R 12 R 13 ); wherein R 12 , R 13 and R 14 , which may be the same or different, are independently selected from hydrogen or C 1 -C 3 alkyl; Z is a C 5 or C 6 cycloalkyl group; and m and n are, independently, integers having the values 1, 2 or 3.
  • R 12 , R 13 and R 14 which may be the same or different, are independently selected from hydrogen and C 1 -C 2 alkyl; Z is a cyclopentyl group; and m and n are, independently, integers having the values of 1 or 2.
  • one of R 1 and R 2 is a phenyl group optionally substituted by one or more groups independently selected from chloro, nitro, methoxy,
  • NHCOR 12 CO 2 H and O(CH 2 ) n NR 12 R 13 ;
  • R 12 and R 13 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.
  • W is a phenyl group optionally substituted by one of more groups independently selected from nitro, methoxy and O(CH 2 ) n NMe 2 and n is an integer having the value 1, 2,3 or 4.
  • n 1 or 2.
  • one of R 1 and R 2 is a phenyl group optionally substituted by NHAc or methoxy.
  • one of R 1 and R 2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC(O)R 12 .
  • one of R 1 and R 2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC(O)Me.
  • R 3 is C 1 -C 2 alkyl or
  • R 12 is hydrogen or C 1 -C 2 alkyl and n is an integer of value 1 or 2.
  • R 3 is methyl or CH 2 C(O)OR 12 and R 12 is hydrogen or methyl.
  • Antibiotics vol XLI No. 4, pp 494-501 (1988) describe structure-cytotoxicity relationship studies on a series of diketopiperazines related to neihumicin, a compound
  • piperafizines A and B have utility as potentiators of the cytotoxicity of vincristine.
  • Compounds of formula A may be prepared by a process which comprises either (i) condensing compound of formula (I) wherein R 2 is as defined above and is optionally protected, with a compound of formula (II):
  • R 1 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'):
  • R 1 is as defined above and is optionally protected, with a compound of formula (III):
  • R 2 CHO (III) wherein R 2 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 R 1 into a different R 1 group.
  • R 1 comprises an ester group
  • R 1 comprises an ester group
  • a compound of formula A in which either or both of R 1 and R 2 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 1 and R 2 includes a -CO 2 H 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 C 1 -C 6 alkyl alcohol in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.
  • a compound of formula A in which either or both of R 1 and R 2 includes a free -CO 2 H group may be converted into a compound of formula A in which the corresponding
  • substituent is a group -CON(R 11 R 12 ), wherein R 11 and R 12 are as defined above, for example by treatment with ammonia or an amine in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.
  • a compound of formula A in which either or both of R 1 and R 2 includes a free -CO 2 H group may be converted into a compound of formula A wherein the corresponding substituent is a -CH 2 OH 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 R 1 and R 2 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 R 1 and/or R 2 in any of the compounds of formulae (I), (I'), (II) and (III) are optionally introduced prior to step (i) or step (ii) when either or both R 1 and R 2 include one or more groups which are sensitive to the condensation reaction conditions or incompatible with the condensation reaction, for example a -COOH, -CH 2 OH or amino group.
  • the protecting groups are then removed at the end of the process. Any conventional protecting group suitable for the group R 1 and/or R 2 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 t-butanol and dimethylformamide (DMF).
  • 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 t-butanol and dimethylformamide (DMF).
  • a base which is potassium t-butoxide, sodium hydr
  • the compounds of formula (I) may be prepared by a process comprising reacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula (III) as defined above, in the presence of a base in an organic solvent.
  • the compounds of formula (I') may be prepared by a process which comprises reacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula (II) as defined above, in the presence of a base in an organic solvent.
  • the resulting compound of formula (I) or (I') can be separated from other reaction products by chromatography.
  • 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-diacetyl-2,5-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
  • 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-2,5-piperazinedione, 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 1,4-diacetyl-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
  • An alternative direct process for the preparation of compounds of formula (A) comprises condensing together 2,5-piperazinedione, 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.
  • R 6 to R 10 are as defined above, X is a halogen and R' is a C 1 -C 6 alkyl group, with ammonia followed by acetic anhydride.
  • R 1 to R 5 , X and R' are as defined above, with ammonia followed by acetic anhydride.
  • X in formula (V) or (V) is typically iodine.
  • R' is, for example, a C 1 -C 4 alkyl group such as a methyl, ethyl, propyl, i-propyl, butyl, sec-butyl or tert-butyl group.
  • 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.
  • Suitable salts include salts with pharmaceutically
  • inorganic bases include ammonia and carbonates,
  • organic bases include aliphatic and aromatic amines such as methylamine, triethylamine, benzylamine, dibenzylamine or ⁇ - or ⁇ -phenylethylamine, and heterocyclic bases such as piperidine, 1-methylpiperidine and
  • hydrochloric acid hydrochloric acid, sulphuric acid and orthophosphoric acid.
  • organic acids include p-toluenesulphonic acid, methansulphonic acid, mucic acid and succinic acid.
  • esters include branched or unbranched, saturated or unsaturatedC 1 -C 6 alkyl esters, for example methyl, ethyl and vinyl esters.
  • the diketopiperazines of formula (A), both novel and known and their pharmaceutically acceptable salts and esters (referred to hereinafter as the "present compounds”) have utility as inhibitors of PAI. Elevated levels of PAI-1, by reducing the net endogenous fibrinolytic capacity, 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
  • Tissue plasminogen activator (tPA) is used as a fibrinolytic agent in the treatment of thrombotic
  • the efficacy of the tPA in this role may be enhanced if it is administered together with a PAI
  • a human or animal e.g. a mammal, can therefore be treated by a method comprising the combined
  • 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.
  • the present compound is formulated for oral or parenteral (intravenous, intramuscular or subcutaneous) administration and the tPA is formulated for intravenous administration.
  • MI myocardial infarction
  • one of the present compounds may be administered to a patient together with tPA to enhance the efficacy of the tPA treatment.
  • 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.
  • 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.
  • plasmin cleaves the chromogenic substrate S2251 (Kabi Vitrum) producing pNA (p-nitroaniline) 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.
  • 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: 10% 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.
  • 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.
  • inhibitor of PAI comprising any one of the present
  • 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.
  • 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
  • Suspensions or solutions for intramuscular injections may contain, together with the active compound, a
  • lidocaine 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.
  • Compound 16 is treated with ammonia and subsequently with acetic anhydride to yield the title compound.
  • 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 120oC. After 21 ⁇ 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.
  • 1,4-Diacetyl-2,5-piperazine dione (8) was prepared by the published procedure (S.M. Marcuccio and J.A. Elix,
  • 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 120-130°C for 2-4h to give the title compound.
  • the crude product was optionally, washed with water, methanol, ethyl acetate or diethylether and optionally recrystallised from methanol as appropriate.
  • Compound 12.1 was treated with 4-(3-dimethylamino)propoxybenzaldehyde in DMF in the presence of Cs 2 CO 3 at a temperature of 80°C-90°C for 2-4 hours.
  • the 2,5-piperazinedione derivative 14.1 was treated with the aldehyde 14.2, the groups Ar and Subst. being as specified below, in DMF in the presence of Cs 2 CO 3 at 80°C- 90°C for 2-4 hours.
  • the compounds of formula (I) listed below were prepared:
  • Example 15 Preparation of compounds of formula (I)
  • the 2,5-piperazinedione derivative 15.1 was treated with the aldehyde 15.2 in which R 20 and R 21 are both H or are both OMe, the substituent Ar and linking group A being as specified below, in DMF in the presence of Cs 2 CO 3 at 80°C to 90°C for 2-4 hours.
  • the compounds of formula (I) listed below were prepared. In 5391, 5394 and 5371 R 20 and R 21 are both H. In 5393 and 5402 R 20 and R 21 are OMe.
  • 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.
  • Hydrochloride salts of the following compounds of formula (I) were prepared by bubbling HCl gas through a solution of the corresponding free base in hot DMF. The salt was recovered in the yield indicated.
  • 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

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Abstract

Dicétopipérazine de la formule (A), dans laquelle R1 et/ou R2, qui peuvent être identiques ou différents, représente(nt): (A) X, ou un groupe phényle substitué par X, C(O)X, OC(O)CH2X, OCH2CH2X, CH2X, CONH(CH2)X, O(CH2)nCH(OH)(CH2)nX ou (a), ou fusionné à un groupe X; (II) un groupe phényle substitué par CH2NR12R13, OC(O)(CH2)nZ, CH(OR12)(OR13), (CH2)nNR14C(O) (CH2)m NR12R13, ou O(CH2)nCH(OH) (CH2)nN(R12R13); (III) un groupe CH=C(W)V; ou (IV) un groupe cyclohexyle; et, le cas échéant, l'élément restant entre R1 et R2 représente un groupe phényle éventuellement substitué par un ou plusieurs groupes indépendamment choisis entre halogène, nitro, méthoxy, NHC(O)R12, CO2H, O(CH2)nN(R12R13) et CH2Y(CH2)nN(R12R13); R3 représente alkyle C1-C4 ou (CH2)nC(O)OR12; Y représente O ou S; Z représente un groupe cycloalkyle C3-C6; W représente hydrogène ou un groupe phényle. L'invention se rapporte également aux sels et esters pharmaceutiquement acceptables de ces composés, lesquels agissent comme inhibiteurs de l'inhibiteur d'activateur du plasminogène.
PCT/GB1995/000302 1994-02-14 1995-02-14 Composes pharmaceutiques a base de piperazine WO1995021832A1 (fr)

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US7288545B2 (en) 2000-05-09 2007-10-30 Angiorx Corporation Piperazinedione compounds
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US7897632B2 (en) 2006-03-09 2011-03-01 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
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US7935704B2 (en) 2003-08-01 2011-05-03 Nereus Pharmaceuticals, Inc. Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof
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US8129527B2 (en) 2006-11-03 2012-03-06 Nereus Pharmacuticals, Inc. Analogs of dehydrophenylahistins and their therapeutic use
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US9453000B2 (en) 2007-08-31 2016-09-27 Eisai R&D Management Co., Ltd. Polycyclic compound
US10076518B2 (en) 2015-03-06 2018-09-18 Beyondspring Pharmaceuticals, Inc. Method of treating a brain tumor
US10155748B2 (en) 2015-07-13 2018-12-18 Beyondspring Pharmaceuticals, Inc. Plinabulin compositions
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US6465485B1 (en) 1997-05-03 2002-10-15 Smithkline Beecham P.L.C. Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors
US6915013B2 (en) 1997-06-09 2005-07-05 Hitachi, Ltd. Encoding method using plus and/or minus rounding of images
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)
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GB9502874D0 (en) 1995-04-05
ZA951180B (en) 1996-08-14
AU693159B2 (en) 1998-06-25
AU1667795A (en) 1995-08-29
CA2182877A1 (fr) 1995-08-17
GB2286395B (en) 1998-08-26
GB9402807D0 (en) 1994-04-06
IL112624A0 (en) 1995-05-26
JPH09509157A (ja) 1997-09-16
EP0745070A1 (fr) 1996-12-04

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