Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-24
1999-05-11
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 544373, 544377, 544385, A61K31/495
Patent
active
059028122
DESCRIPTION:
BRIEF SUMMARY
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 synthesized 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): ##STR2## wherein R.sub.1 is H, a halogen, --COOR.sub.11, C.sub.1 -C.sub.6 alkyl, NO.sub.2, C.sub.1 -C.sub.6 alkoxy, --NHCOCH.sub.3 or CF.sub.3 ; alkyl, NO.sub.2, CN, halogen, C.sub.1 -C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, --NHCOCH.sub.3 or phthalimido; -C.sub.6 alkoxy, NO.sub.2, C.sub.1 -C.sub.6 alkyl, CF.sub.3, CN, --CON(R.sub.11 R.sub.12), --NHCOCH.sub.3, --CO.sub.2 R.sub.11, --CONH(CH.sub.2).sub.n Ph, SR.sub.13 or --(CH.sub.2).sub.n N(R.sub.11 R.sub.12); or R.sub.2 and R.sub.3 together form a methylenedioxy group --OCH.sub.2 O--; R.sub.12); alkoxy; and --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12), --OC(O) (CH.sub.2).sub.n R.sub.11, C.sub.1 -C.sub.6 alkoxy, --(CH.sub.2).sub.n NHCO(CH.sub.2).sub.n CO.sub.2 R.sub.11, --(CH.sub.2).sub.n N(R.sub.11 --O(CH.sub.2).sub.n CO.sub.2 H R.sub.12 is, independently, hydrogen or a straight or branched C.sub.1 -C.sub.6 alkyl and R.sub.13 is straight or branched C.sub.1 -C.sub.6 alkyl; or a pharmaceutically acceptable salt or ester thereof; R.sub.8 are H; R.sub.1 to R.sub.8 are H; and
The numerals 1 to 10 denote ring positions on the phenyl groups in formula A. The letters a and b refer to the two phenyl rings themselves.
A C.sub.1 -C.sub.6 alkyl group is typically a C.sub.1 -C.sub.4 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group. A halogen is, for example, fluorine, chlorine, bromine or iodine.
A C.sub.1 -C.sub.6 alkoxy group is typically a C.sub.1 -C.sub.4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.
A group --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12) is preferably a group --CH.sub.2 O(CH.sub.2).sub.n NMe.sub.2 or --CH.sub.2 S(CH.sub.2).sub.n NMe.sub.2 wherein n is from 1 to 3.
In compounds of formula A free rotation may occur at room temperature about the single bonds connecting rings a and b to the double bonds at positions 3 and 6 of the piperazine-2,5-dione ring. Positions 2 and 6, and positions 3 and 5, in both rings a and b can therefore be considered as equivalent. As a consequence the following pairs of substituents can be viewed as interchangeable: R.sub.1 and R.sub.5 ; and R.sub.2 and R.sub.4.
Preferably one of rings a and b is unsubstituted or is mono-substituted whilst the other ring is unsubstituted or is substituted at one or more of positions 2 to 6. The ring which is mono-substituted may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4. Thus for instance, when ring b is mono-substituted, one of R.sub.6 to R.sub.8 is other than hydrogen, preferably R.sub.7 or R.sub.8, especially R.sub.8. When ring a is mono-substituted, one of R.sub.1 to R.sub.5 is other than hydrogen, preferably R.sub.2 or R.sub.3, especially R.sub.3. When one of rings a and b is mono-substituted the substituent R.sub.1 to R.sub.5, or R.sub.6 to R.sub.8 respectively, is preferably selected from --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12), especially --O(CH.sub.2).sub.2 NMe.sub.2 or --O(CH.sub.2).sub.3 NMe.sub.2 ; --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12); a halogen, for instance fluorine or chlorine; and
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Brocchini Stephen James
Brumwell Julie Elizabeth
Bryans Justin Stephen
Folkes Adrian John
Latham Christopher John
Bernhardt Emily
Xenova Limited
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