Pharmaceutical diketopiperazine compounds

Details Pharmaceutical diketopiperazine compounds Pharmaceutical diketopiperazine compounds

1996-12-17

1998-05-12

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544360, 544363, 544373, 544379, 544385, A61K 31495, C07D40100, C07D40300

Patent

active

057505306

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB95/01180 filed May 24 1995.
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 (I): ##STR4## wherein each of R.sub.7 and R.sub.8 which may be the same or different, is hydrogen or a nitro group; ##STR5## --O-- or --S--, wherein each of R.sub.9 and R.sub.10, which may be the same or different, is hydrogen or a nitro group; alkyl group; and ##STR6## wherein each of R.sub.1 to R.sub.5, which may be the same or different, is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by one or more halogen atoms, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkythio, halogen, hydroxy, nitro, optionally substituted phenyl, nitrobenzyloxy, benzyloxy, cyano, --CH.sub.2 OH, --CH.sub.2 COOH, --CO.sub.2 R.sup.11, --NHCOR.sup.14, --NHSO.sub.2 R.sup.13, --SO.sub.2 R.sup.13, --CON(R.sup.11 R.sup.12), --(CH.sub.2).sub.x N(R.sup.11 R.sup.12), --SOR.sup.13, --SO.sub.2 N(R.sup.11 R.sup.12), --N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.x N(R.sup.11 R.sup.12), --O(CH.sub.2).sub.x CO.sub.2 R.sup.11, --OCOR.sup.11, --CH.sub.2 OCOR.sup.11, --CH.sub.2 NHCOR.sup.11, --CH.sub.2 NHCOOR.sup.13, --CH.sub.2 SR.sup.11, --CH.sub.2 SCOR.sup.11, --CH.sub.2 S(O).sub.y R.sup.13, --CH.sub.2 NHCO(CH.sub.2).sub.x CO.sub.2 R.sup.11, --N(R.sup.11)COR.sup.12, --NHCOCF.sub.3, --NHCO(CH.sub.2).sub.x CO.sub.2 R.sup.11, --NHCO(CH.sub.2).sub.x OCOR.sup.11 and --NHCO(CH.sub.2).sub.x OR.sup.11 wherein x is 0 or is an integer of from 1 to 6, Y is 1 or 2, each of R.sup.11 and R.sup.12 is, independently, H or C.sub.1 -C.sub.6 alkyl, R.sup.13 is C.sub.1 -C.sub.6 alkyl and R.sup.14 is H, C.sub.1 -C.sub.6 alkyl or a thiophene group; and/or any of R.sub.1, and R.sub.2, R.sub.2 and R.sub.3, R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 form, together with the carbon atoms to which they are attached, a furan group, a benzene ring which is optionally substituted or the cyclopentyl moiety of the group ##STR7## (ii) a heterocyclic ring selected from furan, thiophene, pyridine, quinoline and indole, the last of which is optionally N-substituted by C.sub.1 -C.sub.6 alkyl; 3,4-methylenedioxyphenyl group; and and Z is a cyclohexyl group which optionally includes an unsaturated bond and/or a one or two carbon atom bridge, and is optionally substituted by one or more C.sub.1 -C.sub.6 alkyl groups; or a pharmaceutically acceptable salt or ester thereof.
The numerals 1 to 6 denote ring positions on the phenyl group defined under (i) above.
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 alkyl group substituted by halogen may be substituted by 1, 2 or 3 halogen atoms. It may be a perhaloalkyl group, for example trifluoromethyl.
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 C.sub.1 -C.sub.6 alkylthio group is typically a C.sub.1 -C.sub.4 alkylthio group, for example methylthio, ethylthio, propylthio, i-propylthio, n-butylthio, sec-butylthio or tert-butyl

REFERENCES:
T. Yokoi et al "Neihumici, a new cytotoxic . . . " Chemical Abstracts, vol. 109 No. 3, 1988, Columbus, Ohio. Abstract No. 16593a.

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