Pharmaceutical compounds

Details Pharmaceutical compounds Pharmaceutical compounds

1996-09-25

1999-04-06

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514252, 514253, 514255, 544121, 544 357, 544360, 544363, 544364, 544365, 544370, 544372, 544373, 544377, 544379, 544385, A61K 31495, A61K 31535, C07D24108, C07D40106

Patent

active

058918779

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 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): ##STR3## wherein one or both of R.sub.1 and R.sub.2, which may be the same or different, is: OCH.sub.2 CH.sub.2 X, CH.sub.2 X, CONH(CH.sub.2).sub.n X, O(CH.sub.2).sub.n CH(OH)(CH.sub.2).sub.n X or ##STR4## or which is fused to a group X; (II) a phenyl group substituted by CH.sub.2 NR.sub.12 R.sub.13, OC(O)(CH.sub.2).sub.n Z, CH(OR.sub.12)(OR.sub.13), (CH.sub.2).sub.n NR.sub.14 C(O)(CH.sub.2).sub.m NR.sub.12 R.sub.13, --CH.sub.2 NR.sub.12 --(CH.sub.2).sub.n NR.sub.15 R.sub.16 or O(CH.sub.2).sub.n CH (OH)(CH.sub.2).sub.n N (R.sub.12 R.sub.13); R.sub.2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NHC(O)R.sub.12, CO.sub.2 H, O(CH.sub.2).sub.n N(R.sub.12 R.sub.13), CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.12 R.sub.13), C.sub.1 -C.sub.4 alkyl and (CH.sub.2).sub.n C(O)OR.sub.12 ; 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, --(CH.sub.2).sub.n CH.sub.2 OH or SO.sub.2 Me; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O(CH.sub.2).sub.n NR.sub.12 R.sub.13, --N(R.sub.12) (CH.sub.2).sub.n N(R.sub.12 R.sub.13), --(CH.sub.2).sub.n N(R.sub.12 R.sub.13) or --O(CH.sub.2).sub.n O(CH.sub.2).sub.n N(R.sub.12 R.sub.13), 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 C.sub.1 -C.sub.6 alkoxy groups; hydrogen or C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkyl, or R.sub.15 and R.sub.16 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic group; independently selected from nitro, alkoxy, O(CH.sub.2).sub.n NR.sub.12 R.sub.13, and NR.sub.12 R.sub.13 ; and or 4;
A C.sub.1 -C.sub.6 alkyl group is, for example, a C.sub.1 -C.sub.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.
In compounds of formula A free rotation may occur at room temperature about the single bonds connecting substituents R.sub.1 and R.sub.2 to the double bonds at positions 3 and 6 of the piperazine-2,5-dione ring.
In one embodiment at least one of R.sub.1 and R.sub.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.sub.2 X, OCH.sub.2 CH.sub.2 X, or CH.sub.2 X 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 O, N and S, the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, --(CH.sub.2).sub.n CH.sub.2 OH or SO.sub.2 Me, the heterocyclic ring being optionally substituted by hydrogen, halogen, methyl, MeS, phenyl, O(CH.sub.2).sub.n NR.sub.12 R.sub.13, O(CH.sub.2).sub.n N(R.sub.12 R

REFERENCES:
patent: 5750530 (1998-05-01), Bryans et al.
Yokoi et al, Journal of Antibiotics, vol. XLI, pp. 494-501, (1988).
Wu et al, Chemical Abstracts, vol. 113, No. 17408 (1990).
Drug Evalvations by American Medical Association, pp. 745-746, (1993).
Chemical Abstracts, vol. 65, 1966 16969--38-Heterocyclic Compounds 2,5-dioxopipeazines. II Reaction of 2,5-diopiperazine with aldehydes and nitroso compounds, Augustin et al.
The Lancet, Jul. 1987 pp. 3-8 Hamsten et al Plasminogen Activator Inhibitor in Plasma: Risk Factor for Recurrent Myocardial Infarction, Hansten et al.
Circulation vol. 96 No. 3 Aug. 1997 pp. 916-921 Friederick at al Novel Low-Molecular-Weight Inhibitor of PA-1 etc.
Thrombosis and Haemostasis 1996 pp. 808-815 Charlton et al Evaluation of a Low Molecular Weight etc.
Seminars in Thrombosis and Hemostasis vol. 18 No. 1 1992 pp. 67-80 Krishnamurti et al Plasmiogen Activator INhibitor Type 1: Biochemistry and Evidence for Modulation of Fibrinolysis in Vivo.
Chemical Abstracts, vol. 97, No. 6, 1982, Columbus, OH, U.S. abstract No. 40323s p. 70.

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