Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-09
1999-11-16
Mach, D. Margaret M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514279, 514281, 546 15, 546 39, 546 44, C07D21100, C07D47100
Patent
active
059858877
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel aza-anthracyclinone derivatives, their use for the treatment of amyloidosis, methods for their preparation and pharmaceutical compositions containing them.
2. Description of the Background
The relationship between amyloidosis, cell death and loss of tissue function appears to be of relevance for different type of disorders including neurodegenerative disorders. Therefore, the prevention of amyloid formation and/or the induction of amyloid degradation can be an important therapeutic tool for all pathological disorders associated with amyloidosis including AL amyloidosis and neurodegenerative disorders of the Alzheimer's type.
SUMMARY OF THE INVENTION
The present invention provides novel aza-anthracyclinones and their use in the treatment of amyloidosis. The new compounds are characterized by the presence of a bridged heterocyclic ring fused with an anthraquinone system.
The new class of molecules is named anthrazalinone and the parent compound, indicated as anthrazalone, may be considered related to the 8-aza-anthracyclinones ##STR3##
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention provides an anthrazalinone derivative of formula 1 ##STR4## wherein: X.sub.1 and X.sub.2 are independently selected from; ##STR5## wherein n=2 or 3, and C=N(R.sub.9) wherein R.sub.9 is hydroxy or amino-aryl, hydrogen, trifluoroacyl, aralkyl or aryl groups and
amino which may be unsubstitued or mono- or di-substituted by acyl, trifluoroacyl, aralkyl or aryl groups, and group or a group of formula R.sub.C --CH.dbd.CH--, wherein R.sub.C is hydrogen or C.sub.1-5 alkyl, hydrogen, cysteine, phenylalanine or leucine or a synthetic amino acid or a residue of a di- or tri-peptide, for example Gly-Gly, Gly-Phe, Gly-Leu, or Gly-Phe-Leu, Gly-Leu-Phe; and or a saccharide of the formula ##STR6## in which R.sub.13 is amino or aminoacyl, R.sub.14 and R.sub.15 are both hydrogen or one of R.sub.14 or R.sub.15 is hydrogen and the other of R.sub.14 or R.sub.15 is hydroxy or alkoxy or halogen or a group OSO.sub.2 (R.sub.10) as previously defined, CH.sub.2 --O--Ph--(amino) wherein the amino may be unsubstitued or mono- or di-substituted by an alkyl, acyl, trifluoroacyl, aralkyl or aryl group; and CH.sub.2 -amino wherein the amino is mono- or di-substituted by an alkyl, acyl, trifluoroacyl, aralkyl or aryl group or the amino is within an heterocyclic ring, for example a piperidino, pyrrolidino or morpholino ring optionally substituted with C.sub.1-16 alkyl or C.sub.1-16 alkyloxy or aryloxy, formula 1 are those wherein: cysteine, phenylalanine, leucine, or a synthetic amino acid or a residue of a di- or tri-peptide for example Gly-Gly, Gly-Phe, Gly-Leu, Gly-Phe-Leu, Gly-Leu-Phe; and or a saccharide of the formula ##STR7## in which R.sub.13 is amino or aminotrifluoroacetyl or aminoacetyl, R.sub.15 is hydrogen and R.sub.14 is hydroxy or iodine or O-mesyl, CH.sub.2 --O--Ph--NH--COR wherein R is alkyl, aralkyl or aryl, CH.sub.2 -amino wherein the amino is within an heterocyclic ring for example a piperidino, pyrrolidino, morpholino or dihydropyridino ring optionally substituted with C.sub.1-10 alkyl or C.sub.1-5 alkyloxy or aryloxy.
More preferred compounds of formula 1 are those wherein: ##STR8## in which R.sub.13 is amino or aminotrifluoroacetyl or aminoacetyl, R.sub.15 is hydrogen and R.sub.14 is iodine and CH.sub.2 -amino wherein the amino is within a morpholino ring.
Further preferred compounds of the formula 1 are those wherein: hydroxy or methoxy; methoxy and amino; (N-methyl-dihydropyridine)-methyl, nicotyl, glycyl and isoleucyl; and
An "alkyl" group is typically a C.sub.1 -C.sub.16 alkyl group. A C.sub.1 -C.sub.16 alkyl group includes both straight and branched chain alkyl groups. Preferably a C.sub.1 -C.sub.16 alkyl group is a C.sub.1 -C.sub.12 alkyl group such as hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups or a branched chain isomer thereof. Preferably, a C.sub.1 -C.sub.12 alkyl group is a
REFERENCES:
patent: 5637572 (1997-06-01), Merlini et al.
patent: 5731313 (1998-03-01), Suarato et al.
patent: 5744454 (1998-04-01), Suarato et al.
J. Med. Chem., vol. 31(2), pp. 433-444, Grunewald, 1988.
Bandiera Tiziano
Caruso Michele
Faiardi Daniela
Lansen Jacqueline
Suarato Antonino
M. Mach D. Margaret
Pharmacia & Upjohn S.p.A.
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