Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-03-22
2001-06-05
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06242497
ABSTRACT:
The present invention relates to the use of 6,7-substituted-2-aminotetralines and their pharmacologically acceptable salts suitable for the prophylactic and therapeutic treatment of septic shock and for the treatment of inflammatory and/or autoimmune pathologies which will be better defined here below, in which the aetiopathogenetic role of inflammatory cytokines is well established.
6,7-Substituted-2-aminotetralines, which are active in the treatment of septic shock, are well known. EP-A-073086 1, which is incorporated herein for reference purposes, describes a class of such 6,7-substituted-2-aminotetralines and particularly the compound (R,S)-2-amino-6-fluoro-7-methoxytetraline (ST 626).
The 6,7-substituted-2-aminotetralines for the use according to the present invention are also known compounds but for completely different therapeutic applications. In fact, in J Chem Soc (1997), 288-93 they are described as possessing bronchodilatory activity; in Tetrahedron let, 22/38, 3707-10, 1981 they are described as compounds endowed with dopaminergic activity.
It is clear that there is no relationship between the known bronchodilatory and dopaminergic activity of such aminotetralines and their therapeutic activity in septic shock and in inflammatory and/or autoimmune pathologies in which the aetiopathogenetic role of the inflammatory cytokines is well established.
The inflammatory and/or autoimmune pathologies to be treated with the compounds of the invention described herein are, for example, rheumatoid arthritis, pancreatitis, inflammatory bowel disease, systemic lupus erythematosus, glomerulo-nephritis and encephalomyelitis.
Hereinafter, reference will be made only to septic shock, it being understood that the other pathologies due to inflammatory cytokines can also be effectively treated according the invention.
Septic shock is an extremely severe clinical syndrome which may set in as a result of infections mainly caused either by gram-negative or gram-positive bacteria, by protozoa or by viruses, and characterised by leukocytosis, fever, tachycardia, hypotension and renal, respiratory, cardiac and hepatic insufficiency. It should be stressed, however, that the severity of septic shock is independent of the type of micro-organism responsible for the syndrome (Parrillo J. E., Pathogenetic mechanisms of septic shock, N Engl J Med, 328:1471-1477, 1993) but is related to the individual inflammatory response to the antigen responsible for the toxic insult. Despite the significant improvement in antibiotic therapy and in intervention protocols in intensive care units over the past few years, shock remains one of the major causes of morbidity and mortality in hospitalised patients. It is estimated that in the USA it is responsible for approximately 100,000 deaths/year (Glauser M. P., Zanetti G., Baumgartner J. D. and Cohen J., Septic shock: pathogenesis, Lancet, 338:732-736, 1991).
The most decisive and characteristic feature of septic shock is the body's reaction to products deriving from lysis or from microbial metabolism.
The first of these substances to be identified and the one most used in experimental research is lipopolysaccharide (LPS), a constituent of the gram-negative bacterial wall chemically consisting is in a polysaccharide portion which varies according to the bacterial species and a lipid portion (lipid A) which is constant, and present in the blood of septicaemic subjects in the form of micelles. If administered to animals, LPS is capable of reproducing all the cardiocirculatory and neurological symptoms encountered in shock (Olson C., Salzer W. L., McCall C. E., Biochemical, physiological and clinical aspects of endotoxaemia, Molec Aspects Med, 10: 511-629, 1988). It is therefore identifiable as the prime mover in the chain of events, which leads to the triggering of the clinical symptoms via activation of the intrinsic and extrinsic pathways of the coagulative cascade and the secretion of cytokines of mainly macrophage-monocyte origin, such as, for instance, TNF, IL-1 and IL-6.
The increasing importance this syndrome has come to take on over the past few years, its severity and the inadequate therapeutic measures currently available make the rapid discovery of therapeutic agents capable of effectively combating the progression of the disease a highly desirable goal.
It has now been found that a class of known 6,7-substituted 2-aminotetralines exhibits potent activity in the prevention and therapeutic treatment of the above-mentioned pathologies.
6,7-Substituted-2-aminotetralines according to the invention can occur both as free bases with general formula (I):
and as pharmacologically acceptable salts with general formula (II):
wherein:
R is methoxy or hydroxy and
X
−
is the monovalent anion of a pharmacologically acceptable acid.
Among the 6,7-substituted-2-aminotetralines with general formula (I) or (II) the following compounds are particularly preferred wherein:
R=methoxy: (R,S)-2-amino-6,7-dimethoxytetraline hydrochloride (hereinafter: ST 1213)
R=OH: (R, S)-2-amino-6 ,7-dihydroxytetraline hydrochloride (hereinafter: ST 1236).
What is meant by pharmacologically acceptable salts of 6,7-substituted-2-aminotetralines with formula (I) are any of its salts with an acid that does not give rise to unwanted toxic or side effects. Such acids are well known to pharmacologists and to experts in pharmacy and pharmaceutical technology.
Non-limiting examples of such salts are chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, lactate, maleate and acid maleate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate. FDA-approved salts are listed in Int J Pharm 33 (1986), 201-217, which is incorporated herein for reference purposes.
The methodological approach most widely employed for the purposes of assessing the possible protective effect of a substance in septic shock, in preclinical investigation, is the use of experimental models of intoxication with a toxic substance (exo- or endotoxin) injected directly into the laboratory animal or released in massive amounts by the infecting cells with which the animal is inoculated.
REFERENCES:
patent: 5591777 (1997-01-01), Foresta et al.
patent: 5637614 (1997-06-01), Foresta et al.
patent: 5962525 (1999-10-01), Foresta et al.
Foresta Piero
Ruggiero Vito
Henley III Raymond
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p. A.
LandOfFree
Use of 6,7-substituted 2-aminotetralines suitable for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of 6,7-substituted 2-aminotetralines suitable for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of 6,7-substituted 2-aminotetralines suitable for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2524412