Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-07-16
2001-05-01
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S428000, C514S657000
Reexamination Certificate
active
06225501
ABSTRACT:
The present invention relates to S(−)-2-amino-6-fluoro-7-methoxytetraline, a process for its preparation and pharmaceutical compositions comprising same as active ingredient.
S(−)-2-amino-6-fluoro-7-methoxytetraline, both as free base and pharmacologically acceptable salt thereof, is endowed with potent therapeutical activity for treating septic shock.
Septic shock is a clinical syndrome that may set in as a result of severe infections caused by both gram-negative and gram-positive bacteria, by protozoa, or by viruses and is characterized 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 (Parillo J. E., Pathogenetic mechanisms of septic shock,
New Engl. J. Med
., 328:1471-1477, 1993) and is related rather to the extent of the individual inflammatory response to the agent responsible for the toxic insult.
Although there has been a significant improvement in antibiotic therapy and treatment protocols in intensive care units over the past few years, septic shock continues to be one of the major causes of morbidity and mortality in hospitalised patients. It is estimated, in fact, that in the United States it is responsible for more than 100,000 deaths per year (Glauser M. P., Zanetti G., Baumgartner J. D. and Cohen J., Septic shock: pathogenesis.
Lancet
338:732-736, 1991).
The decisive and most influential factor in septic shock is the body's reaction to products deriving from lysis or from microbial metabolism.
Among such substances, the first to be identified and the one most extensively used in experimental research is lipopolysaccharide (LPS), which is present in the walls of gram-negative bacteria and consists chemically of a polysaccharide portion which varies according to bacterial species and a constant lipid portion (lipid A), detectable in micellar form in the blood of septicaemic subjects. If administered to experimental animals, LPS is capable of reproducing all the cardiocirculatory and neurological symptoms encountered in shock (Olson N. C., Salzer W. L., McCall C. E., Biochemical, physiological and clinical aspects of endotoxiemia.
Molec. Aspects Med
., 10:511-629, 1988). It may therefore be regarded as the “prime mover” in the chain of events which, via activation of the intrinsic and extrinsic pathways of the coagulative cascade and the secretion of cytokines such as TNF, IL-1 and g-INF (Bone R. C., A critical evaluation of new agents for the treatment of sepsis.
J. Am. Med. Ass
., 266:1686-1691, 1991), leads to the triggering of the clinical symptoms.
The increasing importance of this syndrome, its severity and the inadequate therapeutic means currently available make the rapid discovery of therapeutic agents capable of effectively combating the progression of the disease a highly desirable goal.
The methodological approach most widely employed for the purposes of assessing the possible protective effect of a substance in septic shock in preclinical investigations is the use of experimental models involving intoxication by a toxic substance (an endo- or exotoxin) injected directly into the laboratory animal or released in massive amounts by the infecting cells with which the animal is inoculated.
2-aminotetralines active for treating septic shock are already known. EP-A-0 730 861, which is incorporated herein by reference, filed in the name of the same applicants as those of the present application, discloses a class of such 6,7-substituted-2-aminotetralines and particularly the racemic compound (R,S)-2-amino-6-fluoro-7-methoxytetraline (ST 626).
It has now been found that the enatiomer S(−)-2-amino-6-fluoro-7-methoxytetraline exhibits a far more potent activity than the racemate (R,S)-2-amino-6-fluoro-7-methoxytetraline (ST 626) for treating septic shock.
S(−)-2-amino-6-fluoro-7-methoxytetraline can occur both as free base having the formula:
and as a salt having the formula:
wherein X
−
is the monovalent anion of a pharmacologically acceptable acid.
What is meant by pharmacologically acceptable salts of S(−)-2-amino-6-fluoro-7-methoxytetraline are any of its salts with an acid that does not give rise to unwanted 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 sulphate, tartrate and acid tatrate.
A process for preparing S(−)-2-amino-6-fluoro-7-methoxytetraline as free base or as a pharmacologically acceptable salt is illustrated in the following reaction scheme:
wherein X
−
is the monovalent anion of a pharmacologically acceptable salt. The process comprises the following steps:
(a) preparing an anhydride 1 by suspending L(+)-aspartic acid in CF
3
COOH, adding cold trifluoroacetic anhydride (e.g. at −20° C.) and then heating the resulting mixture to the reflux temperature until the reaction is completed; then bringing it to dryness and repeatedly washing the residue under stirring with an organic solvent which does not dissolve it;
(b) condensing the anhydride 1 with an excess of 2-fluoroanisole (1.5-3 moles) in the presence of AlCl
3
vigorously stirring with heating (40-60° C.), for 40-50 hours, thus obtaining the acid 2. In order to facilitate the stirring, a solvent (e.g. CH
2
Cl
2
) can be added. The solid thus obtained is filtered off, treated with cooling (0° C.-8° C.) with conc. HCl (e.g. 6M), the acid aqueous phase is extracted with a solvent (e.g. ethyl ether), the organic phase is brought to dryness and the compound 2 is purified by crystallization;
(c) reducing the acid 2 by dissolving it with CF
3
COOH, cooling the solution thus obtained to 0-8° C., adding an excess amount of triethylsilane (e.g. 6M) and cautiously heating the mixture to the reflux temperature until the reaction is completed (about 4 hours). The reaction mixture is brought to dryness, the oily residue is dissolved with an alkaline aqueous solution (pH 10), the undissolved residue is filtered off, the filtrate is acidified (pH 3) and the product is extracted with a precipitating solvent (e.g. CH
2
Cl
2
); the product is brought to dryness and purified by crystallization, thus obtaining the compound 3;
(d) preparing the tretralone 4 from the compound 3 by condensation via Friedel-Crafs reaction, with PCl
5
and AlCl
3
in an inert anhydrous organic solvent;
(e) reducing the tetralone 4 by suspending it in boroetherate trifluoride and adding an excess amount of triethylsilane (molar ratio: 3-6) at 0-8° C. and letting the reaction to proceed at room temperature until the reaction is completed (60-90 hours); adding an aqueous alkaline solution (pH 9), extracting the aqueous phase with a solvent, bringing to dryness and purifying by crystallization, thus obtaining the compound 5;
(f) hydrolyzing the compound 5 with an aqueous alkaline solution, extracting wih a solvent (e.g. ethyl ether), bringing to dryness and purifying by crystallization the S(−)-2-amino-6-fluoro-7-methoxytetraline 6 thus obtained;
(g) in order to optionally obtain the salified tetraline (e.g. as hydrochloride) solubilizing the compound 6 in an organic solvent (e.g. CH
3
OH, ethyl ether), acidifying with the desired H
+
X
−
acid and bringing to dryness and optionally purifying the compound by crystallization.
With reference to the foregoing reaction scheme, the preparation of the compound of the present invention (as hydrochloride) is described hereinbelow.
REFERENCES:
patent: 5591777 (1997-01-01), Foresta
Foresta Piero
Moretti Gian Piero
Killos Paul J.
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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