Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1997-03-28
2001-01-30
Shippen, Michael L. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C554S090000, C554S091000, C554S094000, C554S101000, C554S104000, C554S105000, C554S110000, C560S149000, C560S150000, C560S153000, C560S170000
Reexamination Certificate
active
06180667
ABSTRACT:
The present invention relates to the use of esters of alkanoyl L-carnitines for producing pharmaceutical compositions suitable for treating endotoxic shock.
Since, as it will be described in detail hereinbelow, some of these esters are novel compounds, the present invention also relates to these novel esters.
The esters suitable for the use according to the invention have the formula (I)
wherein:
R is a saturated or unsaturated, straight or branched alkanoyl, having 2-26 carbon atoms, optionally &ohgr;-substituted with a R
2
group selected from trialkylammonium or dialkylsulfonium wherein the alkyl group has 1-3 carbon atoms: hydroxyl; carboxyl; halogen; methanesulfonyl and hydroxysulfonyl;
R
1
is a saturated or unsaturated, straight or branched alkyl having 2-26 carbon atoms, optionally &ohgr;-substituted with R
2
, wherein R
2
has the previously defined meaning, and
X
−
is the anion of a pharmacologically acceptable acid.
Esters of alkanoyl L-carnitines are already known. U.S. Pat. No. 4,439,438 discloses compounds having the foregoing formula (I) wherein R is a straight or branched alkanoyl having 2-4 carbon atoms optionally substituted with halogen atoms or hydroxyl, or pantothenyl or linoleyl; R
1
is an optionally substituted straight or branched alkyl having 1-5 carbon atoms.
These compounds are used for the therapeutical treatment of myocardial hypocontractility and as antidepressants.
Esters of alkanoyl L-carnitines having the formula (I) wherein R is a straight of branched alkanoyl having 2-16 carbon atoms. R
1
is a straight alkyl having 11-16 carbon atoms and X
−
is the anion of a pharmacologically acceptable acid [typically, isovaleryl L-carnitine undecyl ester chloride (ST 722)] were disclosed in EP 0552137 A2 and EP 0552138 A2 both published after the priority date of the present application.
The pharmacological activities reported for these esters comprise the antibacterial activity (particularly against bacterial belonging to the genera Campylobacter and Helicobacter) and the antimycotic activity, particularly against yeast-like fungi (Candida albicans) and filamentous fungi (Aspergillus fumigatus), respectively.
Also EP 0559625, published after the priority date of the present application, discloses esters having the formula (I) wherein R is hydrogen or a saturated or unsaturated, straight or branched alkanoyl having 2-26 carbon atoms and R
1
is a saturated or unsaturated, straight or branched alkyl radical having 4-26 carbon atoms, which are endowed with myorelaxant activity selectively directed towards the gastro-intestinal tract.
The pharmacological properties and therapeutical utilizations described for all the aforesaid known alkanoyl L-carnitine esters are totally remote from and unrelated to the activity (protective action against endotoxic shock) of the compounds of the present invention.
Finally, in order to complete the prior art background relevant to the present invention, reference is made to U.S. Pat. No. 4,771,075 which disloses the use of acetyl L-carnitine (i.e. an alkanoyl carnitine not an ester thereof) for treating various shock conditions, comprising septic shock. In addition to the structural dissimilarity between acetyl carnitine and the aforesaid alkanoyl carnitine esters, a marked superiority of the esters having formula (I) over acetyl carnitine for treating the endotoxic shock has been shown.
It is, therefore, apparent that the compounds having the formula (I) which are not encompassed by the aforesaid prior art references are novel compounds. More specifically, are novel those esters having the formula (I) wherein:
(a) R is a saturated or unsaturated, straight or branched alkanoyl having 2-26 carbon atoms, &ohgr;-substituted with a R
2
group, selected from trialkylammonium or dialkylsulfonium wherein the alkyl group has 1-3 carbon atoms, hydroxyl, carboxyl, halogen, methanesulfonyl and hydroxysulfonyl and
(b) R
1
is a saturated or unsaturated, straight or branched alkyl having 4-26 carbon atoms, &ohgr;-substituted with a R
2
group
or
(b′) R
1
is an alkyl group having 2-3 carbon atoms, provided that R has more than 4 carbon atoms and is not linoleyl or pantothenyl;
(c) R is a saturated or unsaturated, straight or branched alkanoyl having 2-26 carbon atoms, and
R
1
is a saturated or unsaturated, straight or branched alkyl having 2-26 carbon atoms &ohgr;- substituted with a R
2
group provided that:
when R
1
is a straight alkyl having 2 carbon atoms, &ohgr;-substituted with a R
2
group
R is a saturated or unsaturated, straight or branched alkanoyl having 5-17 or 19-26 carbon atoms;
(d) R is a saturated or unsaturated, straight or branched alkanoyl having 2-26 carbon atoms, &ohgr;-substituted with a R
2
group, and
R
1
is a saturated or unsaturated, straight or branched alkyl having 2-26 carbon atoms provided that:
when R
1
is a straight or branched alkkyl having 2-4 carbon atoms and R is a saturated or unsaturated, straight or branched alkanoyl having 2-4 carbon atoms, R
2
as substituent of R is not halogen.
Endotoxic shock is a clinical syndrome associated with a high mortality rate and characterized by various haemodynamic, immunological and biochemical abnomarlities.
Its increasing incidence places it among the most serious nosocomial pathologies, especially in intensive care units, despite the use of a variety of antibiotics, surgical drainage, intervention with vasoactive substances and metabolic support. It is estimated that approximately 100,000 people die of endotoxic shock every year in the USA.
The main cause of this type of pathology is undoudtedly severe infection with Gram-negative bacteria, whose physio-pathological effects are ascribable to LPS, a component of the outer layer of the bacterial membrane capable of causing endotoxic shock by interacting with various components of the host's immune system, particularly macrophages.
This immunocompetent cell population, in fact, releases different endogenous mediators which prove ultimately responsible for the complex pathological picture which ensues.
The fatal outcome of endotoxic shock in man has recently been linked to the systemic release of substantial amounts of various cytokines.
There are, in fact, numerous studies which show that an abnormal modulation of cytokines such as IL-1, IL-6, TNF and IFN-&ggr; is closely related to a severe endotoxic situation.
Other inflammation mediators (PAF, LTD, BK, substance P) would also appear to be involved in the endotoxic physio-pathology.
TNF (Tumor Necrosis Factor) is in any event the cytokine which plays a crucial role as mediator in the host's response to LPS (Tracery K J, Tumor Necrosis Factor (Cachectin) in the Biology of Endotoxic Shock Syndrome. {i Circ. Shock 1991; 35:123-28), since its involvement has been demonstated in various metabolic abnormalities characterizing the course of shock (Starnes H K, Warren R S, Jeevandam M. et al. Tumor Necrosis Factor and the acute metabolic response to tissue injury in man.
J. Clin. Invest.
1988: 82:1321), the negative prognosis of which is often related to excessively high serum concentrations of TNF (Dames P, Reuter A, Gysen P, Demonty J, Lamy M, Franchimont P. Tumor Necrosis Factor and interleukin-1 serum levels during severe sepsis in humans.
Crit. Care Med.
1989; 17:975-978. Debets J M H, Kampmeijer R, Van Der Linden M P M H, Buurman, W A, Vand Der Linen C J. Plasma Tumor Necrosis Factor and mortality in critically ill septic patients.
Crit Care Med.
1989; 17:489-494).
In fact, high levels of TNF are found in the serum of animals experimentally intoxicated with LPS, and animals directly inoculated with TNF develop a toxic syndrome which is indistinguishable from endotoxinaemia (Natanson C, Eichenhols P W, Danner R L. Endotoxin and Tumor Necrosis Factor challenges in dogs simulate the cardiovascular profile of human endotoxic shock.
J. Exp, Med.
1989; 169: 823-832. Beutler B, Milsak I W, Cerami A. Passive immunization against cachectin/Tumor Necrosis Factor protects mice from lethal effect of endotoxin.
Science
19
Foresta Piero
Ruggiero Vito
Scafetta Nazareno
Tinti Maria Ornella
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Shippen Michael L.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
LandOfFree
Esters of acyl L-carnitines and pharmaceutical compositions... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Esters of acyl L-carnitines and pharmaceutical compositions..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Esters of acyl L-carnitines and pharmaceutical compositions... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2439089