Use of etherlysophospholipids as antiinflammatory agents

Details Use of etherlysophospholipids as antiinflammatory agents Use of etherlysophospholipids as antiinflammatory agents

2001-08-23

2003-06-24

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S838000

Reexamination Certificate

active

06583127

ABSTRACT:

This specification recites a number or prior art documents. The disclosure content of said documents is herewith incorporated by reference.
The present invention relates to the use of etherlysophospholipids (ELPs) for the preparation of a medicament for the prevention or treatment of an inflammatory disease without causing or essentially without causing adverse gastrointestinal side effects and/or without inhibition of phospholipase A
2
and prostaglandin E
2
, as well as for preventing or treating ulcerative conditions of the gastrointestinal tract.
The inflammatory response is an essential mechanism of defense of the organism against the attack of infectious agents, and it is also implicated in the pathogenesis of many acute and chronic diseases, including autoimmune disorders. In spite of being needed to fight pathogens, the effects of an inflammatory burst can be devastating. It is therefore often necessary to restrict the symptomatology of inflammation with the use of anti-inflammatory drugs.
Inflammation is a complex process normally triggered by tissue injury that includes activation of a large array of enzymes, the increase in vascular permeability and extravasation of blood fluids, cell migration and release of chemical mediators, all aimed to both destroy and repair the injured tissue.
Inflammation is commonly treated with so-called non-steroid anti-inflammatory drugs (NSAIDs). Although chemically diverse, all NSAIDs act by inhibiting cyclooxygenase (COX) activity, thus resulting in suppression of the production of inflammatory prostaglandins (PG). Two cyclooxygenase enzymes, named COX-1 and COX-2, have been described, which catalyze the synthesis of prostaglandins from arachidonic acid [Xie et al.,
Proc. Natl. Acad. Sci
., 88, 2692 (1991)]. COX-1 is expressed in most tissues and is responsible for the synthesis of. PGs needed to maintain gut and kidney integrity, whereas COX-2 is induced at sites of tissue damage, where it leads to the synthesis of inflammatory PGs and other inflammatory mediators [Kargman et al.,
Gastroenterology
, 111, 445 (1996)].
While protecting from inflammatory damage, all NSAIDs tested so far have important gastrointestinal toxic side effects, mostly due to the inhibition of the synthesis of cytoprotective prostaglandins (mainly PGE
2
). Therefore, anti-inflammatory NSAIDs that act selectively on COX-2, and not on COX-1, have been eagerly searched for and developed. However, COX-2 inhibitors turned out to inhibit inflammation only at concentrations that also inhibited COX-1, and hence provoke mucosal toxicity through suppression of gastric PGE
2
synthesis [Wallace et al.,
Gastroenterology
, 115, 101 (1998)]. Indeed NSAIDs inhibit ulcer healing by interfering with the synthesis of growth factors involved in repair of the gastric mucosa. For example, it has been shown that indomethacin, a potent NSAID, inhibits the production of PGs and of Hepatocyte Growth Factor (HGF), a mediator of epithelial growth and angiogenesis at the site of ulcerative mucosal erosion [Bamba et al.,
Biochem. Biophys. Res. Comm
., 245, 567 (1998)].
Furthermore, the finding that gene-targeted, COX-2 deficient mice are still able to mount a normal inflammatory response, but suffer from kidney dysfunction [Morham et at.,
Cell
, 83, 473 (1995)] has additionally challenged the selective inhibition of COX-2.
Finally, as a result of the inhibition of PG synthesis, the accumulative increase in arachidonic acid enhances the production of leukotrienes by the lipooxygenase enzyme, thus resulting in vasoconstriction, a life-threatening side effect in individuals with asthmatic or circulatory complications [Fosslien E.,
Annals Clin
. &
Lab. Science
, 28, 67 (1998)].
A further group of NSAIDs named etherlysophospholipids (ELPs) or alkyl-lysophospholipids (ALPs) are known for their antineoplastic properties (DE 2,619,686), in particular ET-18-OCH
3
(also known as edelfosine) having the formula:
Edelfosine, one of the best studied ELPs, has been shown to induce cell death by apoptosis selectively on tumor cells, while sparing normal, non-transformed cells [Mollinedo et al.,
Cancer Res
., 57, 1320 (1997)]. Edelfosine and several other ether lipid compounds have undergone phase I/II clinical evaluation for the treatment of cancer or their use as purging agents in autologous bone marrow transplantation [Lohmeyer et al.,
Drugs of the Future
, 19, 1021 (1994)].
Moreover, U.S. Pat. No. 5,266,564 discloses the use of a series of ELPs, including several compounds used in accordance with the present invention, in the treatment of autoimmune diseases, such as rheumatoid arthritis and ankylosing spondylitis.
EP 236,390 B discloses the use of such compounds in the treatment of multiple sclerosis, another autoimmune illness.
From DE 3,941,009 the effectiveness of edelfosine to eliminate activated lymphocytes is known.
Recently, Bosse et al. [
Pathobiology
, 63, 109 (1995)] have described the selective inhibition of adhesion molecule expression in vitro by edelfosine on endothelial cells. Potential anti-inflammatory properties of edelfosine have been mentioned from such capacity of inhibition, but according to the cited article, the in vivo anti-inflammatory activity of edelfosine was not tested in animal models. As is well known in the art, the pharmaceutical in vivo activity of a compound including the potential occurrence of adverse side effects cannot be predicted from in vitro data without further ado.
Thus, no NSAID is available to date that combines potent in vivo anti-inflammatory properties with the lack or a minimum of toxic side effects on the gastrointestinal mucosa [Cryer et al.,
Am. J. Med
., 104, 413 (1998)]. Accordingly, there is a need in the art to develop effective anti-inflammatory agents that are free of or essentially free of toxic gastrointestinal side effects for in vivo therapy in mammals, preferably humans.
The solution to this technical problem is achieved by providing the embodiments characterized in the claims.
Accordingly, the present invention relates to the use of a compound of formula (I):
wherein R
1
is a C
12
-C
18
straight or branched alkyl group;
R
2
is C
1
-C
8
straight or branched alkyl group;
and R
3
is:
or the salts, enantiomers and diastereomers thereof, for the preparation of a pharmaceutical composition for the prevention or treatment of an inflammatory disease.
Unexpectedly, it has now been found that the above recited compounds are useful in the treatment of an inflammatory disease in mammals and do not inhibit the synthesis of prostaglandins, in particular prostaglandin E
2
. It was surprisingly and additionally found that synthesis of phospholipase A is not inhibited. Most advantageously, they do not cause or they essentially do not cause adverse gastrointestinal side effects, thereby obviating the disadvantages associated with the use of traditional NSAIDs. Furthermore, surprisingly it has now been found that the recited compounds are useful in the prevention or treatment of ulcerative conditions of the gastrointestinal tract in mammals. The mammals to which these pharmaceutical compositions are preferably administered are humans. The term “essentially not causing adverse side effects” means, in accordance with the present invention, that the overall well-being of the subject treated is not impaired as a consequence of the administration of the pharmaceutical composition of the invention.
The compounds of formula (I) have one or more asymmetric centres and thus they can exist as enantiomers or diastereomers. The pharmaceutical composition prepared in accordance with the present invention may include both mixtures of and separate individual isomers.
The compounds of formula (I) can be obtained in the form of salts of formulas (Ia) or (Ib)
wherein X
−
is a pharmaceutically acceptable anion, such as chloride, bromide or iodide, and R
1
and R
2
have the above mentioned meanings, or of formulas (Ic) or (Id)
wherein M
+

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