Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-04
2003-04-08
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S455000
Reexamination Certificate
active
06545041
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of pharmaceutical compositions for inhibiting the production or blocking the action of Tumor Necrosis Factor &agr; (TNF-&agr;), and for preventing or alleviating diseases and conditions associated with this cytokine, such as septic shock or cachexia. Said pharmaceutical compositions comprise as their active ingredient the stereospecific (+) enantiomers, having (3S,4S) configuration, of &Dgr;
6
-tetrahydrocannabinol (THC) type compounds of general formula (I), as defined hereinbelow.
BACKGROUND OF THE INVENTION
Tumor necrosis factor alpha (TNF-&agr;) is a pleiotropic cytokine, which has been implicated in inflammatory and immunological responses, as well as in pathogenesis of endotoxic and septic shock (reviewed by Tracey and Cerami, Ann. Rev. Med. 45, 491-503, 1994; Glauser et al. Clin. Infect Dis. 18, suppl. 2, 205-216, 1994). TNF is one of several cytokines released mainly by mononuclear phagocytic cells in response to various stimuli. Though the role of cytokines in pathophysiological states has not been fully elucidated, it appears that TNF-&agr; is a major mediator in the cascade of injury and morbidity.
Among the serious disease states related to the production of TNF-&agr;, a partial list includes the following: septic shock; endotoxic shock; cachexia syndromes associated with bacterial infections (e.g., tuberculosis, meningitis), viral infections (e.g., AIDS), parasite infections (e.g., malaria), and neoplastic disease; autoimmune disease, including some forms of arthritis (especially rheumatoid and degenerative forms); and adverse effects associated with treatment for the prevention of graft rejection.
Septic shock is an often lethal syndrome associated with the massive release of host cytokines due to stimuli present on, or released by, invasive micro-organisms. These invasive stimuli induce polyclonal stimulation of the infected host immune system, and include both lipopolysaccharide (LPS), an endotoxin that stimulates B-cells and macrophages, and superantigens which are exotoxins that stimulate T-cells.
Septic shock has been recognized generally as a consequence of gram-negative bacterial infection, but it is now clear that it can also result from infection with gram positive micro-organisms and probably also by fungi, viruses and parasites. The microorganism itself, its components or products trigger the host cells, especially the macrophages, to release inflammatory mediators such as TNF-&agr;, thereby initiating a cascade of events leading to cachexia, sepsis syndrome and septic shock. TNF-&agr; is a major mediator initiating septic shock, and therefore stands out as a potential therapeutic target (Lynn and Cohen, Clin. Infect. Dis. 20, 143-158, 1995).
Despite vast improvements in intensive care and antibiotic therapy, septic shock remains associated with a very high rate of mortality (30 to 90%). The poor prognosis for this syndrome is due to the fact that this severe complication of infection results in multiple organ failure, even when the actual infection itself is successfully treated. It is, therefore, apparent that effective therapies for this syndrome are an unmet medical need.
Various therapies have been suggested for the treatment of septic shock syndrome, but as yet none of these has proven to be clinically efficacious. Antibodies against TNF-&agr; prevent the detrimental effects of superantigen (Miethke et al., J. Exp. Med. 175, 91-98, 1992) or LPS (Beutler et al., Science 229, 869-871, 1985). The use of anti-TNF antibodies to treat septic shock is disclosed for example in WO 92/16553 (Centocor Inc.). WO 92/01472 (Celltech Ltd.) discloses a multivalent immunoglobulin used to treat diseases associated with elevated cytokine levels. Various cytokines that inhibit TNF secretion can also reduce the toxicity of LPS action (Tzung et al., Eur. J. Immunol. 22, 3097-3101, 1992; Gerard et al., J. Exp. Med. 177, 547-550, 1993).
Soluble forms of the TNF binding protein (TBP) (Nophar et al. EMBO J., 9, 3269-3278, 1990) may prevent the action of TNF by preventing binding to its receptors.
Specific classes of compounds have been suggested for the treatment of diseases associated with elevated TNF or other inflammatory mediators, as disclosed for example in WO 95/11014 (Searle & Co.); WO 95/09627, WO 95/09624 and WO 95/09623 (Smith-Kline Beecham Corp.); WO 95/09619 (Wellcome Found.); WO 95/03051 (Pharmacia AB); WO 95/01980 (Pfizer Inc.); EP 629401 (Bayer AG); WO 93/14082 (SmithKline Beecham Corp.); and WO 89/05145 (Hoechst Roussel Pharm Inc.).
None of these disclosures is relevant to the present invention, which deals with a class of compounds developed as non-psychotropic analogs of tetra-hydrocannabinol (THC), the active ingredient of marijuana. Some of the compounds of general formula (I) are disclosed in U.S. Pat. Nos. 4,179,517 and 4,876,276 and 5,284,867. As disclosed in said U.S. patents, these essentially pure synthetic (+)-(3S,4S)-THC derivatives and analogues are devoid of any undesired cannabimimetic psychotropic side-effects. These known compounds have been described as having analgesic, antiemetic, antiglaucoma and neuroprotective activity.
According to the present invention, it is now disclosed that the said known compounds, as well as some novel compounds, in addition to having said analgesic, antiemetic, neuroprotective and anti-glaucoma activity, are unexpectedly also effective against the diseases and conditions mentioned above, by virtue of their ability to block the production or action of TNF-&agr;.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions for reducing and even preventing morbidity and mortality associated with the production of TNF-&agr;, or other cytokines. The present compositions are also effective in alleviating other cytokine induced damage including the wasting or cachexia associated with AIDS, tuberculosis, neoplasia or trauma, and may prevent or ameliorate other disease states associated with the production of cytokines, including malaria and parasitic infections.
The compositions of the present invention are also effective in the treatment of certain chronic degenerative diseases including arthritis and other autoimmune afflictions which are characterized by production of TNF-&agr;. In this connection, the compositions of the present invention are contemplated as therapeutically effective in the treatment of multiple sclerosis. In addition, the present compositions can be administered to a patient who exhibits the symptoms associated with cachexia due to acquired immune deficiency syndrome, neoplasia, trauma or other wasting syndromes, as well as to those having other autoimmune diseases.
The present invention relates to pharmaceutical compositions for the purposes set out above, in which the active ingredient is a compound of the general formula I:
having the (3S,4S) configuration and being essentially free of the (3R,4R) enantiomer, wherein A - - - B indicates an optional 1(2) or 6(1) double bond,
R is
(a) —Q wherein Q is a heterocyclic moiety having a labile hydrogen atom so that said moiety acts as a carboxylic acid analogue,
(b) —R′X wherein R′ is C
1
-C
5
alkyl and X is halogen, —OR″ wherein R″ is hydrogen, C
1
-C
5
alkyl, or —OC(O)R′″ wherein R′″ is hydrogen or C
1
-C
5
alkyl,
(c) —R′N(R″)
2
wherein R′ is C
1
-C
5
alkyl and each R″, which may be the same or different, is hydrogen or C
1
-C
5
alkyl optionally containing a terminal —OR′″ or —OC(O)R′″ moiety wherein R′″ is hydrogen or C
1
-C
5
alkyl,
(d) —R′ wherein R′ is C
2
-C
5
alkyl,
(e) —R′OR′″ wherein R′ is C
1
-C
5
alkyl and R′″ is hydrogen or C
1
-C
5
alkyl, or
(f) —R′—C(O)OR′″, wherein R′″ may be absent and R′ and R′″ are as defined above;
G is (a) halogen, (b) C
1
-C
5
alkyl, or (c) —OR
1
wherein R
1
is (a′) —R″, wherein R″
Gallily Ruth
Mechoulam Raphael
Shohami Esther
Travers Russell
Winston & Strawn
Yessum Research Development Co. of the Hebrew University of Jeru
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