Prevention of neutrophil recruitment

Details Prevention of neutrophil recruitment Prevention of neutrophil recruitment

2000-03-14

2002-08-13

Carr, Deborah D. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S219000, C558S303000, C568S021000, C568S022000, C568S028000

Reexamination Certificate

active

06433202

ABSTRACT:

BACKGROUND OF THE INVENTION
Aspirin (acetylsalicylic acid, ASA) has been available for use as an analgesic-antipyretic for almost a century and novel therapeutic applications for this drug, for example in lowering the risk of myocardial infarction or as a prophylaxis against colorectal cancer, continue to be uncovered (Weissmann, G. (1991)
Sci. Am.
264, 84-90; Ridker, P. M., Cushman, M., Stampfer, M. J., Tracy, R. P. & Hennekens, C. H. (1997)
N. Engl. J. Med.
336, 973-979; Marcus, A. J. (1995)
N. Engl. J. Med.
333, 656-658). The acetylation of cyclooxygenases I and II (COX I and II) and the subsequent irreversible inhibition of prostaglandin (PG) and thromboxane biosyntheses are well understood mechanisms of some of ASA's pharmacological actions (Marcus, A. J. (1995)
N. Engl. J. Med.
333, 656-658; Herschman, H. R. (1998)
Trends Cardiovasc. Med.
8, 145-150). More recently, ASA was found to cause a switch in eicosanoid biosynthesis as the acetylation of COX II changes the enzyme's activity to produce 15R-hydroxyeicosatetraenoic acid from agonist-released arachidonic acid Herschman, H. R. (1998)
Trends Cardiovasc. Med.
8, 145-150). Human neutrophils, and other cells possessing 5-lipoxygenase, utilize this substrate via transcellular biosynthetic routes to produce 15-epi-lipoxin A
4
(15-epi-LXA
4
) and 15-epi-lipoxin B
4
(15-epi-LXB
4
) (Serhan, C. N. (1997) Prostaglandins 53, 107-137; Chiang, N., Takano, T., Clish, C. B., Petasis, N. A., Tai, H.-H. & Serhan, C. N. (1998)
J. Pharmacol. Exp. Ther.
287, 779-790). These aspirin-triggered lipoxins (ATL) are the endogenous 15R enantiomeric counterparts of lipoxin A
4
(LXA
4
) and lipoxin B
4
(LXB
4
), respectively, and share their bioactivities (Serhan, C. N. (1997)
Prostaglandins
53, 107-137(5)).
Unlike other eicosanoids (e.g., leukotrienes, PGs, etc.), which are generally considered local pro-inflammatory mediators, lipoxins (LX) display potent inhibitory actions in several key events in inflammation, such as polymorphonuclear cell (PMN) chemotaxis, transmigration across endothelial and epithelial cells, and diapedesis from post-capillary venules (Serhan, C. N. (1997)
Prostaglandins
53, 107-137(5)). LX are generated in several pathogenic scenarios in vivo, for example: in lung tissue of patients with severe pulmonary disease; and by PMN from patients with asthma or rheumatoid arthritis, where their presence is proposed to be linked to long-term clinical improvement (Lee, T. H., Crea, A. E., Gant, V., Spur, B. W., Marron, B. E., Nicolaou, K. C., Reardon, E., Brezinski, M. & Serhan, C. N. (1990)
Am. Rev. Respir. Dis.
141, 1453-1458; Chavis, C., Chanez, P., Vachier, I., Bousquet, J., Michel, F. B. & Godard, P. (1995)
Biochem. Biophys. Res. Commun.
207, 273-279; Chavis, C., Vachier, I., Chanez, P., Bousquet, J. & Godard, P. (1996)
J. Exp. Med.
183, 1633-1643; Thomas, E., Leroux, J. L., Blotman, F. & Chavis, C. (1995)
Inflamm. Res.
44, 121-124). Interestingly, ATL show an even greater level of inhibition than native LX in preventing neutrophil adhesion, where they are ~twice as potent (Serhan, C. N. (1997)
Prostaglandins
53, 107-137). ATL are also more potent inhibitors of microbial induction of cytokine release. Specifically, 15-epi-LXA
4
showed greater inhibition than LXA
4
of
S. typhimurium
-induced secretion and gene regulation of the potent leukocyte chemoattractant IL-8, generated by intestinal epithelial cells (Gewirtz, A. T., McCormick, B., Neish, A. S., Petasis, N. A., Gronert, K., Serhan, C. N. & Madara, J. L. (1998)
J. Clin. Invest.
101, 1860-1869). It is therefore likely that, in addition to the inhibition of prostaglandin formation, the benefits of ASA therapy also result from the triggering of novel anti-inflammatory lipid mediators that act locally to down regulate leukocytes.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to compounds having the formulae (I-V):
wherein X is R
1
, OR
1
, or SR
1
;
wherein R
1
is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl
wherein Z
i
, Z
ii
, Z
iii
, Z
iv
and Z
v
are each independently selected from —NO
2
, —CN, —C(═O)—R
1
, —SO
3
H, a hydrogen atom, halogen, methyl, —OR
x
, wherein R
x
is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule; or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q
1
is (C═O), SO
2
or (CN), provided when Q
1
is CN, then X is absent;
wherein Q
3
and Q
4
are each independently O, S or NH;
wherein one of R
2
and R
3
is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;
(c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;
(d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or
(e) R
a
Q
2
R
b
wherein Q
2
is —O— or —S—; wherein R
a
is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein R
b
is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R
b
is 0, then R
b
is a hydrogen atom;
wherein R
4
is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R
5
is
wherein Z
i
, Z
ii
, Z
iii
, Z
iv
and Z
v
are each independently selected from —NO
2
, —CN, —C(═O)—R
1
, —SO
3
H, a hydrogen atom, halogen, methyl, —OR
x
, wherein R
x
is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y
1
is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CH
a
Z
b
where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R
6
is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof excluding 16-phenoxy-LXA
4
and/or 15-epi-16-(para-fluoro)-phenoxy-LXA
4
in certain embodiments.
In preferred embodiments, X is OR
1
wherein R
1
is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or a pharmaceutically acceptable salt, Q
1
is C═O, R
2
and R
3
, if present, are hydrogen atoms, R
4
is a hydrogen atom or methyl, Q
3
and Q
4
, if present, are both O, R
6,
if present, is a hydrogen atom, Y
1
, if present, is OH, T is O and R
5
is a substituted phenyl, e.g.,
wherein Z
i
, Z
ii
, Z
iii
, Z
iv
and Z
v
are each independently selected from —NO
2
, —CN, —C(═O)—R
1
, —SO
3
H, a hydrogen atom, halogen, methyl, —OR
x
, wherein R
x
is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl. In certain embodiments for R
5
, 15-epi-16-para-fluorophenyl, 15-epi-unsubstituted phenyl, 16-parafluorophenyl or 16-phenyoxy are excluded.
In another aspect, the present invention is directed to an in vivo method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation. The method includes administering to a subject an effective anti-inflammatory amount of a pharmaceutical composition including a compound having one of the above-described formulae.
In another aspect, the invention is directed to a method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation. The method includes administering to a subject an effective anti-inflammatory amount of a pharmaceutical composition including a compound having one of the above-described formulae.
In still another aspect, the present invention is directed to pharmaceutical compositions including compounds having the above-described formulae and a pharmaceutically acceptable carrier. In one embodiment, a preferred compound is
In a preferred embodimen

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