Lipoxin A4 analogs

Details Lipoxin A4 analogs Lipoxin A4 analogs

2002-10-22

2004-12-14

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...

C554S062000, C554S085000, C554S103000, C554S108000, C514S376000, C514S386000, C514S558000, C514S559000, C514S560000, C514S552000

Reexamination Certificate

active

06831186

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to lipoxin A
4
analogs, their use in treating inflammatory and autoimmune disorders and pulmonary and respiratory tract inflammation, and pharmaceutical compositions containing the analogs and processes for their preparation.
2. Background of the Invention
Lipoxins, together with leukotrienes, prostaglandins, and thromboxanes, constitute a group of biologically active oxygenated fatty acids collectively referred to as the eicosanoids. Eicosanoids are all synthesised de novo from membrane phospholipid via the arachidonic acid cascade of enzymes. Since their initial discovery in 1984, it has become apparent that lipoxins, which are a structurally unique class of eicosanoids, possess potent anti-inflammatory properties that suggest they may have therapeutic potential (Serhan, C. N.,
Prostaglandins
(1997), Vol. 53, pp. 107-137; O'Meara, Y. M. et al.,
Kidney Int
. (
Suppl
.) (1997), Vol. 58, pp. S56-S61; Brady, H. R. et al.,
Curr. Opin. Nephrol. Hypertens. (
1996), Vol. 5, pp. 20-27; and Serhan, C. N.,
Biochem. Biophys. Acta
. (1994), Vol. 1212, pp. 1-25). Of particular interest is the ability of lipoxins to antagonise the pro-inflammatory functions of leukotrienes in addition to other inflammatory agents such as platelet activating factor, FMLP, immune complexes and TNF&agr;. Lipoxins are thus potent anti-neutrophil (PMN) agents which inhibit PMN chemotaxis, homotypic aggregation, adhesion, migration across endothelial and epithelial cells, margination/diapedesis and tissue infiltration (Lee, T. H., et al.,
Clin. Sci
. (1989), Vol. 77, pp. 195-203; Fiore, S., et al.,
Biochemistry
(1995), Vol. 34, pp. 16678-16686; Papyianni, A., et al.,
J. Immunol
. (1996), Vol. 56, pp. 2264-2272; Hedqvist, P., et al.,
Acta. Physiol. Scand
. (1989), Vol. 137, pp. 157-572; Papyianni, A., et al.,
Kidney Intl
. (1995), Vol. 47, pp. 1295-1302). In addition, lipoxins are able to down-regulate endothelial P-selectin expression and adhesiveness for PMNs (Papyianni, A., et al.,
J. Immunol
. (1996), Vol. 56, pp. 226
4
-2272), bronchial and vascular smooth muscle contraction, mesangial cell contraction and adhesiveness (Dahlen, S. E., et al.,
Adv. Exp. Med Biol. (
1988), Vo. 229, pp. 107-130; Christie, P. E., et al,
Am. Rev. Respir. Dis
. (1992), Vol. 145, pp. 1281-1284; Badr, K. F., et al.,
Proc. Natl. Acad. Sci
. (1989), Vol. 86, pp. 3438-3442; and Brady, H. R., et al.,
Am. J. Physiol
. (1990), Vol. 259, pp. F809-F815) and eosinophil chemotaxis and degranulation (Soyombo, O., et al.,
Allergy
(1994), Vol. 49, pp. 230-234).
This unique anti-inflammatory profile of lipoxins, particularly lipoxin A
4
, has prompted interest in exploiting their potential as therapeutics for the treatment of inflammatory or autoimmune disorders and pulmonary and respiratory tract inflammation. Such disorders and inflammation which exhibit a pronounced inflammatory infiltrate are of particular interest and include dermatologic diseases, such as psoriasis, and rheumatoid arthritis, and respiratory disorders, such as asthma.
As with other endogenous eicosanoids, naturally occurring lipoxins are unstable products which are rapidly metabolized and inactivated (Serhan, C. N.,
Prostaglandins
(1997), Vol. 53, pp. 107-137). This has limited the development of the lipoxin field of research, particularly with respect to in vivo pharmacological assessment of the anti-inflammatory profile of lipoxins. Several U.S. Patents have issued directed to compounds having the active site of lipoxin A
4
, but with a longer tissue half-life. See, e.g, U.S. Pat. Nos. 5,441,951 and 5,648,512, the disclosures of which are incorporated in full by reference herein. These compounds retain lipoxin A
4
receptor binding activity and the potent in vitro and in vivo anti-inflammatory properties of natural lipoxins (Takano, T., et al., J. Clin. Invest.(1998), Vol. 101, pp. 819-826; Scalia, R., et al., Proc. Natl. Acad. Sci. (1997), Vol. 94, pp. 9967-9972; Takano, T., et al.,
J. Exp. Med
. (1997), Vol. 185, pp. 1693-1704; Maddox, J. F., et al., J. Biol. Chem. (1997), Vol. 272, pp. 6972-6978; Serhan, C. N., et al.,
Biochemistry
(1995), Vol. 34, pp. 14609-14615).
All of the references cited herein, including published patent applications and journal articles, are incorporated in full by reference herein.
SUMMARY OF THE INVENTION
This invention is directed to potent, selective and metabolically/chemically stable lipoxin A
4
analogs and their use in treating inflammatory or autoimmune disorders and pulmonary or respiratory tract inflammation in mammals, particularly humans.
In one aspect, the invention is directed to compound of formula (I) or formula (II):
wherein:
each R
1
, R
2
and R
3
are independently halo, —OR
6
, —SR
6
, —S(O)
t
R
7
(where t is 1 or 2) or —N(R
7
)R
8
;
or R
1
and R
2
together with the carbons to which they are attached form a monocyclic heterocyclic structure selected from the following:
or R
1
and R
2
together with the carbons to which they are attached form the following bicyclic heterocyclic structure:
(where q is 0 to 3, p is 1 to 4 and each R
15
is hydrogen, alkyl, aralkyl or aryl);
each R
4
is —R
9
—R
12
, —R
9
—R
13
—R
11
, —R
9
—O—R
10
—R
11
, —R
9
—O—R
12
, —R
9
—C(O)—R
10
—R
11
, —R
9
—N(R
7
)—R
10
—R
11
, —R
9
—S(O)
t
—R
10
—R
11
(where t is 0 to 2), or —R
9
—C(F)
2
—R
9
—R
11
;
each R
5
is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
each R
6
is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R
7
, —C(S)R
7
, —C(O)OR
14
, —C(S)OR
4
, —C(O)N(R
7
)R
8
, or —C(S)N(R
7
)R
8
;
each R
7
is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl; R
8
is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R
7
, —C(O)OR
14
, or cycloalkyl (optionally substituted with one more substituents selected from the group consisting of alkyl, —N(R
7
)
2
, and —C(O)OR
7
);
each R
9
is independently a direct bond or a straight or branched alkylene chain;
each R
10
is independently a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain or a cycloalkylene;
each R
11
is independently —C(O)OR
7
, —C(O)N(R
7
)
2
, —P(O)(OR
7
)
2
, —S(O)
2
OR
7
, —S(O)
2
N(H)R
7
or tetrazole;
R
12
is aryl (substituted by —C(O)OR
7
or —C(O)N(R
7
)
2
and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (substituted by —C(O)OR
7
or —C(O)N(R
7
)
2
and optionally by one or more substituents selected from the group consisting of alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
R
13
is a branched alkylene chain, a straight or branched alkenylene chain or a cycloalkylene; and
R
14
is alkyl, aryl or aralkyl;
as a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof.
In another aspect, this invention is directed to pharmaceutical compositions useful in treating an inflammatory or autoimmune disorder in a mammal, particularly a human, wherein the composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or formula (II) as described above.
In another aspect, this invention is directed to pharmaceutical compositions useful in treating pulmonary or respiratory tract inflammation in a mammal, particularly a human, wherein the composition comprises one or more pharmaceutically acceptable excipient(s) and a therapeutically effective amount of a compound of formula (I) or formula (II) as described above.
In another aspect, this invention is directed to methods of treating an inflammatory or autoimmune disorder in a mammal, particularly a human, wherein the method co

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