Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-10-09
2002-07-16
Kight, John (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S438000, C514S471000, C514S473000, C546S283100, C546S284100, C549S483000, C549S484000, C549S488000, C549S491000, C549S496000, C549S497000, C549S498000, C549S499000, C549S500000, C549S501000, C549S502000
Reexamination Certificate
active
06420392
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the area of compounds, pharmaceutical compositions and methods for the treatment of inflammatory, cardiovascular and immune disorders. The compounds and compositions of the present invention exhibit these biological activities by acting as PAF receptor antagonists and/or by inhibiting the enzyme 5-lipoxygenase.
BACKGROUND OF THE INVENTION
Platelet activating factor (PAF, 1-0-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) is a potent inflammatory phospholipid mediator with a wide variety of biological activities. PAF is generated and released by monocytes, macrophages, polymorphonuclear leukocytes (PMNs), eosinophils, neutrophils, natural killer lymphocytes, platelets and endothelial cells, as well as by renal and cardiac tissues under appropriate immunological and non-immunological stimulation. PAF causes the aggregation and degranulation of platelets at very low concentrations. The potency (active at 10
−12
to 10
−9
M), tissue level (picomoles) and short plasma half life (2-4 minutes) of PAF are similar to those of other lipid mediators such as thromboxane A
2
, prostaglandins, and leukotrienes.
While PAF mediates essential biological responses, it also appears to play a role in pathological immune and inflammatory responses. Many published studies have provided evidence for the involvement of PAF in human diseases, including arthritis, acute inflammation, asthma, endotoxic shock, pain, psoriasis, ophthalmic inflammation, ischemia, gastrointestinal ulceration, myocardial infarction, inflammatory bowel diseases, and acute respiratory distress syndrome. Animal models also demonstrate that PAF is produced or increased in certain pathological states. Thus, compounds and/or pharmaceutical compositions which act as PAF receptor antagonists will be useful in the treatment of these and other disease states in which excessive amounts of PAF are present.
Leukotrienes, like PAF, are potent local mediators, playing a major role in inflammatory and allergic responses, including arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases. Arachidonic acid is oxidized by 5-lipoxygenase to the hydroperoxide 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is converted to leukotriene A
4
, which in turn can be converted to leukotriene B
4
, C
4
, or D
4
. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C
4
, D
4
, and E
4
, all of which are potent bronchoconstrictors. There has been a long established research effort to develop specific receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by these compounds. As such, compounds and/or pharmaceutical compositions which inhibit the 5-lipoxygenase enzyme will be useful in the treatment of disease states in which excessive amounts of leukotrienes are present.
Given the significant number of pathological immune and inflammatory responses that are mediated by PAF and leukotrienes, there remains a need to identify new compounds and compositions that exhibit PAF receptor antagonistic activity and/or inhibit the enzyme 5-lipoxygenase (5-LO).
SUMMARY OF THE INVENTION
2,5-Diaryl tetrahydrothiophenes, tetrahydrofurans and 1,3-diaryl cyclopentanes depicted in Formula 1 are inhibitors of PAF and/or 5-LO. They can be used for the treatment of pathological immune, inflammatory or cardiovascular disorders.
wherein:
and wherein:
W is independently selected from the group consisting of: —AN(OM)C(O)N(R
3
)R
4
, —AN(R
3
)C(O)N(OM)R
4
, —AN(OM)C(O)R
4
, —AC(O)N(OM)R
4
, —N(OM)C(O)N(R
3
)R
4
, —N(R
3
)C(O)N(OM)R
4
, —N(OM)C(O)R
4
, —C(O)N(OM)R
4
, —S(O)
n
R
3
, —S(O)
n
,CH
2
C(O)A, —S(O)
n
—CH
2
CH(OH)A, and —C(O)NHA, X is O, S, S(O) CR
5
;
Y
1
, Y
2
are independently selected from the group consisting of:
(a) hydrogen;
(b) lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, alkylaryl;
(c) —AN(OM)C(O)N(R
3
)R
4
, —AN (R
3
)C(O)N(OM)R
4
, —AN(OM)C(O)R
4
, —AC(O)N(OM)R
4
, —AN(R
3
)C(O)N(OM)R
4
, —C(O)N(OM)R
4
, and —C(O)NHR
3
;
wherein A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkyl-alkoxy, -lower alkyl-heterocycle-lower alkyl-, specifically including —CH
2
-heterocycle-CH
2
—, wherein the heterocycle is preferably furan or pyridine, more preferably, wherein the alkyl substituents are in the 2 and 5 positions of the furan ring, or the 2 and 6 positions of the pyridine ring, lower alkenyl, lower alkynyl, alkaryl or aralkyl; M is selected from hydrogen, a pharmaceutically acceptable cation, and a metabolically cleavable leaving group; R
1
and R
2
are independently selected from hydrogen, lower alkyl, preferably lower alkyl of 1-6 carbon atoms, e.g., methyl, cyclopropyl-methyl, ethyl, isopropyl, butyl, pentyl and hexyl, as well as C
3-8
, cycloalkyl, for example, cyclopentyl, halo lower alkyl, especially C
1-6
haloalkyl, for example, trifluoromethyl, halo, especially fluoro, —COOH; R
3
and R
4
are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl where one or more carbon atoms are replaced by S, N, or O, substituted or unsubstituted cycloalkyl of from 3 to 10 carbon atoms, substituted or unsubstituted cycloalkyl of from 3 to 10 carbon atoms, where one or more carbons are replaced by S, N, or O, preferably lower alkyl, alkenyl, preferably lower alkenyl, alkynyl, preferably lower alkynyl, aryl, preferably phenyl, aralkyl, preferably benzyl, alkaryl, preferably toluyl, C
1-6
alkoxy-C
1-10
alkyl, C
1-6
alkylthio-C
1-10
alkyl, C
1-6
hydroxy-C
1-6
alkyl, C
1-6
carbonyl-C
1-6
alkyl, C
1-6
amino- C
1-6
alkyl;
R
5
is selected from the group consisting of:
(a) hydrogen,
(b) lower alkyl, lower alkenyl, lower alkynyl, alkaryl;
(c) —AN(OM)C(O)N(R
3
)R
4
, —AN(R
3
)C(O)N(OM)R
4
, —AN(OM)C(O)R
4
, —AC(O)N(OM)R
4
, —AC(O)N(OM)R
4
, —AS(O)
n
R
3
, —AS(O)
n
—CH
2
C(O)R
3
, —AS(O)
n
—CH
2
CH(OH)R
3
, —AC(O)NHR
3
,
wherein each n is independently 0, 1 or 2; A is selected from the group consisting of substituted or unsubstituted lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, alkaryl or aralkyl; M is selected from hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group.
Preferred compounds of Formula I have the following structure:
wherein A, R
3
, and R
4
are all independently selected from the groups as defined above, X is N or C—OCH
3
and n is as defined above, and pharmaceutically acceptable salts thereof.
More preferred compounds of Formula I have the following structure:
wherein R
3
and R
4
are independently selected from the groups defined above, preferably R
3
and R
4
are independently selected from the preferred groups defined above; X is N or C—OCH
3
and m is 2-10, and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A. Description and Properties of the Preferred Compounds
The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic hydrocarbon of C
1
to C
10
, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
The term lower alkyl, as used herein, and unless otherwise specified, refers to a C
1
to C
6
saturated straight, branched, or cyclic (in the case of C
5-6
) hydrocarbon, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
The term alkenyl, as referred to herein, and unless otherwise specified, refers to a straight, branched, or cyclic (in the case of C
5-6
) hydrocarbon of C
2
to C
10
with at least one double bond.
The term lower alkenyl, as referred to herein, and unless
Biftu Tesfaye
Cai Xiong
Grewal Gurmit
Hussoin Sajjat
Shen T Y
Corless Peter F.
Covington Raymond
Edwards & Angell LLP
Kight John
Millennium Pharmaceuticals Inc.
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