Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-08
2001-04-24
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S200000, C540S354000, C540S358000, C540S359000, C540S360000, C540S364000
Reexamination Certificate
active
06221860
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel compounds, pharmaceutical compositions thereof, and their use as anti-inflammatory agents in mammals.
BACKGROUND OF THE INVENTION
Coenzyme A-independent transacylase (CoA-IT) is an enzyme responsible for the movement of arachidonate between phospholipid molecular species of inflammatory cells. CoA-IT removes arachidonate from the sn-2 position of 1-acyl-containing phospholipids, such as 1-acyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-acyl-2-arachidonoyl-GPC). It then transfers that arachidonate to a suitable lyso-phospholipid acceptor, such as 1-alkyl-2-lyso-GPC and 1-alkenyl-2-lyso-sn-glycero-3-phospho-ethanolamine (Sugiura et al., J. Biol. Chem. 262: 1199-1205 (1987); Kramer and Deykin, Biol. Chem. 258: 13806-13811 (1983); Chilton et al., J. Biol. Chem. 258: 7268-7271 (1983)). This activity is selective for 20 carbon fatty acyl groups and is the mechanism by which inflammatory cells move arachidonate into specific phospholipid pools prior to its release (Winkler and Chilton, Drug News Perspec. 6: 133-138 (1993); Snyder et al., J. Lipid Mediat. 10: 25-31 (1994)).
Further, a method which antagonises the production of free arachidonic acid, its metabolites or PAF will have clinical utility in the treatment of a variety of allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria, as well as reperfusion injury and other disease involving lipid mediators of inflammation. Many published patent applications or issued U.S. patents exist which describe various compounds having utility as PAF or eicosanoid antagonists. Such patents include U.S. Pat. Nos. 4,788,205, 4,801,598, 4,981,860, 4,992,455, 4,983,592, 5,011,847, 5,019,581 and 5,002,941.
Accordingly, as CoA-IT is involved in arachidonic acid and phospholipid metabolism, inhibition of such an enzyme would be useful for the treatment of inflammatory, allergic and hypersecretory conditions or disease states caused thereby. Therefore, a method by which CoA-IT is inhibited will consequently and preferentially decrease the arachidonate content of 1-alkyl- and 1-alkenyl-linked phospholipids and will therefore decrease the production of pro-inflammatory mediators such as free arachidonic acid, prostaglandins, leukotriene and PAF during an inflammatory response.
There remains a need for treatment, in this field, for compounds which are CoA-IT inhibitors, i.e. compounds which are capable of inhibiting, or interfering with this enzyme and thereby decrease production of the pro-inflammatory mediators.
SUMMARY OF THE INVENTION
This invention also relates to a method of treating or reducing inflammation in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound or composition of Formula (I).
This invention also relates to a method of treating disease or disorders mediated by lipid inflammatory mediators, free arachidonic acid, its metabolites and/or PAF by administering to a patient in need thereof, an effective amount of a compound of Formula (I).
This invention also relates to a method of treating disease or disorders mediated by Coenzyme A independent transacylase (CoA-IT) by administering to a patient in need thereof, an effective amount of a compound or composition of Formula (I).
This invention relates to the novel compounds of Formula (Ia) and pharmaceutically acceptable salts thereof. The present invention also provides for a pharmaceutical composition comprising a pharmaceutical acceptable carrier or diluent and a compound of Formula (Ia), or pharmaceutically acceptable salt thereof.
One aspect of the present invention are the compounds represented by a structure having the formula:
wherein
Y is NH;
X is O or S(O)m;
m is 0 or an integer having a value of 1, or 2;
R
3
is optionally substituted triphenylmethyl;
R
4
is optionally substituted C
1-10
alkyl, (CR
10
R
20
)
n
C(R
10
)=C(R
7
)
2
, or (CR
10
R
20
)n—C≡C—R
5
;
n is an integer having a value of 1 to 4;
R
10
and R
20
are independently hydrogen or C
1-4
alkyl;
R
5
is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C(O)
2
R
6
, or C(O)R
6
wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl moieties may be optionally substituted;
R
6
is C
1-10
alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, or heterocyclicalkyl, all of which may be optionally substituted:
R
7
is independently hydrogen. C
1-10
alkyl, aryl, arylalkyl, heteroaryl. heteroarylalkyl, heterocyclic, or heterocyclicalkyl, all of which may be optionally substituted;
or a pharmaceutically acceptable salt thereof.
REFERENCES:
patent: 4647558 (1987-03-01), Ponsford et al.
Chemical Abstracts 112:76713, “Synthesis of Novel 3-Formamido-3-(Acylamino)monobactams”, Apr. 1989.
Bondinell William E.
Winkler James David
Dinner Dara L.
Kinzig Charles M.
Krass Frederick
SmithKline Beecham Corporation
Venetianer Stephen
LandOfFree
Beta-lactam inhibitors of CoA-IT does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Beta-lactam inhibitors of CoA-IT, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Beta-lactam inhibitors of CoA-IT will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2469160