Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-17
2001-08-14
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S144000
Reexamination Certificate
active
06274578
ABSTRACT:
BACKGROUND OF THE INVENTION
The structure and physical properties of human non-pancreatic secretory phospholipase A
2
(hereinafter called, “sPLA
2
”) has been thoroughly described in two articles, namely, “Cloning and Recombinant Expression of Phospholipase A
2
Present in Rheumatoid Arthritic Synovial Fluid” by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.;
The Journal of Biological Chemistry
, Vol . 264, No. 10, Issue of Apr. 5, 1989; pp. 5335-5338, and “Structure and Properties of a Human Non-pancreatic Phospholipase A
2
” by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake;
The Journal of Biological Chemistry
, Vol. 264, No. 10, Issue of Apr. 5, 1989; pp. 5768-5775, the disclosures of which are incorporated herein by reference.
It is believed that sPLA
2
is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA
2
mediated release of fatty acids (e.g., arachidonic acid) and are highly bioavailable in mammals, especially humans. Such compounds are of value in general treatment of conditions induced and/or maintained by overproduction of sPLA
2
; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc.
Therapeutic agents that may be given orally are, in general, greatly preferred and have enhanced commercial potential because of their inherent ease of use.
U.S. Pat. No. 5,654,326 describes certain indole type sPLA
2
inhibitors and related ester prodrugs. In particular, this patent exemplifies the methyl ester of ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid.
It is desirable to develop more highly available sPLA
2
inhibitors, particularly those suitable for oral administration.
SUMMARY OF THE INVENTION
This invention is the novel compound, ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid N-morpholino ethyl ester; which is highly bioavailable by oral administration.
This invention is a pharmaceutical formulation comprising ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid, N-morpholino ethyl ester in combination with a carrier or diluent.
REFERENCES:
patent: 5654326 (1997-08-01), Bach
patent: 6140327 (2000-10-01), Sawyer
patent: 6177426 (2001-01-01), Denney
patent: WO 98/42343 (1998-10-01), None
patent: WO 99/21559 (1999-05-01), None
patent: WO 99/25339 (1999-05-01), None
Denny et al,Chemical Abstracts, vol. 130, No. 311, 696 (1999).*
Lipsky, James J., The Lancet, vol. 348, pp. 1357-1359, Nov. 16, 1996.
Denney Michael Lyle
Morin John Michael
Sall Daniel Jon
Sawyer Jason Scott
Benjamin Roger S.
Eli Lilly and Company
Ramsuer Robert W.
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