Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-29
2001-08-14
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06274616
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel prodrug form of sPLA
2
inhibitor having exceptionally high bioavailability.
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 April 5, pp. 5335-5338, 1989; 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 April 5, pp. 5768-5775, 1989; 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.
Glycolamide esters as prodrugs are described in the chemical literature, for example; (1) “Evaluation of Glycolamide Esters and Various Other Esters of Aspirin as True Aspirin Prodrugs” by Niels Mork Nielsen and Hans Bundgaard, J. Med. Chem. 1989, Vol. 32, pp. 727-734; and (2) “Glycolamide Esters as Biolabile Prodrugs of Carboxylic Acid Agents: Synthesis, Stability, Bioconversion, and Physicochemical Properties” by Niels Mork Nielsen and Hans Bundgaard, Journal of Pharmaceutical Sciences, Vol. 77, No. 4, April 1988.
U.S. Pat. No. 5,654,326 describes certain indole type sPLA
2
inhibitors. In particular, this patent exemplifies the methyl ester of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-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)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid N,N-diethylglycolamido ester; which is highly bioavailable by oral administration.
This invention is also a pharmaceutical formulation containing the novel compound of the invention.
This invention is also a method of inhibiting sPLA
2
mediated release of fatty acid by contacting sPLA
2
with the novel compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The 1H-indole-3-glyoxylamide Compound of the Invention
The compound of the invention((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid N,N-diethylglycolamido ester; is represented by the structural formula (I);
The N,N-diethylglycolamido ester (I) is an ester form of known sPLA
2
inhibitor ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, represented by the structural formula (II), below;
The compound of formula (II) is described in Example 4 of U.S. Pat. No. 5,654,326 (the disclosure of which is incorporated herein by reference) and European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ., Oct. 4, 1995).
Prodrugs are derivatives of therapeutic agents which have chemically or metabolically cleavable groups and become under physiological conditions known compounds of therapeutic effectiveness.
It is a discovery of this invention that the compound of formula (I) is highly bioavailable upon oral administration compared to other common ester type prodrugs.
Synthesis of the Compound of the Invention
The synthesis of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid N,N-diethylglycolamido ester (compound of formula I, supra.) uses as starting material ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, or a salt thereof (compound of formula II, supra.). This starting material may be prepared by the reaction schemes or method of Example 4 of U.S. Pat. No. 5,654,326 (the disclosure of which is incorporated herein by reference). Similar methods are shown in European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ., Oct. 4, 1995). Other methods well known and recorded in the chemical literature may also be used for preparing the starting material. Procedures useful for the synthesis of the starting material are shown in both Scheme 1 and Example 1 set out below:
To obtain the glyoxylamides substituted in the 4-position with an acidic function linked through an oxygen atom, the reactions outlined in scheme 1 are used (for conversions 1 through 5, see ref. Robin D. Clark, Joseph M. Muchowski, Lawrence E. Fisher, Lee A. Flippin, David B. Repke, Michel Souchet,
Synthesis,
1991, 871-878, the disclosures of which are incorporated herein by reference). The ortho-nitrotoluene, 1, is readily reduced to the 2-methylaniline, 2, using palladium on carbon as catalyst. The reduction can be carried out in ethanol or tetrahydrofuran (THF) or a combination of both, using a low pressure of hydrogen. The aniline, 2, on heating with di-tert-butyl dicarbonate in THF at reflux temperature is converted to the N-tert-butyloxycarbonyl derivative, 3, in good yield. The dilithium salt of the dianion of 3 is generated at −40 to −20° C. in THF using sec-butyllithium and reacted with the appropriately substituted N-methoxy-N-methylalkanamide. This product, 4, may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 1,3-unsubstituted indole 5. The 1,3-unsubstituted indole 5 is reacted with sodium hydride in dimethylformamide at room temperature (20-25° C.) for 0.5-1.0 hour. The resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0-100° C., usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6. This indole, 6, is O-demethylated by stirring with boron tribromide in methylene chloride for approximately 5 hours (see ref. Tsung-Ying Shem and Charles A Winter,
Adv. Drug Res.,
1977, 12, 176, the disclosure of which is incorporated herein by reference). The 4-hydroxyindole, 7, is alkylated with an alpha bromoalkanoic acid ester in dimethylformamide (DMF) using sodium hydride as a base, with reactions conditions similar to that described for the conversion of 5 to 6. The &agr;-((indol-4-yl)oxy)alkanoic acid ester, 8, is reacted with oxalyl chloride in methylene chloride to give 9, which is not purified but reacted directly with ammonia to give the glyoxamide 10. This product is hydrolyzed using 1N sodium hydroxide in methanol. The final glyoxylamide, 11, is isolated either as the free carboxylic acid or as its sodium salt or in both forms.
REFERENCES:
patent: 5641800 (1997-06-01), Bach et al.
patent: 5654326 (1997-08-01), Bach et al.
Denney Michael L
Morin, Jr. John M
Sall Daniel J
Sawyer Jason S
Benjamin Roger S.
Eli Lilly and Company
Reamer James H.
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