Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-04-28
2003-11-11
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S112000
Reexamination Certificate
active
06645976
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel indolizine compounds useful for inhibiting sPLA
2
mediated release of fatty acids for conditions such as septic shock.
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). Such compounds would be 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, gout, glomerulonephritis, and etc.
U.S. Pat. No. 2,825,734 describes the preparation of 3-(2-amino-1-hydroxyethyl) indoles using 3-indole glyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30).
U.S. Pat. No. 2,890,233 describes several amide derivatives of 3-indoleacetic acids.
U.S. Pat. Nos. 3,196,162; 3,242,162; 3,242,163; and 3,242,193 (see, Col. 3, lines 55-60, Example 56) describe indolyl aliphatic acids together with their related esters and amides.
U.S. Pat. No. 3,271,416 describes indolyl aliphatic acids as sun screening agents and intermediates. These acids may be —NH
2
substituted.
U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
U.S. Pat. No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus. These compounds are stated to be analgesics.
U.S. Pat. No. 5,132,319 describes certain 1-(hydroxylaminoalkyl)indoles derivatives as inhibitors of leukotriene biosynthesis.
The article, “Structure-activity relationships leading to WAY-121,520, a tris aryl-type, indomethacin-based, phospholipase A
2
(PLA
2
)/leukotriene biosynthesis inhibitor”, by A Kreft, et. al.,
Agents and Actions, Special Conference
Issue Vol. 39 (1993),pp. C33-C35, ISSN 0065-4299, published by Birkhauser Verlag, Basel Switzerland; (Proceedings of the Sixth International Conference of the Inflammation Research Association, Sep. 20-24, 1992, at White Haven, Pa./USA, Guest Editors, D. W. Morgan and A. K. Welton) describes the inhibition of phospholipase A2 by indomethacin analogs. Indole compounds having benzyl and acidic substituents are described.
The article, (Short communication) entitled, “Indolizine derivatives with biological activity VI 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methylindolizine, benanserin structural analogue” by G M Cingolani, F. Claudi, M. Massi, and F. Venturi,
Eur. J. Med. Chem
. (1990) 25, pp. 709-712 publ. by Elsevier, Paris describes selected indolizines and their activity on smooth muscle.
The article, “Indolizine Analogues of Indomethacin” by C. Casagrande, A. Invernizzi, R. Ferrini, and G. Miragoli,
Il Farmaco
—Ed. Sc.—Vol. 26—fasc. 12, pp. 1059-1073, describes pharmacological tests with selected indomethacin analogues.
European Patent Application No. 0 519 353 (Application No. 92109968.5) describes indolizin derivatives which have pharmacological activities such as inhibitory activity on testosteron reductase.
European Patent Application No. 0 620 214 (Application No. 94302646.8 describes hydrazide derivatives of indoles having sPLA
2
inhibitory activity.
It is desirable to develop new compounds and treatments for sPLA
2
induced diseases.
SUMMARY OF THE INVENTION
This invention is a novel use of indolizine compounds having the nucleus and substituent numbering positions shown in the following formula:
Moreover, this invention is a class of novel indolizine compounds having two general configurations shown in structural formulae “A” and “B” below:
In configuration “A” an acetamide, acetic acid hydrazide or glyoxylamide moiety is present at the 1 position, a large (C
7
-C
30
) organic (e.g., carbocyclic) group is present at the 3 position and an acidic group is at the 7 or 8 positions.
In configuration “B” an acetamide, acetic aced hydrazide or glyoxylamide moiety is present at the 3 position, a large (C
7
-C
30
) organic (e.g., carbocyclic) group is present at the 1 position and an acidic group is at the 5 or 6 positions.
These indolizine-1-functional and indolizine-3-functional compounds of the invention are effective in inhibiting human sPLA
2
mediated release of fatty acids.
This invention is also a pharmaceutical composition containing indolizine-1-functional or indolizine-3-functional compounds selected from the group consisting of the novel indolizine compounds represented by the general formulae “A” and “B” and mixtures thereof.
This invention is also a method of preventing and treating septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, gout, glomerulonephritis, and related diseases by contact with a therapeutically effective amount of indolizine-1-functional and indolizine-3-functional compounds selected from the group consisting of the novel indolizine compounds represented by the general formulae “A” or “B” and mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The indolizine acetamides, acetic acid hydrazides (hereinafter called, “hydrazides”), and glyoxylamides of the invention employ certain defining terms as follows:
The term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.
The term, “alkenyl” employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number ange of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, “hydrocarbyl” means an organic group containing only carbon and hydrogen.
The term, “carbocyclic radical” refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms.
The term, “halo” means fluoro, chloro, bromo, or iodo.
The term, “heterocyclic radical”, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxali
Dillard Robert D.
Hagishita Sanji
Ohtani Mitsuaki
Benjamin Roger S.
Eli Lilly and Company
Kifle Bruck
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