Indene-1-acetamide sPLA2 inhibitors

Details Indene-1-acetamide sPLA2 inhibitors Indene-1-acetamide sPLA2 inhibitors

1994-07-21

2001-04-10

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S561000, C562S428000, C562S441000

Reexamination Certificate

active

06214876

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel indene 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, 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. 3,449,363 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 published by Elsevier, Paris describes selected indolizines and their activity on smooth muscle.
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.
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 indene compounds having the nucleus and substituent numbering shown below:
Moreover, the indene compounds of the invention have the general configurations shown in structural formulae “G” below:
In formula “G” 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 is attached to the indene nucleus with a single, or optionally, a double bond; an acidic group is substituted at the 6 or 7 position, and a small organic group is substituted at the 2 position.
This invention is also a pharmaceutical composition containing indene-1-functional compounds represented by the general formulae “G” 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, and related diseases by contact with a therapeutically effective amount of indene-1-functional compounds selected from the group consisting of the novel indene compounds represented by the general formulae “G”.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The indene 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 range 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, “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 quinoxalinyl.
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. Typical carbocyclic radicals are benzylidene, cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),
where n is a number from 1 to 8.
The term, “non-interfering substituent”, refers to radicals suitable for substitution at positions 4, 5, 6, and/or 7 on the indene nucleus (as hereinafter depicted in Formula I) and radical(s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
alkynyl, C
7
-C
12
aralkyl, C
7
-C
12
alkaryl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C
1
-C
6
alkoxy, C
1
-C
6
alkenyloxy, C
1
-C
6
alkynyloxy, C
2
-C
12
alkoxyalkyl, C
2
-C
12
alkoxyalkyloxy, C
2
-C
12
alkylcarbonyl, C
2
-C
12
alkylcarbonylamino, C
2
-C
12
alkoxyamino, C
2
-C
12
alkoxyaminocarbonyl, C
1
-C
12
alkylamino, C
1
-C
6
alkylthio, C
2
-C
12
alkylthiocarbonyl, C
1
-C
6
alkylsulfinyl, C
1
-C
6
alkyl

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