1H-indole-3-acetamide sPLA2 inhibitors

Details 1H-indole-3-acetamide sPLA2 inhibitors 1H-indole-3-acetamide sPLA2 inhibitors

1997-10-31

2001-06-26

Oswecki, Jane (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S127000, C548S252000, C548S253000, C548S254000, C548S483000, C548S494000, C548S495000, C548S496000

Reexamination Certificate

active

06252084

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel 1H-indole-3-acetamides useful for inhibiting sPLA
2
mediated release of fatty acids for conditions such as septic shock.
2. Background Information
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, pp. 5335-5333, 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 Apr. 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 phosphoilpids. 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.
Indolyl-3 substituted compounds having glyoxylamide functionality are described in U.S. Pat. No. 2,825,734. This patent related to a process for converting glyoxyamides to 3-(2-amino-1-hydroxyethyl) indoles.
U.S. Pat. No. 3,271,416 describes indolyl aliphatic acids as sun screening agents and intermediates. These acids may be —NH
2
substituted (see, definition of M in claim
1
) and require 5- or 6-position substitution with nitrogen or sulfur functional groups.
U.S. Pat. No. 2,890,223 and the article “The Synthesis of Tryptamines Related to Serotonin”, by Elliott Shaw, J. Am. Chem. Soc., Vol. 77, 1955, (pp. 4319-4324) describe several amide derivatives of 3-indoleacetic acids. These compounds are used in the preparation of 5-lower alkoxy tryptamines and are stated to have utility for influencing serotonin related functions in the brain. In addition, the article, “Recherches en serie indolique. VI sur tryptamines substituees”, by Marc Julia, Jean Igolen and Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060-1068, describes certain indole-3-acetamides and their conversion to tryptamine derivatives.
Selected indoyl amide type compounds have been described in the literature for the treatment of arthritic disorders. Thus, 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 salts, esters, and amides, . These compounds are closely related to compounds like indomethacin, have a substituted benzyl group at the 1 position and likely achieve their beneficial action being cyclooxygenase inhibitors.
The article, “Some Analogs of 1-p-Chlorobenzyl-5-methylindole-3-acetic Acid”, by E. Walton, et al., J. Med. Chem., Vol. 11, 1968, pp. 1252-1255, describes the preparation of isomeric methyl 3-(1-p-chlorobenzyl-5-methoxy-3-methylindole-2) propionate.
The article, “2-Aryl-3-Indoleacetamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)” by E. Romeo, et al. The Journal of Pharmacology and Experimental Therapeutics Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3-indolacetamides having research applications in mammalian central nervous systems.
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 the class of compounds known as 1H-indole-3-acetamides to inhibit human sPLA
2
mediated release of fatty acids.
This invention is also novel classes of 1H-indole-3-acetamides having potent and selective effectiveness as inhibitors of human sPLA
2
.
This invention is also pharmaceutical compositions containing the 1H-indole-3-acetamides of the invention.
This invention is also a method of preventing and treating septic shock using the 1H-indole-3-acetamides of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The 1H-indole-3-acetamides 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, “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, pryidinyl, dipyridylyl. phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, 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 are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, biphenyl, indenyl, acenaphthylenyl, and anthracenyl.
The term, “non-interfering substituent”, refers to radicals suitable for substitution at positions 4, 5, 6, and/or 7 on the indole 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, tolulyl, 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
2
-C
12
alkylamino, C
1
-C
6
alkylthio, C
2
-C
12
alkylthiocarbonyl, C
1
-C
6
alkylsulfinyl, C
1
-C
6
alkylsulfonyl, C
1
-C
6
haloalkoxy, C
1
-C
6
haloalkylsulfonyl, C
1
-C
6
haloalkyl, C
1
-C
6
hydroxyalkyl, —C(C)O(C
1
-C
6
alkyl), —(CH
2
)
n
—O—(C
1
-C
6
alkyl), benzyloxy, phenoxy, phenylthio, (—CONHSO
2
R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, —(CH
2
)
n
—CO
2
H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO
3
H, thioacetal, thiocarbonyl, trifluoromethyl, and C
1
-C
6
carbonyl; where n is from 1 to 8.
The term, “amine”, includes primary, secondary and tertiary amines.
The term, “hydrocarbyl” means an organic group containing only carbon and hydrogen.
The term, acidic group, means an organic group which when attached to an indole nucleus, through suitable connecting

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