Naphthyl acetamides as sPLA.sub.2 inhibitors

Details Naphthyl acetamides as sPLA.sub.2 inhibitors Naphthyl acetamides as sPLA.sub.2 inhibitors

1998-06-09

2000-12-12

Killos, Paul J.

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

Organic compounds

Amino nitrogen containing

514617, 562466, C07C23300

Patent

active

061601756

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to novel naphthyl acetamides useful for inhibiting sPLA.sub.2 mediated release of fatty acids for conditions such as septic shock.
The structure and physical properties of human non-pancreatic secretory phospholipase A.sub.2 (hereinafter called, "sPLA.sub.2 ") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A.sub.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.sub.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.sub.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.sub.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.sub.2, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and etc.
The Communication to the Editor by Hayden G. Beaton, et al., Journal of Medicinal Chemistry, 1994, Vols. 37, No. 5 describes various novel (naphthylthio) methyl analogs of nonphospholipid sPLA.sub.2 inhibitors.
It is desireable to develop new compounds and treatments for sPLA.sub.2 induced disesase.
This invention is a novel use of compounds known as naphthyl acetamide compounds of the formula I. ##STR1## where R.sup.1, R.sup.2, R.sup.3 and x are as hereinafter defined. These naphthyl acetamide compounds are effective in inhibiting human sPLA.sub.2 mediated release of fatty acids.
This invention is also a novel class of naphthyl acetamide compounds having potent and selective effectiveness as inhibitors of human sPLA.sub.2.
This invention is also a pharmaceutical composition containing a naphthyl acetamide compound.
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 the naphthyl acetamide compounds of the invention.
The naphthyl 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, "alkynyl" employed alone or in combination with other terms means a straight or branched chain hydrocarbon having the stated number range of carbon atoms, and having a triple bond. The term includes groups such as acetylene, propyne, various butynl isomers and the like.
The term, "halo" means fluoro, chloro, bromo, or iodo.
The term, "non-interfering substituent", refers to radicals suitable for substitution at positions 2 or 3 of the phenyl ring. Illustrative non-interfering radicals are C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkynyl, C.sub.7 -C.sub.12 aralkyl, C.sub.7 -C.sub.12 alkaryl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloa

REFERENCES:
Chemical Abstracts, CA 55:22249b Caold.
J. Med. Chem. (1994), 37(5), 557-9 Coden: JMCMAR; Issn: 0022-2623.
Moszew, et al., Benzyl Derivatives of 1-Napthylacetic Acid as Plant Growth Regulators, Roczniki Chem. 1960, vol. 34, pp. 1387-1396.

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