Substituted tricyclics

Details Substituted tricyclics Substituted tricyclics

2001-06-20

2002-09-10

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S428000

Reexamination Certificate

active

06448284

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel substituted tricyclic organic compounds useful for inhibiting sPLA
2
mediated release of fatty acids for conditions such as septic shock.
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. 5335-5338, 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 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 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-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc.
It is desirable to develop new compounds and treatments for sPLA
2
induced diseases.
SUMMARY OF THE INVENTION
This invention provides tricyclic compounds as depicted in the general formula (I) below:
wherein;
Z is —C═O, —CH
2
,
A is —O(CH
2
)
f
—; —NH(CH
2
)
f
—; —S(CH
2
)
f
—; —(CH
2
)
f
, where f is 1 to 3; —CH═CH—;
 or —(L
a
)—, where —(L
a
)—is an acid linker having an acid linker length of 1 to 7;
R
1′
is —NHNH
2
or —NH
2
;
R
2′
is —CO
2
H; —CO
2
(C
1
-C
4
)alkyl;
 where R
6
and R
7
are each independently —OH or —O(C
1
-C
4
)alkyl; tetrazolyl; —CONR
9
R
10
, where R
9
and R
10
are independently hydrogen, —CF
3
, —(C
1
-C
4
)alkyl, phenyl or —(C
1
-C
4
)alkylphenyl; —SO
2
R
15
; —CONHSO
2
R
15
, where R
15
is hydrogen, aryl, —(C
1
-C
6
)alkyl or —CF
3
; or phenyl substituted with —CO
2
H or —CO
2
(C
1
-C
4
)alkyl;
R
3′
is selected from non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents;
R
4′
is selected from groups (a) and (b) where;
(a) is —(C
5
-C
20
)alkyl, —(C
5
-C
20
)alkenyl, —C
5
-C
20
)alkynyl, carbocyclic radicals, or heterocyclic radicals, or
(b) is a member of (a, substituted with one or more independently selected non-interfering substituents;
or a pharmaceutically acceptable racemate, solvate, optical isomer, prodrug derivative or salt thereof.
These substituted tricyclics are effective in inhibiting human sPLA
2
mediated release of fatty acids.
This invention is also a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluteness, carriers and excipients.
This invention is also a method of inhibiting sPLA
2
comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.
According to a further aspect of the present invention, there is provided a method of selectively inhibiting sPLA
2
in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula I.
This invention, further provides a compound of Formula I for use as a medicament in the treatment of inflammatory diseases such as sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, asthma, rheumatoid arthritis, osteoarthritis, acute bronchitis, chronic bronchitis, Inflammatory Bowel Disease, apoptosis, stroke, cystic fibrosis, allergic rhinitis, acute bronchiolitis, chronic bronchiolitis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with “vasculitic syndromes”, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing) miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, systemic lupus eryzhrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA
2
mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, 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, tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term “alkyl” includes —(C
1
-C
2
)alkyl, —(C
1
-C
4
)alkyl, —(C
1
-C6)alkyl, —(C
5
-C
14
)alkyl, and —(C
1
-C
10
)alkyl.
The term “alkenyl” as used herein represents an olefinically unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains.
The term “alkynyl” denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes.
The term “halo” means chloro, fluoro, bromo or iodo.
The term “—(C
1
-C
4
)alkoxy”, as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups, attached to the remainder of the molecule by the oxygen atom.
The term “phenyl(C
1
-C
4
)alkyl” refers to a straight or branched chain alkyl group having from one to four carbon atoms attached to a phenyl ring which chain is attached to the remainder of the molecule. Typical phenylalkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, and phenylbutyl.
The term “aryl” means an aromatic carbocyclic structure having six to ten carbon atoms. Examples of such ring structures are phenyl, naphthyl and the like.
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

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