Substituted tricyclics

Details Substituted tricyclics Substituted tricyclics

2000-10-13

2004-03-30

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Carboxylic acid esters

Reexamination Certificate

active

06713645

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 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-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc.
It is desirable to develop new compounds and treatments for sPLA
2
induced diseases.
Alexander, et al., U.S. Pat. Nos. 3,939,177 and 3,979,391, disclose 1,2,3,4-tetrahydrocarbazoles useful as antibacterial agents.
SUMMARY OF THE INVENTION
This invention provides tricyclic compounds as depicted in the general formula (I) below:
wherein;
A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position;
one of B or D is nitrogen and the other is carbon;
Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at the 1-, 2-, or 3-position, or a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position;
is a double or single bond;
R
20
is selected from groups (a), (b) and (c) 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
(c) is the group —(L)—R
80
; where, —(L)— is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in —(L)— are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only, (v) carbon, hydrogen, and one sulfur only, and (vi) and carbon, hydrogen, and oxygen only; and where R
80
is a group selected from (a) or (b);
R
21
is a non-interfering substituent;
R1′ is —NHNH
2
, —NH
2
or —CONH
2
;
R
2′
is selected from the group consisting of —OH, and —O(CH
2
)
t
R
5′
where
R
5′
is H, —CN, —NH
2
, —CONH
2
, —CONR
9
R
10
—NHSO
2
R
15
; —CONHSO
2
R
15
, where R
15
is —(C
1
-C
6
)alkyl or —CF
3
; phenyl or phenyl substituted with —CO
2
H or —CO
2
(C
1
-C
4
)alkyl; and —(L
a
)— (acidic group), wherein —(L
a
)— is an acid linker having an acid linker length of 1 to 7 and t is 1-5;
R
3′
is selected from non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof;
provided that; when R
3′
is H, R
20
is benzyl and m is 1 or 2; R
2′
cannot be —O(CH
2
)
m
H; and
provided that when D is nitrogen, the heteroatom of Z is selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-position.
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 diluents, 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, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, 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 erythrematosis, 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.
This invention provides, in addition, a process for preparing compounds of formula II
wherein;
Z is cyclohexenyl, or phenyl,
R
21
is a non-interfering substituent;
R
1
is —NHNH
2
or —NH
2
;
R
2
is selected from the group consisting of —OH and —O(CH
2
)
m
R
5
where
R
5
is H, —CO
2
H, —CONH
2
, —CO
2
(C
1
-C
4
alkyl)
 where R
6
and R
7
are each independently —OH or —O(C
1
-C
4
)alkyl; —SO
3
H, —SO
3
(C1-C4 alkyl), tetrazolyl, —CN, —NH
2
, —NHSO
2
R
15
, —CONHSO
2
R
15
; where R
15
is —(C
1
-C
6
)alkyl or —CF
3
; phenyl or phenyl substituted with —CO
2
H or —CO
2
(C
1
-C
4
)alkyl where m is 1-3;
R
3
is H, —O(C
1
-C
4
)alkyl, halo, —(C
1
-C
6
)alkyl, phenyl, —(C
1
-C
4
)alkylphenyl; phenyl substituted with —(C
1
-C
6
)alkyl, halo, or —CF
3
; —CH
2
OSi(C
1
-C
6
)alkyl, furyl, thiophenyl, —(C
1
-C
6
)hydroxyalkyl, —(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkoxy(C
1
-C
6
)alkenyl; or —(CH
2
)
n
R
8
where R
8
is H, —CONH
2
, —NR
9
R
10
, —CN or phenyl where R
9
and R
10
are independently hydrogen, —CF
3
, phenyl, —(C
1
-C
4
)alkyl, —(C
1
-C
4
)

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