Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-09
2004-06-29
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S248000, C544S234000, C544S344000
Reexamination Certificate
active
06756376
ABSTRACT:
DESCRIPTION
Tricyclic azaindolizine derivatives having an sPLA
2
-inhibitory activities
1. Technical Field
The present invention relates to tricyclic azaindolizine derivatives effective for inhibiting sPLA
2
-mediated fatty acid release.
2. Background Art
sPLA
2
(secretory phospholipase A
2
) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA
2
-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA
2
. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA
2
, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA
2
is considered to be extremely wide and, besides, its action is potent.
As examples of sPLA
2
inhibitors are described indole derivatives [EP-620214 (JP Laid-Open No. 010838/95), EP-620215 (JP Laid-Open No. 025850/95), EP-675110 (JP Laid-Open No. 285933/95), and WO 96/03376], indene derivatives (WO 96/03120), indolizine derivatives (WO 96/03383), naphtyl derivatives (WO 97/21664 and WO 9721716), and carbazole derivatives (WO 98/18464), pyrazine derivatives (WO99/51605), and the like.
DISCLOSURE OF INVENTION
The object of the present invention is to provide tricyclic azaindolizine derivatives having sPLA
2
-inhibitory activities and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, and cardiac infarction.
The present invention relates to I) a compound represented by the formula (I):
wherein E is N or C—R
4
;
when E is N, G is C—R
25
, or when E is C—R
4
, G is N;
R
1
is a group selected from (a) C1 to C20 alkyl, C1 to C20 alkenyl, C1 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, or (c) —(L
1
)—R
5
wherein L
1
is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R
5
is a group selected from the groups (a) and (b);
one of R
5
and R
4
is —(L
2
)-(acidic group) wherein L
2
is an acid linker having an acid linker length of 1 to 6 and the other is a hydrogen atom;
A ring is a group represented by the formula:
wherein R
2
is CONH
2
, CONHNH
2
or CSNH
2
;
R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
26
, and R
27
are each independently a hydrogen atom, or lower alkyl;
R
24
and R
25
are each independently a hydrogen atom, C1 to C6 alkyl, aryl, a halogen or aralkyl;
its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
In more detail, the present invention relates to II)-XVI).
II) A compound represented by the formula (II):
wherein R
24
and A ring are as defined above;
J is N or C—R
8
; when J is N, G is C—R
25
(wherein R
25
is as defined above), or when
J is C—R
8
, G is N;
R
6
is —(CH
2
)
m
—R
9
wherein m is an integer from 1 to 6, and R
5
is (d) a group represented by the formula:
wherein a, c, e, n, q, t and v are each independently 0, 1, or 2; R
10
and R
11
are each independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, and C1 to C10 haloalkyl; &agr; is an oxygen atom or a sulfur atom; &bgr; is —CH
2
— or —(CH
2
)
2
—; &ggr; is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are each independently an integer from 0 to 5; r is an integer from 0 to 7; and u is an integer from 0 to 4, or R
9
is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, phenyl, and a halogen;
one of R
7
and R
5
is hydrogen and the other is —(L
3
)—R
12
wherein L
3
is represented by the formula:
wherein M is —CH
2
—, —O—, —N(R
15
)—, or —S—; R
13
and R
14
are each independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R
15
is a hydrogen atom or C1 to C6 alkyl; and
R
12
is represented by the formula:
wherein R
16
is a hydrogen atom, a metal, or C1 to C10 alkyl; R
17
is independently a hydrogen atom or C1 to C10 alkyl; h is an integer from 1 to 8; its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R
10
or R
11
may be different from one another. When R
10
is a substituent on the naphthyl group, the substituent may substitute at any arbitrary position on the naphthyl group. —CH
2
— and —(CH
2
)
2
— in &bgr; may be substituted with R
10
.
III) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in I) or II), wherein R
1
and R
6
are represented by the formula:
wherein R
10
, R
11
, b, d, f, p, r, u, w, &agr;, &bgr;, and &ggr; are as defined above.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R
10
or R
11
may be different from one another. When R
10
is a substituent on the naphthyl group, the substituent may substitute at any arbitrary position on the naphthyl group. —CH
2
— and —(CH
2
)
2
— in &bgr; may be substituted with R
10
.
IV) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to III), wherein R
11
and R
6
are represented by the formula:
wherein R
10
, R
11
, d, p, u, and w are as defined above.
When the above p, u, and/or w are 2 or more, a plural number of R
10
or R
11
may be different from one another.
V) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to IV), wherein R
3
and R
7
are —O—(CH
2
)
m
—COOH (m is as defined above) or —O—CH(—R
30
)—COOH (R
30
is a hydrogen atom or C1-C3 alkyl).
VI) A compound represented by the formula (III):
wherein G, J, R
10
, R
30
, A ring, and m are as defined above; B ring is a benzene ring or a cyclohexane ring; R
38
is hydrogen atom or C1-C3 alkyl, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
VII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to VI), wherein said R
2
is —CONH
2
.
VIII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as claimed in any one of I) to VII), wherein R
18
, R
19
, R
20
, R
21
, R
22
, and R
23
are hydrogen atoms.
IX) A pharmaceutical composition containing a compound as claimed in any one of I) to VIII) as an active ingredient.
X) A pharmaceutical composition as claimed in IX), which is for inhibiting sPLA
2
.
XI) A pharmaceutical composition as claimed in IX), which is for inhibiting type I sPLA
2
.
XII) A pharmaceutical composition as claimed in IX), which is for inhibiting type II sPLA
2
.
XIII) A pharmaceutical composition as claimed in IX), which is for inhibiting type V sPLA
2
.
XIV) A pharmaceutical composition as claimed in IX), which is for inhibiting type X sPLA
2
.
XV) Use of a compound of any one of I) to VIII) for preparation of a pharmaceutical composition for treating
Adachi Makoto
Fuji Masahiro
Okada Tetsuo
Foley and Lardner
McKenzie Thomas
Raymond Richard L.
Shionogi & Co. Ltd.
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