Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-22
2004-03-09
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, C514S256000, C544S338000, C544S344000, C544S380000
Reexamination Certificate
active
06703385
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a tricyclic compound effective for inhibiting sPLA
2
-mediated fatty acid release.
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.
Examples of sPLA
2
inhibitors include compounds described in EP-620214 (JP Laid-Open No. 010838/95, U.S. Pat. No. 5,578,634), EP-620215 (JP Laid-Open No. 025850/95, U.S. Pat. No. 5,684,034), EP-675110 (JP Laid-Open No. 285933/95, U.S. Pat. No. 5,654,326), WO 96/03120 (JP Laid-Open No. 505336/98), WO 96/03376 (JP Laid-Open No. 503208/98, U.S. Pat. No. 5,641,800), WO 96/03383 (JP Laid-Open No. 505584/98), WO 97/21664 (EP-779271), WO 97/21716 (EP-779273), WO 98/18464 (EP839806), WO98/24437(EP846687), WO98/24756, WO98/24794, WO98/25609, WO99/51605, WO99/59999 and the like, or parabromophenacylbromide, mepacrine, manoaride, theilocien A and the like.
DISCLOSURE OF INVENTION
The object of the present invention is to provide tricyclic compounds having sPLA
2
inhibitory activity and being useful for treatment or prevention of inflammatory diseases.
The present invention relates to I) a compound represented by the formula (I):
wherein R
1
is (a) C1 to C20 alkyl, C2 to C20 alkenyl, C2 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);
R
2
is a group represented by the formula:
wherein R
18
and R
19
are independently a hydrogen atom, C1 to C3 alkyl or a halogen; G
1
and G
2
are independently an oxygen atom or a sulfur atom; and G
3
is —NH
2
or —NHNH
2
;
Q
1
is a nitrogen atom or C—R
4
;
one of R
3
and R
4
is —(L
2
)-(acidic group) wherein L
2
is an acid linker having an acid linker length of 1 to 5 and the other is a hydrogen atom, provided that when Q
1
is nitrogen, R
3
is —(L
2
)-(acidic group) wherein L
2
and acidic group are as defined above;
R
21
and R
22
are independently a hydrogen atom, C1 to C6 alkyl, aryl, a halogen or aralkyl;
X is —CR
23
R
24
—, O, or S, wherein R
23
and R
24
are independently a hydrogen atom or C1 to C6 alkyl;
Y is a bond or —CR
25
R
26
—, wherein R
25
and R
26
are independently a hydrogen atom or C1 to C6 alkyl;
Z is CHR
A
, CR
A
, N, or NR
B
—, wherein R
A
is a hydrogen atom, alkyloxycarbonyl, or carboxy; R
B
is a hydrogen atom or acyl;
a broken line ( - - - ) represents the presence or absence of a bond,
its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
In more detail, the present invention relates to II)-XIV).
II) A compound represented by the formula (II):
wherein R
2
, R
21
, R
22
, X, Y, Z, and - - - are as defined above;
R
6
is —(CH
2
)
m
—R
9
wherein m is an integer from 0 to 6, and R
9
is (d) a group represented by the formula:
wherein a, c, e, n, q, t and v are independently an integer from 0 to 2; R
10
and R
11
are 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 5; f, p, and w are 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; Q
2
is a nitrogen atom or C—R
8
;
one of R
7
and R
8
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 independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R
15
is 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; R
35
is C1-C5 alkyl or phenyl; h is an integer from 1 to 8; and the other is hydrogen atom;
provided that R
7
is —(L
3
)—R
12
, wherein L
3
and R
12
are as defined above, when Q
2
is a nitrogen atom,
its prodrug, their pharmaceutically acceptable salt, or solvate 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 be substituted 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 solvate thereof as described in above I) or II), wherein said 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 be substituted 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 solvate thereof as described in any one of I) to III), wherein said R
1
and R
6
are represented by the formula:
wherein R
10
, R
11
, 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 solvate thereof as described in any one of I) to IV), wherein said R
3
and R
7
are —O—(CH
2
)
g
—COOH (g is an integer from 1 to 6).
VI) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to V), wherein said R
2
is —COCONH
2
.
VII) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to VI), wherein said both R
21
and R
22
are hydrogen atoms.
VIII) A compound represented by the formula (III):
wherein R
10
, X, Y, Z, g, and - - - are as defined above, Q
3
is a nitrogen atom, or CH,
its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
IX) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to VIII), wherein said (X, Y, Z) is (CH
2
, CH
2
, CH), (CH
2
, CH
2
, CH
2
), (CH
2
, CH
2
, NR
B
), (S, single bond, CR
A
), or (S, single bond, CH), wherein R
A
and R
B
are as defined above.
X) A pharmaceutical composition containing a
Adachi Makoto
Fuji Masahiro
Ogawa Tomoyuki
Ohtani Mitsuaki
Foley & Lardner
Patel Sudhaker B.
Raymond Richard L.
Shionogi & Co. Ltd.
LandOfFree
Tricyclic compounds having sPLA2-inhibitory activities does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tricyclic compounds having sPLA2-inhibitory activities, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tricyclic compounds having sPLA2-inhibitory activities will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3191039