Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2002-02-01
2004-01-06
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C546S086000, C546S087000, C546S089000, C546S093000, C546S094000, C546S023000, C544S063000, C544S234000, C544S230000, C544S232000, C514S292000, C514S294000, C514S248000, C514S211100, C514S215000, C540S542000, C540S548000
Reexamination Certificate
active
06673781
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 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 R
1
is a group selected from (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);
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;
A ring is a group represented by the formula:
wherein R
2
is CONH
2
or CONHNH
2
;
R
18
, R
19
, R
20
, R
22
, and R
23
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)-XIII).
II) A compound represented by the formula (II):
wherein R
24
, R
25
, and A ring are as defined above;
R
6
is —(CH)
m
—R
9
wherein m is an integer from 1 to 6, and R
9
is (d) a group represented by the formula:
wherein a, c, e, n, q, t and v are each independently an integer from 0 to 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, optionally substituted heteroaryl 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
8
is —(L
3
)—R
12
wherein L
3
is represented by the formula:
wherein M is —CH
2
—, —O—, —N(R
5
)—, 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 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 described in 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 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 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 hydrate thereof as described in any one of I) to IV), wherein said R
3
and R
7
are —O—(CH
2
)
m
—COOH (m is as defined above).
VI) A compound represented by the formula (III):
wherein R
10
, A ring, and m are as defined above,
its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
VII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as described 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 described in any one of I) to VII), wherein said R
18
, R
19
, R
20
, R
21
, R
22
, and R
23
are hydrogen atoms.
IX) A pharmaceutical composition containing a compound as described in any one of I) to VIII) as an active ingredient.
X) A pharmaceutical composition as described in IX), which is for inhibiting sPLA
2
.
XI) A pharmaceutical composition as described in IX), which is for treatment or prevention of inflammatory diseases.
XII) Use of a compound of any one of I) to VII) for preparation of a pharmaceutical composition for treating inflammatory diseases.
XIII) A method for treating a mammal, including a human, to alleviate the pathological effects of inflammatory diseases, which comprises administration to said mammal of a compound as described in any one of I) to VIII) in a pharmaceutically effective amount.
In the present specification, the term “alkyl” employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon
Adachi Makoto
Fuji Masahiro
Ogawa Tomoyuki
Ohtani Mitsuaki
Okada Tetsuo
Berch Mark L.
Habte Kahsay
Shionogi & Co. Ltd.
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