Pyrrolotriazine derivatives having spla2-inhibitory activities

Details Pyrrolotriazine derivatives having spla2-inhibitory activities Pyrrolotriazine derivatives having spla2-inhibitory activities

2002-02-20

2004-09-07

Shah, Mukund (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S183000

Reexamination Certificate

active

06787545

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pyrrolotriazine derivative 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, arterial sclerosis, stroke, cerebral infarction, inflammatory colitis, psoriasis, heart failure, cardiac infarction, and the like. 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, W098/25609, W099/51605, W099/59999 and the like, or parabromophenacylbromide, mepacrine, manoaride, theilocien A
1
and the like.
DISCLOSURE OF INVENTION
The object of the present invention is to provide pyrrolotriazine derivatives having sPLA
2
inhibitory activity and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injuries, bronchial asthma, allergic rhinitis, rheumatoid arthritis, arterial sclerosis, stroke, cerebral infarction, inflammatory colitis, psoriasis, heart failure, and cardiac infarction.
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 hydrogen atom or a group containing 1 to 4 non-hydrogen atoms;
R
A
is a group represented by the formula:
wherein R
6
and R
7
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
;
R
3
is —(L
2
)—(acidic group) wherein L
2
is an acid linker having an acid linker length of 1 to 5;
R
4
is a hydrogen atom, C1 to C6 alkyl, aryl, a halogen or aralkyl, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
In more detail, the present invention relates to II) to XVII).
II) A compound represented by the formula (II):
wherein R
8
is —(CH
2
)
m
—R
12
wherein m is an integer from 1 to 6, and R
12
is (d) a group represented by the formula:
wherein a, c, e, n, q, and t are independently an integer from 0 to 2; R
13
and R
14
are independently selected from the group consisting of a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heterocyclic groups, and C1 to C10 haloalkyl; a is an oxygen atom or a sulfur atom; L
3
is —(CH
2
)v—, —C═C—, —C≡C—, —O—, or —S— wherein v is an integer from 0 to 2; &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 independently an integer from 0 to 5; g is an integer from 0 to 2; r is an integer from 0 to 7; and u is an integer from 0 to 4, or (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, aryl, and a halogen;
R
9
is C1 to C3 alkyl, C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio;
R
10
is -(L
4
)-R
15
wherein L
4
is represented by the formula:
wherein M is —CH
2
—, —O—, —N(R
18
)—, or —S—; R
16
and R
17
are independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R
18
is a hydrogen atom or C1 to C6 alkyl; and
R
15
is represented by the formula:
wherein R
19
is a hydrogen atom, a metal, or C1 to C10 alkyl; R
20
is independently a hydrogen atom or C1 to C10 alkyl; h is an integer from 1 to 8;
R
11
is a non-interfering substituent selected from the group consisting of a hydrogen atom, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C3 to C8 cycloalky, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxyalkyl, C2 to C12 alkyloxyalkyloxy, C2 to C12 alkylcarbonyl, C2 to C12 alkylcarbonylamino, C2 to C12 alkyloxyamino, C2 to C12 alkyloxyaminocarbonyl, C1 to C12 alkylamino, C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl, C1 to C8 alkylsulfinyl, C1 to C8 alkylsulfonyl, C2 to C8 haloalkyloxy, C1 to C8 haloalkylsulfonyl, C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl, —C(O)O(C1 to C8 alkyl), —(CH
2
)z-O—(C1 to C8 alkyl), benzyloxy, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, —(CONHSO
2
R
21
) wherein R
21
is C1 to C6 alkyl or aryl, formyl, amino, amidino, halogen, carboxy, —(CH
2
)z-COOH wherein z is an integer from 1 to 8, cyano, cyanoguanidyl, guanidino, hydrazide, hydrazino, hydroxy, hydroxyamino, nitro, phosphono, and —SO
3
H; and
R
B
is a group represented by the formula:
wherein Z is —NH
2
or —NHNH
2
, 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
13
or R
14
may be different from one another. When R
13
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
13
.
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
8
are represented by the formula:
wherein R
13
, R
14
, b, d, f, g, p, r, u, w, &agr;, &bgr;, and &ggr; are as defined above; L
5
is a bond, —CH
2
—, —C═C—, —C≡C—, —O—, or —S—.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R
13
or R
14
may bc different from one another. When R
13
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
13
.
IV) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to III), wherein said R
2
and R
9
are C1 to C3 alkyl or C3 to C4 cycloalkyl.
V) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to IV), wherein said L
2
and L
4
are —O—CH
2
—.
VI) A compound represented by the formula (III):
wherein R
22
is a group represented by the formula:
wherein L
5
is a bond, —CH
2
—, —C═C—, —C≡C—, —O—, or —S—; R
13
and R
14
are indepe

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