Pyrrolo[1,2-b] pyridazine derivatives having sPLA2...

Details Pyrrolo[1,2-b] pyridazine derivatives having sPLA2... Pyrrolo[1,2-b] pyridazine derivatives having sPLA2...

2000-10-18

2002-10-29

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S248000, C544S119000, C544S235000, C548S517000, C548S527000, C548S557000

Reexamination Certificate

active

06472389

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pyrrolo[1,2-b]pyridazine 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, 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.
There are known, as examples of sPLA
2
inhibitor, indole derivatives in EP-620214 (JP Laid-Open No. 010838/95), EP-620215 (JP Laid-Open No. 025850/95), EP-675110 (JP Laid-Open No. 285933/95), WO 96/03376, and WO 99/00360; indene derivatives in WO 96/03120; indolizine derivatives in WO 96/03383; naphthalene derivatives in WO 97/21664 and WO 97/21716; tricyclic derivatives in WO 98/18464; pyrazole derivatives in WO 98/24437; phenylacetamide derivatives in WO 98/24756; phenyl glyoxamide derivatives in WO 98/24794; pyrrole derivatives in WO 98/25609.
DISCLOSURE OF INVENTION
The present invention provides pyrrolo[1,2-b]pyridazine derivatives having sPLA
2
inhibiting activity and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, psoriasis, cardiac failure, 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) C6 to C20 alkyl, C6 to C20 alkenyl, C6 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, and (c) —(L
1
)—R
6
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
6
is a group selected from the groups (a) and (b);
R
2
is hydrogen atom or a group containing 1 to 4 non-hydrogen atoms;
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
and R
5
are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent(s), heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent(s); and
R
A
is a group represented by the formula:
 wherein L
7
is a divalent linker group selected from a bond or a divalent group selected from —CH
2
—, —O—, —S—, —NH—, or —CO—, R
27
and R
28
are independently hydrogen atom, C1 to C3 alkyl or a halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is —NH
2
or —NHNH
2
; the prodrugs thereof, or their pharmaceutically acceptable salts; or their solvates.
In more detail, the present invention relates to ii) a compound represented by the formula (II):
where R
7
is —(CH
2
)m—R
2
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 a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C1 0 haloalkyl, &agr; is an oxygen atom or a sulfur atom, L
5
is —(CH
2
)v—, —C═C—, —C≡C—, —O—, or —S—, 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 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, aryl, and a halogen;
R
8
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
9
is —(L
3
)—R
15
wherein L
3
is represented by the formula:
 wherein M is —CH
2
—, —O—, —N(R
24
)—, or —S—, R
16
and R
17
are independently hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R
24
is hydrogen atom or C1 to C6 alkyl, and R
15
is represented by the formula:
 wherein R
18
is hydrogen atom, a metal, or C1 to C10 alkyl, R
19
is independently hydrogen atom, or C1 to C10 alkyl, and t is an integer from 1 to 8;
R
10
and R
11
are independently hydrogen atom or a non-interfering substituent selected from C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C7 to C12 alkaryl, C3 to C8 cycloalkyl, 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
25
), —CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, —(CH
2
)
z
—CO
2
H, cyano, cyanoguanidinyl, guanidino, hydrazido, hydrazino, hydrazide, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO
3
H, thioacetal, thiocarbonyl, or carbonyl, R
25
is C1 to C6 alkyl or aryl, z is an integer from 1 to 8; and R
B
is a group represented by the formula:
 wherein Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
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.
iii) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in above i) or ii), wherein said R
1
and R
7
are independently represented by the formula:
wherein R
13
, R
14
, b, d, f, g, p, r, u, w, &agr;, &bgr;, and &ggr; are the same as defined above, L
6
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 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.
iv) A compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of i) to iii), wherein R
2
and R
8
are C1 to C3 alkyl or C3 to C4 cycloalkyl.
v) A compound, the prodrugs thereof, or their pharmaceutically a

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