Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-15
2002-05-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S196000, C544S208000, C544S209000, C544S182000, C514S242000
Reexamination Certificate
active
06384032
ABSTRACT:
BACKGROUND OF THE INVENTION
Cytokines such as interleukin-12 (IL-12) mediate the acute phase response to inflammatory stimuli, enhance the microbicidal functions of macrophages and other cells, and promote specific lymphocyte responses. See, e.g., Fearon and Locksley, Science 272:50 (1996).
Recently, in vivo studies revealed that inhibition of IL-12 production has therapeutic effects against inflammatory disorders such as sepsis (Zisman et al., Eur. J. Immunol. 27:2994 (1997)), collagen induced arthritis (Malfait et al., Clin. Exp. Immunol. 111:377 (1998)), established colitis (U.S. Pat. No. 5,853,697), experimental autoimmune encephalomyelitis (Leonard et al., J. Exp. Med. 181:381 (1995)), experimental autoimmune uveoretinitis (Yokoi et al., Eur. J. Immunol. 27:641 (1997)), psoriasis (Turka et al., Mol. Med. 1:690 (1995)), and cyclophosphamide induced diabetes (Rothe et al., Diabetologia 40:641 (1997)).
Production of IL-12 can be inhibited by anti-IL-12 antibodies. However, long term treatments of chronic diseases with such antibodies are expensive. Also, antibodies can be unstable after administration. Thus, there exists a need for use of small non-protein compounds instead of anti-IL-12 antibodies to inhibit the production of IL-12.
SUMMARY OF THE INVENTION
An aspect of this invention relates to a compound of formula (I):
X is triazinyl. L
1
is —A
1
—B
1
—, in which —A
1
— is —(CH(R
a
))
m
—, —O—, —S—, or —N(R
b
)— and —B
1
— is —(CH(R
c
))
n
— or a bond. Each of R
a
and R
c
, independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. R
b
is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Each of m and n, independently, is 1-8. W is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. L
2
is —A
2
—B
2
—, in which A
2
is a bond, —N(R
1
)—, or —(—C(R
2
)(R
3
)—)
p
—, and B
2
is a bond, —N═C(R
4
)—, —C(R
5
)═N—, —C(R
6
)═C(R
7
)—, —N(R
8
)═N(R
9
)—, —N(R
10
)—C(R
11
)(R
12
)—, —O—C(R
13
)(R
14
)—, —CO—C(R
15
)(R
16
)—, —CO—N(R
17
)—, —N(R
18
)—CO—, —CO—, —CO—O—, —CO—S—, —S—C(R
19
)(R
20
)—, —CS—C(R
21
)(R
22
)—, —CS—N(R
23
)—, —N(R
24
)—CS—, —CS—, —SO
2
—, provided that —A
2
—B
2
— cannot be a bond. —A
2
—B
2
— together is —O—, —S—, —(—O—(CH
2
)
q
—O—)
r
—, —(—N(R
25
)—(CH
2
)
8
—CO—)
t
—, or —(—N(R
26
)—(CH
2
)
u
—N(R
27
)—)
v
—. Each of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
, and R
27
, independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxyalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Each of p, q, r, s, t, u, and v, independently, is 1, 2, or 3. Y is —R′—L′—R″ wherein R′ is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which optionally being substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino. L′ is a bond, —O—, —S—, —N(R
28
)—, —N(R
29
)—CO—, —CO—N(R
30
)—, —CO—O—, or —O—CO—. Each of R
28
, R
29
, and R
30
, independently, is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R″ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxyalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. Z is morpholinyl which is optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy.
Another aspect of this invention relates to a method of inhibiting IL-12 production, which includes administering to a patient in need thereof an effective amount of a compound of formula (I), supra. X is triazinyl. L
1
is —A
1
—B
1
—, in which —A
1
— is —(CH(R
a
))
m
—, —O—, —S—, or —N(R
b
)— and —B
1
— is —(CH(R
c
))
n
— or a bond. Each of R
a
and R
c
, independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, R
b
is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Each of m and n, independently, is 1-8. W is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. L
2
is —A
2
—B
2
—, in which A
2
is a bond, —N(R
1
)—, or —(—C(R
2
)(R
3
)—)
p
—, and B
2
is a bond, —N═C(R
4
)—, —C(R
5
)═N—, —C(R
6
)═C(R
7
)—, —N(R
8
)═N(R
9
)—, —N(R
10
)—C(R
11
)(R
12
)—, —O—C(R
13
)(R
14
)—, —CO—C(R
15
)(R
16
)—, —CO-—N(R
17
)—, —N(R
18
)—CO—, —CO—, —CO—O—, —CO—S—, —S—C(R
19
)(R
20
)—, —CS—C(R
21
)(R
22
)—, —CS—N(R
23
)—, —N(R
24
)—CS—, —CS—, —SO
2
—, provided that —A
2
—B
2
— cannot be a bond. —A
2
—B
2
— together is —O—, —S—, —(—O—(CH
2
)
q
—O—)
r
—, —(—N(R
25
)—(CH
2
)
s
—CO—)
t
—, or —(—N(R
26
)—(CH
2
)
u
—N(R
27
)—)
v
—. Each of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
,R
16
, R
17
, R
18
, R
19
, R
20
, r
21
, R
22
, R
23
, R
24
, R
25
, R
26
, and R
27
, independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Each of p, q, r, s, t, u, and v, independently, is 1, 2, or 3. Y is —R′—L′—R″ wherein R′ is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino. L′ is a bond, —O—, —S—, —N(R
28
)—, —N(R
29
)—CO—, —CO—N(R
30
)—, —CO—O—, or —O—CO—. Each of R
28
, R
29
, and R
30
, independently, is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R″ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which optionally being substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. Z is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, ami
Brunkhorst Beatrice
Gillies Stephen
Ono Mitsunori
Vo Nha Huu
Wada Yumiko
Balasubramanian Venkataraman
Fish & Richardson P.C.
Raymond Richard L.
Shionogi Bioresearch Corp.
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