Triazine compounds

Details Triazine compounds Triazine compounds

2001-11-30

2004-01-20

Raymond, Richard L. (Department: 1628)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S231500, C514S241000, C544S196000, C544S208000, C544S209000, C544S112000, C544S060000

Reexamination Certificate

active

06680315

ABSTRACT:

BACKGROUND
Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) composed of two subunits (p35 and p40), and plays key roles in immune responses by bridging innate resistance and antigen-specific adaptive immunity. Trinchieri (1993)
Immunol Today
14: 335. For example, it promotes type 1 T helper cell (Th1) responses and, hence, cell-mediated immunity. Chan et al. (1991)
J Exp Med
173: 869; Seder et al. (1993)
Proc Natl Acad Sci USA
90: 10188; Manetti et al. (1993)
J Exp Med
177: 1199; and Hsieh et al. (1993)
Science
260: 547. Overproduction of IL-12 causes excessive Th1 responses, and may result in inflammatory disorders, insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, or sepsis. See, for example, Gately et al. (1998)
Annu Rev Immunol.
16: 495; and Abbas et al. (1996)
Nature
383: 787. Thus, inhibiting IL-12 overproduction is an approach to treat the just-mentioned diseases. Trembleau et al. (1995)
Immmunol. Today
16: 383; and Adorini et al. (1997)
Chem. Immunol.
68: 175. For example, overproduction of IL-12 and the resultant excessive Th1 type responses can be suppressed by modulating IL-12 production. A compound that down-regulates IL-12 production can be used for treating inflammatory diseases. Ma et al. (1998)
Eur Cytokine Netw
9: 54.
SUMMARY
This invention is based on the identification of new compounds from a library of 80,000 compounds, which were screened for their abilities to inhibit IL-12 overproduction. In one aspect, this invention features triazine compounds of formula (I)
wherein R
1
is
[referred to hereinafter as NC(R
a
R
b
)], aryl, or heteroaryl; each of R
2
, R
4
, and R
5
, independently, is R
c
, halogen, nitro, nitroso, cyano, azide, isothionitro, SR
c
, or OR
c
; R
3
is R
c
, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, OR
c
, OC(O)R
c
, SO
2
R
c
, S(O)R
c
, S(O
2
)NR
c
R
d
, SR
c
, NR
c
R
d
, NR
c
COR
d
, NR
c
C(O)OR
d
, NR
c
C(O)NR
c
R
d
, NR
c
SO
2
R
d
, COR
c
, C(O)OR
c
, or C(O)NR
c
R
d
; n is 0, 1, 2, 3, 4, 5, 6, or 7; X is O, S, S(O), S(O
2
), or NR
c
; Y is a covalent bond, CH
2
, C(O), C═N—R
c
, C═N—OR
c
, C═N—SR
c
, O, S, S(O), or S(O
2
); Z is N; and W is O, S, S(O), S(O
2
), NR
c
, or NC(O)R
c
; in which each of R
a
and R
b
, independently, is H, alkyl, aryl, heteroaryl; and each of R
c
and R
d
, independently, is H, alkyl, or alkylcarbonyl. Note that the left atom shown in any substituted group described above is closest to the tirazine ring. Also note that when n is 2 or greater, the just-described triazine compound may have two or more different C(R
2
R
4
) moieties. The same rule applies to other similar situations.
Referring to formula (I), a subset of the triazine compounds of this invention is featured by that R
1
is NC(R
a
R
b
). In these compounds, W can be O; R
5
can be H or alkyl; X can be NR
c
; R
c
can be H, methyl, ethyl, or acetyl; Y can be or CH
2
, and n can be 0, 1, 2, 3, or 4. In some embodiments, R
3
is aryl, heteroaryl (e.g., pyridinyl), OR
c
, SR
c
, C(O)OR
c
, or C(O)NR
c
R
d
. In other embodiments, R
3
is
in which each of A and A′, independently, is O, S, or NH; each of R
e
and R
f
, independently, is H, alkyl, aryl, or heteroaryl; and m is 1 or 2.
In this subset of triazine compounds, R
a
or R
b
, preferably, is
in which B is NR
i
, O, or S; B′ is N or CR
i
; R
g
is H, alkyl, or alkoxyl; R
h
is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; R
i
is H, alkyl, or alkylcarbonyl; p is 0, 1, or 2; and q is 0, 1, 2, 3, or 4. Preferably, B is NR
i
; B′ is CH; R
g
is H, methyl, ethyl, methoxy, or ethoxy; R
h
is F, Cl, CN, methoxy, methyl, or ethoxy; R
i
is H, methyl, ethyl, or acetyl; and q is 0, 1, or 2.
Another subset of the triazine compounds of this invention is featured by that R
i
is aryl or heteroaryl. In these compounds, W can be O; R
5
can be H or alkyl; X can be NR
c
; R
c
can be H, methyl, ethyl, or acetyl; Y can be O or CH
2
, and n can be 0, 1, 2, 3, or 4. In some embodiments, R
3
is aryl, heteroaryl (e.g., pyridinyl), OR
c
, SR
c
, C(O)OR
c
, or C(O)NR
c
R
d
. In other embodiments, R
3
is
in which each of A and A′, independently, is O, S, or NH; each of R
e
and R
f
, independently, is H, alkyl, aryl, or heteroaryl; and m is 1 or 2.
In this second subset of triazine compounds, R
1
, preferably, is
in which D is O, S, or NR
m
; D′ is N or CR
m
; R
j
is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; R
k
is aryl or hetereoaryl; R
1
is H, alkyl, or alkylcarbonyl; R
m
is H, alkyl, or alkylcarbonyl; r is 0, 1, or 2; s is 0 or 1; t is 0, 1, 2, 3, or 4; and u is 0, 1, 2, 3, 4, or 5. Preferably, R
1
is
and R
j
is methyl, ethyl, propyl, or benzyl; and r can be 1 or 2.
In another aspect, this invention also features triazine compounds of formula (I), wherein R
1
is NC(R
a
R
b
), aryl, or heteroaryl; each of R
2
, R
4
, and R
5
, independently, is R
c
, halogen, nitro, nitroso, cyano, azide, isothionitro, SR
c
, or OR
c
; R
3
is R
c
, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, OR
c
, OC(O)R
c
, SO
2
R
c
, S(O)R
c
, S(O
2
)NR
c
R
d
, SR
c
, NR
c
R
d
, NR
c
COR
d
, NR
c
C(O)OR
d
, NR
c
C(O)NR
c
R
d
, NR
c
SO
2
R
d
, COR
c
, C(O)OR
c
, or C(O)NR
c
R
d
; n is 0, 1, 2, 3, 4, 5, 6, or 7; X is O, S, S(O), S(O
2
), or NR
c
; Y is a covalent bond, CH
2
, C(O), C═N—R
c
, C═N—OR
c
, C═N—SR
c
, O, S, S(O), S(O
2
), or NR
c
; Z is CH; and W is O, S, S(O), S(O
2
), NR
c
, or NC(O)R
c
; in which each of R
a
and R
b
, independently, is H, alkyl, aryl, heteroaryl; and each of R
c
and R
d
, independently, is H, alkyl, or alkylcarbonyl. A subset of the triazine compounds is featured by that R
1
is NC(R
a
R
b
); and another subset is featured by that R
1
is aryl or heteroaryl.
Alkyl, alkenyl, alkynyl, aryl, heteroaryl (e.g., pyridinyl), cyclyl, heterocyclyl mentioned herein include both substituted and unsubstituted moieties. The term “substituted” refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen, hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro, mercapto, carbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfoamido, C
1
~C
6
alkyl, C
1
~C
6
alkenyl, C
1
~C
6
alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkoxy, aryl, heteroaryl cyclyl, and heterocyclyl are optionally substituted with C
1
~C
6
alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano, or nitro. The term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl.
Set forth below are exemplary compounds (Compounds 1-12) of this invention:
In still another aspect, this invention features a pharmaceutical composition that contains a pharmaceutically acceptable carrier and an effective amount of at least one of the above-described triazine compounds.
In further another aspect, the present invention features a method for treating an IL-12 overproduction-related disorder (e.g., rheumatoid arthritis, sepsis, Crohn's disease, multiple Sclerosis, psoriasis, or insulin-dependent diabetes). The method includes administering to a subject in need thereof an effective amount of a triazine compound of formula (I), wherein R
1
is NC(R
a
R
b
), aryl, or heteroaryl; each of R
2
, R
4
, and R
5
, independently, is R
c
, halogen, nitro, nitroso, cyano, azide, isothionitro, SR
c
, or OR
c
; R
3
is R
c
, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocycl

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