Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-30
2004-02-17
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S231500, C514S256000, C514S269000, C544S060000, C544S114000, C544S311000
Reexamination Certificate
active
06693097
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, such as 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)
Immunol. 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
In one aspect, this invention features pyrimidine compounds of formula (I):
[referred to hereinafter as NC(R
a
R
b
)], aryl, or heteroaryl; each of R
2
and R
4
, independently, is R
c
, halogen, nitro, cyano, isothionitro, SR
c
, or OR
c
; or R
2
and R
4
, taken together, is carbonyl; R
3
is R
c
, alkenyl, alkynyl, 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
; R
5
is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; 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 N or CH; one of U and V is N, and the other is CR
c
; 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, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. Note that the left atom shown in any substituted group described above is closest to the pyrimidine ring. Also note that when n is 2 or greater, the just-described pyrimidine 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 pyrimidine compounds of this invention is featured by that R
1
is NC(R
a
R
b
). In these compounds, U can be N, V can be CH, Z can be N, and W can be O. In addition, 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 subset of pyrimidine 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, NO
2
, CN, alkyl, aryl, heteroaryl, 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
; 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, propyl, cyclopropyl, methoxy, or ethoxy; R
h
is F, Cl, CN, methyl, methoxy, ethoxy, OC(O)CH
3
, OC(O)C
2
H
5
, C(O)OH, C(O)OC
2
H
5
, C(O)NH
2
, NHC(O)CH
3
, or S(O
2
)NH
2
; R
i
is H, methyl, ethyl, or acetyl; and q is 0, 1, or 2.
Another subset of the pyrimidine compounds of this invention is featured by that R
1
is aryl or heteroaryl. In these compounds, U can be N, V can be CH, Z can be N, and W can be O. In addition, 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 pyrimidine compounds, R
1
, preferably, is
in which D is O, S, or NR
m
; R
j
is benzo, halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; R
m
is H, alkyl, or alkylcarbonyl; and r is 0, 1, or 2. Preferably, R
1
is
and R
j
is methyl, ethyl, propyl, or benzo; and r can be 1 or 2.
Alkyl, alkenyl, alkynyl, aryl, heteroaryl (e.g., pyridinyl), cyclyl, heterocyclyl mentioned above 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 of this invention:
In another aspect, this invention features a pharmaceutical composition that contains a pharmaceutically acceptable carrier and an effective amount of at least one of the pyrimidine compounds of this invention.
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 mellitus). The method includes administering to a subject in need thereof an effective amount of one or more pyrimidine compounds of this invention.
The pyrimidine compounds of this invention include the compounds themselves, as well as their salts and their prodrugs, if applicable. Such salts, for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the pyrimidine compounds described above.
In addition, some of the pyrimidine compounds of this invention have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isom
Kostik Elena
Koya K.
Ono Mitsunori
Przewloka Teresa
Sun Lijun
Balasubramanian Venkataraman
Raymond Richard L.
Synta Pharmaceuticals Corp.
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